ISSN 1866-8836
Клеточная терапия и трансплантация
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Video Lection

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Video Lection

" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(3) "500" ["~SORT"]=> string(3) "500" ["CODE"]=> string(36) "vkhozhdenie-v-mitoz-i-vykhod-iz-nego" ["~CODE"]=> string(36) "vkhozhdenie-v-mitoz-i-vykhod-iz-nego" ["EXTERNAL_ID"]=> string(3) "440" ["~EXTERNAL_ID"]=> string(3) "440" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(85) "Вхождение в митоз и выход из него (Видеолекция)" ["ELEMENT_META_KEYWORDS"]=> string(73) "митоз ооциты цитокинез осфорилирование" ["ELEMENT_META_DESCRIPTION"]=> string(130) "Вхождение в митоз и выход из него (Видеолекция)Getting in and out of mitosis (Video Lecture)" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(3903) "<p> Клетки входят в митоз (в более общем виде – в М-фазу цикла), когда активируются комплексы CDK1/циклин. Фосфорилирование при посредстве этих и других митотических протеинкиназ отвечает за реорганизацию клетки и запуск перехода в метафазу.<br> Наша работа проводилась в основном на ооцитах и яйцеклетках лягушек и клеточных экстрактах. Нашей целью было выяснить, сколько белков должно быть фосфорилировано, чтобы достичь этого состояния и пытались оценить число митотических «мишеней» для различных сочетаний циклина и CDK на определенный момент.<br> Выход из митоза, начинающийся с перехода от метафазы к анафазе, происходит тогда, когда активируется фактор, способствующий анафазе (АРС/С), который метит полиубикитиновыми цепями небольшое число целевых белков, включая циклины и секурин, что обозначает их как мишени для протеолиза в протеасомах. При этом хроматиды разделяются и движутся к противоположным полюсам клетки, где они деконденсируются и снова формируют функционально активное клеточное ядро. При цитокинезе идет разделение на две дочерние клетки. Митотические фосфопротеины возвращаются к своему интерфазному (гипо- или нефосфорилированному) состоянию.<br> Недавно мы случайно открыли, что фактор, ответственный за это дефосфорилирование после митоза, совершенно неактивен в экстрактах из клеток М-фазы (состояние митоза), и реактивируется при выходе клеток из митоза. Это объясняет, каким образом белки могут почти полностью переходить в гиперфосфорилированное состояние: здесь не только активируются киназы, но и отключаются фосфатазы, противодействующие этому. Представлены доказательства, которые привели нас к такому заключению. Они получены при исследованиях экстрактов яйцеклеток лягушки, выведенных из цитостатического блока путем добавления CaCl2, а также того факта, что кальцинейрин (протеинфосфатаза 2В) играет роль в уходе от сцепления с CSF. Однако реальная работа по восстановлению белков в их интерфазном гиперфосфорилированном состоянии осуществляется фактором, который мы назвали фосфатазой Х. 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Тим Хант

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Клетки входят в митоз (в более общем виде – в М-фазу цикла), когда активируются комплексы CDK1/циклин. Фосфорилирование при посредстве этих и других митотических протеинкиназ отвечает за реорганизацию клетки и запуск перехода в метафазу.
Наша работа проводилась в основном на ооцитах и яйцеклетках лягушек и клеточных экстрактах. Нашей целью было выяснить, сколько белков должно быть фосфорилировано, чтобы достичь этого состояния и пытались оценить число митотических «мишеней» для различных сочетаний циклина и CDK на определенный момент.
Выход из митоза, начинающийся с перехода от метафазы к анафазе, происходит тогда, когда активируется фактор, способствующий анафазе (АРС/С), который метит полиубикитиновыми цепями небольшое число целевых белков, включая циклины и секурин, что обозначает их как мишени для протеолиза в протеасомах. При этом хроматиды разделяются и движутся к противоположным полюсам клетки, где они деконденсируются и снова формируют функционально активное клеточное ядро. При цитокинезе идет разделение на две дочерние клетки. Митотические фосфопротеины возвращаются к своему интерфазному (гипо- или нефосфорилированному) состоянию.
Недавно мы случайно открыли, что фактор, ответственный за это дефосфорилирование после митоза, совершенно неактивен в экстрактах из клеток М-фазы (состояние митоза), и реактивируется при выходе клеток из митоза. Это объясняет, каким образом белки могут почти полностью переходить в гиперфосфорилированное состояние: здесь не только активируются киназы, но и отключаются фосфатазы, противодействующие этому. Представлены доказательства, которые привели нас к такому заключению. Они получены при исследованиях экстрактов яйцеклеток лягушки, выведенных из цитостатического блока путем добавления CaCl2, а также того факта, что кальцинейрин (протеинфосфатаза 2В) играет роль в уходе от сцепления с CSF. Однако реальная работа по восстановлению белков в их интерфазном гиперфосфорилированном состоянии осуществляется фактором, который мы назвали фосфатазой Х. Принадлежность и регуляция этого фактора подлежит дальнейшему обсуждению.

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Tim Hunt

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Cell Cycle Control Laboratory, Cancer Research UK, South Mimms, UK

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Cells enter mitosis (more generally, M-phase, and much of our work has been in frog oocytes and eggs and extracts thereof) when CDK1/cyclin complexes are activated. Phosphorylation by these, and other mitotic protein kinases, is responsible for reorganizing the cell and initiating progression to metaphase.
We would like to know how many proteins needs to be phosphorylated how much to bring about this state of affairs, and have been trying to enumerate the mitotic targets for various cyclin-CDK combinations for some time. I’ll talk about our approaches, difficulties and findings.
Exit from mitosis, starting at the metaphase to anaphase transition, occurs when the anaphasepromoting factor (APC/ C) is activated and tags a small number of target proteins, including cyclins and securin, with polyubiquitin chains that signal their proteolysis by the proteasome. Chromatids part and move to opposite poles of the cell where they decondense and re-form a functional nucleus.
Cytokinesis separates the two daughter cells. Mitotic phosphoproteins revert to their interphase un- or hypo-phosphorylated state.
We recently made the accidental discovery that the activity responsible for this postmitotic dephosphorylation is almost completely inactive in M-phase cell extracts, and is reactivated when cells exit mitosis. This explains how proteins can become almost completely converted to hyperphosphorylated states: not only are kinases activated, but the counteracting phosphatase(s) are concomitantly shut down. I will present the evidence that has led us to this conclusion. It stems from studies of frog egg extracts released from cytostatic factor (CSF) arrest by added CaCl2, and the discovery that calcineurin (protein phosphatase 2B) plays a role in escaping the clutches of CSF. But the real work of restoring proteins to their interphase state of hypophosphorylation is performed by an activity we call ‘Phosphatase X’, whose identity and regulation I shall discuss.

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Видеолекция


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Tim Hunt

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Tim Hunt

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Cells enter mitosis (more generally, M-phase, and much of our work has been in frog oocytes and eggs and extracts thereof) when CDK1/cyclin complexes are activated. Phosphorylation by these, and other mitotic protein kinases, is responsible for reorganizing the cell and initiating progression to metaphase.
We would like to know how many proteins needs to be phosphorylated how much to bring about this state of affairs, and have been trying to enumerate the mitotic targets for various cyclin-CDK combinations for some time. I’ll talk about our approaches, difficulties and findings.
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Cytokinesis separates the two daughter cells. Mitotic phosphoproteins revert to their interphase un- or hypo-phosphorylated state.
We recently made the accidental discovery that the activity responsible for this postmitotic dephosphorylation is almost completely inactive in M-phase cell extracts, and is reactivated when cells exit mitosis. This explains how proteins can become almost completely converted to hyperphosphorylated states: not only are kinases activated, but the counteracting phosphatase(s) are concomitantly shut down. I will present the evidence that has led us to this conclusion. It stems from studies of frog egg extracts released from cytostatic factor (CSF) arrest by added CaCl2, and the discovery that calcineurin (protein phosphatase 2B) plays a role in escaping the clutches of CSF. But the real work of restoring proteins to their interphase state of hypophosphorylation is performed by an activity we call ‘Phosphatase X’, whose identity and regulation I shall discuss.

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Cells enter mitosis (more generally, M-phase, and much of our work has been in frog oocytes and eggs and extracts thereof) when CDK1/cyclin complexes are activated. Phosphorylation by these, and other mitotic protein kinases, is responsible for reorganizing the cell and initiating progression to metaphase.
We would like to know how many proteins needs to be phosphorylated how much to bring about this state of affairs, and have been trying to enumerate the mitotic targets for various cyclin-CDK combinations for some time. I’ll talk about our approaches, difficulties and findings.
Exit from mitosis, starting at the metaphase to anaphase transition, occurs when the anaphasepromoting factor (APC/ C) is activated and tags a small number of target proteins, including cyclins and securin, with polyubiquitin chains that signal their proteolysis by the proteasome. Chromatids part and move to opposite poles of the cell where they decondense and re-form a functional nucleus.
Cytokinesis separates the two daughter cells. Mitotic phosphoproteins revert to their interphase un- or hypo-phosphorylated state.
We recently made the accidental discovery that the activity responsible for this postmitotic dephosphorylation is almost completely inactive in M-phase cell extracts, and is reactivated when cells exit mitosis. This explains how proteins can become almost completely converted to hyperphosphorylated states: not only are kinases activated, but the counteracting phosphatase(s) are concomitantly shut down. I will present the evidence that has led us to this conclusion. It stems from studies of frog egg extracts released from cytostatic factor (CSF) arrest by added CaCl2, and the discovery that calcineurin (protein phosphatase 2B) plays a role in escaping the clutches of CSF. But the real work of restoring proteins to their interphase state of hypophosphorylation is performed by an activity we call ‘Phosphatase X’, whose identity and regulation I shall discuss.

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Cell Cycle Control Laboratory, Cancer Research UK, South Mimms, UK

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Cell Cycle Control Laboratory, Cancer Research UK, South Mimms, UK

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Тим Хант

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Тим Хант

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Фосфорилирование при посредстве этих и других митотических протеинкиназ отвечает за реорганизацию клетки и запуск перехода в метафазу.<br> Наша работа проводилась в основном на ооцитах и яйцеклетках лягушек и клеточных экстрактах. Нашей целью было выяснить, сколько белков должно быть фосфорилировано, чтобы достичь этого состояния и пытались оценить число митотических «мишеней» для различных сочетаний циклина и CDK на определенный момент.<br> Выход из митоза, начинающийся с перехода от метафазы к анафазе, происходит тогда, когда активируется фактор, способствующий анафазе (АРС/С), который метит полиубикитиновыми цепями небольшое число целевых белков, включая циклины и секурин, что обозначает их как мишени для протеолиза в протеасомах. При этом хроматиды разделяются и движутся к противоположным полюсам клетки, где они деконденсируются и снова формируют функционально активное клеточное ядро. При цитокинезе идет разделение на две дочерние клетки. Митотические фосфопротеины возвращаются к своему интерфазному (гипо- или нефосфорилированному) состоянию.<br> Недавно мы случайно открыли, что фактор, ответственный за это дефосфорилирование после митоза, совершенно неактивен в экстрактах из клеток М-фазы (состояние митоза), и реактивируется при выходе клеток из митоза. Это объясняет, каким образом белки могут почти полностью переходить в гиперфосфорилированное состояние: здесь не только активируются киназы, но и отключаются фосфатазы, противодействующие этому. Представлены доказательства, которые привели нас к такому заключению. Они получены при исследованиях экстрактов яйцеклеток лягушки, выведенных из цитостатического блока путем добавления CaCl2, а также того факта, что кальцинейрин (протеинфосфатаза 2В) играет роль в уходе от сцепления с CSF. Однако реальная работа по восстановлению белков в их интерфазном гиперфосфорилированном состоянии осуществляется фактором, который мы назвали фосфатазой Х. Принадлежность и регуляция этого фактора подлежит дальнейшему обсуждению. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3873) "

Клетки входят в митоз (в более общем виде – в М-фазу цикла), когда активируются комплексы CDK1/циклин. Фосфорилирование при посредстве этих и других митотических протеинкиназ отвечает за реорганизацию клетки и запуск перехода в метафазу.
Наша работа проводилась в основном на ооцитах и яйцеклетках лягушек и клеточных экстрактах. Нашей целью было выяснить, сколько белков должно быть фосфорилировано, чтобы достичь этого состояния и пытались оценить число митотических «мишеней» для различных сочетаний циклина и CDK на определенный момент.
Выход из митоза, начинающийся с перехода от метафазы к анафазе, происходит тогда, когда активируется фактор, способствующий анафазе (АРС/С), который метит полиубикитиновыми цепями небольшое число целевых белков, включая циклины и секурин, что обозначает их как мишени для протеолиза в протеасомах. При этом хроматиды разделяются и движутся к противоположным полюсам клетки, где они деконденсируются и снова формируют функционально активное клеточное ядро. При цитокинезе идет разделение на две дочерние клетки. Митотические фосфопротеины возвращаются к своему интерфазному (гипо- или нефосфорилированному) состоянию.
Недавно мы случайно открыли, что фактор, ответственный за это дефосфорилирование после митоза, совершенно неактивен в экстрактах из клеток М-фазы (состояние митоза), и реактивируется при выходе клеток из митоза. Это объясняет, каким образом белки могут почти полностью переходить в гиперфосфорилированное состояние: здесь не только активируются киназы, но и отключаются фосфатазы, противодействующие этому. Представлены доказательства, которые привели нас к такому заключению. Они получены при исследованиях экстрактов яйцеклеток лягушки, выведенных из цитостатического блока путем добавления CaCl2, а также того факта, что кальцинейрин (протеинфосфатаза 2В) играет роль в уходе от сцепления с CSF. Однако реальная работа по восстановлению белков в их интерфазном гиперфосфорилированном состоянии осуществляется фактором, который мы назвали фосфатазой Х. Принадлежность и регуляция этого фактора подлежит дальнейшему обсуждению.

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Клетки входят в митоз (в более общем виде – в М-фазу цикла), когда активируются комплексы CDK1/циклин. Фосфорилирование при посредстве этих и других митотических протеинкиназ отвечает за реорганизацию клетки и запуск перехода в метафазу.
Наша работа проводилась в основном на ооцитах и яйцеклетках лягушек и клеточных экстрактах. Нашей целью было выяснить, сколько белков должно быть фосфорилировано, чтобы достичь этого состояния и пытались оценить число митотических «мишеней» для различных сочетаний циклина и CDK на определенный момент.
Выход из митоза, начинающийся с перехода от метафазы к анафазе, происходит тогда, когда активируется фактор, способствующий анафазе (АРС/С), который метит полиубикитиновыми цепями небольшое число целевых белков, включая циклины и секурин, что обозначает их как мишени для протеолиза в протеасомах. При этом хроматиды разделяются и движутся к противоположным полюсам клетки, где они деконденсируются и снова формируют функционально активное клеточное ядро. При цитокинезе идет разделение на две дочерние клетки. Митотические фосфопротеины возвращаются к своему интерфазному (гипо- или нефосфорилированному) состоянию.
Недавно мы случайно открыли, что фактор, ответственный за это дефосфорилирование после митоза, совершенно неактивен в экстрактах из клеток М-фазы (состояние митоза), и реактивируется при выходе клеток из митоза. Это объясняет, каким образом белки могут почти полностью переходить в гиперфосфорилированное состояние: здесь не только активируются киназы, но и отключаются фосфатазы, противодействующие этому. Представлены доказательства, которые привели нас к такому заключению. Они получены при исследованиях экстрактов яйцеклеток лягушки, выведенных из цитостатического блока путем добавления CaCl2, а также того факта, что кальцинейрин (протеинфосфатаза 2В) играет роль в уходе от сцепления с CSF. Однако реальная работа по восстановлению белков в их интерфазном гиперфосфорилированном состоянии осуществляется фактором, который мы назвали фосфатазой Х. Принадлежность и регуляция этого фактора подлежит дальнейшему обсуждению.

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Видеолекция


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Видеолекция


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Introduction

AKI remains a common, serious, and essentially treatment resistant syndrome of rapidly declining renal function. The mortality rates from AKI range from 15% in the general community to 80% for patients with multi-organ failure or for those who develop it post-operatively [1]. Even when renal function appears to fully recover after AKI, it is now recognized that a significant proportion of patients develop end stage renal disease (ESRD) as a consequence of undiagnosed, incompletely resolved AKI, characterized by continued inflammatory and fibrotic processes, and microvascular rarefaction [2]. Consequently, those patients who seemingly recover from AKI frequently go on to develop chronic kidney disease (CKD), eventually requiring chronic hemodialysis or a renal transplant [3]. 

AKI is most frequently seen in patients with shock, sepsis, trauma, and after major surgery.  Patients undergoing cardiac surgery are at particularly high risk with up to 30% of all cardiac surgery patients developing AKI [4]. Many studies of cardiac patients have consistently found certain factors to be associated with increased risk of developing AKI following surgery. These risks include but are not limited to: the type of procedure performed (valve procedures are found to be of particularly high risk); patient age greater than 65; female patient gender; pre-operative serum creatinine value above 1.2 mg/dL, or underlying renal disease; pre-operative capillary glucose above 140 mg/dL; congestive heart failure; combined surgeries; on-pump vs. off pump surgery; and cardiopulmonary bypass surgery time greater than two hours [4-6]. The treatment resistant nature of AKI, combined with high morbidity and mortality, as well as the now recognized frequent progression of AKI to chronic kidney disease (CKD) underscores the urgent need for advances in treatment modalities.

Recent studies from our laboratory have led to the development of a novel approach to AKI treatment. This treatment administers allogeneic or syngeneic MSC to prevent further damage and to facilitate repair of acutely injured kidneys [7-9]. We observed that immediate (post reflow) or delayed (24 hrs post reflow) treatment of I/R AKI in rats with either autologous or allogeneic MSC significantly protects renal function, improves survival and hastens renal repair, mediated by complex paracrine mechanisms (anti-apoptotic, mitogenic, anti-inflammatory, vasculoprotective, angiogenic, anti-fibrotic) 7-10]. The striking hypoimmunogenic and immune modulating properties of MSC make their therapeutic use in allogeneic protocols possible and safe, as has been demonstrated in numerous clinical (www.clinicaltrials.gov) and pre-clinical trials [11, 12]. 

Compared to vehicle treated animals with I/R AKI, early allogeneic MSC therapy has important late benefits (3 months post AKI) such as maintained creatinine clearance, decreased interstitial fibrosis, and down regulation of pro-fibrotic gene expression levels in the kidney (TGFβ, PAI-1, TIMP-1). In addition, MSC therapy for AKI results in well maintained microvascular density in the kidney, while there is significant micorvascular rarefaction in vehicle treated animals [7]. In AKI, administered MSC do not engraft and disappear from the kidney and other organs within 1 to 3 days.

The aforementioned preclinical studies indicate that effective and specific treatment of AKI with MSC is an intervention that also prevents progressive loss of renal function, a complication that is increasingly recognized to result in ESRD in patients in whom AKI was not diagnosed and treated early after a renal insult [13]. Accordingly, a Phase I Clinical Trial employing this treatment is currently underway (www.clinicaltrials.gov; NCT00733876). This safety trial involves administration of MSC to fifteen patients divided into three cohorts of five patients each. Each cohort receives a defined dose of MSC, low, intermediate or high. As of this writing, dosing of the first cohort is complete, and we report here the outcomes of the first cohort of five patients.

Study Design and Methods

The FDA and the Institutional Review Board of Intermountain Medical Center, Murray, Utah, the site where the trial is carried out, approved the design and conduct of this Phase I Clinical Safety Trial. In addition, prior to initiation of the trial an independent Data Safety and Monitoring Board (DSMB) was appointed, consisting of a general nephrologists, a nephrologist/medical epidemiologist, and a cardiovascular surgeon. This DSMB reviewed the trial protocol and approved the trial, and continues to monitor the clinical data from all enrolled and treated subjects.

The study design is a Phase 1 Safety Trial. The primary objective is to test whether infusion of allogeneic MSC into the suprarenal aorta of patients who have undergone on-pump cardiac surgery (Coronary Artery Bypass Grafting and/or valve surgery) and who are at high risk for AKI following surgery is safe. This is assessed by monitoring patients post operatively for the occurrence of adverse events (AEs) and serious adverse events (SAEs) that are related to the MSC therapy. Specifically, detailed, monthly examinations for six months regarding the development of AEs or SAEs are carried out, and the study subjects are reassessed annually for another three years.

The major endpoint to be measured is safety, as documented by the comparative incidence of Adverse Events, Severe Adverse Events and complications in patients receiving cell-based therapies vs. historical controls for this patient population. AEs will be recorded throughout the course of the study and classified as immediate, postoperative, or delayed. Both common, expected and unusual AEs are listed below. 

Potential immediate or early AEs related to the infusion of MSC via a femoral catheter into the suprarenal aorta include femoral catheter related complications such as bleeding at the catheter insertion site, infections, cholesterol plaque dislodgement and secondary visceral or peripheral embolic events.

Immediate AEs and SAEs occurring at the time of operation and immediately post-op (up to 24 hours post-op) include the following: post-operative compromise of heart function due to an unexpected ischemic event;  post-operative marked impairment of renal function due to an unexpected ischemic coronary or other event (bleeding, hypotension, heart failure);  perioperative complications that will require additional time in order to address these. 

Later, post-operative complications (1-30 days post-op) include delayed deterioration in renal function post-op, requiring or not requiring dialysis; bleeding requiring >6 units of blood transfusion; arrhythmia requiring cardioversion; mediastinitis; cerebral vascular accident; prolonged ventilator support (> 24 hours postoperatively); reintubation; acute myocardial infarction; wound infection or hematoma; pericarditis; pneumonia; pulmonary embolism; bacteremia, sepsis, shock; multiorgan failure; death.  

Delayed (more than 30 days after operation) AEs and SAEs include: dialysis dependency due to irreversible loss of kidney function; arrhythmia requiring cardioversion; mediastinitis; cerebral vascular accident; acute myocardial infarction; wound infection or hematoma; pneumonia; pulmonary embolism; malignancy; ectopic differentiation of MSC into mesodermal cells (bone, cartilage, fat); death.

The secondary objective of this trial is preliminary efficacy of MSC administration for the potential prevention and treatment of post-operative AKI. Although a priori underpowered, preliminary efficacy in this trial is nevertheless assessed by determining the comparative frequency and severity of post-operative AKI using standard and novel biomarkers of AKI (serum creatinine, BUN, urine output, creatinine clearance, electrolyte, acid-base balance, serum cystatin C, IL-18 and NGAL levels), need for temporary or permanent dialysis, length of hospital stay, and associated 30 day mortality. Study data are compared to published historical data that are collected and available for analysis from the Society of Thoracic Surgeons (www.STS.org). Historical data from this data base are collected and analyzed from all participating centers in the USA, and sub-analyzed for a reporting institution, such as IMC, and comparable institutions. 

The trial is currently conducted in one center, IMC in Murray, Utah. Allogeneic MSC, derived from healthy, screened donors, using FDA approved protocols, are culture expanded under cGMP conditions at the University of Utah Cell Therapy Facility, Salt Lake City, Utah. MSC are administered in a dose escalation protocol to a total of 15 patients who have undergone elective, on-pump cardiac surgery (CABG and/or valve replacement). Five patients each receive low, medium or high dose of allogeneic MSC via a femoral catheter into the suprarenal aorta immediately after the patient comes off pump and is hemodynamically stable.  
 
Low, Intermediate and High Doses of allogeneic MSC are defined per FDA approved protocol, and are infused into the suprarenal aorta in 50 ml of normal saline via a femoral catheter.

The enrollment and exclusion criteria for the trial are summarized in Table 1, below.

Table 1.

2008_Gooch_Tab01.jpg

Results

Five eligible patients were enrolled for treatment with the lowest MSC dose. The clinical data on these study subjects are reported with their consent and approval of the IRB. The patients’ pre-operative AKI risk factors and surgical procedures are listed in Table 2. All patients underwent on-pump cardiac surgery for CABG and/or valve repair. All patients had at least one risk factor for post-operative development of AKI.

Table 2.

2008_Gooch_Tab02.jpg


As stated in the introduction, several cardiac surgery associated factors have been identified as increasing the risk of post-operative AKI. These include the type of surgical procedure being performed, with multiple and/or valve procedures specifically being associated with higher risk; and the length of time on the bypass pump, with a bypass pump time of greater than 2 hours being associated with higher risk [4-6]. Table 3 lists the intra-operative risk factors for each of the five subjects.

Table 3.

2008-2-en-Gooch-et-al-Table-3.jpg


Serum creatinine values for each of the five subjects, as markers of renal function, prior to and following surgery up to the present are shown on Figure 1.

Figure 1.

2008_Gooch_Fig01.jpg


These data demonstrate that none of the first five study subjects developed significant AKI in the immediate postoperative time in the hospital, nor did patients 001-004 after discharge. Subject 005’s post-discharge data are pending. Significantly, no patient required dialysis immediately or later after surgery, and no expected or therapy-specific AEs or SAEs were observed. However, subject 004 died suddenly at home at 26 days after surgery and MSC administration. Both the principal investigator and the members of the DSMB determined that the patient’s death was not related to the study drug or its mode of administration. This SAE was immediately reported to the FDA, IRB and DSMB. The remaining four subjects are doing well as of the time of this report.

Discussion

This report summarizes the clinical course of the first five subjects in this first clinical safety trial world wide in which study subjects received allogeneic MSC after completion of on-pump cardiac surgery. It demonstrates that up to this point after surgery and discharge from the hospital infusion of allogeneic MSC at this low dose is safe, as no AEs or SAEs related to this novel therapy have been observed. Specifically, renal function was well preserved postoperatively, and none of the patients required hemodialysis. The sudden death of patient 004 at 26 days after surgery and MSC administration was judged by both the principal investigator and the members of the DSMB as being unrelated to the administration of allogeneic MSC. 

Since close follow-up of each patient is continued for six months, and annual follow-up is conducted for another three years, it is possible that late AEs or SAEs may develop. This may include cardiovascular and pulmonary AEs detailed above, as well as the remote possibility of ectopic differentiation (e.g., in lungs or kidneys) of residual MSC into bone, fat or cartilage cells or oncogenic transformation. However, our detailed pre-clinical studies in experimental animals as well as numerous ongoing clinical trails with MSC (www.clinicaltrials.gov) make the latter AEs unlikely, since we have demonstrated that administered allogeneic MSC do not remain in the animal for more than three days, and that they do not differentiate into target cells and engraft in the kidney that is injured by experimental ischemia and reperfusion, the model that most closely resembles human ischemic AKI. 

In the next groups of subjects, the acute and late safety of higher doses of allogeneic MSC will be assessed. At this point, the safety of the higher doses is not predictable and will have to be investigated. However, both our animal data and all reported clinical trials in which similar MSC doses were administered did not result in AEs or SAEs [7, 8, 10];(www.clinicaltrials.gov). It will finally be of interest to determine whether the obtained data from all 15 study subjects will allow an assessment of the preliminary efficacy of allogeneic MSC therapy in this cohort of high risk patients. If demonstrated, using relevant historical controls, it would be the basis for the conduct of a Phase II trial, in which the efficacy of this novel cell-based therapy is tested. 

Acknowledgements

We greatly appreciate the excellent work of the University of Utah Cell Therapy facility and its director Dr. Linda Kelley. In this facility, all allogeneic MSC that were administered were characterized, culture expanded and release tested under cGMP conditions. The constructive contributions of the members of the DSMB (Drs. Carl Kablitz, Srinivasan Beddhu and David Affleck) are greatly valued. The conduct of this trial is funded and sponsored by AlloCure, Inc., and partially supported by the National Kidney Foundation (UT, ID), and the Western Institute for Biomedical Research.

References

1. Nickolas TL, O'Rourke MJ, Yang J, Sise ME, Canetta PA, et al. Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med. 2008;148(11):810-9.

2. Goldberg R, Dennen P. Long-term outcomes of acute kidney injury. Adv Chronic Kidney Dis. 2008;15(3):297-307.

3. Girardi AC, Fukuda LE, Rossoni LV, Malnic G, Reboucas NA. Dipeptidyl peptidase IV inhibition downregulates Na+ - H+ exchanger NHE3 in rat renal proximal tubule. Am J Physiol Renal Physiol. 2008;294(2):F414-22.

4. Rosner MH, Okusa MD. Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol. 2006;1(1):19-32.

5. Hsu CY, Ordonez JD, Chertow GM, Fan D, McCulloch CE, et al. The risk of acute renal failure in patients with chronic kidney disease. Kidney Int. 2008;74(1):101-7.

6. Palomba H, de Castro I, Neto AL, Lage S, Yu L. Acute kidney injury prediction following elective cardiac surgery: AKICS Score. Kidney Int. 2007;72(5):624-31.

7. Togel F, Cohen A, Zhang P, Yang Y, Hu Z, et al. Autologous and allogeneic marrow stromal cells are safe and effective for the treatment of acute kidney injury. Stem Cells Dev. 2008.

8. Togel F, Weiss K, Yang Y, Hu Z, Zhang P, et al. Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am J Physiol Renal Physiol. 2007;292(5):F1626-35.

9. Togel F, Westenfelder C. Adult bone marrow-derived stem cells for organ regeneration and repair. Dev Dyn. 2007;236(12):3321-31.

10. Togel F, Hu Z, Weiss K, Isaac J, Lange C, et al. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 2005;289(1):F31-42.

11. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371(9624):1579-86.

12. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol.  2003;57(1):11-20.

13. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. Jama. 2005;294(7):813-8.

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Introduction

AKI remains a common, serious, and essentially treatment resistant syndrome of rapidly declining renal function. The mortality rates from AKI range from 15% in the general community to 80% for patients with multi-organ failure or for those who develop it post-operatively [1]. Even when renal function appears to fully recover after AKI, it is now recognized that a significant proportion of patients develop end stage renal disease (ESRD) as a consequence of undiagnosed, incompletely resolved AKI, characterized by continued inflammatory and fibrotic processes, and microvascular rarefaction [2]. Consequently, those patients who seemingly recover from AKI frequently go on to develop chronic kidney disease (CKD), eventually requiring chronic hemodialysis or a renal transplant [3]. 

AKI is most frequently seen in patients with shock, sepsis, trauma, and after major surgery.  Patients undergoing cardiac surgery are at particularly high risk with up to 30% of all cardiac surgery patients developing AKI [4]. Many studies of cardiac patients have consistently found certain factors to be associated with increased risk of developing AKI following surgery. These risks include but are not limited to: the type of procedure performed (valve procedures are found to be of particularly high risk); patient age greater than 65; female patient gender; pre-operative serum creatinine value above 1.2 mg/dL, or underlying renal disease; pre-operative capillary glucose above 140 mg/dL; congestive heart failure; combined surgeries; on-pump vs. off pump surgery; and cardiopulmonary bypass surgery time greater than two hours [4-6]. The treatment resistant nature of AKI, combined with high morbidity and mortality, as well as the now recognized frequent progression of AKI to chronic kidney disease (CKD) underscores the urgent need for advances in treatment modalities.

Recent studies from our laboratory have led to the development of a novel approach to AKI treatment. This treatment administers allogeneic or syngeneic MSC to prevent further damage and to facilitate repair of acutely injured kidneys [7-9]. We observed that immediate (post reflow) or delayed (24 hrs post reflow) treatment of I/R AKI in rats with either autologous or allogeneic MSC significantly protects renal function, improves survival and hastens renal repair, mediated by complex paracrine mechanisms (anti-apoptotic, mitogenic, anti-inflammatory, vasculoprotective, angiogenic, anti-fibrotic) 7-10]. The striking hypoimmunogenic and immune modulating properties of MSC make their therapeutic use in allogeneic protocols possible and safe, as has been demonstrated in numerous clinical (www.clinicaltrials.gov) and pre-clinical trials [11, 12]. 

Compared to vehicle treated animals with I/R AKI, early allogeneic MSC therapy has important late benefits (3 months post AKI) such as maintained creatinine clearance, decreased interstitial fibrosis, and down regulation of pro-fibrotic gene expression levels in the kidney (TGFβ, PAI-1, TIMP-1). In addition, MSC therapy for AKI results in well maintained microvascular density in the kidney, while there is significant micorvascular rarefaction in vehicle treated animals [7]. In AKI, administered MSC do not engraft and disappear from the kidney and other organs within 1 to 3 days.

The aforementioned preclinical studies indicate that effective and specific treatment of AKI with MSC is an intervention that also prevents progressive loss of renal function, a complication that is increasingly recognized to result in ESRD in patients in whom AKI was not diagnosed and treated early after a renal insult [13]. Accordingly, a Phase I Clinical Trial employing this treatment is currently underway (www.clinicaltrials.gov; NCT00733876). This safety trial involves administration of MSC to fifteen patients divided into three cohorts of five patients each. Each cohort receives a defined dose of MSC, low, intermediate or high. As of this writing, dosing of the first cohort is complete, and we report here the outcomes of the first cohort of five patients.

Study Design and Methods

The FDA and the Institutional Review Board of Intermountain Medical Center, Murray, Utah, the site where the trial is carried out, approved the design and conduct of this Phase I Clinical Safety Trial. In addition, prior to initiation of the trial an independent Data Safety and Monitoring Board (DSMB) was appointed, consisting of a general nephrologists, a nephrologist/medical epidemiologist, and a cardiovascular surgeon. This DSMB reviewed the trial protocol and approved the trial, and continues to monitor the clinical data from all enrolled and treated subjects.

The study design is a Phase 1 Safety Trial. The primary objective is to test whether infusion of allogeneic MSC into the suprarenal aorta of patients who have undergone on-pump cardiac surgery (Coronary Artery Bypass Grafting and/or valve surgery) and who are at high risk for AKI following surgery is safe. This is assessed by monitoring patients post operatively for the occurrence of adverse events (AEs) and serious adverse events (SAEs) that are related to the MSC therapy. Specifically, detailed, monthly examinations for six months regarding the development of AEs or SAEs are carried out, and the study subjects are reassessed annually for another three years.

The major endpoint to be measured is safety, as documented by the comparative incidence of Adverse Events, Severe Adverse Events and complications in patients receiving cell-based therapies vs. historical controls for this patient population. AEs will be recorded throughout the course of the study and classified as immediate, postoperative, or delayed. Both common, expected and unusual AEs are listed below. 

Potential immediate or early AEs related to the infusion of MSC via a femoral catheter into the suprarenal aorta include femoral catheter related complications such as bleeding at the catheter insertion site, infections, cholesterol plaque dislodgement and secondary visceral or peripheral embolic events.

Immediate AEs and SAEs occurring at the time of operation and immediately post-op (up to 24 hours post-op) include the following: post-operative compromise of heart function due to an unexpected ischemic event;  post-operative marked impairment of renal function due to an unexpected ischemic coronary or other event (bleeding, hypotension, heart failure);  perioperative complications that will require additional time in order to address these. 

Later, post-operative complications (1-30 days post-op) include delayed deterioration in renal function post-op, requiring or not requiring dialysis; bleeding requiring >6 units of blood transfusion; arrhythmia requiring cardioversion; mediastinitis; cerebral vascular accident; prolonged ventilator support (> 24 hours postoperatively); reintubation; acute myocardial infarction; wound infection or hematoma; pericarditis; pneumonia; pulmonary embolism; bacteremia, sepsis, shock; multiorgan failure; death.  

Delayed (more than 30 days after operation) AEs and SAEs include: dialysis dependency due to irreversible loss of kidney function; arrhythmia requiring cardioversion; mediastinitis; cerebral vascular accident; acute myocardial infarction; wound infection or hematoma; pneumonia; pulmonary embolism; malignancy; ectopic differentiation of MSC into mesodermal cells (bone, cartilage, fat); death.

The secondary objective of this trial is preliminary efficacy of MSC administration for the potential prevention and treatment of post-operative AKI. Although a priori underpowered, preliminary efficacy in this trial is nevertheless assessed by determining the comparative frequency and severity of post-operative AKI using standard and novel biomarkers of AKI (serum creatinine, BUN, urine output, creatinine clearance, electrolyte, acid-base balance, serum cystatin C, IL-18 and NGAL levels), need for temporary or permanent dialysis, length of hospital stay, and associated 30 day mortality. Study data are compared to published historical data that are collected and available for analysis from the Society of Thoracic Surgeons (www.STS.org). Historical data from this data base are collected and analyzed from all participating centers in the USA, and sub-analyzed for a reporting institution, such as IMC, and comparable institutions. 

The trial is currently conducted in one center, IMC in Murray, Utah. Allogeneic MSC, derived from healthy, screened donors, using FDA approved protocols, are culture expanded under cGMP conditions at the University of Utah Cell Therapy Facility, Salt Lake City, Utah. MSC are administered in a dose escalation protocol to a total of 15 patients who have undergone elective, on-pump cardiac surgery (CABG and/or valve replacement). Five patients each receive low, medium or high dose of allogeneic MSC via a femoral catheter into the suprarenal aorta immediately after the patient comes off pump and is hemodynamically stable.  
 
Low, Intermediate and High Doses of allogeneic MSC are defined per FDA approved protocol, and are infused into the suprarenal aorta in 50 ml of normal saline via a femoral catheter.

The enrollment and exclusion criteria for the trial are summarized in Table 1, below.

Table 1.

2008_Gooch_Tab01.jpg

Results

Five eligible patients were enrolled for treatment with the lowest MSC dose. The clinical data on these study subjects are reported with their consent and approval of the IRB. The patients’ pre-operative AKI risk factors and surgical procedures are listed in Table 2. All patients underwent on-pump cardiac surgery for CABG and/or valve repair. All patients had at least one risk factor for post-operative development of AKI.

Table 2.

2008_Gooch_Tab02.jpg


As stated in the introduction, several cardiac surgery associated factors have been identified as increasing the risk of post-operative AKI. These include the type of surgical procedure being performed, with multiple and/or valve procedures specifically being associated with higher risk; and the length of time on the bypass pump, with a bypass pump time of greater than 2 hours being associated with higher risk [4-6]. Table 3 lists the intra-operative risk factors for each of the five subjects.

Table 3.

2008-2-en-Gooch-et-al-Table-3.jpg


Serum creatinine values for each of the five subjects, as markers of renal function, prior to and following surgery up to the present are shown on Figure 1.

Figure 1.

2008_Gooch_Fig01.jpg


These data demonstrate that none of the first five study subjects developed significant AKI in the immediate postoperative time in the hospital, nor did patients 001-004 after discharge. Subject 005’s post-discharge data are pending. Significantly, no patient required dialysis immediately or later after surgery, and no expected or therapy-specific AEs or SAEs were observed. However, subject 004 died suddenly at home at 26 days after surgery and MSC administration. Both the principal investigator and the members of the DSMB determined that the patient’s death was not related to the study drug or its mode of administration. This SAE was immediately reported to the FDA, IRB and DSMB. The remaining four subjects are doing well as of the time of this report.

Discussion

This report summarizes the clinical course of the first five subjects in this first clinical safety trial world wide in which study subjects received allogeneic MSC after completion of on-pump cardiac surgery. It demonstrates that up to this point after surgery and discharge from the hospital infusion of allogeneic MSC at this low dose is safe, as no AEs or SAEs related to this novel therapy have been observed. Specifically, renal function was well preserved postoperatively, and none of the patients required hemodialysis. The sudden death of patient 004 at 26 days after surgery and MSC administration was judged by both the principal investigator and the members of the DSMB as being unrelated to the administration of allogeneic MSC. 

Since close follow-up of each patient is continued for six months, and annual follow-up is conducted for another three years, it is possible that late AEs or SAEs may develop. This may include cardiovascular and pulmonary AEs detailed above, as well as the remote possibility of ectopic differentiation (e.g., in lungs or kidneys) of residual MSC into bone, fat or cartilage cells or oncogenic transformation. However, our detailed pre-clinical studies in experimental animals as well as numerous ongoing clinical trails with MSC (www.clinicaltrials.gov) make the latter AEs unlikely, since we have demonstrated that administered allogeneic MSC do not remain in the animal for more than three days, and that they do not differentiate into target cells and engraft in the kidney that is injured by experimental ischemia and reperfusion, the model that most closely resembles human ischemic AKI. 

In the next groups of subjects, the acute and late safety of higher doses of allogeneic MSC will be assessed. At this point, the safety of the higher doses is not predictable and will have to be investigated. However, both our animal data and all reported clinical trials in which similar MSC doses were administered did not result in AEs or SAEs [7, 8, 10];(www.clinicaltrials.gov). It will finally be of interest to determine whether the obtained data from all 15 study subjects will allow an assessment of the preliminary efficacy of allogeneic MSC therapy in this cohort of high risk patients. If demonstrated, using relevant historical controls, it would be the basis for the conduct of a Phase II trial, in which the efficacy of this novel cell-based therapy is tested. 

Acknowledgements

We greatly appreciate the excellent work of the University of Utah Cell Therapy facility and its director Dr. Linda Kelley. In this facility, all allogeneic MSC that were administered were characterized, culture expanded and release tested under cGMP conditions. The constructive contributions of the members of the DSMB (Drs. Carl Kablitz, Srinivasan Beddhu and David Affleck) are greatly valued. The conduct of this trial is funded and sponsored by AlloCure, Inc., and partially supported by the National Kidney Foundation (UT, ID), and the Western Institute for Biomedical Research.

References

1. Nickolas TL, O'Rourke MJ, Yang J, Sise ME, Canetta PA, et al. Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med. 2008;148(11):810-9.

2. Goldberg R, Dennen P. Long-term outcomes of acute kidney injury. Adv Chronic Kidney Dis. 2008;15(3):297-307.

3. Girardi AC, Fukuda LE, Rossoni LV, Malnic G, Reboucas NA. Dipeptidyl peptidase IV inhibition downregulates Na+ - H+ exchanger NHE3 in rat renal proximal tubule. Am J Physiol Renal Physiol. 2008;294(2):F414-22.

4. Rosner MH, Okusa MD. Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol. 2006;1(1):19-32.

5. Hsu CY, Ordonez JD, Chertow GM, Fan D, McCulloch CE, et al. The risk of acute renal failure in patients with chronic kidney disease. Kidney Int. 2008;74(1):101-7.

6. Palomba H, de Castro I, Neto AL, Lage S, Yu L. Acute kidney injury prediction following elective cardiac surgery: AKICS Score. Kidney Int. 2007;72(5):624-31.

7. Togel F, Cohen A, Zhang P, Yang Y, Hu Z, et al. Autologous and allogeneic marrow stromal cells are safe and effective for the treatment of acute kidney injury. Stem Cells Dev. 2008.

8. Togel F, Weiss K, Yang Y, Hu Z, Zhang P, et al. Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am J Physiol Renal Physiol. 2007;292(5):F1626-35.

9. Togel F, Westenfelder C. Adult bone marrow-derived stem cells for organ regeneration and repair. Dev Dyn. 2007;236(12):3321-31.

10. Togel F, Hu Z, Weiss K, Isaac J, Lange C, et al. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 2005;289(1):F31-42.

11. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371(9624):1579-86.

12. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol.  2003;57(1):11-20.

13. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. Jama. 2005;294(7):813-8.

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На этом основании в настоящее время проводится одобренная FDA I фаза клинических испытаний (<a href="http://www.clinicaltrials.gov" target="_blank">www.clinicaltrials.gov</a>; NCT00733876) больных, которые имели высокий риск развития тяжелой ОПП после хирургии на открытом сердце. В рамках испытаний безопасности метода, инфузии аллогенных МСК проводили больным после завершения хирургического вмешательства при аорто-коронарном шунтировании или хирургии клапанов сердца. В исследовании участвовали лица старше 65 лет с наличием почечных заболеваний, сахарного диабета, артериальной гипертензии, коронарной болезни сердца, тяжелой сердечной недостаточности и/или хронической обструктивной болезни легких. Введение МСК проводили по возрастающей, причем первым пяти больным проводилась инфузия клеток в определенной низкой дозе на кг массы тела через бедренный катетер, помещенный в надпочечную часть аорты. Данное сообщение содержит обобщенные сведения о клиническом течении у этих пяти больных, которых лечили по этому протоколу. Почечная функция не нарушалась после операции ни у одного из больных, и на текущий момент не выявлено побочных эффектов или тяжелых негативных явлений. Однако один из больных внезапно скончался через 26 суток после выписки по причинам, которые были расценены главным исследователем и членами Совета по мониторингу данных и безопасности, как не относящиеся к препарату и способу его применения. Следующая группа из пяти больных получит MСК в средней дозе на кг массы тела, и, если при этой дозе не возникнут проблемы с безопасностью, то еще пять больных будут пролечены при высокой дозе МСК на кг массы тела. Предварительная эффективность терапии МСК для профилактики и лечения послеоперационного ОПП в этом контингенте высокого риска (кардиохирургических больных) будет определяться по сравнению исходов у испытуемых лиц (частоты, тяжести и длительности послеоперационного ОПП, временной или постоянной зависимости от диализа, длительности госпитализации или гибели до 30 сут.), и в большой группе больных исторического контроля (база данных на <a href="http://www.STS.org" target="_blank">www.STS.org</a>).<br /> " ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(419) "Первичный отчет о фазе I клинических испытаний: профилактика и лечение острого послеоперационного повреждения почек аллогенными мезенхимными стволовыми клетками у кардиохирургических больных при операциях на открытом сердце" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(419) "Первичный отчет о фазе I клинических испытаний: профилактика и лечение острого послеоперационного повреждения почек аллогенными мезенхимными стволовыми клетками у 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послеоперационного повреждения почек аллогенными мезенхимными стволовыми клетками у кардиохирургических больных при операциях на открытом сердце" ["SECTION_PICTURE_FILE_ALT"]=> string(419) "Первичный отчет о фазе I клинических испытаний: профилактика и лечение острого послеоперационного повреждения почек аллогенными мезенхимными стволовыми клетками у кардиохирургических больных при операциях на открытом сердце" ["SECTION_PICTURE_FILE_TITLE"]=> string(419) "Первичный отчет о фазе I клинических испытаний: профилактика и лечение острого послеоперационного повреждения почек аллогенными мезенхимными стволовыми клетками у кардиохирургических больных при операциях на открытом сердце" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "pervichnyy-otchet-o-faze-i-klinicheskikh-ispytaniy-profilaktika-i-lechenie-ostrogo-posleoperatsionno" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(419) "Первичный отчет о фазе I клинических испытаний: профилактика и лечение острого послеоперационного повреждения почек аллогенными мезенхимными стволовыми клетками у кардиохирургических больных при операциях на открытом сердце" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(419) "Первичный отчет о фазе I клинических испытаний: профилактика и лечение острого послеоперационного повреждения почек аллогенными мезенхимными стволовыми клетками у кардиохирургических больных при операциях на открытом сердце" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "pervichnyy-otchet-o-faze-i-klinicheskikh-ispytaniy-profilaktika-i-lechenie-ostrogo-posleoperatsionno" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "pervichnyy-otchet-o-faze-i-klinicheskikh-ispytaniy-profilaktika-i-lechenie-ostrogo-posleoperatsionno" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "pervichnyy-otchet-o-faze-i-klinicheskikh-ispytaniy-profilaktika-i-lechenie-ostrogo-posleoperatsionno" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(2) "10" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" 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Г., Ланге К., Цандер А. Р., Ху Дж., Пул С., Жанг П., Вестенвельдер К.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(233) "

Гуч А., Доти Дж., Флорес Дж., Свенсон Л., Тегель Ф., Райсс Р. Г., Ланге К., Цандер А. Р., Ху Дж., Пул С., Жанг П., Вестенвельдер К.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10881" ["VALUE"]=> array(2) { ["TEXT"]=> string(4416) "<p class="bodytext">Наши обширные данные доклинического исследования, показывают, что острое повреждение почек (ОПП), индуцированное ишемией/реперфузией – резистентное к лечению осложнение у больных - может эффективно лечиться путем назначения аллогенных мезенхимных стволовых клеток (МСК). На этом основании в настоящее время проводится одобренная FDA I фаза клинических испытаний (<a href="http://www.clinicaltrials.gov" target="_blank">www.clinicaltrials.gov</a>; NCT00733876) больных, которые имели высокий риск развития тяжелой ОПП после хирургии на открытом сердце. В рамках испытаний безопасности метода, инфузии аллогенных МСК проводили больным после завершения хирургического вмешательства при аорто-коронарном шунтировании или хирургии клапанов сердца. В исследовании участвовали лица старше 65 лет с наличием почечных заболеваний, сахарного диабета, артериальной гипертензии, коронарной болезни сердца, тяжелой сердечной недостаточности и/или хронической обструктивной болезни легких. Введение МСК проводили по возрастающей, причем первым пяти больным проводилась инфузия клеток в определенной низкой дозе на кг массы тела через бедренный катетер, помещенный в надпочечную часть аорты. Данное сообщение содержит обобщенные сведения о клиническом течении у этих пяти больных, которых лечили по этому протоколу. Почечная функция не нарушалась после операции ни у одного из больных, и на текущий момент не выявлено побочных эффектов или тяжелых негативных явлений. Однако один из больных внезапно скончался через 26 суток после выписки по причинам, которые были расценены главным исследователем и членами Совета по мониторингу данных и безопасности, как не относящиеся к препарату и способу его применения. Следующая группа из пяти больных получит MСК в средней дозе на кг массы тела, и, если при этой дозе не возникнут проблемы с безопасностью, то еще пять больных будут пролечены при высокой дозе МСК на кг массы тела. Предварительная эффективность терапии МСК для профилактики и лечения послеоперационного ОПП в этом контингенте высокого риска (кардиохирургических больных) будет определяться по сравнению исходов у испытуемых лиц (частоты, тяжести и длительности послеоперационного ОПП, временной или постоянной зависимости от диализа, длительности госпитализации или гибели до 30 сут.), и в большой группе больных исторического контроля (база данных на <a href="http://www.STS.org" target="_blank">www.STS.org</a>).<br /> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4330) "

Наши обширные данные доклинического исследования, показывают, что острое повреждение почек (ОПП), индуцированное ишемией/реперфузией – резистентное к лечению осложнение у больных - может эффективно лечиться путем назначения аллогенных мезенхимных стволовых клеток (МСК). На этом основании в настоящее время проводится одобренная FDA I фаза клинических испытаний (www.clinicaltrials.gov; NCT00733876) больных, которые имели высокий риск развития тяжелой ОПП после хирургии на открытом сердце. В рамках испытаний безопасности метода, инфузии аллогенных МСК проводили больным после завершения хирургического вмешательства при аорто-коронарном шунтировании или хирургии клапанов сердца. В исследовании участвовали лица старше 65 лет с наличием почечных заболеваний, сахарного диабета, артериальной гипертензии, коронарной болезни сердца, тяжелой сердечной недостаточности и/или хронической обструктивной болезни легких. Введение МСК проводили по возрастающей, причем первым пяти больным проводилась инфузия клеток в определенной низкой дозе на кг массы тела через бедренный катетер, помещенный в надпочечную часть аорты. Данное сообщение содержит обобщенные сведения о клиническом течении у этих пяти больных, которых лечили по этому протоколу. Почечная функция не нарушалась после операции ни у одного из больных, и на текущий момент не выявлено побочных эффектов или тяжелых негативных явлений. Однако один из больных внезапно скончался через 26 суток после выписки по причинам, которые были расценены главным исследователем и членами Совета по мониторингу данных и безопасности, как не относящиеся к препарату и способу его применения. Следующая группа из пяти больных получит MСК в средней дозе на кг массы тела, и, если при этой дозе не возникнут проблемы с безопасностью, то еще пять больных будут пролечены при высокой дозе МСК на кг массы тела. Предварительная эффективность терапии МСК для профилактики и лечения послеоперационного ОПП в этом контингенте высокого риска (кардиохирургических больных) будет определяться по сравнению исходов у испытуемых лиц (частоты, тяжести и длительности послеоперационного ОПП, временной или постоянной зависимости от диализа, длительности госпитализации или гибели до 30 сут.), и в большой группе больных исторического контроля (база данных на www.STS.org).
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10843" ["VALUE"]=> string(29) "10.3205/ctt-2008-en-000028.01" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(29) "10.3205/ctt-2008-en-000028.01" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10863" ["VALUE"]=> array(2) { ["TEXT"]=> string(516) "<p class="Autor">Anna Gooch<sup>1</sup>, John Doty<sup>2</sup>, Jean Flores<sup>2</sup>, LeAnne Swenson<sup>2</sup>, Florian E Toegel<sup>1,3</sup>, George R Reiss<sup>4</sup>, Claudia Lange<sup>5</sup>, Axel R Zander<sup>5</sup>, Zhuma Hu<sup>1</sup>, Scott Poole<sup>1</sup>, Ping Zhang<sup>1</sup> and Christof Westenfelder<sup>1,6</sup> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(350) "

Anna Gooch1, John Doty2, Jean Flores2, LeAnne Swenson2, Florian E Toegel1,3, George R Reiss4, Claudia Lange5, Axel R Zander5, Zhuma Hu1, Scott Poole1, Ping Zhang1 and Christof Westenfelder1,6 

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1Division of Nephrology, Department of Medicine, University of Utah Health Sciences Center and George E. Wahlen VA HCS, Salt Lake City, Utah, USA; 2Division of Cardiovascular Surgery, Intermountain Medical Center, Murray, Utah, USA; 3Jacobi Hospital, Albert Einstein College of Medicine affiliated Medical Center, Bronx, New York, USA; 4Division of Cardiovascular Surgery, Department of Surgery, University of Utah Health Sciences Center, and Research Service, George E. Wahlen VA HCS, Salt Lake City, Utah, USA; 5Bone Marrow Transplantation Center, University of Hamburg, Germany; 6Department of Physiology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
 
Correspondence:
Christof Westenfelder, MD, Section of Nephrology (111 N), George E. Wahlen VA Health Sciences Center, 500 Foothill Blvd., Salt Lake City, UT 84148, USA
E-mail: christof.westenfelder@spam is badhsc.utah.edu

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10914" ["VALUE"]=> array(2) { ["TEXT"]=> string(2409) "<p class="bodytext">Based on our extensive pre-clinical data that show that ischemia/reperfusion-induced Acute Kidney Injury (AKI), an essentially treatment resistant complication in patients, can be effectively treated by the administration of allogeneic Mesenchymal Stem Cells (MSC), an FDA approved, Phase I Clinical Trial (<a href="http://www.clinicaltrials.gov" target="_blank">www.clinicaltrials.gov</a>; NCT00733876) in patients who are at high risk of developing severe AKI post open heart surgery is currently being conducted. In this safety trial, patients who are undergoing on-pump coronary artery bypass surgery or cardiac valve repair, who are older than 65 years, with underlying renal disease, diabetes mellitus, hypertension, coronary artery disease, congestive heart failure and/or chronic obstructive pulmonary disease will be infused with allogeneic MSC following completion of surgery. The MSC are dosed in an escalating fashion, the initial five patients being infused via a femoral catheter that is placed into the suprarenal aorta with a defined low dose of MSC/kg body weight. This report summarizes the clinical course of the first five patients that have been treated according to this protocol. The renal function did not deteriorate post operatively in any of these patients, nor were adverse (AE) or severe adverse events (SAE) observed to date. However, one patient died suddenly 26 days after discharge from causes that both the principal investigator and the members of the Data and Safety Monitoring Board judged as being unrelated to the study drug and its route of administration. The next group of five study subjects will receive an intermediate dose of MSC/kg body weight, and if no safety concerns arise with this dose, the final five patients will be treated with a high dose of MSC/kg body weight. Preliminary efficacy of MSC therapy in the prevention and treatment of post-operative AKI in this high risk cohort of cardiac surgery patients will be assessed by comparing outcomes in study subjects (frequency, severity and duration of post-operative AKI, dialysis dependency [temporary, permanent], length of stay, and death at 30 days) to those in a large number of historical controls (data base at <a href="http://www.STS.org" target="_blank">www.STS.org</a>).<br /><br />" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2317) "

Based on our extensive pre-clinical data that show that ischemia/reperfusion-induced Acute Kidney Injury (AKI), an essentially treatment resistant complication in patients, can be effectively treated by the administration of allogeneic Mesenchymal Stem Cells (MSC), an FDA approved, Phase I Clinical Trial (www.clinicaltrials.gov; NCT00733876) in patients who are at high risk of developing severe AKI post open heart surgery is currently being conducted. In this safety trial, patients who are undergoing on-pump coronary artery bypass surgery or cardiac valve repair, who are older than 65 years, with underlying renal disease, diabetes mellitus, hypertension, coronary artery disease, congestive heart failure and/or chronic obstructive pulmonary disease will be infused with allogeneic MSC following completion of surgery. The MSC are dosed in an escalating fashion, the initial five patients being infused via a femoral catheter that is placed into the suprarenal aorta with a defined low dose of MSC/kg body weight. This report summarizes the clinical course of the first five patients that have been treated according to this protocol. The renal function did not deteriorate post operatively in any of these patients, nor were adverse (AE) or severe adverse events (SAE) observed to date. However, one patient died suddenly 26 days after discharge from causes that both the principal investigator and the members of the Data and Safety Monitoring Board judged as being unrelated to the study drug and its route of administration. The next group of five study subjects will receive an intermediate dose of MSC/kg body weight, and if no safety concerns arise with this dose, the final five patients will be treated with a high dose of MSC/kg body weight. Preliminary efficacy of MSC therapy in the prevention and treatment of post-operative AKI in this high risk cohort of cardiac surgery patients will be assessed by comparing outcomes in study subjects (frequency, severity and duration of post-operative AKI, dialysis dependency [temporary, permanent], length of stay, and death at 30 days) to those in a large number of historical controls (data base at www.STS.org).

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Anna Gooch1, John Doty2, Jean Flores2, LeAnne Swenson2, Florian E Toegel1,3, George R Reiss4, Claudia Lange5, Axel R Zander5, Zhuma Hu1, Scott Poole1, Ping Zhang1 and Christof Westenfelder1,6 

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Anna Gooch1, John Doty2, Jean Flores2, LeAnne Swenson2, Florian E Toegel1,3, George R Reiss4, Claudia Lange5, Axel R Zander5, Zhuma Hu1, Scott Poole1, Ping Zhang1 and Christof Westenfelder1,6 

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Based on our extensive pre-clinical data that show that ischemia/reperfusion-induced Acute Kidney Injury (AKI), an essentially treatment resistant complication in patients, can be effectively treated by the administration of allogeneic Mesenchymal Stem Cells (MSC), an FDA approved, Phase I Clinical Trial (www.clinicaltrials.gov; NCT00733876) in patients who are at high risk of developing severe AKI post open heart surgery is currently being conducted. In this safety trial, patients who are undergoing on-pump coronary artery bypass surgery or cardiac valve repair, who are older than 65 years, with underlying renal disease, diabetes mellitus, hypertension, coronary artery disease, congestive heart failure and/or chronic obstructive pulmonary disease will be infused with allogeneic MSC following completion of surgery. The MSC are dosed in an escalating fashion, the initial five patients being infused via a femoral catheter that is placed into the suprarenal aorta with a defined low dose of MSC/kg body weight. This report summarizes the clinical course of the first five patients that have been treated according to this protocol. The renal function did not deteriorate post operatively in any of these patients, nor were adverse (AE) or severe adverse events (SAE) observed to date. However, one patient died suddenly 26 days after discharge from causes that both the principal investigator and the members of the Data and Safety Monitoring Board judged as being unrelated to the study drug and its route of administration. The next group of five study subjects will receive an intermediate dose of MSC/kg body weight, and if no safety concerns arise with this dose, the final five patients will be treated with a high dose of MSC/kg body weight. Preliminary efficacy of MSC therapy in the prevention and treatment of post-operative AKI in this high risk cohort of cardiac surgery patients will be assessed by comparing outcomes in study subjects (frequency, severity and duration of post-operative AKI, dialysis dependency [temporary, permanent], length of stay, and death at 30 days) to those in a large number of historical controls (data base at www.STS.org).

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Based on our extensive pre-clinical data that show that ischemia/reperfusion-induced Acute Kidney Injury (AKI), an essentially treatment resistant complication in patients, can be effectively treated by the administration of allogeneic Mesenchymal Stem Cells (MSC), an FDA approved, Phase I Clinical Trial (www.clinicaltrials.gov; NCT00733876) in patients who are at high risk of developing severe AKI post open heart surgery is currently being conducted. In this safety trial, patients who are undergoing on-pump coronary artery bypass surgery or cardiac valve repair, who are older than 65 years, with underlying renal disease, diabetes mellitus, hypertension, coronary artery disease, congestive heart failure and/or chronic obstructive pulmonary disease will be infused with allogeneic MSC following completion of surgery. The MSC are dosed in an escalating fashion, the initial five patients being infused via a femoral catheter that is placed into the suprarenal aorta with a defined low dose of MSC/kg body weight. This report summarizes the clinical course of the first five patients that have been treated according to this protocol. The renal function did not deteriorate post operatively in any of these patients, nor were adverse (AE) or severe adverse events (SAE) observed to date. However, one patient died suddenly 26 days after discharge from causes that both the principal investigator and the members of the Data and Safety Monitoring Board judged as being unrelated to the study drug and its route of administration. The next group of five study subjects will receive an intermediate dose of MSC/kg body weight, and if no safety concerns arise with this dose, the final five patients will be treated with a high dose of MSC/kg body weight. Preliminary efficacy of MSC therapy in the prevention and treatment of post-operative AKI in this high risk cohort of cardiac surgery patients will be assessed by comparing outcomes in study subjects (frequency, severity and duration of post-operative AKI, dialysis dependency [temporary, permanent], length of stay, and death at 30 days) to those in a large number of historical controls (data base at www.STS.org).

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Wahlen VA HCS, Salt Lake City, Utah, USA; <sup>2</sup>Division of Cardiovascular Surgery, Intermountain Medical Center, Murray, Utah, USA; <sup>3</sup>Jacobi Hospital, Albert Einstein College of Medicine affiliated Medical Center, Bronx, New York, USA; <sup>4</sup>Division of Cardiovascular Surgery, Department of Surgery, University of Utah Health Sciences Center, and Research Service, George E. Wahlen VA HCS, Salt Lake City, Utah, USA; <sup>5</sup>Bone Marrow Transplantation Center, University of Hamburg, Germany; <sup>6</sup>Department of Physiology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA <br /> <br /> <b>Correspondence: </b><br> Christof Westenfelder, MD, Section of Nephrology (111 N), George E. Wahlen VA Health Sciences Center, 500 Foothill Blvd., Salt Lake City, UT 84148, USA<br> E-mail: <a href="javascript:linkTo_UnCryptMailto('qempxs.glvmwxsj2aiwxirjiphivDlwg2yxel2ihy');" class="mail">christof.westenfelder@<span style="display:none;">spam is bad</span>hsc.utah.edu</a> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1168) "

1Division of Nephrology, Department of Medicine, University of Utah Health Sciences Center and George E. Wahlen VA HCS, Salt Lake City, Utah, USA; 2Division of Cardiovascular Surgery, Intermountain Medical Center, Murray, Utah, USA; 3Jacobi Hospital, Albert Einstein College of Medicine affiliated Medical Center, Bronx, New York, USA; 4Division of Cardiovascular Surgery, Department of Surgery, University of Utah Health Sciences Center, and Research Service, George E. Wahlen VA HCS, Salt Lake City, Utah, USA; 5Bone Marrow Transplantation Center, University of Hamburg, Germany; 6Department of Physiology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
 
Correspondence:
Christof Westenfelder, MD, Section of Nephrology (111 N), George E. Wahlen VA Health Sciences Center, 500 Foothill Blvd., Salt Lake City, UT 84148, USA
E-mail: christof.westenfelder@spam is badhsc.utah.edu

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1Division of Nephrology, Department of Medicine, University of Utah Health Sciences Center and George E. Wahlen VA HCS, Salt Lake City, Utah, USA; 2Division of Cardiovascular Surgery, Intermountain Medical Center, Murray, Utah, USA; 3Jacobi Hospital, Albert Einstein College of Medicine affiliated Medical Center, Bronx, New York, USA; 4Division of Cardiovascular Surgery, Department of Surgery, University of Utah Health Sciences Center, and Research Service, George E. Wahlen VA HCS, Salt Lake City, Utah, USA; 5Bone Marrow Transplantation Center, University of Hamburg, Germany; 6Department of Physiology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
 
Correspondence:
Christof Westenfelder, MD, Section of Nephrology (111 N), George E. Wahlen VA Health Sciences Center, 500 Foothill Blvd., Salt Lake City, UT 84148, USA
E-mail: christof.westenfelder@spam is badhsc.utah.edu

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array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "10881" ["VALUE"]=> array(2) { ["TEXT"]=> string(4416) "<p class="bodytext">Наши обширные данные доклинического исследования, показывают, что острое повреждение почек (ОПП), индуцированное ишемией/реперфузией – резистентное к лечению осложнение у больных - может эффективно лечиться путем назначения аллогенных мезенхимных стволовых клеток (МСК). На этом основании в настоящее время проводится одобренная FDA I фаза клинических испытаний (<a href="http://www.clinicaltrials.gov" target="_blank">www.clinicaltrials.gov</a>; NCT00733876) больных, которые имели высокий риск развития тяжелой ОПП после хирургии на открытом сердце. В рамках испытаний безопасности метода, инфузии аллогенных МСК проводили больным после завершения хирургического вмешательства при аорто-коронарном шунтировании или хирургии клапанов сердца. В исследовании участвовали лица старше 65 лет с наличием почечных заболеваний, сахарного диабета, артериальной гипертензии, коронарной болезни сердца, тяжелой сердечной недостаточности и/или хронической обструктивной болезни легких. Введение МСК проводили по возрастающей, причем первым пяти больным проводилась инфузия клеток в определенной низкой дозе на кг массы тела через бедренный катетер, помещенный в надпочечную часть аорты. Данное сообщение содержит обобщенные сведения о клиническом течении у этих пяти больных, которых лечили по этому протоколу. Почечная функция не нарушалась после операции ни у одного из больных, и на текущий момент не выявлено побочных эффектов или тяжелых негативных явлений. Однако один из больных внезапно скончался через 26 суток после выписки по причинам, которые были расценены главным исследователем и членами Совета по мониторингу данных и безопасности, как не относящиеся к препарату и способу его применения. Следующая группа из пяти больных получит MСК в средней дозе на кг массы тела, и, если при этой дозе не возникнут проблемы с безопасностью, то еще пять больных будут пролечены при высокой дозе МСК на кг массы тела. Предварительная эффективность терапии МСК для профилактики и лечения послеоперационного ОПП в этом контингенте высокого риска (кардиохирургических больных) будет определяться по сравнению исходов у испытуемых лиц (частоты, тяжести и длительности послеоперационного ОПП, временной или постоянной зависимости от диализа, длительности госпитализации или гибели до 30 сут.), и в большой группе больных исторического контроля (база данных на <a href="http://www.STS.org" target="_blank">www.STS.org</a>).<br /> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4330) "

Наши обширные данные доклинического исследования, показывают, что острое повреждение почек (ОПП), индуцированное ишемией/реперфузией – резистентное к лечению осложнение у больных - может эффективно лечиться путем назначения аллогенных мезенхимных стволовых клеток (МСК). На этом основании в настоящее время проводится одобренная FDA I фаза клинических испытаний (www.clinicaltrials.gov; NCT00733876) больных, которые имели высокий риск развития тяжелой ОПП после хирургии на открытом сердце. В рамках испытаний безопасности метода, инфузии аллогенных МСК проводили больным после завершения хирургического вмешательства при аорто-коронарном шунтировании или хирургии клапанов сердца. В исследовании участвовали лица старше 65 лет с наличием почечных заболеваний, сахарного диабета, артериальной гипертензии, коронарной болезни сердца, тяжелой сердечной недостаточности и/или хронической обструктивной болезни легких. Введение МСК проводили по возрастающей, причем первым пяти больным проводилась инфузия клеток в определенной низкой дозе на кг массы тела через бедренный катетер, помещенный в надпочечную часть аорты. Данное сообщение содержит обобщенные сведения о клиническом течении у этих пяти больных, которых лечили по этому протоколу. Почечная функция не нарушалась после операции ни у одного из больных, и на текущий момент не выявлено побочных эффектов или тяжелых негативных явлений. Однако один из больных внезапно скончался через 26 суток после выписки по причинам, которые были расценены главным исследователем и членами Совета по мониторингу данных и безопасности, как не относящиеся к препарату и способу его применения. Следующая группа из пяти больных получит MСК в средней дозе на кг массы тела, и, если при этой дозе не возникнут проблемы с безопасностью, то еще пять больных будут пролечены при высокой дозе МСК на кг массы тела. Предварительная эффективность терапии МСК для профилактики и лечения послеоперационного ОПП в этом контингенте высокого риска (кардиохирургических больных) будет определяться по сравнению исходов у испытуемых лиц (частоты, тяжести и длительности послеоперационного ОПП, временной или постоянной зависимости от диализа, длительности госпитализации или гибели до 30 сут.), и в большой группе больных исторического контроля (база данных на www.STS.org).
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(4330) "

Наши обширные данные доклинического исследования, показывают, что острое повреждение почек (ОПП), индуцированное ишемией/реперфузией – резистентное к лечению осложнение у больных - может эффективно лечиться путем назначения аллогенных мезенхимных стволовых клеток (МСК). На этом основании в настоящее время проводится одобренная FDA I фаза клинических испытаний (www.clinicaltrials.gov; NCT00733876) больных, которые имели высокий риск развития тяжелой ОПП после хирургии на открытом сердце. В рамках испытаний безопасности метода, инфузии аллогенных МСК проводили больным после завершения хирургического вмешательства при аорто-коронарном шунтировании или хирургии клапанов сердца. В исследовании участвовали лица старше 65 лет с наличием почечных заболеваний, сахарного диабета, артериальной гипертензии, коронарной болезни сердца, тяжелой сердечной недостаточности и/или хронической обструктивной болезни легких. Введение МСК проводили по возрастающей, причем первым пяти больным проводилась инфузия клеток в определенной низкой дозе на кг массы тела через бедренный катетер, помещенный в надпочечную часть аорты. Данное сообщение содержит обобщенные сведения о клиническом течении у этих пяти больных, которых лечили по этому протоколу. Почечная функция не нарушалась после операции ни у одного из больных, и на текущий момент не выявлено побочных эффектов или тяжелых негативных явлений. Однако один из больных внезапно скончался через 26 суток после выписки по причинам, которые были расценены главным исследователем и членами Совета по мониторингу данных и безопасности, как не относящиеся к препарату и способу его применения. Следующая группа из пяти больных получит MСК в средней дозе на кг массы тела, и, если при этой дозе не возникнут проблемы с безопасностью, то еще пять больных будут пролечены при высокой дозе МСК на кг массы тела. Предварительная эффективность терапии МСК для профилактики и лечения послеоперационного ОПП в этом контингенте высокого риска (кардиохирургических больных) будет определяться по сравнению исходов у испытуемых лиц (частоты, тяжести и длительности послеоперационного ОПП, временной или постоянной зависимости от диализа, длительности госпитализации или гибели до 30 сут.), и в большой группе больных исторического контроля (база данных на www.STS.org).
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Introduction

An adult organism develops from the most primitive stem cell (SC) called a zygote, which is an oocyte that is fertilized by a sperm cell. This totipotent zygote, the “mother of all stem cells” in the developing body, first gives rise to pluripotent (P)SCs that form morula and, subsequently, to the SCs committed to trophoblasts that will give rise to the placenta and the pluripotent SC population that forms the inner cell mass of the blastocyst. The cells from the inner cell mass of the blastocyst will give rise to the epiblast, a part of the developing embryo, which is the origin of SCs committed to all the three germ layers (meso-, ecto-, and endoderm) [1-5].

Thus, the epiblast could be considered the origin for the SCs committed for all the organs and tissues in developing the embryo proper. PSCs in the epiblast undergo a sequence of specification events, first into multipotent and subsequently into versatile tissue-committed SCs, which play a role in the formation and rejuvenation of various organs [5-7]. The most important questions emerge of whether some of these primitive epiblast-forming PSCs can “escape” specification into more differentiated populations of SCs and retain their pluripotential character, thus surviving among differentiated daughter tissue-committed SCs. Conversely, would all of them undergo tissue/organ specific differentiation and then “disappear” after embryogenesis, and not be found in the adult body (Figure 1)?

2008_Ratajczak_Fig01.png

Figure 1. Potential VSELs contribution to tissue rejuvenation. Panel A: VSELs deposited in adult tissues during embryogenesis/gastrulation may become eliminated after giving rise to TCSCs. Panel B: Conversely, they may survive among TCSCs and serve as a potential back-up/reserve source of TCSCs.

Recently, our group obtained several pieces of evidence that may lend some support for the first possibility. Accordingly, we have identified a population of very primitive SCs in adult tissues that express many markers characteristic for epiblast Scs [8]. Based on this we named these rare cells “very small embryonic like stem cells (VSELs).” We hypothesized that they are deposited during early gastrulation in developing tissues/organs, survive into adulthood, and play an important role as a back-up population of PSCs in the turnover of tissue-specific/committed SCs (TCSCs) [5, 7, 8].

The presence of pluripotent VSELs in adult tissues may reconcile all previously published data stating that adult tissues may contain a population of PSCs [9, 10]. The existence of such cells had been postulated by several investigators [11, 12]. However, such cells were never purified and identified at the single cell level. Their presence was accepted mainly based on experiments showing that some populations of cells were enriched with adherent cell populations isolated from the bone marrow (BM) or that certain solid organs contain some primitive cells that may differentiate into various tissues.

Accordingly, several populations of non-hematopoietic primitive SCs have been described in the BM and other adult tissues, including: i) mesenchymal (M)SCs [13]; ii) multipotent adult progenitor cells (MAPCs) [14]; iii) marrow-isolated adult multilineage inducible (MIAMI) cells [15]; iv) multipotent adult (MA)SCs [16]; and v) Omnicytes [17, 18]. It is conceivable that all these cells are closely related, overlapping populations of SCs described by different investigators and given various names according to circumstance. Furthermore, the potential relationship between these cells and VSELs is not clear. Since MSCs, MAPCs, MIAMIs, and MASCs are largely derived from the adherent fraction of BM- or adult organ-derived cells, these cells could potentially contain some VSELs attached to or associated with them due to emperipolesis. This requires further investigation.

“Of germ line and soma”: germ line as origin and skeleton of the SC system in the adult body

From a developmental point of view, cells that are “immortal” in mammals are those that belong to the germ line. Accordingly, the germ line passes genomic and mitochondrial DNA to the next generations and creates “mortal soma”, which helps the germ line to fulfill this reproductive mission [19-21]. The most primitive cell in the germ line is the above-mentioned zygote, which is a result of fusion of two gametes (germ cells), i.e., the oocyte and sperm, during the process of fertilization. Germ line potential is subsequently maintained in blastomers of morula and in the cells of the inner cell mass of the blastocyst. At the level of the blastocyst, however, a part of the cells that surrounds the blastula “buds out” from the germ line lineage and differentiates toward throphoblasts, which give rise to the placenta. After implantation of the blastocyst in the uterus, a germ line potential is maintained in the epiblast [19-21].

In mice, at 7.25 days post-conception (dpc), a part of epiblast PSCs is specified into a population of primordial germ cells (PGCs) that will migrate to the genital ridgesahre    where they subsequently differentiate into oocytes or sperm during gametogenesis [6, 22]. Shortly after PGC specification, the remaining epiblast PSCs, which we envision to be related to the germ line lineage, become specified to multipotent/unipotent SCs for developing tissues and organs [20]. These primitive epiblast/germ line-derived PCSs, as we hypothesize, are not completely eliminated from the developing organism by the differentiation process. We believe that some of them survive (e.g., VSELs?) among tissue-committed SCs [20].

PGCs are the most important population of SCs. As precursors of germ cells/gametes, they are directly responsible for passing genetic information on to the next generation. However, these developmentally early cells, if isolated from the developing embryo after 11 dpc (at the time while they migrate to genital ridges) and cultured ex vivo, surprisingly will undergo rapid terminal differentiation or apoptosis [23]. Interestingly, they also do not complement blastocyst development, are not able to provide fully functional nuclei during nuclear transfer in the process of clonote formation, and do not grow teratomas  [20, 24-26]. Therefore, these cells lack the currently approved criteria of pluripotentiality. This also indicates that PGCs have to be somehow protected from uncontrolled expansion by certain important regulatory mechanisms.
 
One explanation for this obvious lack of pluripotentiality is that PGCs undergo epigenetic modification and erasure of the somatic imprint on differently methylated regions (DMRs) of somatic imprinted genes [27, 28]. Somatic imprinted genes show a different methylation pattern in some of the genes located either on maternal or paternal chromosomes (e.g., H19, Igf-2, Igf-2R, Snrpn). As a result of the imprint, for example, Igf-2 is expressed from the paternal and H19 is expressed from the maternal chromosome [20, 27, 28].

The process of erasure of the somatic imprint occurs very early during gastrulation when the PGCs begin to migrate to the genital ridges [27, 28]. It is one of the basic mechanisms that prevents their uncontrolled proliferation, parthenogenesis, and prevents potential teratoma formation by these cells. Thus, the proper somatic imprint seems to be required for PSCs to be able to complement blastocyst development, provide nuclei for clonote formation after nuclear transfer, and to grow teratomas in immunodeficient mice. Because migrating PGCs erase the imprint, they are not able to display these “golden standard” pluripotency criteria in appropriate experimental models [26-28].

However, if plated over murine fetal fibroblasts in the presence of selected growth factors, i.e., leukemia inhibitory factor (LIF), basic fibroblast growth factor (bFGF), and kit ligand, PGCs may undergo epigenetic changes forced by in vitro culture conditions that regain the somatic imprint, which endows them with “immortality” [29, 30]. Thus, this change of “PGC fate” is connected with a proper re-methylation of somatic imprinted genes. This immortalized population of PGCs known as embryonic germ cells (EGCs) is in many aspects the equivalent to embryonic (E)SCs [31]. For example, similarly to ESCs, EGCs contribute to all three germ layers including the germ cell lineage after injection into a blastocyst (blastocyst complementation assay), provide functional nuclei for clonote after nuclear transfer, and, after injection into living mice, these cells form teratomas [21, 31]. Thus, it is evident that a proper somatic imprint is vital for cells from the germ line to retain full pluripotentiality. Based on this, we postulate that erasure of the somatic imprint of some crucial developmentally genes is involved in controlling the quiescent status of VSELs [20, 32]. However, as in the case of PGCs, this process should be potentially reversible. As such, we will have to focus on reestablishing the proper somatic imprint in these cells. We envision that such reverted VSELs could potentially become equivalent to cells isolated from the embryos, e.g., after nuclear transfer or even to inducible (i)PSCs [33, 34].

The hunt for PSCs in the adult body

The presence of PSCs in adult tissues was postulated in the past by several investigators, but such cells were never purified at the single cell level. A few years ago, our team began to search for such cells in murine BM. Based on our preliminary experimental data, we assumed that the cells we were looking for would be CD133+ CXCR4+ in mice and humans as well as Sca-1+ in mice. We also assumed that they would be negative in both species for the pan-hematopoietic marker, which is the CD45 antigen (CD45-) [8, 35, 36]. In addition, our preliminary chemotactic experiments revealed that BM contains a very rare population of small cells (3-5 µm in diameter) that robustly respond by chemotaxis to stromal-derived factor-1 (SDF-1), which is a ligand for the CXCR4 receptor [37]. These small CXCR4+ cells expressed some early developmental markers characteristic for very primitive cells [8, 37].

Based on this information, we decided to sort a population of small (<6 µm) Sca-1+lin-CD45- cells from the murine BM and other tissues. By employing a fluorescence activated cell sorter (FACS), we isolated a population of rare Sca-1+Lin-CD45- cells from several adult tissues including BM, brain, liver, pancreas, kidney, muscles, heart, testes, and thymus [9]. As determined by real time RT-PCR (RQ-PCR) by employing sequence specific primers and by immunohistochemistry, these cells express several markers of PSCs such as SSEA-1, Oct-4, Nanog, and Rex-1 as well as Rif-1 telomerase protein [8, 9]. Based on the expression of these early developmental markers and morphology, we named these cells “very small embryonic-like stem cells (VSELs)” [8].

To isolate VSELs from the BM by FACS, we employed a novel size-based approach controlled by size bead markers (Figure 2). The overall sorting strategy was to gate in regions containing small events (2–10 µm), which is shown as Region R1 on the dot plot (Figure 2: Panel A). This region mostly contains cell debris, but also includes some rare nucleated cell events. Because it is well known that most of the sorting protocols exclude events smaller than 6 µm in diameter that contain cell debris, erythrocytes, and platelets, small VSELs are usually excluded from the sorted cell populations. Thus, in our sorting strategy to isolate VSELs and define a region of cells from which we could sort these cells, the size of the sorted cells was controlled by beads with predefined sizes (1, 2, 4, 6, 10, and 15 µm in diameter) (Figure 2: Panel A).

2008_Ratajczak_Fig02.png


Figure 2. Sorting strategy for isolation of murine BM-derived VSELs by FACS.
BM-derived VSELs were sorted by MoFlo cell sorter (Dako, Glostrup, DEN) following immunofluorescence staining for Sca-1, CD45, and hematopoietic Lin. Panel A: Distribution of six predefined, sized beads populations according to their FSCs vs. SSCs (forward and side scatter characteristics, respectively). Gate R1 includes objects between 2 to 10µm in size after comparison to bead particles with standard sizes of 1, 2, 4, 6, 10, and 15µm (Flow Cytometry Size beads, Invitrogen; Molecular Probes, Carlsbad, CA, USA). Panel B: BMNCs visualized on dot plots showing their FSC and SSC signals related to the size and granularity/complexity of the cell, respectively. Small, agranular cells included in Region R1 are further visualized based on the expression of Sca-1 and Lin markers (Panel D). Region R2 includes only Sca-1+/Lin-, which are subsequently sorted based on CD45 marker expression into CD45- and CD45+ subpopulations visualized on histogram (Panel C). Sca-1+/Lin-/CD45- cells (VSELs) are sorted as events enclosed in a logical gate including Regions R1, R2, and R3, while Sca-1+/Lin-/CD45+ cells (HSCs) from gate include Regions R1, R2, and R4. Approximate percent contents of each cellular subpopulation are indicated on the plots.

The events enclosed in region R1 (Figure 2: Panel B), which include an average of ~50% of total collected events, are further analyzed for the expression of Sca-1 and lineage markers (Lin). The Sca-1+Lin- events shown in region R2 (Figure 2: Panel D) consist of 0.38 ± 0.05% of total analyzed BM nucleated cells (BMNCs) on average. Cells from region R2 are subsequently sorted according to the expression of CD45- as Sca-1+Lin-CD45- (region R3) and Sca-1+Lin-CD45+ (region R4) subpopulations (Figure 2: Panel C) that contain VSELs and HSCs, respectively. We found that VSELs comprise ~0.03% while HSCs are ~0.35% of total BMNCs (Figure 2: Panel C). We found that 95% of Sca-1+Lin-CD45- (VSELs) are located within the 2–6 µm size range, while 86% of Sca-1+Lin-CD45+ (HSCs) are found in the 6–10 µm size range [36]. Thus, by employing flow cytometry and the size marker beads, we confirmed our previous transmission electron microscopy (TEM) data showing that the majority of Sca-1+Lin-CD45- cells isolated from adult BM are unusually small (<6 µm) [8]. In conclusion, VSELs are larger than PB platelets and smaller than erythrocytes. Direct TEM analysis revealed that these cells display several features typical for ESCs such as small size, a large nucleus surrounded by a narrow rim of cytoplasm, and open-type chromatin (euchromatin).

ImageStream system (ISS) analysis was also employed to further evaluate the morphological features of VSELs [36]. The ISS-based analysis is a new flow cytometry-based analytical strategy that employs flow cytometry combined with microscopy. This allows for statistical analyses of various cellular parameters as well as direct visualization of cells acquired by FACS in suspension during flow analysis via high-resolution brightfield, darkfield, and fluorescence images [36]. The high resolution of ISS imaging enables the identification of objects as small as 1 µm in diameter [38-40].

In employing ISS analysis, we confirmed with greater precision that VSELs are ~3.6 μm in diameter, while Sca-1+Lin-CD45+ HSCs are larger at ~6.5 μm in diameter. We also noticed that VSELs have a significantly higher (P < 0.05) nuclear/cytoplasmic ratio as compared with HSCs (1.47 ± 0.17 and 0.82 ± 0.03, respectively). Furthermore, VSELs had significantly lower (P < 0.05) cytoplasmic area as compared with HSCs (5.41 ± 0.58 and 33.78 ± 1.68, respectively) [36]. Despite their small size, VSELs possess diploid DNA. They do not express MHC-1 and HLA-DR antigens and are CD90- CD105- CD29- [41].

Interestingly, if plated over a C2C12 murine sarcoma cell feeder layer, ~5–10% of purified VSELs are able to form spheres that resemble embryoid bodies. Cells from these VSEL-derived spheres (VSEL-DSs) are composed of immature cells with large nuclei containing euchromatin and are CXCR4+SSEA-1+Oct-4+, just like purified VSELs [8>]. Similar spheres were also formed by VSELs isolated from murine fetal liver, spleen, thymus, and kidney. Interestingly, formation of VSEL-DSs was associated with a young age in mice with no VSEL-DSs observed in cells isolated from older mice (> 2 years) [10]. This age-dependent content of VSELs in BM may somehow explain why the regeneration processes is more efficient in younger individuals. There are also differences in the content of these cells among BM mononuclear cells (MNCs) between long- and short-lived mouse strains. The concentration of these cells is much higher in the BM of long-lived (e.g., C57Bl6) as compared to short-lived (DBA/2J) mice [8]. In the future, it would be interesting to identify the genes responsible for tissue distribution and expansion of these cells, as they could be involved in controlling the life span of mammals.

Furthermore, since VSELs express several markers of PGCs (fetal-type alkaline phosphatase, Oct-4, SSEA-1, CXCR4, Mvh, Stella, Fragilis, Nobox, Hdac6), they could be closely related to a population of epiblast-derived PGCs. VSELs are also highly mobile and respond robustly to an SDF-1 gradient, adhere to fibronectin and fibrinogen, and may interact with BM-derived stromal fibroblasts [8]. Confocal microscopy and time-lapse studies revealed that these cells attach rapidly to, migrate beneath, and undergo emperipolesis in marrow-derived fibroblasts. This is explainable by fibroblasts secreting SDF-1 and other chemoattractants, which may create a homing environment for small CXCR4+ VSELs [8]. This robust interaction of VSELs with BM-derived fibroblasts has an important implication. It is possible that isolated BM and other tissues’ fibroblastic cells (e.g., MSCs, USSCs, MACSs, MAPCs, or MIAMI cells) may be to some degree contaminated by these tiny cells from the beginning. This observation may explain the unexpected plasticity of marrow-derived fibroblastic cells, e.g., MSCs.

Recently, evidence has also mounted to suggest that similar cells corresponding to those found in murine tissues are also present particularly in the human BM, umbilical cord blood (UCB), and mobilized (m)PB (Table I). Overall, it is anticipated that VSELs could become an important source of PSCs for regeneration. Thus, researchers working with animal models must determine whether these cells could be efficiently employed in the clinic or whether they are merely developmental remnants found in the BM that cannot be harnessed effectively for regeneration. Our initial collaborative studies indicate an efficacy of these cells in improving heart function in an animal model of acute myocardiac infarction in mice [42, 43]. We anticipate seeing similar phenomena in humans.

Table I. Morphological and phenotypic comparison of murine and human VSELs.

2008_Ratajczak_Tab01.png

VSELs as circulating “paramedics” in the body

Our data also indicates that VSELs may be released during stress situations or tissue/organ injury from their tissue niches and circulate in the PB both in humans (e.g., after heart infarct or stroke) and in mice (e.g., after granulocyte colony growth factor [G-CSF]-induced mobilization, experimental heart infarct and stroke, as well as liver and skeletal muscle injury) [44-46]. The trafficking of VSELs is orchestrated by several chemotactic factors that are upregulated in damaged tissues during tissue organ injury such as α-chemokine SDF-1, hepatocyte growth factor/scatter factor (HGF/SF), LIF, and vascular endothelial growth factor (VEGF) [47-50]. Complement cascade cleavage fragments also play an important role in this process, such as C3a anaplylatoxin for example, which enhances responsiveness of VSELs to SDF-1 gradient (Figure 3). Thus, a concept emerged where chemotactic factors that are upregulated in damaged tissues may orchestrate the release of non-hematopoietic SCs from BM into mPB.

For instance, in a murine model of G-CSF-induced mobilization, we noticed that VSELs are detectable at a very low level in steady state conditions in murine PB (~160 cells/ml) and that their number increases ~6 times during G-CSF-induced mobilization events [44]. Increases in the number of these cells circulating in PB are further supported by an increase in expression of mRNA for early developmental markers expressed in VSELs, such as the embryonic transcription factors Oct-4, Nanog, and Rex-1 as well as the expression of Rif1 and Dppa3 [44]. Furthermore, at the same time, MNCs mobilized into PB are highly enriched for mRNA for several early developmental tissue-specific markers, a phenomenon that could be explained as mentioned above by the open-type status of chromatin in these cells. Finally, we sorted these rare cells from murine PB by FACS for immunofluorescence staining and provided evidence that they express SSEA-1 antigen on the surface and Oct-4 in the nucleus.

To provide evidence that mobilized VSELs not only express PSC markers but also are able to differentiate into cells from all three germ layers, we performed differentiation studies in vitro. To provide such proof, VSELs were cultured in appropriate differentiation media on the layer of BM-derived stromal support. We found that mobilized VSELs are able to differentiate into cardiomyocytes, neurons, and pancreatic cell-like clusters [44]. The analysis of DNA content in GFP+ cells isolated from the co-cultures excluded the contribution of cell fusion to this effect. Thus, these experiments revealed the in vitro pluripotency of VSELs mobilized by G-CSF and circulating in mPB by demonstrating their ability to differentiate into cells from all three germ layers. We envision that VSELs mobilized into PB in humans, such as after G-CSF administration, could be harvested by leucopheresis as a potential source of SCs for regenerative medicine.

2008_Ratajczak_Fig03.png


Figure 3. VSELs are mobilized into PB.

Panel A: Under normal steady state conditions, VSELs may circulate in PB to keep a pool of SCs in balance in distant niches of the same tissue. 
Panel B: The number of these cells increases during stress related to organ/tissue damage. During organ damage (e.g., heart infarct), the level of SDF-1 is upregulated in the affected tissues and C3 becomes activated leading to the accumulation of C3 cleavage fragments (C3a and desArgC3a). C3 cleavage fragments enhance/prime the responsiveness of circulating CXCR4+ SCs to an SDF-1 gradient. This leads to more efficient chemoattraction of SCs for potential regeneration of the damaged tissue by creating “a super gradient,” as shown in Panel B for infracted myocardium, for example. In addition to SDF-1, other chemoattractants also play important roles here (e.g., HGF/SF, LIF, and VEGF).


Do Oct-4+ VSELs initiate tumor development?

Several investigators have proposed theories regarding cancer formation in the germ cell compartment. Accordingly, Recamier (1829), Remak (1854), and Virchow (1958) proposed that cancer arises from embryo-like cells. Subsequently, Durante and J. Cohnheim in 1874 and 1875, respectively, suggested adult tissues contain embryonic remnants that normally lie dormant, but can be activated to become cancerous. In 1910, Wright proposed the germinal cell origin of Willm’s tumor (nephroblastoma) and in 1911, J. Beard postulated that tumors arise from displaced trophoblast or activated germ cells. We envision the Oct-4+ VSEL recently identified in adult tissues could unify and fully support all these theories. First, we envision that if the genomic imprint in VSELs is not erased, they may retain post-developmental in vivo pluripotency and grow teratomas and teratocarcinomas [5, 20]. Second, if they are closely related to migratory PGCs, which go astray from the major migratory route to the genital ridges, they may ultimately give rise to germinomas and seminomas, for example. Third, if these cells acquire critical mutations, they may develop into the several types of pediatric sarcomas (e.g., rhabdomyosarcoma, neuroblastoma, Ewing-sarcoma, or Willm's tumor). In support of this, there is a strong correlation between the number of these Oct-4+ cells that persist in postnatal tissues and the coincidence with these types of tumors in pediatric patients. Finally, it is possible that these cells, if mobilized at the wrong time into the PB and deposited in areas of chronic inflammation, may not play a role in regeneration but may contribute to the development of other malignancies (e.g., stomach cancer or lung cancer). To support this further, several tumor types may express embryonic markers including Oct-4 and, as reported, BM-derived SCs that may develop in the presence of carcinogens to some sarcomas or teratomas. Furthermore, we hypothesize that VSELs hiding among BM-derived fibroblasts could also be responsible for sarcoma formation by MSC cells. Circulating VSELs also could be also chemoattracted by the hypoxic/chemoattractant-rich environment of a growing tumor and provide stroma and vessels for expanding that tumor. Finally, it is also possible that circulating VSELs or cells very closely related to this population may also act in progressive fibrosis of some organs such as the lung.

Closing remarks

Several attempts have been made in the past few years to purify a population of PSCs from adult tissues including BM, UCB, and mPB that could give rise in vitro to cells from all three germ layers (meso-, ecto-, and endoderm) [8, 16, 44] and in vivo as well as in mice after injection into the developing blastocyst that would contribute to the development of multiple organs and tissues. In contrast to positive data in vitro, this latter criterion for pluripotentiality in vivo for several potential candidates for PSCs has not yet been demonstrated in a reproducible manner with any SC type isolated from the adult tissues. This is also true for VSELs. The reason for this could be that PSCs deposited in adult tissues erase the imprint on some crucial maternal or paternal imprinted genes. This phenomenon keeps these cells under control from unleashed proliferation and not only prevents the possibility of teratoma formation in vivo by these cells, but also simultaneously will affect their ability to complete blastocyst development after injection into developing blastocyst.

VSELs isolated from adult tissues are an alternative and not ethically controversial source of SCs for regenerative medicine. However, there are several missing answers to this timely issue, especially in view of the current and widely performed clinical trials with BM-derived SCs in cardiology and neurology, before VSELs can find their potential application in regenerative medicine.

First, there is the obvious problem of isolating a sufficient number of VSELs from the BM, UCB, or mPB. The number of these cells among BM MNCs is very low. For example, VSELs represent ~1 cell in 105 of BM MNCs [8, 35, 36]. Furthermore, our data shows that these cells are enriched in the BM of young mammals and their number decreases with age. It is also likely that if VSELs are released from the BM, even if they are able to home to the areas of tissue/organ injury, they may function only in the regeneration of minor tissue injuries. Heart infarct or stroke, on the other hand, may involve severe tissue damage beyond the effective repair capacity of these rare cells. Second, the allocation of these cells to the damaged areas depends on homing signals that may be inefficient in the presence of proteolytic enzymes released from leukocytes and macrophages associated with damaged tissue. For example, matrix metalloproteinases (MMPs) released from inflammatory cells may degrade SDF-1 locally and perturb homing of CXCR4+ SCs [51]. Thus, VSEL-SCs may potentially circulate as a homeless population of SCs in PB and return to the BM or home to other organs. Third, to reveal their full regenerative potential, these cells have to be fully functional. We cannot exclude the possibility that VSEL-SCs, while residing or being trapped in the BM, not only erase appropriate methylation on differently methylated regions of some important somatic imprinted genes but also are not fully functional and remain locked in a dormant state. They require the appropriate activation signals by unidentified factors. Finally, we have to develop efficient ex vivo culture conditions that will allow for efficient expansion of VSEL-SCs without supportive feeder layer cells (e.g., C2C12, BM-derived fibroblasts).

Nevertheless, our data strongly indicates that VSEL-SCs could potentially provide a therapeutic alternative to the controversial use of human ESCs and strategies based on therapeutic cloning. Hence, while the ethical debate on the application of ESCs in therapy continues, the potential of VSELs is ripe for exploration. The current work in our laboratory indicates that VSELs could be efficiently employed in the realm of regenerative medicine and that they are physiologically more important than merely being potential developmental remnants. Finally, we believe that the controlled modulation of somatic imprint status in VSELs such as we hypothesized, a proper de novo methylation of somatic imprinted genes on maternal and paternal chromosomes, could increase a regenerative power of these cells. The coming years will bring important answers to these questions.

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Introduction

An adult organism develops from the most primitive stem cell (SC) called a zygote, which is an oocyte that is fertilized by a sperm cell. This totipotent zygote, the “mother of all stem cells” in the developing body, first gives rise to pluripotent (P)SCs that form morula and, subsequently, to the SCs committed to trophoblasts that will give rise to the placenta and the pluripotent SC population that forms the inner cell mass of the blastocyst. The cells from the inner cell mass of the blastocyst will give rise to the epiblast, a part of the developing embryo, which is the origin of SCs committed to all the three germ layers (meso-, ecto-, and endoderm) [1-5].

Thus, the epiblast could be considered the origin for the SCs committed for all the organs and tissues in developing the embryo proper. PSCs in the epiblast undergo a sequence of specification events, first into multipotent and subsequently into versatile tissue-committed SCs, which play a role in the formation and rejuvenation of various organs [5-7]. The most important questions emerge of whether some of these primitive epiblast-forming PSCs can “escape” specification into more differentiated populations of SCs and retain their pluripotential character, thus surviving among differentiated daughter tissue-committed SCs. Conversely, would all of them undergo tissue/organ specific differentiation and then “disappear” after embryogenesis, and not be found in the adult body (Figure 1)?

2008_Ratajczak_Fig01.png

Figure 1. Potential VSELs contribution to tissue rejuvenation. Panel A: VSELs deposited in adult tissues during embryogenesis/gastrulation may become eliminated after giving rise to TCSCs. Panel B: Conversely, they may survive among TCSCs and serve as a potential back-up/reserve source of TCSCs.

Recently, our group obtained several pieces of evidence that may lend some support for the first possibility. Accordingly, we have identified a population of very primitive SCs in adult tissues that express many markers characteristic for epiblast Scs [8]. Based on this we named these rare cells “very small embryonic like stem cells (VSELs).” We hypothesized that they are deposited during early gastrulation in developing tissues/organs, survive into adulthood, and play an important role as a back-up population of PSCs in the turnover of tissue-specific/committed SCs (TCSCs) [5, 7, 8].

The presence of pluripotent VSELs in adult tissues may reconcile all previously published data stating that adult tissues may contain a population of PSCs [9, 10]. The existence of such cells had been postulated by several investigators [11, 12]. However, such cells were never purified and identified at the single cell level. Their presence was accepted mainly based on experiments showing that some populations of cells were enriched with adherent cell populations isolated from the bone marrow (BM) or that certain solid organs contain some primitive cells that may differentiate into various tissues.

Accordingly, several populations of non-hematopoietic primitive SCs have been described in the BM and other adult tissues, including: i) mesenchymal (M)SCs [13]; ii) multipotent adult progenitor cells (MAPCs) [14]; iii) marrow-isolated adult multilineage inducible (MIAMI) cells [15]; iv) multipotent adult (MA)SCs [16]; and v) Omnicytes [17, 18]. It is conceivable that all these cells are closely related, overlapping populations of SCs described by different investigators and given various names according to circumstance. Furthermore, the potential relationship between these cells and VSELs is not clear. Since MSCs, MAPCs, MIAMIs, and MASCs are largely derived from the adherent fraction of BM- or adult organ-derived cells, these cells could potentially contain some VSELs attached to or associated with them due to emperipolesis. This requires further investigation.

“Of germ line and soma”: germ line as origin and skeleton of the SC system in the adult body

From a developmental point of view, cells that are “immortal” in mammals are those that belong to the germ line. Accordingly, the germ line passes genomic and mitochondrial DNA to the next generations and creates “mortal soma”, which helps the germ line to fulfill this reproductive mission [19-21]. The most primitive cell in the germ line is the above-mentioned zygote, which is a result of fusion of two gametes (germ cells), i.e., the oocyte and sperm, during the process of fertilization. Germ line potential is subsequently maintained in blastomers of morula and in the cells of the inner cell mass of the blastocyst. At the level of the blastocyst, however, a part of the cells that surrounds the blastula “buds out” from the germ line lineage and differentiates toward throphoblasts, which give rise to the placenta. After implantation of the blastocyst in the uterus, a germ line potential is maintained in the epiblast [19-21].

In mice, at 7.25 days post-conception (dpc), a part of epiblast PSCs is specified into a population of primordial germ cells (PGCs) that will migrate to the genital ridgesahre    where they subsequently differentiate into oocytes or sperm during gametogenesis [6, 22]. Shortly after PGC specification, the remaining epiblast PSCs, which we envision to be related to the germ line lineage, become specified to multipotent/unipotent SCs for developing tissues and organs [20]. These primitive epiblast/germ line-derived PCSs, as we hypothesize, are not completely eliminated from the developing organism by the differentiation process. We believe that some of them survive (e.g., VSELs?) among tissue-committed SCs [20].

PGCs are the most important population of SCs. As precursors of germ cells/gametes, they are directly responsible for passing genetic information on to the next generation. However, these developmentally early cells, if isolated from the developing embryo after 11 dpc (at the time while they migrate to genital ridges) and cultured ex vivo, surprisingly will undergo rapid terminal differentiation or apoptosis [23]. Interestingly, they also do not complement blastocyst development, are not able to provide fully functional nuclei during nuclear transfer in the process of clonote formation, and do not grow teratomas  [20, 24-26]. Therefore, these cells lack the currently approved criteria of pluripotentiality. This also indicates that PGCs have to be somehow protected from uncontrolled expansion by certain important regulatory mechanisms.
 
One explanation for this obvious lack of pluripotentiality is that PGCs undergo epigenetic modification and erasure of the somatic imprint on differently methylated regions (DMRs) of somatic imprinted genes [27, 28]. Somatic imprinted genes show a different methylation pattern in some of the genes located either on maternal or paternal chromosomes (e.g., H19, Igf-2, Igf-2R, Snrpn). As a result of the imprint, for example, Igf-2 is expressed from the paternal and H19 is expressed from the maternal chromosome [20, 27, 28].

The process of erasure of the somatic imprint occurs very early during gastrulation when the PGCs begin to migrate to the genital ridges [27, 28]. It is one of the basic mechanisms that prevents their uncontrolled proliferation, parthenogenesis, and prevents potential teratoma formation by these cells. Thus, the proper somatic imprint seems to be required for PSCs to be able to complement blastocyst development, provide nuclei for clonote formation after nuclear transfer, and to grow teratomas in immunodeficient mice. Because migrating PGCs erase the imprint, they are not able to display these “golden standard” pluripotency criteria in appropriate experimental models [26-28].

However, if plated over murine fetal fibroblasts in the presence of selected growth factors, i.e., leukemia inhibitory factor (LIF), basic fibroblast growth factor (bFGF), and kit ligand, PGCs may undergo epigenetic changes forced by in vitro culture conditions that regain the somatic imprint, which endows them with “immortality” [29, 30]. Thus, this change of “PGC fate” is connected with a proper re-methylation of somatic imprinted genes. This immortalized population of PGCs known as embryonic germ cells (EGCs) is in many aspects the equivalent to embryonic (E)SCs [31]. For example, similarly to ESCs, EGCs contribute to all three germ layers including the germ cell lineage after injection into a blastocyst (blastocyst complementation assay), provide functional nuclei for clonote after nuclear transfer, and, after injection into living mice, these cells form teratomas [21, 31]. Thus, it is evident that a proper somatic imprint is vital for cells from the germ line to retain full pluripotentiality. Based on this, we postulate that erasure of the somatic imprint of some crucial developmentally genes is involved in controlling the quiescent status of VSELs [20, 32]. However, as in the case of PGCs, this process should be potentially reversible. As such, we will have to focus on reestablishing the proper somatic imprint in these cells. We envision that such reverted VSELs could potentially become equivalent to cells isolated from the embryos, e.g., after nuclear transfer or even to inducible (i)PSCs [33, 34].

The hunt for PSCs in the adult body

The presence of PSCs in adult tissues was postulated in the past by several investigators, but such cells were never purified at the single cell level. A few years ago, our team began to search for such cells in murine BM. Based on our preliminary experimental data, we assumed that the cells we were looking for would be CD133+ CXCR4+ in mice and humans as well as Sca-1+ in mice. We also assumed that they would be negative in both species for the pan-hematopoietic marker, which is the CD45 antigen (CD45-) [8, 35, 36]. In addition, our preliminary chemotactic experiments revealed that BM contains a very rare population of small cells (3-5 µm in diameter) that robustly respond by chemotaxis to stromal-derived factor-1 (SDF-1), which is a ligand for the CXCR4 receptor [37]. These small CXCR4+ cells expressed some early developmental markers characteristic for very primitive cells [8, 37].

Based on this information, we decided to sort a population of small (<6 µm) Sca-1+lin-CD45- cells from the murine BM and other tissues. By employing a fluorescence activated cell sorter (FACS), we isolated a population of rare Sca-1+Lin-CD45- cells from several adult tissues including BM, brain, liver, pancreas, kidney, muscles, heart, testes, and thymus [9]. As determined by real time RT-PCR (RQ-PCR) by employing sequence specific primers and by immunohistochemistry, these cells express several markers of PSCs such as SSEA-1, Oct-4, Nanog, and Rex-1 as well as Rif-1 telomerase protein [8, 9]. Based on the expression of these early developmental markers and morphology, we named these cells “very small embryonic-like stem cells (VSELs)” [8].

To isolate VSELs from the BM by FACS, we employed a novel size-based approach controlled by size bead markers (Figure 2). The overall sorting strategy was to gate in regions containing small events (2–10 µm), which is shown as Region R1 on the dot plot (Figure 2: Panel A). This region mostly contains cell debris, but also includes some rare nucleated cell events. Because it is well known that most of the sorting protocols exclude events smaller than 6 µm in diameter that contain cell debris, erythrocytes, and platelets, small VSELs are usually excluded from the sorted cell populations. Thus, in our sorting strategy to isolate VSELs and define a region of cells from which we could sort these cells, the size of the sorted cells was controlled by beads with predefined sizes (1, 2, 4, 6, 10, and 15 µm in diameter) (Figure 2: Panel A).

2008_Ratajczak_Fig02.png


Figure 2. Sorting strategy for isolation of murine BM-derived VSELs by FACS.
BM-derived VSELs were sorted by MoFlo cell sorter (Dako, Glostrup, DEN) following immunofluorescence staining for Sca-1, CD45, and hematopoietic Lin. Panel A: Distribution of six predefined, sized beads populations according to their FSCs vs. SSCs (forward and side scatter characteristics, respectively). Gate R1 includes objects between 2 to 10µm in size after comparison to bead particles with standard sizes of 1, 2, 4, 6, 10, and 15µm (Flow Cytometry Size beads, Invitrogen; Molecular Probes, Carlsbad, CA, USA). Panel B: BMNCs visualized on dot plots showing their FSC and SSC signals related to the size and granularity/complexity of the cell, respectively. Small, agranular cells included in Region R1 are further visualized based on the expression of Sca-1 and Lin markers (Panel D). Region R2 includes only Sca-1+/Lin-, which are subsequently sorted based on CD45 marker expression into CD45- and CD45+ subpopulations visualized on histogram (Panel C). Sca-1+/Lin-/CD45- cells (VSELs) are sorted as events enclosed in a logical gate including Regions R1, R2, and R3, while Sca-1+/Lin-/CD45+ cells (HSCs) from gate include Regions R1, R2, and R4. Approximate percent contents of each cellular subpopulation are indicated on the plots.

The events enclosed in region R1 (Figure 2: Panel B), which include an average of ~50% of total collected events, are further analyzed for the expression of Sca-1 and lineage markers (Lin). The Sca-1+Lin- events shown in region R2 (Figure 2: Panel D) consist of 0.38 ± 0.05% of total analyzed BM nucleated cells (BMNCs) on average. Cells from region R2 are subsequently sorted according to the expression of CD45- as Sca-1+Lin-CD45- (region R3) and Sca-1+Lin-CD45+ (region R4) subpopulations (Figure 2: Panel C) that contain VSELs and HSCs, respectively. We found that VSELs comprise ~0.03% while HSCs are ~0.35% of total BMNCs (Figure 2: Panel C). We found that 95% of Sca-1+Lin-CD45- (VSELs) are located within the 2–6 µm size range, while 86% of Sca-1+Lin-CD45+ (HSCs) are found in the 6–10 µm size range [36]. Thus, by employing flow cytometry and the size marker beads, we confirmed our previous transmission electron microscopy (TEM) data showing that the majority of Sca-1+Lin-CD45- cells isolated from adult BM are unusually small (<6 µm) [8]. In conclusion, VSELs are larger than PB platelets and smaller than erythrocytes. Direct TEM analysis revealed that these cells display several features typical for ESCs such as small size, a large nucleus surrounded by a narrow rim of cytoplasm, and open-type chromatin (euchromatin).

ImageStream system (ISS) analysis was also employed to further evaluate the morphological features of VSELs [36]. The ISS-based analysis is a new flow cytometry-based analytical strategy that employs flow cytometry combined with microscopy. This allows for statistical analyses of various cellular parameters as well as direct visualization of cells acquired by FACS in suspension during flow analysis via high-resolution brightfield, darkfield, and fluorescence images [36]. The high resolution of ISS imaging enables the identification of objects as small as 1 µm in diameter [38-40].

In employing ISS analysis, we confirmed with greater precision that VSELs are ~3.6 μm in diameter, while Sca-1+Lin-CD45+ HSCs are larger at ~6.5 μm in diameter. We also noticed that VSELs have a significantly higher (P < 0.05) nuclear/cytoplasmic ratio as compared with HSCs (1.47 ± 0.17 and 0.82 ± 0.03, respectively). Furthermore, VSELs had significantly lower (P < 0.05) cytoplasmic area as compared with HSCs (5.41 ± 0.58 and 33.78 ± 1.68, respectively) [36]. Despite their small size, VSELs possess diploid DNA. They do not express MHC-1 and HLA-DR antigens and are CD90- CD105- CD29- [41].

Interestingly, if plated over a C2C12 murine sarcoma cell feeder layer, ~5–10% of purified VSELs are able to form spheres that resemble embryoid bodies. Cells from these VSEL-derived spheres (VSEL-DSs) are composed of immature cells with large nuclei containing euchromatin and are CXCR4+SSEA-1+Oct-4+, just like purified VSELs [8>]. Similar spheres were also formed by VSELs isolated from murine fetal liver, spleen, thymus, and kidney. Interestingly, formation of VSEL-DSs was associated with a young age in mice with no VSEL-DSs observed in cells isolated from older mice (> 2 years) [10]. This age-dependent content of VSELs in BM may somehow explain why the regeneration processes is more efficient in younger individuals. There are also differences in the content of these cells among BM mononuclear cells (MNCs) between long- and short-lived mouse strains. The concentration of these cells is much higher in the BM of long-lived (e.g., C57Bl6) as compared to short-lived (DBA/2J) mice [8]. In the future, it would be interesting to identify the genes responsible for tissue distribution and expansion of these cells, as they could be involved in controlling the life span of mammals.

Furthermore, since VSELs express several markers of PGCs (fetal-type alkaline phosphatase, Oct-4, SSEA-1, CXCR4, Mvh, Stella, Fragilis, Nobox, Hdac6), they could be closely related to a population of epiblast-derived PGCs. VSELs are also highly mobile and respond robustly to an SDF-1 gradient, adhere to fibronectin and fibrinogen, and may interact with BM-derived stromal fibroblasts [8]. Confocal microscopy and time-lapse studies revealed that these cells attach rapidly to, migrate beneath, and undergo emperipolesis in marrow-derived fibroblasts. This is explainable by fibroblasts secreting SDF-1 and other chemoattractants, which may create a homing environment for small CXCR4+ VSELs [8]. This robust interaction of VSELs with BM-derived fibroblasts has an important implication. It is possible that isolated BM and other tissues’ fibroblastic cells (e.g., MSCs, USSCs, MACSs, MAPCs, or MIAMI cells) may be to some degree contaminated by these tiny cells from the beginning. This observation may explain the unexpected plasticity of marrow-derived fibroblastic cells, e.g., MSCs.

Recently, evidence has also mounted to suggest that similar cells corresponding to those found in murine tissues are also present particularly in the human BM, umbilical cord blood (UCB), and mobilized (m)PB (Table I). Overall, it is anticipated that VSELs could become an important source of PSCs for regeneration. Thus, researchers working with animal models must determine whether these cells could be efficiently employed in the clinic or whether they are merely developmental remnants found in the BM that cannot be harnessed effectively for regeneration. Our initial collaborative studies indicate an efficacy of these cells in improving heart function in an animal model of acute myocardiac infarction in mice [42, 43]. We anticipate seeing similar phenomena in humans.

Table I. Morphological and phenotypic comparison of murine and human VSELs.

2008_Ratajczak_Tab01.png

VSELs as circulating “paramedics” in the body

Our data also indicates that VSELs may be released during stress situations or tissue/organ injury from their tissue niches and circulate in the PB both in humans (e.g., after heart infarct or stroke) and in mice (e.g., after granulocyte colony growth factor [G-CSF]-induced mobilization, experimental heart infarct and stroke, as well as liver and skeletal muscle injury) [44-46]. The trafficking of VSELs is orchestrated by several chemotactic factors that are upregulated in damaged tissues during tissue organ injury such as α-chemokine SDF-1, hepatocyte growth factor/scatter factor (HGF/SF), LIF, and vascular endothelial growth factor (VEGF) [47-50]. Complement cascade cleavage fragments also play an important role in this process, such as C3a anaplylatoxin for example, which enhances responsiveness of VSELs to SDF-1 gradient (Figure 3). Thus, a concept emerged where chemotactic factors that are upregulated in damaged tissues may orchestrate the release of non-hematopoietic SCs from BM into mPB.

For instance, in a murine model of G-CSF-induced mobilization, we noticed that VSELs are detectable at a very low level in steady state conditions in murine PB (~160 cells/ml) and that their number increases ~6 times during G-CSF-induced mobilization events [44]. Increases in the number of these cells circulating in PB are further supported by an increase in expression of mRNA for early developmental markers expressed in VSELs, such as the embryonic transcription factors Oct-4, Nanog, and Rex-1 as well as the expression of Rif1 and Dppa3 [44]. Furthermore, at the same time, MNCs mobilized into PB are highly enriched for mRNA for several early developmental tissue-specific markers, a phenomenon that could be explained as mentioned above by the open-type status of chromatin in these cells. Finally, we sorted these rare cells from murine PB by FACS for immunofluorescence staining and provided evidence that they express SSEA-1 antigen on the surface and Oct-4 in the nucleus.

To provide evidence that mobilized VSELs not only express PSC markers but also are able to differentiate into cells from all three germ layers, we performed differentiation studies in vitro. To provide such proof, VSELs were cultured in appropriate differentiation media on the layer of BM-derived stromal support. We found that mobilized VSELs are able to differentiate into cardiomyocytes, neurons, and pancreatic cell-like clusters [44]. The analysis of DNA content in GFP+ cells isolated from the co-cultures excluded the contribution of cell fusion to this effect. Thus, these experiments revealed the in vitro pluripotency of VSELs mobilized by G-CSF and circulating in mPB by demonstrating their ability to differentiate into cells from all three germ layers. We envision that VSELs mobilized into PB in humans, such as after G-CSF administration, could be harvested by leucopheresis as a potential source of SCs for regenerative medicine.

2008_Ratajczak_Fig03.png


Figure 3. VSELs are mobilized into PB.

Panel A: Under normal steady state conditions, VSELs may circulate in PB to keep a pool of SCs in balance in distant niches of the same tissue. 
Panel B: The number of these cells increases during stress related to organ/tissue damage. During organ damage (e.g., heart infarct), the level of SDF-1 is upregulated in the affected tissues and C3 becomes activated leading to the accumulation of C3 cleavage fragments (C3a and desArgC3a). C3 cleavage fragments enhance/prime the responsiveness of circulating CXCR4+ SCs to an SDF-1 gradient. This leads to more efficient chemoattraction of SCs for potential regeneration of the damaged tissue by creating “a super gradient,” as shown in Panel B for infracted myocardium, for example. In addition to SDF-1, other chemoattractants also play important roles here (e.g., HGF/SF, LIF, and VEGF).


Do Oct-4+ VSELs initiate tumor development?

Several investigators have proposed theories regarding cancer formation in the germ cell compartment. Accordingly, Recamier (1829), Remak (1854), and Virchow (1958) proposed that cancer arises from embryo-like cells. Subsequently, Durante and J. Cohnheim in 1874 and 1875, respectively, suggested adult tissues contain embryonic remnants that normally lie dormant, but can be activated to become cancerous. In 1910, Wright proposed the germinal cell origin of Willm’s tumor (nephroblastoma) and in 1911, J. Beard postulated that tumors arise from displaced trophoblast or activated germ cells. We envision the Oct-4+ VSEL recently identified in adult tissues could unify and fully support all these theories. First, we envision that if the genomic imprint in VSELs is not erased, they may retain post-developmental in vivo pluripotency and grow teratomas and teratocarcinomas [5, 20]. Second, if they are closely related to migratory PGCs, which go astray from the major migratory route to the genital ridges, they may ultimately give rise to germinomas and seminomas, for example. Third, if these cells acquire critical mutations, they may develop into the several types of pediatric sarcomas (e.g., rhabdomyosarcoma, neuroblastoma, Ewing-sarcoma, or Willm's tumor). In support of this, there is a strong correlation between the number of these Oct-4+ cells that persist in postnatal tissues and the coincidence with these types of tumors in pediatric patients. Finally, it is possible that these cells, if mobilized at the wrong time into the PB and deposited in areas of chronic inflammation, may not play a role in regeneration but may contribute to the development of other malignancies (e.g., stomach cancer or lung cancer). To support this further, several tumor types may express embryonic markers including Oct-4 and, as reported, BM-derived SCs that may develop in the presence of carcinogens to some sarcomas or teratomas. Furthermore, we hypothesize that VSELs hiding among BM-derived fibroblasts could also be responsible for sarcoma formation by MSC cells. Circulating VSELs also could be also chemoattracted by the hypoxic/chemoattractant-rich environment of a growing tumor and provide stroma and vessels for expanding that tumor. Finally, it is also possible that circulating VSELs or cells very closely related to this population may also act in progressive fibrosis of some organs such as the lung.

Closing remarks

Several attempts have been made in the past few years to purify a population of PSCs from adult tissues including BM, UCB, and mPB that could give rise in vitro to cells from all three germ layers (meso-, ecto-, and endoderm) [8, 16, 44] and in vivo as well as in mice after injection into the developing blastocyst that would contribute to the development of multiple organs and tissues. In contrast to positive data in vitro, this latter criterion for pluripotentiality in vivo for several potential candidates for PSCs has not yet been demonstrated in a reproducible manner with any SC type isolated from the adult tissues. This is also true for VSELs. The reason for this could be that PSCs deposited in adult tissues erase the imprint on some crucial maternal or paternal imprinted genes. This phenomenon keeps these cells under control from unleashed proliferation and not only prevents the possibility of teratoma formation in vivo by these cells, but also simultaneously will affect their ability to complete blastocyst development after injection into developing blastocyst.

VSELs isolated from adult tissues are an alternative and not ethically controversial source of SCs for regenerative medicine. However, there are several missing answers to this timely issue, especially in view of the current and widely performed clinical trials with BM-derived SCs in cardiology and neurology, before VSELs can find their potential application in regenerative medicine.

First, there is the obvious problem of isolating a sufficient number of VSELs from the BM, UCB, or mPB. The number of these cells among BM MNCs is very low. For example, VSELs represent ~1 cell in 105 of BM MNCs [8, 35, 36]. Furthermore, our data shows that these cells are enriched in the BM of young mammals and their number decreases with age. It is also likely that if VSELs are released from the BM, even if they are able to home to the areas of tissue/organ injury, they may function only in the regeneration of minor tissue injuries. Heart infarct or stroke, on the other hand, may involve severe tissue damage beyond the effective repair capacity of these rare cells. Second, the allocation of these cells to the damaged areas depends on homing signals that may be inefficient in the presence of proteolytic enzymes released from leukocytes and macrophages associated with damaged tissue. For example, matrix metalloproteinases (MMPs) released from inflammatory cells may degrade SDF-1 locally and perturb homing of CXCR4+ SCs [51]. Thus, VSEL-SCs may potentially circulate as a homeless population of SCs in PB and return to the BM or home to other organs. Third, to reveal their full regenerative potential, these cells have to be fully functional. We cannot exclude the possibility that VSEL-SCs, while residing or being trapped in the BM, not only erase appropriate methylation on differently methylated regions of some important somatic imprinted genes but also are not fully functional and remain locked in a dormant state. They require the appropriate activation signals by unidentified factors. Finally, we have to develop efficient ex vivo culture conditions that will allow for efficient expansion of VSEL-SCs without supportive feeder layer cells (e.g., C2C12, BM-derived fibroblasts).

Nevertheless, our data strongly indicates that VSEL-SCs could potentially provide a therapeutic alternative to the controversial use of human ESCs and strategies based on therapeutic cloning. Hence, while the ethical debate on the application of ESCs in therapy continues, the potential of VSELs is ripe for exploration. The current work in our laboratory indicates that VSELs could be efficiently employed in the realm of regenerative medicine and that they are physiologically more important than merely being potential developmental remnants. Finally, we believe that the controlled modulation of somatic imprint status in VSELs such as we hypothesized, a proper de novo methylation of somatic imprinted genes on maternal and paternal chromosomes, could increase a regenerative power of these cells. The coming years will bring important answers to these questions.

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В недавних исследованиях наша группа провела идентификацию небольших по размеру стволовых клеток в костном мозге мыши и других органах взрослыго организма. Эти клетки экспрессируют маркеры, характерные для стволовых клеток, происходящих эпибласта/зародышевых клеток. Мы назвали эти клетки «очень маленькими стволовыми клетками, схожими с эмбриональным» (МСКЭ). Мы предположили, что эти клетки, которые накапливаются в период ранней гаструляции в развивающихся тканях/органах, играют важную роль в обороте тканеспецифических/коммитированных популяций СК. На основании этого, мы допускаем, что зародышевая линия клеток является не только источником, но и «основой или костяком» для фракции стволовых клеток во взрослом организме. Мы показали, что МСКЭ могут быть мобилизованы в периферическую кровь, и число этих циркулирующих клеток повышается в период стресса и повреждений тканей/органов (например, при инфаркте миокарда, инсульте). Кроме того, наши данные указывают на то, что МСКЭ защищены от неконтролируемой пролиферации и образования тератом вследствие уникального типа метилирования отдельных генов, который реализуется по механизму соматического геномного импринтинга. 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Ратайчак М.З., Кучал М., Шин Д.М., Руи Л., Друкала Ю., Марлиш В., Ратайчак Я., Зуба-Сурма Э.К.

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Накапливаются сведения о том, что ткани взрослого организма содержат популяцию весьма примитивных плюрипотентных стволовых клеток (СК). В недавних исследованиях наша группа провела идентификацию небольших по размеру стволовых клеток в костном мозге мыши и других органах взрослыго организма. Эти клетки экспрессируют маркеры, характерные для стволовых клеток, происходящих эпибласта/зародышевых клеток. Мы назвали эти клетки «очень маленькими стволовыми клетками, схожими с эмбриональным» (МСКЭ). Мы предположили, что эти клетки, которые накапливаются в период ранней гаструляции в развивающихся тканях/органах, играют важную роль в обороте тканеспецифических/коммитированных популяций СК. На основании этого, мы допускаем, что зародышевая линия клеток является не только источником, но и «основой или костяком» для фракции стволовых клеток во взрослом организме. Мы показали, что МСКЭ могут быть мобилизованы в периферическую кровь, и число этих циркулирующих клеток повышается в период стресса и повреждений тканей/органов (например, при инфаркте миокарда, инсульте). Кроме того, наши данные указывают на то, что МСКЭ защищены от неконтролируемой пролиферации и образования тератом вследствие уникального типа метилирования отдельных генов, который реализуется по механизму соматического геномного импринтинга. Наконец, мы предполагаем, что МСКЭ в патологических ситуациях могут быть вовлечены в развитие некоторых злокачественных заболеваний (например, таратом, герминальных опухолей, сарком в детском возрасте).

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Mariusz Z. Ratajczak1,2, Magda Kucia1, Dong-Myung Shin1, Liu Rui1, Justyna Drukala1, Wojtek Marlicz2, Janina Ratajczak1, Ewa K. Zuba-Surma1

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1Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA; 
2Department of Physiopathology, Pomeranian Medical University, Szczecin, Poland

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Accumulating evidence demonstrates that adult tissue contains a population of very primitive pluripotent stem cells (PSCs). Recently, our group identified a population of very small SCs in murine bone marrow (BM) and other adult organs that express several markers characteristic for epiblast/germ line-derived SCs. We named these rare cells “very small embryonic like stem cells (VSELs).” We hypothesized that these cells, which are deposited during early gastrulation in developing tissues/organs, play an important role in the turnover of tissue-specific/committed SCs. Based on this, we envision that germ line is not only the origin but also a “basis/skeleton” for the SC compartment in adult life forms. We noticed that VSELs could be mobilized into peripheral blood (PB) and the number of these cells circulating in PB increases during stress and tissue/organ injuries (e.g., heart infarct, stroke). Furthermore, our data indicates that VSELs are protected from uncontrolled proliferation and teratoma formation by a unique pattern of methylation of selected somatic imprinted genes. Finally, we envision that in pathological situations, VSELs could be involved in the development of some malignancies (e.g., teratomas, germinal tumors, pediatric sarcomas).

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Ratajczak<sup>1,2</sup>, Magda Kucia<sup>1</sup>, Dong-Myung Shin<sup>1</sup>, Liu Rui<sup>1</sup>, Justyna Drukala<sup>1</sup>, Wojtek Marlicz<sup>2</sup>, Janina Ratajczak<sup>1</sup>, Ewa K. Zuba-Surma<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(256) "

Mariusz Z. Ratajczak1,2, Magda Kucia1, Dong-Myung Shin1, Liu Rui1, Justyna Drukala1, Wojtek Marlicz2, Janina Ratajczak1, Ewa K. Zuba-Surma1

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Mariusz Z. Ratajczak1,2, Magda Kucia1, Dong-Myung Shin1, Liu Rui1, Justyna Drukala1, Wojtek Marlicz2, Janina Ratajczak1, Ewa K. Zuba-Surma1

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Accumulating evidence demonstrates that adult tissue contains a population of very primitive pluripotent stem cells (PSCs). Recently, our group identified a population of very small SCs in murine bone marrow (BM) and other adult organs that express several markers characteristic for epiblast/germ line-derived SCs. We named these rare cells “very small embryonic like stem cells (VSELs).” We hypothesized that these cells, which are deposited during early gastrulation in developing tissues/organs, play an important role in the turnover of tissue-specific/committed SCs. Based on this, we envision that germ line is not only the origin but also a “basis/skeleton” for the SC compartment in adult life forms. We noticed that VSELs could be mobilized into peripheral blood (PB) and the number of these cells circulating in PB increases during stress and tissue/organ injuries (e.g., heart infarct, stroke). Furthermore, our data indicates that VSELs are protected from uncontrolled proliferation and teratoma formation by a unique pattern of methylation of selected somatic imprinted genes. Finally, we envision that in pathological situations, VSELs could be involved in the development of some malignancies (e.g., teratomas, germinal tumors, pediatric sarcomas).

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Accumulating evidence demonstrates that adult tissue contains a population of very primitive pluripotent stem cells (PSCs). Recently, our group identified a population of very small SCs in murine bone marrow (BM) and other adult organs that express several markers characteristic for epiblast/germ line-derived SCs. We named these rare cells “very small embryonic like stem cells (VSELs).” We hypothesized that these cells, which are deposited during early gastrulation in developing tissues/organs, play an important role in the turnover of tissue-specific/committed SCs. Based on this, we envision that germ line is not only the origin but also a “basis/skeleton” for the SC compartment in adult life forms. We noticed that VSELs could be mobilized into peripheral blood (PB) and the number of these cells circulating in PB increases during stress and tissue/organ injuries (e.g., heart infarct, stroke). Furthermore, our data indicates that VSELs are protected from uncontrolled proliferation and teratoma formation by a unique pattern of methylation of selected somatic imprinted genes. Finally, we envision that in pathological situations, VSELs could be involved in the development of some malignancies (e.g., teratomas, germinal tumors, pediatric sarcomas).

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1Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA; 
2Department of Physiopathology, Pomeranian Medical University, Szczecin, Poland

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1Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA; 
2Department of Physiopathology, Pomeranian Medical University, Szczecin, Poland

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Ратайчак М.З., Кучал М., Шин Д.М., Руи Л., Друкала Ю., Марлиш В., Ратайчак Я., Зуба-Сурма Э.К.

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Ратайчак М.З., Кучал М., Шин Д.М., Руи Л., Друкала Ю., Марлиш В., Ратайчак Я., Зуба-Сурма Э.К.

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Накапливаются сведения о том, что ткани взрослого организма содержат популяцию весьма примитивных плюрипотентных стволовых клеток (СК). В недавних исследованиях наша группа провела идентификацию небольших по размеру стволовых клеток в костном мозге мыши и других органах взрослыго организма. Эти клетки экспрессируют маркеры, характерные для стволовых клеток, происходящих эпибласта/зародышевых клеток. Мы назвали эти клетки «очень маленькими стволовыми клетками, схожими с эмбриональным» (МСКЭ). Мы предположили, что эти клетки, которые накапливаются в период ранней гаструляции в развивающихся тканях/органах, играют важную роль в обороте тканеспецифических/коммитированных популяций СК. На основании этого, мы допускаем, что зародышевая линия клеток является не только источником, но и «основой или костяком» для фракции стволовых клеток во взрослом организме. Мы показали, что МСКЭ могут быть мобилизованы в периферическую кровь, и число этих циркулирующих клеток повышается в период стресса и повреждений тканей/органов (например, при инфаркте миокарда, инсульте). Кроме того, наши данные указывают на то, что МСКЭ защищены от неконтролируемой пролиферации и образования тератом вследствие уникального типа метилирования отдельных генов, который реализуется по механизму соматического геномного импринтинга. Наконец, мы предполагаем, что МСКЭ в патологических ситуациях могут быть вовлечены в развитие некоторых злокачественных заболеваний (например, таратом, герминальных опухолей, сарком в детском возрасте).

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Накапливаются сведения о том, что ткани взрослого организма содержат популяцию весьма примитивных плюрипотентных стволовых клеток (СК). В недавних исследованиях наша группа провела идентификацию небольших по размеру стволовых клеток в костном мозге мыши и других органах взрослыго организма. Эти клетки экспрессируют маркеры, характерные для стволовых клеток, происходящих эпибласта/зародышевых клеток. Мы назвали эти клетки «очень маленькими стволовыми клетками, схожими с эмбриональным» (МСКЭ). Мы предположили, что эти клетки, которые накапливаются в период ранней гаструляции в развивающихся тканях/органах, играют важную роль в обороте тканеспецифических/коммитированных популяций СК. На основании этого, мы допускаем, что зародышевая линия клеток является не только источником, но и «основой или костяком» для фракции стволовых клеток во взрослом организме. Мы показали, что МСКЭ могут быть мобилизованы в периферическую кровь, и число этих циркулирующих клеток повышается в период стресса и повреждений тканей/органов (например, при инфаркте миокарда, инсульте). Кроме того, наши данные указывают на то, что МСКЭ защищены от неконтролируемой пролиферации и образования тератом вследствие уникального типа метилирования отдельных генов, который реализуется по механизму соматического геномного импринтинга. Наконец, мы предполагаем, что МСКЭ в патологических ситуациях могут быть вовлечены в развитие некоторых злокачественных заболеваний (например, таратом, герминальных опухолей, сарком в детском возрасте).

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Introduction

Mesenchymal stem cells (MSC) constitute a rare population of multipotent progenitors capable of both supporting hematopoiesis and differentiating into at least osteogenic, adipogenic and chondrogenic lineages [1-3]. Moreover, they exhibit immunomodulatory activity, induce immunotolerance in case of allogenic transplantation [4], and posess the ability to expand in relatively simple in vitro systems [5-7]. These characteristics make MSCs very promising candidates in the development of new cell-based therapeutic strategies, such as the treatment of tissue injuries or the supportive application by hematopoietic stem cell transplantation. Taking into consideration that the number of MSCs and their differentiation capacity decline with age [8], most relevant is the search for alternative sources of these cells.

The advantages of umbilical cord blood (UCB), as a source of stem cells, include their accessibility, non-invasive sampling and, thus, their safety for potential donors [9-11]. Another reason for this study was due to some controversial data about amounts of mesenchymal precursors in UCB [12-17]. Mesenchymal precursors (CFU-F) are found in foetal blood in the early gestational period at concentrations equal to their amounts in the bone-marrow of newborns [18]. However, after the second trimester, the number of MSCs decreases considerably, and, at birth, their frequency in UCB is quite accidental [12,19]. The  need for testing of some standards for culturing adhesive cell fractions from UCB, as well as assessment of their contents and functional characteristics provided other motivations for this study.

Materials and Methods

Collection of UCB
UCB samples (mean volume of 60 ml) from full-term deliveries were collected from the unborn placenta after obtaining the mothers' informed consent. A sterile bag system containing citrate phosphate dextrose (CPD) anticoagulant within the collection bag (manufactured by Terumo, Japan) was used. The units were stored at room temperature before processing (up to 33 hours).

Isolation and Culture of Adherent Cells from UCB
To isolate mononuclear cells (MNCs), each UCB unit was diluted 1:1 with phosphate-buffered saline (PBS)/2 mM EDTA (Biolot, Russia), and carefully loaded onto Ficoll-Hypaque solution (Lympho separation medium, ICN, USA, d=1.077). Following a density gradient centrifugation at 435 g for 30 minutes at room temperature, MNCs were removed from the interphase layer and washed two to three times with PBS/EDTA. UCB-derived MNCs were set at a density of 1 x 106/cm2 into six-well culture plates (Corning, USA) containing DMEM low-glucose medium (Gibco, USA) with 20% fetal calf serum (FCS) from selected lots, penicillin 100 UI/ml, and streptomycin 0.1 mg/ml (Gibco, USA).
After overnight incubation at 37°C in a humidified atmosphere containing 5% carbon dioxide, nonadherent cells were removed and fresh medium was added to the wells. Cell cultures were maintained, and remaining nonadherent cells were discarded via the complete exchange of culture medium every 7 days. Culture plates were screened continuously to detect developing colonies of adherent cells. The number of fibroblast colony forming units (CFU-F) was calculated by counting the number of colonies per 108 MNCs.
Fibroblast-like cells were detached between days 16 through 20 after initial plating using 0.04% Trypsin/0.03% EDTA (Gibco, USA). The recovered cells were replated at a density of 4,000 to 5,000 cells/cm2.

Collection and Isolation of Control MSCs from Bone Marrow
MSCs from bone marrow (BM) were obtained by bone marrow puncture. BM cells were aspirated into a 5-ml syringe containing CPD anticoagulant. A total of six samples were obtained, with the donor age ranging from 24 to 56 years. To isolate MSCs from BM, the aspirate was diluted 1:5 and processed as described above. In contrast to MNCs from UCB samples, BM-derived MNCs were cultured at a density of 1 x 106 cells/cm2 in T75 culture flasks (Corning, USA), and the first change of medium was performed 3 days after initial plating. Two weeks later, at reaching 80%–90% confluence, MSCs were detached using trypsin and replated as described for the UCB-derived adherent cells.

Primary Fibroblasts as Controls
Primary cultures of normal human dermal fibroblasts served as negative control in differentiation and comparative gene expression studies. Culture conditions were comparable to BM MSC’s expansion: DMEM low glucose medium (Gibco, USA) containing 20% fetal calf serum (FCS), penicillin 100 UI/ml, and streptomycin 0.1 mg/ml (Gibco, USA).

Immune Phenotypic Analysis
To analyze the cell-surface expression of typical marker proteins in UCB- and BM-derived adherent cells, each from primary culture and second passage, these were labeled with the following anti-human antibodies: CD34 PE; CD34 FITC, CD45 FITC; CD45 PE; CD14 FITC; CD31 PE; CD31 FITC; CD61 FITC; CD3 FITC; CD19 PE; CD117 PE; HLA ABC FITC; HLA DR,DP,DQ FITC; CD 90 PE (Becton Dickinson, USA). Murine isotype antibodies (Becton Dickinson, USA) served as respective controls. Ten thousand labeled cell aliquotes were analyzed using a FACScan flow cytometer running CellQuest software (Becton Dickinson, USA).

Aiming at a subset analysis of the population, we employed the following indices:
•    hematopoietic cells index – CD45+ to CD45- cells
•    myeloid cell maturation index – CD14+ to CD45+ cells
•    hematopoietic progenitor cell index  – CD34+CD45+ to CD45+ cells
•    endothelial cell-precursors index – CD34+CD45- to CD45- cells
•    mesenchymal precursors index – CD90+CD31- to CD45-  cells

In vitro Osteogenic and Adipogenic Differentiation Studies
To induce osteogenic differentiation, the cells were seeded at a density of 3.1 x 103 cells/cm2 and cultured in six-well microplates (Costar, USA), until they reached approximately 80% confluence. Additional culture was performed in osteogenic differentiation medium supplemented with 0.1 µM dexamethasone, 10 mM ß-glycerophosphate, 0.05 mM ascorbate, and 10% FCS. The onset of osteoblast formation was evaluated after 3 weeks via calcium accumulation. Accumulation of mineralized calcium phosphate was assessed with von Kossa staining after the protocol from Cheng et al. [20], with a few modifications. The cells were fixed for 15 minutes in 10% formalin (Sigma-Aldrich), and, after washing, they were incubated with 5% silver nitrate (Sigma-Aldrich) for 15 to 30 minutes. Pyrogallol 1% (Merck, Canada) and sodium thiosulfate 5% (Sigma-Aldrich) were used to develop and register a resulting image. In addition, the mineralized matrix was also evaluated by Alizarin-red S staining using 4% formaldehyde for fixation and 1% aqueous Alizarin-Red S (Sigma-Aldrich) solution.

Adipogenic differentiation was induced according to the protocol of Pittenger et al. [2]. Special induction medium, containing DMEM (high glucose), 1 µM dexamethasone, 0.5 mM 3-isobutyl-1-methyl-xanthine, 10 µg/ml recombinant human (rh) insulin, 0.2 mM indomethacin, and 20% FCS, was added for 2 to 3 days to the culture microplates. It was then replaced by maintenance medium containing only rh-insulin and 20% FCS. Induction of adipogenic differentiation was apparent via the intracellular accumulation of lipid-rich vacuoles that stained with Oil Red O (Sigma-Aldrich). The cells were fixed with 10% formalin, washed, and stained with a working solution of 0.18% Oil Red O for 5 minutes.

In vitro Model for Studying Colony-stimulating Activity of UCB cells
An essential property of mesenchymal stem cells is their capacity to support hematopoiesis. In order to assess the hemostimulating capacity of the UCB monolayer culture, a modified technique proposed by Afanasyev [21,22] was used (Figure 1). This method determines the clonogenic capacity of granulocytic-macrophage colony forming units (CFU-GM) in “agar drop-liquid medium” culture.

ce2eb0c8ca.png


Figure 1. Agar drop-liquid culture system[22]

A-medium; B-feeder cells; C,D,E-colonies; F-clusters; G-agar


The monolayer culture of UCB-derived adherent cells (confluence rate: 70–80%) was used as a source of colony-stimulating activity of MSC from UCB. The cells (CFU-GM) from the UCB mononuclear fraction were targeted in this assay, providing clonal growth in agar cultures. Semisolid agar drops containing target cells were prepared on dry surfaces of sterile Petri dishes. The resulting semisolid drops were transferred to the dishes, and co-incubated for 7 days in the following four versions: 1) with complete culture medium only; 2) with medium containing standard-type leukocyte feeder; 3) with UCB confluent monolayer culture; 4) with both UCB confluent monolayer culture and standard-type leukocyte feeder. Each experiment was performed at least twice.

Colony-forming ability (CFA) and cluster-forming ability (ClFA) were classified according to the number of cells in the colonies (small colonies: containing 20–40 cells; medium-size colonies: 41–100 cells; and large colonies: more than 100 cells) and clusters (large clusters: 10–19 cells; small clusters: 5–9 cells). Depending on the total number of colonies and clusters, the cloning efficiency (CE) per 1х105 explanted mononuclear cells was assessed. A “colony-to-cluster” ratio (Co-Cl) and percentage of large colonies (LC) were supplemental parameters assessed in these cell cultures. Using such parameters, the proliferative potential of the target progenitor cells was tested.

Total RNA Isolation and RT-PCR

Total RNA was extracted from 3 to 30 x105 MSCs using Trizol Reagents (Invitrogen, USA), according to the manufacturer’s instructions. mRNA was subject to reverse transcription (RT) using Superscript II Kit (Invitrogen, USA), again using the manufacturer’s instructions. The resulting cDNA was amplified using an ABI GeneAmp PCR System 2400 (Perkin Elmer Applied Biosystems, Boston, MA) at 94°C for 40 seconds, 56°C for 50 seconds, and 72°C for 60 seconds for 35 cycles, after initial denaturation at 94°C for 5 minutes. Primers used for PCR are listed in Table 1. Fifteen microliters of PCR reaction were fractionated by agarose gel electrophoresis.

c673f09dc2.png

Table 1. Primers used for RT-PCR

Statistical Analysis
The statistical significance of the inter-group differences was evaluated with the Mann-Whitney test. The degrees of correlations between the parameters were evaluated by the Spearman test. The differences were considered significant by p values <0.05. The Statistica 6.0 software package was used for all statistical analyses.

Results and Discussion

In most cases, the cultures of plastic-adherent cells proved to be heterogenous. Two main morphological cell types were discernable: spindle-shaped cells that are presumably regarded as mesenchymal stem cells (MSC), and polygonal cells that are most likely of hematopoietic origin (Figure 2).

62f925886e.png

Figure 2. Heterogeneous UCB culture. No colony formation was observed. UCB samples produced a minimal, non-confluent adherent layer of heterogeneous cells. 


In some UCB samples, clonal growth was observed, however the mean cell number per colony did not increase over 100 cells (Figure 3). Large colonies were detectable in 3 of the 40 UCB samples under study. These colonies (>1000 cells per colony) consisted of closely packed, spindle-shaped cells, typical of fibroblast morphology cells.

6043526b24.png

Figure 3. CFU-F in UCB culture. Adherently growing cells of fibroblastic morphology formed big colonies in 3 UCB samples.

The Phenotypic Composition of UCB Monolayer Cultures
Our efforts to define a distinct phenotype characteristic for MSC have been confounded by the fact that these cells can express a range of cell lineage-specific antigens [2,23].

During analysis of the predominant cellular types, it was discovered that the major fraction (median 60.17%) of plastic-adherent cells from UCB were of hematopoietic origin (CD45+) (Table 2). One-third of the CD45-positive cells belonged to the CD14-positive population fraction (median 14.81%). Cells in the monolayer with an osteoclast-like phenotype (CD45+CD61+) constituted approximately 1.5%. The cells phenotypically comparable with hematopoietic stem cells (HSC-like cells: CD34+CD45+, CD34+HLA DR-, CD117+) were present at a low concentration in the UCB monolayer culture - less than 1.5%.

adf136cb4d.png

Table 2. The composition of the UCB monolayer culture. 

The numbers of endothelial-like cells in the monolayer cultures were comparable to HSC-like cells. With this background, a heterogenous population of CD45-CD31+ phenotype was the most prominent one.

Despite a lack of specific markers that could characterize a population of MSC’s, we attempted to determine the quantity of these cells in the culture, based upon the fact that mesenchymal stem cells of the bone marrow do not express common leucocytic antigen CD45 and HLA class II antigens but do express class I HLA antigens and the CD90 marker. In this connection, we studied the following populations of phenotypically MSC-like cells: CD45-HLA ABC+ and CD90+CD31-.

Aiming for further validation of available cultural conditions for expansion of MSCs and endothelial precursors, we assessed the following factors influencing the terms of cultivation period in a primary culture under the conditions of initial culture and subsequent passages. During long term cultures (Table 3), the index of cells with hematopoietic markers decreased progressively, and the index of myeloid cell maturation decreased as well, providing evidence of the elimination of hematopoietic cells during the cultivation. We have revealed that the index of HSC-like cells (hematopoietic progenitor cell index) increases during prolonged cultivation, i.e. an index, reflecting a ratio of cells, phenotypically similar to hematopoietic stem cells, to the total number of СD45+-cells (CD34+CD45+, CD117+). This fact implies that this population is eliminated slower than other hematopoietic cells recovered in the UCB monolayer culture.

2b2ee34a8e.png

Table 3. Influence of cultivation period on composition of primary UCB culture

Moreover, the percentage of CD34+HLA DR- cells increases (37.33 to 81.98, p=0.001) in relation to general CD34-positive population, thus supposing that these cells undergo selective proliferation under the given cultural conditions. This result could indirectly confirm a theory that this population is presented via stromal component [24,25]. In the course of long-term cultivation, the index of endothelial cells is shown to be increased (0.013 to 0.025, p=0.02). This fact proves these cultural conditions are favorable for endothelial precursors' maintenance. When assessing the fractions that include mesenchymal precursors, we have found a tendency for an increase in the relative amounts of the CD45-HLA ABC+ subpopulation. However, when analyzing these populations with regard of all non-hematopoietic cells, we did not observe such a tendency. This fact may reflect the persistance of a steady phenotype of these cell populations upon durable cultivation.

During the process of culture passage, we could reveal a decrease of the hematopoietic cell index (3.19 to 1.6, p<0.016) (Table 4). This data may show the inability of the majority of hematopoietic cells for repeated adhesion, thus resulting in their elimination from the monolayer culture. At the same time, the cells phenotypically similar to HSC-like cells (CD34+CD45+) and lymphocytes (CD3+), were still able to adhere recurrently, when compared with other hematopoietic cells. Among cell populations containing mesenchymal precursors, it was noticed that the cells expressed class I HLA antigens, possessed a reduced adhesive ability, and were subject to elimination with sequential passing.

0627143d40.png

Table 4. Influence of culture passage on the structure of primary UCB culture

When comparing the phenotypical composition of mononuclear fraction and monolayer culture from UCB (Table 5) we discovered that the percentage of cells with CD34+CD45+ phenotype in the culture decreased considerably, along with an increased percentage of cells with СD34+HLA DR- phenotype. Therefore, we can suggest that these cultural conditions may be applied for isolation of the given cell type.

2b2ee34a8e.png

Table 5. The phenotypic composition of the mononuclear fraction and monolayer culture of UCB

This may be also proven by the data from semi-solid methylcellulose culture. The cells from monolayer cultures under study were incapable of forming hematopoietic colonies in the presence of standard hematopoietic growth factors (SCF, GM-CSF, IL-3, IL-6, G-CSF, EPO). This may result from a deficiency of clonogenic precursors in the monolayer, as well as an absence of clonogenic potential among hematopoietic stem-like cells.

The fraction of endothelial cells was higher in the monolayer culture. The percentage of hematopoietic-stem-like-cells and endothelial precursors decreased considerably during the initiation of the culture (38.87 to 1.34, p<0,02).
Analogous to Bieback's paper [12], when assessing the time parameters of sampling and storage of umbilical blood specimens we have revealed a tendency towards a decreased concentration of mesenchymal like stem-cells in the monolayer culture, when a prolonged time-period prior to processing umbilical blood sample with subsequent cultivation occurs (data not shown).

In vitro differentiation of UCB-derived MSC-like cells into adipocytes and osteocytes
Taking the lack of specific markers for identification of mesenchymal precursors into consideration, we tried to reveal the functional characteristics of the given types of cells and to assess the differential potentials in the framework of orthodox plasticity. It is shown that the cells of the UCB monolayer culture are capable of dividing and differentiating to adipocytes and osteoblasts, as was proven by their specific staining (Figure 4). In this figure (upper picture), red lipid inclusions are readily seen in differentiated adipocytes. In the lower picture, calcium insertions in the osteocytes are stainable red or black. In some cultures, however, induction of differentiation initiated detachment of most cells from plastic surface. As a result, the present conditions for differentiation of mesenchymal stem cells from BM are not quite appropriate for induced differentiation of UCB-derived mesenchymal precursors.

4fd0d633ec.png


Figure 4. Differentiation assay of BM and UCB monolayer culture. Formation of mineralized matrix by Alizarin Red and von Kossa staining evidenced osteogenic differentiation. Adipogenic differentiation was evidenced by the formation of lipid vacuoles in phase-contrast photograph and by oil-red O staining.


Ability of UCB monolayer culture to support ex vivo expansion of CFU-GM
Concerning efficiency of CFU-GM cloning, the UCB monolayer culture does not differ from standard leucocytic feeder. However, when using umbilical cord blood culture as a feeder, UCB-generated growth-promoting capacity and percentage of large colonies were higher (data not shown). Additional analysis (Table 6) leads us to suggest that hematopoietic cells from a UCB monolayer culture have certain advantage over non-hematopoietic cells in terms of colony-stimulation activity (r=0.71, p=0.035), at least in this in vitro model. With respect to non-hematopoietic cells, growth of cellular elements bearing MSC-markers (CD90+CD31-) was accompanied by significant increase in CFU-GM proliferative activity (r=0.82, p=0.007). Higher percentages of monocytes/macrophages, as among hematopoietic elements, is accompanied by growing numbers of large colonies (r=0.67, p=0.045), without producing any significant impact upon cloning efficiency of the progenitors.

31ac8e4d57.png

Table 6. Hemostimulating capacity of UCB-culture


Some references in the literature contain similar data obtained with another model, i.e., target cells were incubated with UCB cells in suspension cultures, followed by methyl cellulose cultures of non-attached cell populations in presence of standard growth factors, such as SCF, GM-CSF, G-CSF, IL3, IL6 and EPO [26,27]. Within our model, only umbilical cord blood cells of a monolayer culture were used as the colony stimulation source.

Comparative gene expression studies
When assessing the expression of some genes, we have found that the mRNA profile of bone marrow culture did not differ from the cells of UCB culture. Thrombopoietin was an exception, since specific mRNA was not detectable in the 1st passage culture of UCB cells (Table 7).

a29b2b50b8.png

Table 7. mRNA profile of MSC-like cells from different sources

Conclusions

•    Increased cultivation time of UCB mononuclear fraction (over 23 days) leads  to a gradual elimination of hematopoietic cells from the culture and an increase in mesenchymal stem cells and endothelial progenitor cells.
•    Cellular phenotype in the culture changes during passages, i.e., the quantity of hematopoietic cells is considerably decreased. This results in increased concentration of non-hematopoietic components the of umbilical blood monolayer culture during serial passaging.
•    An increased time period of UCB sampling is associated with a decrease in the relative quantity of mesenchymal-like stem cells, along with an increase in the concentration of endothelial precursors in the culture.
•    Mesenсhymal stem-like-cells of UCB have the capacity to differentiate into adipogenic and osteogenic lineages, thus suggesting their functional consistency.
•    The adhesive fraction of the primary monolayer culture exerts a stimulatory effect upon the colony formation of GM precursors, being similar in type and degree of influence to a standard peripheral blood feeder. The primary effect upon their proliferative capacity may be produced by cellular elements with MSC (CD90+CD31-) markers.
•    An increased time interval during sampling and storage of UCB leads to a decrease in the  hemostimulating capacity.
•    The variable contents of MSC-like cells and CFU-F in umbilical cord blood and/or their reduced repopulation ability may limit their application as an alternative source of MSCs.

References

1. Minguell JJ. Mesenchymal stem cells. Exp Biol Med. 2001;226:507-520.

2. Pittenger M, Mackay A, Beck S, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;84:143-147.

3. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276:71-74.

4. Le Blanc K, Ringden O. Mesenchymal stem cells, properties and role in clinical bone marrow transplantation. Curr Opin Immunol. 2006;18:586-591.

5. Friedenstein AJ, Chailakhyan RK, Latsinik NV, et al. Stromal cells responsible for transferring the microenvironment of the haematopoietic tissues: Cloning in vitro and retransplantation in vivo. Transplantation. 1974;17:331-340.

6. Friedenstein AJ, Deriglasova UF, Kulagina, et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp. Hematol. 1974;2:83-92.

7. Javazon EH, Beggs KJ, Flake AW. Mesenchymal stem cells: paradoxes of passaging. Exp Hematol. 2004;32:414-425.

8. Mueller SM, Glowacki J. Age-related decline in the osteogenic potential of human bone marrow cells cultured in three-dimensional collagen sponges. О Cell Biochem. 2001;82:583-590.

9. Vladimiskaya EB, Mayorova OA, Roumiantsev SA, Roumiantsev AG. Biological bases and therapy prospects with the stem cells. Moscow: Medpractica; 2005. 391 p.

10. Broxmeyer HE. Proliferation, self-renewal, and survival characteristics of cord blood hematopoietic stem and progenitor cells. In: Broxmeyer HE, ed. Cord Blood: Biology, Immunology, Banking, and Clinical Transplantation. Bethesda, MD: American Association of Blood Banking. 2004:1-21.

11. Broxmeyer HE. Biology of cord blood cells and future prospects for enhanced clinical benefit. Cytotherapy. 2005;7(3):209-218.

12. Bieback K, Kern S, Kluter H, et al. Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells. 2004;22:625-634.

13. Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. 2000;109:235-242.

14. Koegler G, Sensken S, Airey J, et al. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med. 2004;200:123-135.

15. Lee MW, Choi J, Yang MS, et al. Mesenchymal stem cells from cryopreserved human umbilical cord blood. Biochem Biophys Res Comm. 2004;320:273-278.

16. Mareschi K, Biasin E, Piacibello W, et al. Isolation of human mesenchymal stem cells: bone marrow versus umbilical cord blood. Haematologica. 2001;86:1099-1100.

17. Wexler S, Donaldson C, Denning-Kendall P, et al. Adult bone marrow is a rich source of human mesenchymal ‘stem’ cells but umbilical cord and mobilized adult blood are not. Br J Haematol. 2003;121:368-374.

18. Campagnoli C, Roberts I, Kumar S, Bennett P, Bellantuono I, Fisk N. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow Blood. 2001;98:2396-2402.

19. Goodwin HS, Bicknese AR, Chien SN, et al. Multilineage differentiation activity by cells isolated from umbilical cord blood: expression of bone, fat and neural markers. Biol Blood Marrow Transpl. 2001;7:581-588.

20. Cheng SL, Yang JW, Rifas L, et al. Differentiation of human bone marrow osteogenic stromal cells in vitro: induction of the osteoblast phenotype by dexamethasone. Endocrinology. 1994;134:277-286.

22. Afanasiev ВV, Almazov VA. Human hematopoietic progenitor cells. Leningrad: Nauka; 1985. 204 p.

23. Haynesworth SE, Baber MA, Caplan AI. Cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies. Bone. 1992;13:69-80.

24. Huang S, Terstappen LW. Formation of haematopoietic microenvironment and haematopoietic stem cell from single human bone marrow stem cells. Nature. 1992;360:745-749.

25. Islam A. Hematopoietic stem cells: A new concept. Leuk Res. 1985;9:1415.

26. Ye ZQ, Burkholder JK, Qiu P, Schultz JC, Shahidi NT, Yang NS. Establishment of an adherent cell feeder layer from human umbilical cord blood for support of long-term hematopoietic progenitor cell growth. Proc Natl Acad Sci USA. 1994;91:12140-12144.

27. Lu-Lu L, Liu Y-J, Yang S-G, Zhao Q-J, Wang X, Gong W, et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica. 2006;91:1017-1026.


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Introduction

Mesenchymal stem cells (MSC) constitute a rare population of multipotent progenitors capable of both supporting hematopoiesis and differentiating into at least osteogenic, adipogenic and chondrogenic lineages [1-3]. Moreover, they exhibit immunomodulatory activity, induce immunotolerance in case of allogenic transplantation [4], and posess the ability to expand in relatively simple in vitro systems [5-7]. These characteristics make MSCs very promising candidates in the development of new cell-based therapeutic strategies, such as the treatment of tissue injuries or the supportive application by hematopoietic stem cell transplantation. Taking into consideration that the number of MSCs and their differentiation capacity decline with age [8], most relevant is the search for alternative sources of these cells.

The advantages of umbilical cord blood (UCB), as a source of stem cells, include their accessibility, non-invasive sampling and, thus, their safety for potential donors [9-11]. Another reason for this study was due to some controversial data about amounts of mesenchymal precursors in UCB [12-17]. Mesenchymal precursors (CFU-F) are found in foetal blood in the early gestational period at concentrations equal to their amounts in the bone-marrow of newborns [18]. However, after the second trimester, the number of MSCs decreases considerably, and, at birth, their frequency in UCB is quite accidental [12,19]. The  need for testing of some standards for culturing adhesive cell fractions from UCB, as well as assessment of their contents and functional characteristics provided other motivations for this study.

Materials and Methods

Collection of UCB
UCB samples (mean volume of 60 ml) from full-term deliveries were collected from the unborn placenta after obtaining the mothers' informed consent. A sterile bag system containing citrate phosphate dextrose (CPD) anticoagulant within the collection bag (manufactured by Terumo, Japan) was used. The units were stored at room temperature before processing (up to 33 hours).

Isolation and Culture of Adherent Cells from UCB
To isolate mononuclear cells (MNCs), each UCB unit was diluted 1:1 with phosphate-buffered saline (PBS)/2 mM EDTA (Biolot, Russia), and carefully loaded onto Ficoll-Hypaque solution (Lympho separation medium, ICN, USA, d=1.077). Following a density gradient centrifugation at 435 g for 30 minutes at room temperature, MNCs were removed from the interphase layer and washed two to three times with PBS/EDTA. UCB-derived MNCs were set at a density of 1 x 106/cm2 into six-well culture plates (Corning, USA) containing DMEM low-glucose medium (Gibco, USA) with 20% fetal calf serum (FCS) from selected lots, penicillin 100 UI/ml, and streptomycin 0.1 mg/ml (Gibco, USA).
After overnight incubation at 37°C in a humidified atmosphere containing 5% carbon dioxide, nonadherent cells were removed and fresh medium was added to the wells. Cell cultures were maintained, and remaining nonadherent cells were discarded via the complete exchange of culture medium every 7 days. Culture plates were screened continuously to detect developing colonies of adherent cells. The number of fibroblast colony forming units (CFU-F) was calculated by counting the number of colonies per 108 MNCs.
Fibroblast-like cells were detached between days 16 through 20 after initial plating using 0.04% Trypsin/0.03% EDTA (Gibco, USA). The recovered cells were replated at a density of 4,000 to 5,000 cells/cm2.

Collection and Isolation of Control MSCs from Bone Marrow
MSCs from bone marrow (BM) were obtained by bone marrow puncture. BM cells were aspirated into a 5-ml syringe containing CPD anticoagulant. A total of six samples were obtained, with the donor age ranging from 24 to 56 years. To isolate MSCs from BM, the aspirate was diluted 1:5 and processed as described above. In contrast to MNCs from UCB samples, BM-derived MNCs were cultured at a density of 1 x 106 cells/cm2 in T75 culture flasks (Corning, USA), and the first change of medium was performed 3 days after initial plating. Two weeks later, at reaching 80%–90% confluence, MSCs were detached using trypsin and replated as described for the UCB-derived adherent cells.

Primary Fibroblasts as Controls
Primary cultures of normal human dermal fibroblasts served as negative control in differentiation and comparative gene expression studies. Culture conditions were comparable to BM MSC’s expansion: DMEM low glucose medium (Gibco, USA) containing 20% fetal calf serum (FCS), penicillin 100 UI/ml, and streptomycin 0.1 mg/ml (Gibco, USA).

Immune Phenotypic Analysis
To analyze the cell-surface expression of typical marker proteins in UCB- and BM-derived adherent cells, each from primary culture and second passage, these were labeled with the following anti-human antibodies: CD34 PE; CD34 FITC, CD45 FITC; CD45 PE; CD14 FITC; CD31 PE; CD31 FITC; CD61 FITC; CD3 FITC; CD19 PE; CD117 PE; HLA ABC FITC; HLA DR,DP,DQ FITC; CD 90 PE (Becton Dickinson, USA). Murine isotype antibodies (Becton Dickinson, USA) served as respective controls. Ten thousand labeled cell aliquotes were analyzed using a FACScan flow cytometer running CellQuest software (Becton Dickinson, USA).

Aiming at a subset analysis of the population, we employed the following indices:
•    hematopoietic cells index – CD45+ to CD45- cells
•    myeloid cell maturation index – CD14+ to CD45+ cells
•    hematopoietic progenitor cell index  – CD34+CD45+ to CD45+ cells
•    endothelial cell-precursors index – CD34+CD45- to CD45- cells
•    mesenchymal precursors index – CD90+CD31- to CD45-  cells

In vitro Osteogenic and Adipogenic Differentiation Studies
To induce osteogenic differentiation, the cells were seeded at a density of 3.1 x 103 cells/cm2 and cultured in six-well microplates (Costar, USA), until they reached approximately 80% confluence. Additional culture was performed in osteogenic differentiation medium supplemented with 0.1 µM dexamethasone, 10 mM ß-glycerophosphate, 0.05 mM ascorbate, and 10% FCS. The onset of osteoblast formation was evaluated after 3 weeks via calcium accumulation. Accumulation of mineralized calcium phosphate was assessed with von Kossa staining after the protocol from Cheng et al. [20], with a few modifications. The cells were fixed for 15 minutes in 10% formalin (Sigma-Aldrich), and, after washing, they were incubated with 5% silver nitrate (Sigma-Aldrich) for 15 to 30 minutes. Pyrogallol 1% (Merck, Canada) and sodium thiosulfate 5% (Sigma-Aldrich) were used to develop and register a resulting image. In addition, the mineralized matrix was also evaluated by Alizarin-red S staining using 4% formaldehyde for fixation and 1% aqueous Alizarin-Red S (Sigma-Aldrich) solution.

Adipogenic differentiation was induced according to the protocol of Pittenger et al. [2]. Special induction medium, containing DMEM (high glucose), 1 µM dexamethasone, 0.5 mM 3-isobutyl-1-methyl-xanthine, 10 µg/ml recombinant human (rh) insulin, 0.2 mM indomethacin, and 20% FCS, was added for 2 to 3 days to the culture microplates. It was then replaced by maintenance medium containing only rh-insulin and 20% FCS. Induction of adipogenic differentiation was apparent via the intracellular accumulation of lipid-rich vacuoles that stained with Oil Red O (Sigma-Aldrich). The cells were fixed with 10% formalin, washed, and stained with a working solution of 0.18% Oil Red O for 5 minutes.

In vitro Model for Studying Colony-stimulating Activity of UCB cells
An essential property of mesenchymal stem cells is their capacity to support hematopoiesis. In order to assess the hemostimulating capacity of the UCB monolayer culture, a modified technique proposed by Afanasyev [21,22] was used (Figure 1). This method determines the clonogenic capacity of granulocytic-macrophage colony forming units (CFU-GM) in “agar drop-liquid medium” culture.

ce2eb0c8ca.png


Figure 1. Agar drop-liquid culture system[22]

A-medium; B-feeder cells; C,D,E-colonies; F-clusters; G-agar


The monolayer culture of UCB-derived adherent cells (confluence rate: 70–80%) was used as a source of colony-stimulating activity of MSC from UCB. The cells (CFU-GM) from the UCB mononuclear fraction were targeted in this assay, providing clonal growth in agar cultures. Semisolid agar drops containing target cells were prepared on dry surfaces of sterile Petri dishes. The resulting semisolid drops were transferred to the dishes, and co-incubated for 7 days in the following four versions: 1) with complete culture medium only; 2) with medium containing standard-type leukocyte feeder; 3) with UCB confluent monolayer culture; 4) with both UCB confluent monolayer culture and standard-type leukocyte feeder. Each experiment was performed at least twice.

Colony-forming ability (CFA) and cluster-forming ability (ClFA) were classified according to the number of cells in the colonies (small colonies: containing 20–40 cells; medium-size colonies: 41–100 cells; and large colonies: more than 100 cells) and clusters (large clusters: 10–19 cells; small clusters: 5–9 cells). Depending on the total number of colonies and clusters, the cloning efficiency (CE) per 1х105 explanted mononuclear cells was assessed. A “colony-to-cluster” ratio (Co-Cl) and percentage of large colonies (LC) were supplemental parameters assessed in these cell cultures. Using such parameters, the proliferative potential of the target progenitor cells was tested.

Total RNA Isolation and RT-PCR

Total RNA was extracted from 3 to 30 x105 MSCs using Trizol Reagents (Invitrogen, USA), according to the manufacturer’s instructions. mRNA was subject to reverse transcription (RT) using Superscript II Kit (Invitrogen, USA), again using the manufacturer’s instructions. The resulting cDNA was amplified using an ABI GeneAmp PCR System 2400 (Perkin Elmer Applied Biosystems, Boston, MA) at 94°C for 40 seconds, 56°C for 50 seconds, and 72°C for 60 seconds for 35 cycles, after initial denaturation at 94°C for 5 minutes. Primers used for PCR are listed in Table 1. Fifteen microliters of PCR reaction were fractionated by agarose gel electrophoresis.

c673f09dc2.png

Table 1. Primers used for RT-PCR

Statistical Analysis
The statistical significance of the inter-group differences was evaluated with the Mann-Whitney test. The degrees of correlations between the parameters were evaluated by the Spearman test. The differences were considered significant by p values <0.05. The Statistica 6.0 software package was used for all statistical analyses.

Results and Discussion

In most cases, the cultures of plastic-adherent cells proved to be heterogenous. Two main morphological cell types were discernable: spindle-shaped cells that are presumably regarded as mesenchymal stem cells (MSC), and polygonal cells that are most likely of hematopoietic origin (Figure 2).

62f925886e.png

Figure 2. Heterogeneous UCB culture. No colony formation was observed. UCB samples produced a minimal, non-confluent adherent layer of heterogeneous cells. 


In some UCB samples, clonal growth was observed, however the mean cell number per colony did not increase over 100 cells (Figure 3). Large colonies were detectable in 3 of the 40 UCB samples under study. These colonies (>1000 cells per colony) consisted of closely packed, spindle-shaped cells, typical of fibroblast morphology cells.

6043526b24.png

Figure 3. CFU-F in UCB culture. Adherently growing cells of fibroblastic morphology formed big colonies in 3 UCB samples.

The Phenotypic Composition of UCB Monolayer Cultures
Our efforts to define a distinct phenotype characteristic for MSC have been confounded by the fact that these cells can express a range of cell lineage-specific antigens [2,23].

During analysis of the predominant cellular types, it was discovered that the major fraction (median 60.17%) of plastic-adherent cells from UCB were of hematopoietic origin (CD45+) (Table 2). One-third of the CD45-positive cells belonged to the CD14-positive population fraction (median 14.81%). Cells in the monolayer with an osteoclast-like phenotype (CD45+CD61+) constituted approximately 1.5%. The cells phenotypically comparable with hematopoietic stem cells (HSC-like cells: CD34+CD45+, CD34+HLA DR-, CD117+) were present at a low concentration in the UCB monolayer culture - less than 1.5%.

adf136cb4d.png

Table 2. The composition of the UCB monolayer culture. 

The numbers of endothelial-like cells in the monolayer cultures were comparable to HSC-like cells. With this background, a heterogenous population of CD45-CD31+ phenotype was the most prominent one.

Despite a lack of specific markers that could characterize a population of MSC’s, we attempted to determine the quantity of these cells in the culture, based upon the fact that mesenchymal stem cells of the bone marrow do not express common leucocytic antigen CD45 and HLA class II antigens but do express class I HLA antigens and the CD90 marker. In this connection, we studied the following populations of phenotypically MSC-like cells: CD45-HLA ABC+ and CD90+CD31-.

Aiming for further validation of available cultural conditions for expansion of MSCs and endothelial precursors, we assessed the following factors influencing the terms of cultivation period in a primary culture under the conditions of initial culture and subsequent passages. During long term cultures (Table 3), the index of cells with hematopoietic markers decreased progressively, and the index of myeloid cell maturation decreased as well, providing evidence of the elimination of hematopoietic cells during the cultivation. We have revealed that the index of HSC-like cells (hematopoietic progenitor cell index) increases during prolonged cultivation, i.e. an index, reflecting a ratio of cells, phenotypically similar to hematopoietic stem cells, to the total number of СD45+-cells (CD34+CD45+, CD117+). This fact implies that this population is eliminated slower than other hematopoietic cells recovered in the UCB monolayer culture.

2b2ee34a8e.png

Table 3. Influence of cultivation period on composition of primary UCB culture

Moreover, the percentage of CD34+HLA DR- cells increases (37.33 to 81.98, p=0.001) in relation to general CD34-positive population, thus supposing that these cells undergo selective proliferation under the given cultural conditions. This result could indirectly confirm a theory that this population is presented via stromal component [24,25]. In the course of long-term cultivation, the index of endothelial cells is shown to be increased (0.013 to 0.025, p=0.02). This fact proves these cultural conditions are favorable for endothelial precursors' maintenance. When assessing the fractions that include mesenchymal precursors, we have found a tendency for an increase in the relative amounts of the CD45-HLA ABC+ subpopulation. However, when analyzing these populations with regard of all non-hematopoietic cells, we did not observe such a tendency. This fact may reflect the persistance of a steady phenotype of these cell populations upon durable cultivation.

During the process of culture passage, we could reveal a decrease of the hematopoietic cell index (3.19 to 1.6, p<0.016) (Table 4). This data may show the inability of the majority of hematopoietic cells for repeated adhesion, thus resulting in their elimination from the monolayer culture. At the same time, the cells phenotypically similar to HSC-like cells (CD34+CD45+) and lymphocytes (CD3+), were still able to adhere recurrently, when compared with other hematopoietic cells. Among cell populations containing mesenchymal precursors, it was noticed that the cells expressed class I HLA antigens, possessed a reduced adhesive ability, and were subject to elimination with sequential passing.

0627143d40.png

Table 4. Influence of culture passage on the structure of primary UCB culture

When comparing the phenotypical composition of mononuclear fraction and monolayer culture from UCB (Table 5) we discovered that the percentage of cells with CD34+CD45+ phenotype in the culture decreased considerably, along with an increased percentage of cells with СD34+HLA DR- phenotype. Therefore, we can suggest that these cultural conditions may be applied for isolation of the given cell type.

2b2ee34a8e.png

Table 5. The phenotypic composition of the mononuclear fraction and monolayer culture of UCB

This may be also proven by the data from semi-solid methylcellulose culture. The cells from monolayer cultures under study were incapable of forming hematopoietic colonies in the presence of standard hematopoietic growth factors (SCF, GM-CSF, IL-3, IL-6, G-CSF, EPO). This may result from a deficiency of clonogenic precursors in the monolayer, as well as an absence of clonogenic potential among hematopoietic stem-like cells.

The fraction of endothelial cells was higher in the monolayer culture. The percentage of hematopoietic-stem-like-cells and endothelial precursors decreased considerably during the initiation of the culture (38.87 to 1.34, p<0,02).
Analogous to Bieback's paper [12], when assessing the time parameters of sampling and storage of umbilical blood specimens we have revealed a tendency towards a decreased concentration of mesenchymal like stem-cells in the monolayer culture, when a prolonged time-period prior to processing umbilical blood sample with subsequent cultivation occurs (data not shown).

In vitro differentiation of UCB-derived MSC-like cells into adipocytes and osteocytes
Taking the lack of specific markers for identification of mesenchymal precursors into consideration, we tried to reveal the functional characteristics of the given types of cells and to assess the differential potentials in the framework of orthodox plasticity. It is shown that the cells of the UCB monolayer culture are capable of dividing and differentiating to adipocytes and osteoblasts, as was proven by their specific staining (Figure 4). In this figure (upper picture), red lipid inclusions are readily seen in differentiated adipocytes. In the lower picture, calcium insertions in the osteocytes are stainable red or black. In some cultures, however, induction of differentiation initiated detachment of most cells from plastic surface. As a result, the present conditions for differentiation of mesenchymal stem cells from BM are not quite appropriate for induced differentiation of UCB-derived mesenchymal precursors.

4fd0d633ec.png


Figure 4. Differentiation assay of BM and UCB monolayer culture. Formation of mineralized matrix by Alizarin Red and von Kossa staining evidenced osteogenic differentiation. Adipogenic differentiation was evidenced by the formation of lipid vacuoles in phase-contrast photograph and by oil-red O staining.


Ability of UCB monolayer culture to support ex vivo expansion of CFU-GM
Concerning efficiency of CFU-GM cloning, the UCB monolayer culture does not differ from standard leucocytic feeder. However, when using umbilical cord blood culture as a feeder, UCB-generated growth-promoting capacity and percentage of large colonies were higher (data not shown). Additional analysis (Table 6) leads us to suggest that hematopoietic cells from a UCB monolayer culture have certain advantage over non-hematopoietic cells in terms of colony-stimulation activity (r=0.71, p=0.035), at least in this in vitro model. With respect to non-hematopoietic cells, growth of cellular elements bearing MSC-markers (CD90+CD31-) was accompanied by significant increase in CFU-GM proliferative activity (r=0.82, p=0.007). Higher percentages of monocytes/macrophages, as among hematopoietic elements, is accompanied by growing numbers of large colonies (r=0.67, p=0.045), without producing any significant impact upon cloning efficiency of the progenitors.

31ac8e4d57.png

Table 6. Hemostimulating capacity of UCB-culture


Some references in the literature contain similar data obtained with another model, i.e., target cells were incubated with UCB cells in suspension cultures, followed by methyl cellulose cultures of non-attached cell populations in presence of standard growth factors, such as SCF, GM-CSF, G-CSF, IL3, IL6 and EPO [26,27]. Within our model, only umbilical cord blood cells of a monolayer culture were used as the colony stimulation source.

Comparative gene expression studies
When assessing the expression of some genes, we have found that the mRNA profile of bone marrow culture did not differ from the cells of UCB culture. Thrombopoietin was an exception, since specific mRNA was not detectable in the 1st passage culture of UCB cells (Table 7).

a29b2b50b8.png

Table 7. mRNA profile of MSC-like cells from different sources

Conclusions

•    Increased cultivation time of UCB mononuclear fraction (over 23 days) leads  to a gradual elimination of hematopoietic cells from the culture and an increase in mesenchymal stem cells and endothelial progenitor cells.
•    Cellular phenotype in the culture changes during passages, i.e., the quantity of hematopoietic cells is considerably decreased. This results in increased concentration of non-hematopoietic components the of umbilical blood monolayer culture during serial passaging.
•    An increased time period of UCB sampling is associated with a decrease in the relative quantity of mesenchymal-like stem cells, along with an increase in the concentration of endothelial precursors in the culture.
•    Mesenсhymal stem-like-cells of UCB have the capacity to differentiate into adipogenic and osteogenic lineages, thus suggesting their functional consistency.
•    The adhesive fraction of the primary monolayer culture exerts a stimulatory effect upon the colony formation of GM precursors, being similar in type and degree of influence to a standard peripheral blood feeder. The primary effect upon their proliferative capacity may be produced by cellular elements with MSC (CD90+CD31-) markers.
•    An increased time interval during sampling and storage of UCB leads to a decrease in the  hemostimulating capacity.
•    The variable contents of MSC-like cells and CFU-F in umbilical cord blood and/or their reduced repopulation ability may limit their application as an alternative source of MSCs.

References

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10. Broxmeyer HE. Proliferation, self-renewal, and survival characteristics of cord blood hematopoietic stem and progenitor cells. In: Broxmeyer HE, ed. Cord Blood: Biology, Immunology, Banking, and Clinical Transplantation. Bethesda, MD: American Association of Blood Banking. 2004:1-21.

11. Broxmeyer HE. Biology of cord blood cells and future prospects for enhanced clinical benefit. Cytotherapy. 2005;7(3):209-218.

12. Bieback K, Kern S, Kluter H, et al. Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells. 2004;22:625-634.

13. Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. 2000;109:235-242.

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18. Campagnoli C, Roberts I, Kumar S, Bennett P, Bellantuono I, Fisk N. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow Blood. 2001;98:2396-2402.

19. Goodwin HS, Bicknese AR, Chien SN, et al. Multilineage differentiation activity by cells isolated from umbilical cord blood: expression of bone, fat and neural markers. Biol Blood Marrow Transpl. 2001;7:581-588.

20. Cheng SL, Yang JW, Rifas L, et al. Differentiation of human bone marrow osteogenic stromal cells in vitro: induction of the osteoblast phenotype by dexamethasone. Endocrinology. 1994;134:277-286.

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Однако присутствие в прилипающей фракции пуповинной крови МСК до сих пор не является очевидным. Данное исследование выполнено с целью определения состава и ряда функциональных свойств МСК-подобных клеток в монослойной культуре пуповинной крови (МКПК) человека. </p> <h2>Материалы и методы</h2> <p> Исследовали сорок три образца пуповинной крови, полученые в срочных родах на фоне неосложненной беременности у рожениц при атравматичном заборе. Исследования проводили после  19-31 часов хранения образца. Ядросодержащие клетки выделяли на градиенте плотности фиколла (1,077 г/мл), затем помещали в полную культуральную среду, содержащую среду DMEM LG, эмбриональную телячью сыворотку - 30%, пенициллин  (100 Ед/мл), стрептомицин (0,1 мг/мл). Анализ фенотипа монослойной культуры ПК и ее мононуклеарной фракции проводили на проточном цитофлюориметре FACScan. Были использованы следующие конъюгированные флюорохромами антитела: CD34 PE; CD34 FITC, CD45 FITC; CD45 PE; CD14 FITC; CD31 PE; CD31 FITC; CD61 FITC; CD3 FITC; CD19 PE; CD117 PE; HLA ABC FITC; HLA DR.  С целью определения гемостимулирующих свойств монослойной культуры ПК проводили клонирование гранулоцитарно-макрофагальных предшественников (КОЕ-ГМ) в культуральной системе «агаровая капля-жидкая среда». В качестве источника колониестимулирующей активности ПК использовали МКПК. Клетками-мишенями были КОЕ-ГМ мононуклеарной фракции ПК, дающие клональный рост в агаровой культуре. Для индукции дифференцировки МСК-подобных клеток ПК в адипогенном и остеогенном направлении клетки помещали в полную среду с добавлением  дексаметазона (1х10<sup>-7</sup> М); инсулина (1х10<sup>-9</sup> М) или β-глицерофосфата (7х10<sup>-3</sup> М); дексаметазона (1х10<sup>-8</sup> М); аскорбиновой кислоты (2х10<sup>-4</sup> М) соответственно. Оценка экспрессии генов (CDH11,VCAM1, ITGB1, IL6ST, TFRC, ALCAM, MPL, TPO, ENG, NT5E, IL6R, BGLAP, COL1A2, AFP, LPL, ACTA1, TNNI3, TPM1)  проводилось методом RT-PCR (амплификация продуктов обратной транскрипции). </p> <h2>Результаты</h2> <p> В большинстве случаев культура клеток, прилипших к пластику была гетерогенна: наблюдали узкие веретенообразные клетки и большие полигональные. В ряде образцов обнаруживали небольшие колонии (до 100 клеток). В 3 из 43 исследованных образцов ПК наблюдали крупные колонии, численностью более 1000 плотноупакованных, имеющих типичную для фибробластов веретенообразную форму клеток. При анализе преобладающих клеточных типов было выявлено, что большую часть прикрепленных к пластику клеток составляли гемопоэтические клетки (медиана 60,17%). Около трети от всей СD45-положительной популяции составляли СD14-положительные клетки. Остальные негемопоэтические клетки представляли собой фенотипически гетерогенную популяцию. На фоне длительного культивирования и последовательного пассирования фенотип культуры меняется – отмечается элиминация из культуры гемопоэтических клеток и увеличение доли МСК и ЭКП. При инициации культуры значительно изменяется соотношение ГСК- и ЭКП-подобных клеток среди CD34-положительной популяции в пользу ЭКП. МСК-подобные клетки МКПК способны к дифференцировке в адипоциты и остеобласты, что подтверждается специфической окраской и свидетельствует в пользу их функциональной состоятельности. В ряде культур индукция дифференцировки инициировала открепление большей части клеток. Прилипающая фракция первичной монослойной культуры оказывает стимулирующее влияние на колониеобразование КОЕ-ГМ, по характеру и силе воздействия близкое стандартному лейкоцитарному фидеру. Преимущественное влияние на их пролиферативную активность оказывают клеточные элементы с маркерами МСК (CD90<sup>+</sup>CD31<sup>-</sup>). 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["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "5617" ["VALUE"]=> string(19) "14.11.2008 00:01:00" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(19) "14.11.2008 00:01:00" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" 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string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "5619" ["VALUE"]=> string(19) "26.12.2008 00:01:00" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(19) "26.12.2008 00:01:00" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "5620" ["VALUE"]=> string(3) "148" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "148" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(4) { [0]=> string(4) "5817" [1]=> string(4) "5818" [2]=> string(4) "5819" [3]=> string(4) "5820" } ["VALUE"]=> array(4) { [0]=> string(3) "148" [1]=> string(3) "467" [2]=> string(3) "468" [3]=> string(2) "34" } ["DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(4) { [0]=> string(3) "148" [1]=> string(3) "467" [2]=> string(3) "468" [3]=> string(2) "34" } ["~DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "5625" ["VALUE"]=> array(2) { ["TEXT"]=> string(155) "<p class="Autor">Бархатов И. М., Румянцев С. А., Владимирская Е. Б., Афанасьев Б. В.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(133) "

Бархатов И. М., Румянцев С. А., Владимирская Е. Б., Афанасьев Б. В.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "5626" ["VALUE"]=> array(2) { ["TEXT"]=> string(8344) "<h2>Резюме</h2> <h2>Введение </h2> <p class="bodytext"> В условиях монослойной культуры клетки пуповинной крови способны прикрепляться к пластику и по своей морфологии напоминают культивируемые в сходных условиях мезенхимальные стволовые клетки (МСК) костного мозга. Однако присутствие в прилипающей фракции пуповинной крови МСК до сих пор не является очевидным. Данное исследование выполнено с целью определения состава и ряда функциональных свойств МСК-подобных клеток в монослойной культуре пуповинной крови (МКПК) человека. </p> <h2>Материалы и методы</h2> <p> Исследовали сорок три образца пуповинной крови, полученые в срочных родах на фоне неосложненной беременности у рожениц при атравматичном заборе. Исследования проводили после  19-31 часов хранения образца. Ядросодержащие клетки выделяли на градиенте плотности фиколла (1,077 г/мл), затем помещали в полную культуральную среду, содержащую среду DMEM LG, эмбриональную телячью сыворотку - 30%, пенициллин  (100 Ед/мл), стрептомицин (0,1 мг/мл). Анализ фенотипа монослойной культуры ПК и ее мононуклеарной фракции проводили на проточном цитофлюориметре FACScan. Были использованы следующие конъюгированные флюорохромами антитела: CD34 PE; CD34 FITC, CD45 FITC; CD45 PE; CD14 FITC; CD31 PE; CD31 FITC; CD61 FITC; CD3 FITC; CD19 PE; CD117 PE; HLA ABC FITC; HLA DR.  С целью определения гемостимулирующих свойств монослойной культуры ПК проводили клонирование гранулоцитарно-макрофагальных предшественников (КОЕ-ГМ) в культуральной системе «агаровая капля-жидкая среда». В качестве источника колониестимулирующей активности ПК использовали МКПК. Клетками-мишенями были КОЕ-ГМ мононуклеарной фракции ПК, дающие клональный рост в агаровой культуре. Для индукции дифференцировки МСК-подобных клеток ПК в адипогенном и остеогенном направлении клетки помещали в полную среду с добавлением  дексаметазона (1х10<sup>-7</sup> М); инсулина (1х10<sup>-9</sup> М) или β-глицерофосфата (7х10<sup>-3</sup> М); дексаметазона (1х10<sup>-8</sup> М); аскорбиновой кислоты (2х10<sup>-4</sup> М) соответственно. Оценка экспрессии генов (CDH11,VCAM1, ITGB1, IL6ST, TFRC, ALCAM, MPL, TPO, ENG, NT5E, IL6R, BGLAP, COL1A2, AFP, LPL, ACTA1, TNNI3, TPM1)  проводилось методом RT-PCR (амплификация продуктов обратной транскрипции). </p> <h2>Результаты</h2> <p> В большинстве случаев культура клеток, прилипших к пластику была гетерогенна: наблюдали узкие веретенообразные клетки и большие полигональные. В ряде образцов обнаруживали небольшие колонии (до 100 клеток). В 3 из 43 исследованных образцов ПК наблюдали крупные колонии, численностью более 1000 плотноупакованных, имеющих типичную для фибробластов веретенообразную форму клеток. При анализе преобладающих клеточных типов было выявлено, что большую часть прикрепленных к пластику клеток составляли гемопоэтические клетки (медиана 60,17%). Около трети от всей СD45-положительной популяции составляли СD14-положительные клетки. Остальные негемопоэтические клетки представляли собой фенотипически гетерогенную популяцию. На фоне длительного культивирования и последовательного пассирования фенотип культуры меняется – отмечается элиминация из культуры гемопоэтических клеток и увеличение доли МСК и ЭКП. При инициации культуры значительно изменяется соотношение ГСК- и ЭКП-подобных клеток среди CD34-положительной популяции в пользу ЭКП. МСК-подобные клетки МКПК способны к дифференцировке в адипоциты и остеобласты, что подтверждается специфической окраской и свидетельствует в пользу их функциональной состоятельности. В ряде культур индукция дифференцировки инициировала открепление большей части клеток. Прилипающая фракция первичной монослойной культуры оказывает стимулирующее влияние на колониеобразование КОЕ-ГМ, по характеру и силе воздействия близкое стандартному лейкоцитарному фидеру. Преимущественное влияние на их пролиферативную активность оказывают клеточные элементы с маркерами МСК (CD90<sup>+</sup>CD31<sup>-</sup>). Удлинение временных параметров получения и хранения образцов ПК приводят к снижению гемостимулирующей активности. При сравнении экспрессии ряда генов выявлено, что профиль экспрессии МСК костного мозга и клеток МКПК идентичен за исключением тромбопоэтина, экспрессия гена которого не отмечалась в МКПК. </p> <h2>Заключение</h2> <p> Пуповинная кровь содержит субпопуляции клеток негемопоэтического происхождения,  фенотипически и функционально сходных с МСК костного мозга. Однако их низкая концентрация, а также сниженная репопулирующая активность в стандартных культуральных условиях, ставят под сомнение возможное использование ПК в качестве альтернативного источника МСК. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(8142) "

Резюме

Введение

В условиях монослойной культуры клетки пуповинной крови способны прикрепляться к пластику и по своей морфологии напоминают культивируемые в сходных условиях мезенхимальные стволовые клетки (МСК) костного мозга. Однако присутствие в прилипающей фракции пуповинной крови МСК до сих пор не является очевидным. Данное исследование выполнено с целью определения состава и ряда функциональных свойств МСК-подобных клеток в монослойной культуре пуповинной крови (МКПК) человека.

Материалы и методы

Исследовали сорок три образца пуповинной крови, полученые в срочных родах на фоне неосложненной беременности у рожениц при атравматичном заборе. Исследования проводили после  19-31 часов хранения образца. Ядросодержащие клетки выделяли на градиенте плотности фиколла (1,077 г/мл), затем помещали в полную культуральную среду, содержащую среду DMEM LG, эмбриональную телячью сыворотку - 30%, пенициллин  (100 Ед/мл), стрептомицин (0,1 мг/мл). Анализ фенотипа монослойной культуры ПК и ее мононуклеарной фракции проводили на проточном цитофлюориметре FACScan. Были использованы следующие конъюгированные флюорохромами антитела: CD34 PE; CD34 FITC, CD45 FITC; CD45 PE; CD14 FITC; CD31 PE; CD31 FITC; CD61 FITC; CD3 FITC; CD19 PE; CD117 PE; HLA ABC FITC; HLA DR.  С целью определения гемостимулирующих свойств монослойной культуры ПК проводили клонирование гранулоцитарно-макрофагальных предшественников (КОЕ-ГМ) в культуральной системе «агаровая капля-жидкая среда». В качестве источника колониестимулирующей активности ПК использовали МКПК. Клетками-мишенями были КОЕ-ГМ мононуклеарной фракции ПК, дающие клональный рост в агаровой культуре. Для индукции дифференцировки МСК-подобных клеток ПК в адипогенном и остеогенном направлении клетки помещали в полную среду с добавлением  дексаметазона (1х10-7 М); инсулина (1х10-9 М) или β-глицерофосфата (7х10-3 М); дексаметазона (1х10-8 М); аскорбиновой кислоты (2х10-4 М) соответственно. Оценка экспрессии генов (CDH11,VCAM1, ITGB1, IL6ST, TFRC, ALCAM, MPL, TPO, ENG, NT5E, IL6R, BGLAP, COL1A2, AFP, LPL, ACTA1, TNNI3, TPM1)  проводилось методом RT-PCR (амплификация продуктов обратной транскрипции).

Результаты

В большинстве случаев культура клеток, прилипших к пластику была гетерогенна: наблюдали узкие веретенообразные клетки и большие полигональные. В ряде образцов обнаруживали небольшие колонии (до 100 клеток). В 3 из 43 исследованных образцов ПК наблюдали крупные колонии, численностью более 1000 плотноупакованных, имеющих типичную для фибробластов веретенообразную форму клеток. При анализе преобладающих клеточных типов было выявлено, что большую часть прикрепленных к пластику клеток составляли гемопоэтические клетки (медиана 60,17%). Около трети от всей СD45-положительной популяции составляли СD14-положительные клетки. Остальные негемопоэтические клетки представляли собой фенотипически гетерогенную популяцию. На фоне длительного культивирования и последовательного пассирования фенотип культуры меняется – отмечается элиминация из культуры гемопоэтических клеток и увеличение доли МСК и ЭКП. При инициации культуры значительно изменяется соотношение ГСК- и ЭКП-подобных клеток среди CD34-положительной популяции в пользу ЭКП. МСК-подобные клетки МКПК способны к дифференцировке в адипоциты и остеобласты, что подтверждается специфической окраской и свидетельствует в пользу их функциональной состоятельности. В ряде культур индукция дифференцировки инициировала открепление большей части клеток. Прилипающая фракция первичной монослойной культуры оказывает стимулирующее влияние на колониеобразование КОЕ-ГМ, по характеру и силе воздействия близкое стандартному лейкоцитарному фидеру. Преимущественное влияние на их пролиферативную активность оказывают клеточные элементы с маркерами МСК (CD90+CD31-). Удлинение временных параметров получения и хранения образцов ПК приводят к снижению гемостимулирующей активности. При сравнении экспрессии ряда генов выявлено, что профиль экспрессии МСК костного мозга и клеток МКПК идентичен за исключением тромбопоэтина, экспрессия гена которого не отмечалась в МКПК.

Заключение

Пуповинная кровь содержит субпопуляции клеток негемопоэтического происхождения,  фенотипически и функционально сходных с МСК костного мозга. Однако их низкая концентрация, а также сниженная репопулирующая активность в стандартных культуральных условиях, ставят под сомнение возможное использование ПК в качестве альтернативного источника МСК.

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Barkhatov I. M.1, Roumiantsev S. A.2, Vladimirskaya E. B.2, Afanasyev B. V.1

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1Saint-Petersburg Pavlov State Medical University, Russia;
2Russian Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

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Summary

Objectives

It’s known that during cultivation, adherent cells of umbilical cord blood (UCB) form a monolayer reminiscent, in its composition, of the stromal monolayer of bone marrow (BM) culture. However, the presence of mesenchymal stem cells (MSCs) in UCB still remains uncertain. This study was performed to investigate the composition and some functional characteristics of MSC-like cell populations revealed in the cord blood monolayer culture.

Materials and methods

Forty-three human UCB samples were under study. All the samples were obtained during full-term deliveries. To produce monolayer cultures, mononuclear cell fractions from UCB were cultivated in a culture medium containing DMEM with 20% FCS, supplied with 1% Pen/Strep. Phenotypic patterns of UCB culture were assessed with a panel of monoclonal antibodies specific for CD34; CD117; CD45; CD14; CD3; CD19; CD31; CD90; HLA DR; and HLA ABC. To determine the functional characteristics of MSCs derived from UCB culture, their differentiation ability and stimulation of hematopoietic colony formation activity were evaluated.

Results

In most cases, the cultures of plastic-adherent cells proved to be heterogeneous. Both spindle-shaped and polygonal cells were observed. In some samples, clonal growth could be detected. However, the number of fibroblastoid cells did not increase 100 cells per colony. Large colonies were registered in three UCB samples of the 43 under study. As evidenced by immune phenotyping, the monolayer UCB cultures were rather polymorphic and dissimilar in each sample. Most of the cells present in the cultures were macrophages (CD45+). However, we also found different amounts of presumably mesenchymal cells, including cells with an endothelial phenotype (CD34+CD31+).

Specific staining showed that the cells from a UCB monolayer culture have the capacity to differentiate into adipocytes and osteoblasts. In some cultures, however, induction of differentiation lead to the detachment of a major cell fraction. Hemostimulatory ability of UCB monolayer cultures depended on the phenotype composition of the monolayer culture. CD45+ and CD14+ cells, evidently, are stimulatory for granulocyte-macrophage colony formation. Moreover, levels of non-hematopoietic subpopulations (CD90+CD31-) in UCB cultures showed a direct correlation with the numbers of CFU-GM colonies produced.

Conclusion

UCB contains a subpopulation of non-hematopoietic cells possessing phenotypic and some functional characteristics of bone marrow derived mesenchymal stem cells. However, the low content and variable numbers of such cells provide some doubts on the viability of UCB as an alternative source for MSC.

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M.<sup>1</sup>, Roumiantsev S. A.<sup>2</sup>, Vladimirskaya E. B.<sup>2</sup>, Afanasyev B. V.<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(141) "

Barkhatov I. M.1, Roumiantsev S. A.2, Vladimirskaya E. B.2, Afanasyev B. V.1

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Barkhatov I. M.1, Roumiantsev S. A.2, Vladimirskaya E. B.2, Afanasyev B. V.1

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Summary

Objectives

It’s known that during cultivation, adherent cells of umbilical cord blood (UCB) form a monolayer reminiscent, in its composition, of the stromal monolayer of bone marrow (BM) culture. However, the presence of mesenchymal stem cells (MSCs) in UCB still remains uncertain. This study was performed to investigate the composition and some functional characteristics of MSC-like cell populations revealed in the cord blood monolayer culture.

Materials and methods

Forty-three human UCB samples were under study. All the samples were obtained during full-term deliveries. To produce monolayer cultures, mononuclear cell fractions from UCB were cultivated in a culture medium containing DMEM with 20% FCS, supplied with 1% Pen/Strep. Phenotypic patterns of UCB culture were assessed with a panel of monoclonal antibodies specific for CD34; CD117; CD45; CD14; CD3; CD19; CD31; CD90; HLA DR; and HLA ABC. To determine the functional characteristics of MSCs derived from UCB culture, their differentiation ability and stimulation of hematopoietic colony formation activity were evaluated.

Results

In most cases, the cultures of plastic-adherent cells proved to be heterogeneous. Both spindle-shaped and polygonal cells were observed. In some samples, clonal growth could be detected. However, the number of fibroblastoid cells did not increase 100 cells per colony. Large colonies were registered in three UCB samples of the 43 under study. As evidenced by immune phenotyping, the monolayer UCB cultures were rather polymorphic and dissimilar in each sample. Most of the cells present in the cultures were macrophages (CD45+). However, we also found different amounts of presumably mesenchymal cells, including cells with an endothelial phenotype (CD34+CD31+).

Specific staining showed that the cells from a UCB monolayer culture have the capacity to differentiate into adipocytes and osteoblasts. In some cultures, however, induction of differentiation lead to the detachment of a major cell fraction. Hemostimulatory ability of UCB monolayer cultures depended on the phenotype composition of the monolayer culture. CD45+ and CD14+ cells, evidently, are stimulatory for granulocyte-macrophage colony formation. Moreover, levels of non-hematopoietic subpopulations (CD90+CD31-) in UCB cultures showed a direct correlation with the numbers of CFU-GM colonies produced.

Conclusion

UCB contains a subpopulation of non-hematopoietic cells possessing phenotypic and some functional characteristics of bone marrow derived mesenchymal stem cells. However, the low content and variable numbers of such cells provide some doubts on the viability of UCB as an alternative source for MSC.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2886) "

Summary

Objectives

It’s known that during cultivation, adherent cells of umbilical cord blood (UCB) form a monolayer reminiscent, in its composition, of the stromal monolayer of bone marrow (BM) culture. However, the presence of mesenchymal stem cells (MSCs) in UCB still remains uncertain. This study was performed to investigate the composition and some functional characteristics of MSC-like cell populations revealed in the cord blood monolayer culture.

Materials and methods

Forty-three human UCB samples were under study. All the samples were obtained during full-term deliveries. To produce monolayer cultures, mononuclear cell fractions from UCB were cultivated in a culture medium containing DMEM with 20% FCS, supplied with 1% Pen/Strep. Phenotypic patterns of UCB culture were assessed with a panel of monoclonal antibodies specific for CD34; CD117; CD45; CD14; CD3; CD19; CD31; CD90; HLA DR; and HLA ABC. To determine the functional characteristics of MSCs derived from UCB culture, their differentiation ability and stimulation of hematopoietic colony formation activity were evaluated.

Results

In most cases, the cultures of plastic-adherent cells proved to be heterogeneous. Both spindle-shaped and polygonal cells were observed. In some samples, clonal growth could be detected. However, the number of fibroblastoid cells did not increase 100 cells per colony. Large colonies were registered in three UCB samples of the 43 under study. As evidenced by immune phenotyping, the monolayer UCB cultures were rather polymorphic and dissimilar in each sample. Most of the cells present in the cultures were macrophages (CD45+). However, we also found different amounts of presumably mesenchymal cells, including cells with an endothelial phenotype (CD34+CD31+).

Specific staining showed that the cells from a UCB monolayer culture have the capacity to differentiate into adipocytes and osteoblasts. In some cultures, however, induction of differentiation lead to the detachment of a major cell fraction. Hemostimulatory ability of UCB monolayer cultures depended on the phenotype composition of the monolayer culture. CD45+ and CD14+ cells, evidently, are stimulatory for granulocyte-macrophage colony formation. Moreover, levels of non-hematopoietic subpopulations (CD90+CD31-) in UCB cultures showed a direct correlation with the numbers of CFU-GM colonies produced.

Conclusion

UCB contains a subpopulation of non-hematopoietic cells possessing phenotypic and some functional characteristics of bone marrow derived mesenchymal stem cells. However, the low content and variable numbers of such cells provide some doubts on the viability of UCB as an alternative source for MSC.

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1Saint-Petersburg Pavlov State Medical University, Russia;
2Russian Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

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1Saint-Petersburg Pavlov State Medical University, Russia;
2Russian Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

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Бархатов И. М., Румянцев С. А., Владимирская Е. Б., Афанасьев Б. В.

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Бархатов И. М., Румянцев С. А., Владимирская Е. Б., Афанасьев Б. В.

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["~VALUE"]=> string(3) "148" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(61) "Ildar M. Barkhatov" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "5626" ["VALUE"]=> array(2) { ["TEXT"]=> string(8344) "<h2>Резюме</h2> <h2>Введение </h2> <p class="bodytext"> В условиях монослойной культуры клетки пуповинной крови способны прикрепляться к пластику и по своей морфологии напоминают культивируемые в сходных условиях мезенхимальные стволовые клетки (МСК) костного мозга. Однако присутствие в прилипающей фракции пуповинной крови МСК до сих пор не является очевидным. Данное исследование выполнено с целью определения состава и ряда функциональных свойств МСК-подобных клеток в монослойной культуре пуповинной крови (МКПК) человека. </p> <h2>Материалы и методы</h2> <p> Исследовали сорок три образца пуповинной крови, полученые в срочных родах на фоне неосложненной беременности у рожениц при атравматичном заборе. Исследования проводили после  19-31 часов хранения образца. Ядросодержащие клетки выделяли на градиенте плотности фиколла (1,077 г/мл), затем помещали в полную культуральную среду, содержащую среду DMEM LG, эмбриональную телячью сыворотку - 30%, пенициллин  (100 Ед/мл), стрептомицин (0,1 мг/мл). Анализ фенотипа монослойной культуры ПК и ее мононуклеарной фракции проводили на проточном цитофлюориметре FACScan. Были использованы следующие конъюгированные флюорохромами антитела: CD34 PE; CD34 FITC, CD45 FITC; CD45 PE; CD14 FITC; CD31 PE; CD31 FITC; CD61 FITC; CD3 FITC; CD19 PE; CD117 PE; HLA ABC FITC; HLA DR.  С целью определения гемостимулирующих свойств монослойной культуры ПК проводили клонирование гранулоцитарно-макрофагальных предшественников (КОЕ-ГМ) в культуральной системе «агаровая капля-жидкая среда». В качестве источника колониестимулирующей активности ПК использовали МКПК. Клетками-мишенями были КОЕ-ГМ мононуклеарной фракции ПК, дающие клональный рост в агаровой культуре. Для индукции дифференцировки МСК-подобных клеток ПК в адипогенном и остеогенном направлении клетки помещали в полную среду с добавлением  дексаметазона (1х10<sup>-7</sup> М); инсулина (1х10<sup>-9</sup> М) или β-глицерофосфата (7х10<sup>-3</sup> М); дексаметазона (1х10<sup>-8</sup> М); аскорбиновой кислоты (2х10<sup>-4</sup> М) соответственно. Оценка экспрессии генов (CDH11,VCAM1, ITGB1, IL6ST, TFRC, ALCAM, MPL, TPO, ENG, NT5E, IL6R, BGLAP, COL1A2, AFP, LPL, ACTA1, TNNI3, TPM1)  проводилось методом RT-PCR (амплификация продуктов обратной транскрипции). </p> <h2>Результаты</h2> <p> В большинстве случаев культура клеток, прилипших к пластику была гетерогенна: наблюдали узкие веретенообразные клетки и большие полигональные. В ряде образцов обнаруживали небольшие колонии (до 100 клеток). В 3 из 43 исследованных образцов ПК наблюдали крупные колонии, численностью более 1000 плотноупакованных, имеющих типичную для фибробластов веретенообразную форму клеток. При анализе преобладающих клеточных типов было выявлено, что большую часть прикрепленных к пластику клеток составляли гемопоэтические клетки (медиана 60,17%). Около трети от всей СD45-положительной популяции составляли СD14-положительные клетки. Остальные негемопоэтические клетки представляли собой фенотипически гетерогенную популяцию. На фоне длительного культивирования и последовательного пассирования фенотип культуры меняется – отмечается элиминация из культуры гемопоэтических клеток и увеличение доли МСК и ЭКП. При инициации культуры значительно изменяется соотношение ГСК- и ЭКП-подобных клеток среди CD34-положительной популяции в пользу ЭКП. МСК-подобные клетки МКПК способны к дифференцировке в адипоциты и остеобласты, что подтверждается специфической окраской и свидетельствует в пользу их функциональной состоятельности. В ряде культур индукция дифференцировки инициировала открепление большей части клеток. Прилипающая фракция первичной монослойной культуры оказывает стимулирующее влияние на колониеобразование КОЕ-ГМ, по характеру и силе воздействия близкое стандартному лейкоцитарному фидеру. Преимущественное влияние на их пролиферативную активность оказывают клеточные элементы с маркерами МСК (CD90<sup>+</sup>CD31<sup>-</sup>). Удлинение временных параметров получения и хранения образцов ПК приводят к снижению гемостимулирующей активности. При сравнении экспрессии ряда генов выявлено, что профиль экспрессии МСК костного мозга и клеток МКПК идентичен за исключением тромбопоэтина, экспрессия гена которого не отмечалась в МКПК. </p> <h2>Заключение</h2> <p> Пуповинная кровь содержит субпопуляции клеток негемопоэтического происхождения,  фенотипически и функционально сходных с МСК костного мозга. Однако их низкая концентрация, а также сниженная репопулирующая активность в стандартных культуральных условиях, ставят под сомнение возможное использование ПК в качестве альтернативного источника МСК. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(8142) "

Резюме

Введение

В условиях монослойной культуры клетки пуповинной крови способны прикрепляться к пластику и по своей морфологии напоминают культивируемые в сходных условиях мезенхимальные стволовые клетки (МСК) костного мозга. Однако присутствие в прилипающей фракции пуповинной крови МСК до сих пор не является очевидным. Данное исследование выполнено с целью определения состава и ряда функциональных свойств МСК-подобных клеток в монослойной культуре пуповинной крови (МКПК) человека.

Материалы и методы

Исследовали сорок три образца пуповинной крови, полученые в срочных родах на фоне неосложненной беременности у рожениц при атравматичном заборе. Исследования проводили после  19-31 часов хранения образца. Ядросодержащие клетки выделяли на градиенте плотности фиколла (1,077 г/мл), затем помещали в полную культуральную среду, содержащую среду DMEM LG, эмбриональную телячью сыворотку - 30%, пенициллин  (100 Ед/мл), стрептомицин (0,1 мг/мл). Анализ фенотипа монослойной культуры ПК и ее мононуклеарной фракции проводили на проточном цитофлюориметре FACScan. Были использованы следующие конъюгированные флюорохромами антитела: CD34 PE; CD34 FITC, CD45 FITC; CD45 PE; CD14 FITC; CD31 PE; CD31 FITC; CD61 FITC; CD3 FITC; CD19 PE; CD117 PE; HLA ABC FITC; HLA DR.  С целью определения гемостимулирующих свойств монослойной культуры ПК проводили клонирование гранулоцитарно-макрофагальных предшественников (КОЕ-ГМ) в культуральной системе «агаровая капля-жидкая среда». В качестве источника колониестимулирующей активности ПК использовали МКПК. Клетками-мишенями были КОЕ-ГМ мононуклеарной фракции ПК, дающие клональный рост в агаровой культуре. Для индукции дифференцировки МСК-подобных клеток ПК в адипогенном и остеогенном направлении клетки помещали в полную среду с добавлением  дексаметазона (1х10-7 М); инсулина (1х10-9 М) или β-глицерофосфата (7х10-3 М); дексаметазона (1х10-8 М); аскорбиновой кислоты (2х10-4 М) соответственно. Оценка экспрессии генов (CDH11,VCAM1, ITGB1, IL6ST, TFRC, ALCAM, MPL, TPO, ENG, NT5E, IL6R, BGLAP, COL1A2, AFP, LPL, ACTA1, TNNI3, TPM1)  проводилось методом RT-PCR (амплификация продуктов обратной транскрипции).

Результаты

В большинстве случаев культура клеток, прилипших к пластику была гетерогенна: наблюдали узкие веретенообразные клетки и большие полигональные. В ряде образцов обнаруживали небольшие колонии (до 100 клеток). В 3 из 43 исследованных образцов ПК наблюдали крупные колонии, численностью более 1000 плотноупакованных, имеющих типичную для фибробластов веретенообразную форму клеток. При анализе преобладающих клеточных типов было выявлено, что большую часть прикрепленных к пластику клеток составляли гемопоэтические клетки (медиана 60,17%). Около трети от всей СD45-положительной популяции составляли СD14-положительные клетки. Остальные негемопоэтические клетки представляли собой фенотипически гетерогенную популяцию. На фоне длительного культивирования и последовательного пассирования фенотип культуры меняется – отмечается элиминация из культуры гемопоэтических клеток и увеличение доли МСК и ЭКП. При инициации культуры значительно изменяется соотношение ГСК- и ЭКП-подобных клеток среди CD34-положительной популяции в пользу ЭКП. МСК-подобные клетки МКПК способны к дифференцировке в адипоциты и остеобласты, что подтверждается специфической окраской и свидетельствует в пользу их функциональной состоятельности. В ряде культур индукция дифференцировки инициировала открепление большей части клеток. Прилипающая фракция первичной монослойной культуры оказывает стимулирующее влияние на колониеобразование КОЕ-ГМ, по характеру и силе воздействия близкое стандартному лейкоцитарному фидеру. Преимущественное влияние на их пролиферативную активность оказывают клеточные элементы с маркерами МСК (CD90+CD31-). Удлинение временных параметров получения и хранения образцов ПК приводят к снижению гемостимулирующей активности. При сравнении экспрессии ряда генов выявлено, что профиль экспрессии МСК костного мозга и клеток МКПК идентичен за исключением тромбопоэтина, экспрессия гена которого не отмечалась в МКПК.

Заключение

Пуповинная кровь содержит субпопуляции клеток негемопоэтического происхождения,  фенотипически и функционально сходных с МСК костного мозга. Однако их низкая концентрация, а также сниженная репопулирующая активность в стандартных культуральных условиях, ставят под сомнение возможное использование ПК в качестве альтернативного источника МСК.

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Резюме

Введение

В условиях монослойной культуры клетки пуповинной крови способны прикрепляться к пластику и по своей морфологии напоминают культивируемые в сходных условиях мезенхимальные стволовые клетки (МСК) костного мозга. Однако присутствие в прилипающей фракции пуповинной крови МСК до сих пор не является очевидным. Данное исследование выполнено с целью определения состава и ряда функциональных свойств МСК-подобных клеток в монослойной культуре пуповинной крови (МКПК) человека.

Материалы и методы

Исследовали сорок три образца пуповинной крови, полученые в срочных родах на фоне неосложненной беременности у рожениц при атравматичном заборе. Исследования проводили после  19-31 часов хранения образца. Ядросодержащие клетки выделяли на градиенте плотности фиколла (1,077 г/мл), затем помещали в полную культуральную среду, содержащую среду DMEM LG, эмбриональную телячью сыворотку - 30%, пенициллин  (100 Ед/мл), стрептомицин (0,1 мг/мл). Анализ фенотипа монослойной культуры ПК и ее мононуклеарной фракции проводили на проточном цитофлюориметре FACScan. Были использованы следующие конъюгированные флюорохромами антитела: CD34 PE; CD34 FITC, CD45 FITC; CD45 PE; CD14 FITC; CD31 PE; CD31 FITC; CD61 FITC; CD3 FITC; CD19 PE; CD117 PE; HLA ABC FITC; HLA DR.  С целью определения гемостимулирующих свойств монослойной культуры ПК проводили клонирование гранулоцитарно-макрофагальных предшественников (КОЕ-ГМ) в культуральной системе «агаровая капля-жидкая среда». В качестве источника колониестимулирующей активности ПК использовали МКПК. Клетками-мишенями были КОЕ-ГМ мононуклеарной фракции ПК, дающие клональный рост в агаровой культуре. Для индукции дифференцировки МСК-подобных клеток ПК в адипогенном и остеогенном направлении клетки помещали в полную среду с добавлением  дексаметазона (1х10-7 М); инсулина (1х10-9 М) или β-глицерофосфата (7х10-3 М); дексаметазона (1х10-8 М); аскорбиновой кислоты (2х10-4 М) соответственно. Оценка экспрессии генов (CDH11,VCAM1, ITGB1, IL6ST, TFRC, ALCAM, MPL, TPO, ENG, NT5E, IL6R, BGLAP, COL1A2, AFP, LPL, ACTA1, TNNI3, TPM1)  проводилось методом RT-PCR (амплификация продуктов обратной транскрипции).

Результаты

В большинстве случаев культура клеток, прилипших к пластику была гетерогенна: наблюдали узкие веретенообразные клетки и большие полигональные. В ряде образцов обнаруживали небольшие колонии (до 100 клеток). В 3 из 43 исследованных образцов ПК наблюдали крупные колонии, численностью более 1000 плотноупакованных, имеющих типичную для фибробластов веретенообразную форму клеток. При анализе преобладающих клеточных типов было выявлено, что большую часть прикрепленных к пластику клеток составляли гемопоэтические клетки (медиана 60,17%). Около трети от всей СD45-положительной популяции составляли СD14-положительные клетки. Остальные негемопоэтические клетки представляли собой фенотипически гетерогенную популяцию. На фоне длительного культивирования и последовательного пассирования фенотип культуры меняется – отмечается элиминация из культуры гемопоэтических клеток и увеличение доли МСК и ЭКП. При инициации культуры значительно изменяется соотношение ГСК- и ЭКП-подобных клеток среди CD34-положительной популяции в пользу ЭКП. МСК-подобные клетки МКПК способны к дифференцировке в адипоциты и остеобласты, что подтверждается специфической окраской и свидетельствует в пользу их функциональной состоятельности. В ряде культур индукция дифференцировки инициировала открепление большей части клеток. Прилипающая фракция первичной монослойной культуры оказывает стимулирующее влияние на колониеобразование КОЕ-ГМ, по характеру и силе воздействия близкое стандартному лейкоцитарному фидеру. Преимущественное влияние на их пролиферативную активность оказывают клеточные элементы с маркерами МСК (CD90+CD31-). Удлинение временных параметров получения и хранения образцов ПК приводят к снижению гемостимулирующей активности. При сравнении экспрессии ряда генов выявлено, что профиль экспрессии МСК костного мозга и клеток МКПК идентичен за исключением тромбопоэтина, экспрессия гена которого не отмечалась в МКПК.

Заключение

Пуповинная кровь содержит субпопуляции клеток негемопоэтического происхождения,  фенотипически и функционально сходных с МСК костного мозга. Однако их низкая концентрация, а также сниженная репопулирующая активность в стандартных культуральных условиях, ставят под сомнение возможное использование ПК в качестве альтернативного источника МСК.

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Introduction

Graft-versus-host disease (GVHD) remains a major obstacle to successful allogeneic hematopoietic stem cell transplantation (HSCT), causing significant morbidity and mortality, especially in a case of allogeneic unrelated and haploidentical settings. The ability to prevent and treat GVHD is a key to success. A calcineurin inhibitor in combination with methotrexate is still the basic regimen for prophylaxis of both acute GVHD (aGVHD) and chronic GVHD (chGVHD). Steroid therapy still represents the first-line treatment for established GVHD, with a response rate of 30 to 50 %. However, the outcome for patients with severe, steroid-resistant, acute GVHD is poor, and overall survival is low, despite of steady increasing repertoire of available drugs. Improved knowledge of GVHD pathophysiology has led to rational approaches to both prophylaxis and therapy.

Within bone marrow (BM) stroma, there exist subsets of non-hematopoietic cells referred to as mesenchymal stem cells, or mesenchymal stromal cells [1]. MSCs comprise a population of nonhematopoietic bone marrow cells that possess an extensive proliferative potential and ability to differentiate into various cell types [2]. Therefore, it may be used to improve rate and quality of haematopoietic engraftment by regenerating the marrow microenvironment [1,3,5].

MSCs play a significant role in bone marrow microenvironment. The major function of these cells is to provide mechanical support to hematopoietic cells. MCSs express a large number of adhesion molecules, extracellular matrix proteins, cytokines and growth factor receptors, associated with their function and cell interactions within bone marrow stroma [2]. Moreover, MSCs are known to produce a variety of cytokines that are involved in homing (stromal derived factor-1, SDF-1), or proliferation and differentiation of hematopoietic cells (GM-CSF, SCF, IL-6). E.g., the engrafted MSCs may support human hematopoiesis via secreted factors and by physical interactions with hematopoietic cells [7,13].

Moreover, MSCs are able of modifying cellular immune response by multiple mechanisms, suppressing various T cell, B cell and NK cell functions [4,6,8,9], thus suggesting their possible use for treatment of immune-mediated disorders, like as GVHD [11,12]. Thus, MSC are currently under investigation for their potential reparative and immunosuppressive effects.

An opportunity of tolerance induction to allogeneic or xenogeneic grafts following incompatible bone marrow stem cell transplantation into a mismatched recipient was proposed since 1984 [14]. However, only in 2002 it has been clearly demonstrated that human MSCs may inhibit proliferation of T cells [6,8,9]. MSCs are generally considered to be poorly immunogenic cells, since they do not express neither HLA MHC class II antigens, FAS ligand, nor costimulatory molecules, such as В7-1, В7-2, CD40, CD40L on their surface [10]. In addition, MSCs are able to suppress a variety of T-, B-, and NK cell functions, and may affect also dendritic cell activities [9]. However, little is known about probable molecular mechanism(s) responsible for these effects.

Hence, potential applications of MSCs for prophylaxis and treatment of both acute and chronic severe GVHD seem to be quite reasonable [15,16,17]. Co-transplantation of allogeneic MSC and allogeneic HSCs could provide some beneficial effects, such as enhanced engraftment, acceleration of immune reconstitution and suppression of GVHD in HSCT.

The aim of our present study was to test a hypothesis that co-transplantations of MSCs could be used either for GVHD prophylaxis, or treatment of severe acute or chronic GVHD following allogeneic HSCT.

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Table 1. MSCs phenotype

Patients and methods

Eligible for current study were children and adults (their age ranged from 6 to 53) with different hematological malignancies, such as acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), non-Hodgkin lymphoma (NHL), myelodisplastic syndrome (MDS), chronic myeloid leukemia (CML).

From October 2005 to May 2008, eight patients received co-transplantation of HSC and MSCs for speeding up engraftment and prophylaxis of GVHD.

Sixteen pts received isolated infusions of MSCs for treatment of steroid-resistant GVHD. Patients or/and their caregivers were fully informed about all aspects of their participation in the study. A signed informed consent form was obtained in all cases.

When performing MSC co-transplantation, related allo-HSCTs were performed in five patients, unrelated allo-HSCTs, in two cases, and haploidentical HCST in one patient. The source of HSC was BM (six cases), peripheral blood stem cells (PBSC) in one patient, and a combination of BM and PBSC in one case.
Seven patients received nonmyeloablative conditioning regimen (fludarabine+melphalan in five pts, fludarabine+busulfan in two pts), and one patient was subject to a myeloablative treatment (busulfane+cyclophosphamide).

Acute GVHD prophylaxis was cyclosporineA (CsA) and methotrexate (Mtx) (short course) in seven patients and CsA and mycophenotate mofetil (MMF) in one case. Patients and transplant characteristics are presented in Table 2 and 3.

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Table 2. Patient’s and transplant’s characteristics

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Table 3. Number of MSC’s infusion and dosage of MSCs

MSCs were harvested from the BM of HLA-identical sibling in cases of related allo-HSCT (n=5), or from the BM of haploidentical donors in cases of unrelated allo-HSCT (n=3).

Before starting the treatment, BM was aspirated from MSC donor, MSCs been collected and selected. Bone marrow-derived MSCs for transplantation were produced by “Trans-Technology” Ltd Company (license № 99-01-002224 dd. 14.07.2005). Generally, in vitro MSC processing included their specific selection and expansion in culture during 21-28 days, until achieving sufficient therapeutical dose MSC for co-transplantation into HSC recipient (2.0x10^6 cells/kg body weight). (Figure 1 and Table 3). This study used PCR-based testing of common infectious pathogens in bone marrow.

The patients were given in vitro expanded MSCs intravenously 24 hours before HSC infusion. Design of use MSCs shown in Fig.1.

79c2d980ff.jpg

Figure 1. Design of usage of MSC for allogeneic hematopoietic stem cell transplantation

Isolated infusions of MSCs was performed in cases of steroid-resistant acute or chronic GVHD in patients after unrelated HSCT. Two patients had a mismatch in C locus, one, in DRB1 locus, one in B and C locus, one in DRB1 and C locus and three patients were haploidentical to their donors.

Ten patients received single MSC doses, five recipients - 2 doses, and one patient received three MSC doses (Table 2).

For thirteen patients, PBSCs were used as an HSC source. In cases of haplo-HSCT, HSCs represented a combination of G-CSF-primed marrow cells and T-cell depleted PBSCs (CliniMacs technique, Miltenyi Biotec).

MSCs were harvested from the BM of third-party donors in all cases before transplantation, and were cryopreserved until their use.

Results and discussion

A total of thirty-one infusions of mesenchymal stem cells were performed. Eight patients received co-transplantation of HSC and MSCs aiming to improve engraftment, and for GVHD prophylaxis. Sixteen patients received isolated infusions of MSCs for treatment of acute or chronic steroid-resistant GVHD.         
Among them, ten patients received single MSC doses, five patients were treated with double MSC infusions, and one patient has got three doses (Table 3). MSC infusion was well tolerated, safe, without immediate infusion-related or late MSC-associated toxicities. Due to rather different indications for MSC infusions in cases of MSC co-transplantation versus isolated infusions, their results will be reviewed and discussed separately.

Results of MSCs use for speeding up engraftment and prevention of GVHD (co-transplantation of MSC and HSC)
According to peripheral leukocyte recovery, HSC engraftment was observed in seven pts (D+16 to +38), whereas platelet reconstitution proceeded by D+14 to +45 post-transplant. Hence, infusion of MSCs before HSCs did not improve engraftment rates as compared to HSCT without co-infusion of MSCs during conditioning (Table 4). After co-transplantation, six patients remained alive between 3 and 25 months. Severe aGVHD (grade III to IV) was not observed in MSC group. Six patients had aGVHD stage 0-I, and one patient exhibited stage II aGVHD. Chronic GVHD was not registered.

bb6e52dab3.jpg

Table 4. Result of usage of MSC after co-transplantation


Additional infusions of MSCs for treatment of GVHD were not required due to the absence of severe GVHD. Two patients of this group died. In first case, graft failure was observed by D+16, complicated with disseminated intravenous coagulation and cerebral stroke. The second patient had disease progression and died at D+186. No treatment-related toxicities could be immediately ascribed to infusions of MSCs. 

Overall 2.5 years relapse-free survival was 71%. No clinical complications were detected that could be attributed to MSC treatment.

Since non-myelоablative conditioning was used for 88% of co-transplanted patients, we have also compared the outcomes in these cases with general group after HSCT with reduced conditioning regimen.  

Overall survival in MSC-treated group proved to be significantly higher, i.e., 71% after co-transplantation versus 34% after HSCT without MSCs (P=0,05). However, these data are rather preliminary and need further confirmation in larger series.

Mean incidence of infections in co-transplanted group was lower (25% against 48% in HSCT group). Two of eight patients developed respiratory, severe CMV and Aspergillus infection.

Result of MSC use for treatment of GVHD

Acute GVHD with involvement of skin was diagnosed in all patients (n=16), isolated involvement of skin (stage II-III) was detectable in eight patients. Combined aGVHD grade II with involvement of skin and liver was registered in one case, liver and gut GVHD, grade II-III was evident in four patients, and gut GVHD grade II-IV was found in three cases. One, two, or three MSC doses were administered, respectively, to ten, five, and one patient. Therefore, a total of twenty-three MSC infusions were performed. In ten patients, MSCs were used for treatment of acute GVHD, and in six cases they were applied for therapy of chronic GVHD.

After isolated infusions of MSCs in steroid-resistant aGVHD, a partial response (PR) was observed in five cases, complete response in two cases, without improvement in three cases. (Tab.5). Hence, after infusion of MSCs in the patients with aGVHD, a detectable response was observed in seven pts of ten (overall response rate 70%). Positive results of MSC administration for treatment of chGVHD were observed in 67%.

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Table 5. Result of use MSC for treatment of GVHD


The median MSC dose did not differ for those patients who responded to the therapy, as compared with nonresponder group (2.0 x 10^6/kg b.w.of recipient). Six patients who responded to the first infusion were given a second infusion, to prevent GVHD recurrence upon reduction of immunosuppressive drug treatment. Two patients had complete response but received several (two or three) doses of MSCs because of GVHD recurrence. Four patients had partial responses and were given multiple (two or three) doses. Six of ten patients with involvement of one or two organs in aGVHD did respond to the therapy, as compared to four (of ten) patients with involvement of three organs.

Median time interval from onset of aGVHD to the start of treatment with MSC was 36 days (range 3-116).

Five patients were alive at the time of data analysis (May of 2008), with a median follow-up of 6,3 months (3-14,5 months) after infusion of MSCs.

Three patients had recurrences of their basic diseases, one with NHL, one with acute lymphoblastic leukaemia, and one with acute myeloid leukaemia. Fatal outcome was registered in all these cases. Acute GVHD was the most common cause of death in other cases (six patients of ten), with or without concomitant infection. One patient died with multiorgan failure. Infections in patients who died with acute or chronic GVHD included cytomegalovirus, aspergillosis and an unidentified pathogen.

In more than a half of patients with both acute and chGVHD, a single MSC dose produced a response, whereas in a few patients with partial response or with recurrence of acute or chronic GVHD, several doses were needed to induce a lasting response.

We have analyzed dependence of the response to MSCs infusion of various factors, such as conditioning regimen, GVHD prophylaxis, transplant type, donor and recipient characteristics. However, no significant differences were found, probably because of small and variable group of patients. There was relation between the treatment given before infusion of MSCs and response. In case of MSC infusion in the patients (n=7) after myeloablative HSCT, immunosupression and result of treatment of acute GVHD were better than after non-myeloablative regimen (Figure 2). Usage of ALG (Atgam by Pfizer) in GVHD prophylaxis did worsen the response to GVHD treatment with MSCs (Figure 3). In cases of HLA mismatch, HSCT response to MSCs infusion was more significant than after full-match HSCs. Patients transplanted from donor of opposite sex exhibited a more pronounced response to MSCs. ABO-incompatibility between donor and recipient did not influence response to MSCs. There are no differences in reactions to MSCs after GVHD prophylaxis with cyclosporine A versus tacrolimus.

Efficiency of MSCs therapy of GVHD with depending on:

57c03ae1c5.jpg

Figure 2. Conditioning regimen

e69e593eba.jpg

Figure 3. Usage of ALG

Conclusions

1.   MSCs infusion in patients, who underwent allo-HSCT, is well-tolerated, safe, without immediate infusion-related or late MSC-associated toxicities.
2.   Infusion of MSCs before HSCs transplantation did not influence duration of engraftment.
3.   Infusion of MSCs during conditioning therapy before HSCT may prevent severe acute and chronic GVHD.
4.   Infusion of MSCs for treatment-resistant both acute and chronic GVHD lead to reduction of GVHD grade in some patients.
5.   Usage MSCs before HSC transplantation did not increase frequency of malignancy relapses.
6.   Usage of MSCs seems to be more effective in patients after HSCT with myeloablative regimen and GVHD prophylaxis without ATG.
7.   Large randomized clinical trials are necessary for evaluation of therapeutic effect of MSCs in allo-HSCT patients.

References

1. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow: analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6:230-47.

2. Haynesworth SE, Goshima J, Goldberg VM, Caplan AI. Characterization of cells with osteogenic potential from human marrow. Bone. 1992;13:81-88.

3. Koc ON, Gerson SL, Cooper BW, et al. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol. 2000;18:307-16.

4. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringdén O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol. 2003;57:11-20.

5. Noort WA, Kruisselbrink AB, in’t Anker PS, et al. Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34 (+) cells in NOD/SCID mice. Exp Hematol. 2002;30:870-78.

6. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30:42-48.

7. Le Blanc K, Samuelsson H, Gustafsson B, et al. Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells. Leukemia. 2007;21:1733-38.

8. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815-22.

9. Maitra B, Szekely E, Gjini K, Laughlin MJ, Dennis J, Haynesworth SE, and Koc ON. Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation. Bone Marrow Transplantation. 2004;33:597-604.

10. Eliopoulos N, Stagg J, Lejeune L, Pommey S, and Galipeau J. Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice. Blood. 2005 Dec 15;106(13).

11. Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant. 1995;16:557-64.

12. Fibbe WE and Noort WA. Mesenchymal stem cell and hematopoietic stem cell transplantation. Ann N Y Acad Sci. 2003;996:235-244.

13. Ball LM, Bernardo ME, Roelofs H, et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood. 2007;110:2764-67.

14. Friedenstein AJ, Chailakhyan RK, Gerasimov UV. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet. 1987;20:263-72.

15. Ringden O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation. 2006;81:1390-97.

16. Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439-41.

17. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo M, Remberger M, Dini G, Egeler R, Bacigalupo A, Fibbe W, Ringden O. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008 May 10;371.

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Introduction

Graft-versus-host disease (GVHD) remains a major obstacle to successful allogeneic hematopoietic stem cell transplantation (HSCT), causing significant morbidity and mortality, especially in a case of allogeneic unrelated and haploidentical settings. The ability to prevent and treat GVHD is a key to success. A calcineurin inhibitor in combination with methotrexate is still the basic regimen for prophylaxis of both acute GVHD (aGVHD) and chronic GVHD (chGVHD). Steroid therapy still represents the first-line treatment for established GVHD, with a response rate of 30 to 50 %. However, the outcome for patients with severe, steroid-resistant, acute GVHD is poor, and overall survival is low, despite of steady increasing repertoire of available drugs. Improved knowledge of GVHD pathophysiology has led to rational approaches to both prophylaxis and therapy.

Within bone marrow (BM) stroma, there exist subsets of non-hematopoietic cells referred to as mesenchymal stem cells, or mesenchymal stromal cells [1]. MSCs comprise a population of nonhematopoietic bone marrow cells that possess an extensive proliferative potential and ability to differentiate into various cell types [2]. Therefore, it may be used to improve rate and quality of haematopoietic engraftment by regenerating the marrow microenvironment [1,3,5].

MSCs play a significant role in bone marrow microenvironment. The major function of these cells is to provide mechanical support to hematopoietic cells. MCSs express a large number of adhesion molecules, extracellular matrix proteins, cytokines and growth factor receptors, associated with their function and cell interactions within bone marrow stroma [2]. Moreover, MSCs are known to produce a variety of cytokines that are involved in homing (stromal derived factor-1, SDF-1), or proliferation and differentiation of hematopoietic cells (GM-CSF, SCF, IL-6). E.g., the engrafted MSCs may support human hematopoiesis via secreted factors and by physical interactions with hematopoietic cells [7,13].

Moreover, MSCs are able of modifying cellular immune response by multiple mechanisms, suppressing various T cell, B cell and NK cell functions [4,6,8,9], thus suggesting their possible use for treatment of immune-mediated disorders, like as GVHD [11,12]. Thus, MSC are currently under investigation for their potential reparative and immunosuppressive effects.

An opportunity of tolerance induction to allogeneic or xenogeneic grafts following incompatible bone marrow stem cell transplantation into a mismatched recipient was proposed since 1984 [14]. However, only in 2002 it has been clearly demonstrated that human MSCs may inhibit proliferation of T cells [6,8,9]. MSCs are generally considered to be poorly immunogenic cells, since they do not express neither HLA MHC class II antigens, FAS ligand, nor costimulatory molecules, such as В7-1, В7-2, CD40, CD40L on their surface [10]. In addition, MSCs are able to suppress a variety of T-, B-, and NK cell functions, and may affect also dendritic cell activities [9]. However, little is known about probable molecular mechanism(s) responsible for these effects.

Hence, potential applications of MSCs for prophylaxis and treatment of both acute and chronic severe GVHD seem to be quite reasonable [15,16,17]. Co-transplantation of allogeneic MSC and allogeneic HSCs could provide some beneficial effects, such as enhanced engraftment, acceleration of immune reconstitution and suppression of GVHD in HSCT.

The aim of our present study was to test a hypothesis that co-transplantations of MSCs could be used either for GVHD prophylaxis, or treatment of severe acute or chronic GVHD following allogeneic HSCT.

1f04aab3ee.jpg

Table 1. MSCs phenotype

Patients and methods

Eligible for current study were children and adults (their age ranged from 6 to 53) with different hematological malignancies, such as acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), non-Hodgkin lymphoma (NHL), myelodisplastic syndrome (MDS), chronic myeloid leukemia (CML).

From October 2005 to May 2008, eight patients received co-transplantation of HSC and MSCs for speeding up engraftment and prophylaxis of GVHD.

Sixteen pts received isolated infusions of MSCs for treatment of steroid-resistant GVHD. Patients or/and their caregivers were fully informed about all aspects of their participation in the study. A signed informed consent form was obtained in all cases.

When performing MSC co-transplantation, related allo-HSCTs were performed in five patients, unrelated allo-HSCTs, in two cases, and haploidentical HCST in one patient. The source of HSC was BM (six cases), peripheral blood stem cells (PBSC) in one patient, and a combination of BM and PBSC in one case.
Seven patients received nonmyeloablative conditioning regimen (fludarabine+melphalan in five pts, fludarabine+busulfan in two pts), and one patient was subject to a myeloablative treatment (busulfane+cyclophosphamide).

Acute GVHD prophylaxis was cyclosporineA (CsA) and methotrexate (Mtx) (short course) in seven patients and CsA and mycophenotate mofetil (MMF) in one case. Patients and transplant characteristics are presented in Table 2 and 3.

1736520aa0.jpg

Table 2. Patient’s and transplant’s characteristics

3ae6004922.jpg

Table 3. Number of MSC’s infusion and dosage of MSCs

MSCs were harvested from the BM of HLA-identical sibling in cases of related allo-HSCT (n=5), or from the BM of haploidentical donors in cases of unrelated allo-HSCT (n=3).

Before starting the treatment, BM was aspirated from MSC donor, MSCs been collected and selected. Bone marrow-derived MSCs for transplantation were produced by “Trans-Technology” Ltd Company (license № 99-01-002224 dd. 14.07.2005). Generally, in vitro MSC processing included their specific selection and expansion in culture during 21-28 days, until achieving sufficient therapeutical dose MSC for co-transplantation into HSC recipient (2.0x10^6 cells/kg body weight). (Figure 1 and Table 3). This study used PCR-based testing of common infectious pathogens in bone marrow.

The patients were given in vitro expanded MSCs intravenously 24 hours before HSC infusion. Design of use MSCs shown in Fig.1.

79c2d980ff.jpg

Figure 1. Design of usage of MSC for allogeneic hematopoietic stem cell transplantation

Isolated infusions of MSCs was performed in cases of steroid-resistant acute or chronic GVHD in patients after unrelated HSCT. Two patients had a mismatch in C locus, one, in DRB1 locus, one in B and C locus, one in DRB1 and C locus and three patients were haploidentical to their donors.

Ten patients received single MSC doses, five recipients - 2 doses, and one patient received three MSC doses (Table 2).

For thirteen patients, PBSCs were used as an HSC source. In cases of haplo-HSCT, HSCs represented a combination of G-CSF-primed marrow cells and T-cell depleted PBSCs (CliniMacs technique, Miltenyi Biotec).

MSCs were harvested from the BM of third-party donors in all cases before transplantation, and were cryopreserved until their use.

Results and discussion

A total of thirty-one infusions of mesenchymal stem cells were performed. Eight patients received co-transplantation of HSC and MSCs aiming to improve engraftment, and for GVHD prophylaxis. Sixteen patients received isolated infusions of MSCs for treatment of acute or chronic steroid-resistant GVHD.         
Among them, ten patients received single MSC doses, five patients were treated with double MSC infusions, and one patient has got three doses (Table 3). MSC infusion was well tolerated, safe, without immediate infusion-related or late MSC-associated toxicities. Due to rather different indications for MSC infusions in cases of MSC co-transplantation versus isolated infusions, their results will be reviewed and discussed separately.

Results of MSCs use for speeding up engraftment and prevention of GVHD (co-transplantation of MSC and HSC)
According to peripheral leukocyte recovery, HSC engraftment was observed in seven pts (D+16 to +38), whereas platelet reconstitution proceeded by D+14 to +45 post-transplant. Hence, infusion of MSCs before HSCs did not improve engraftment rates as compared to HSCT without co-infusion of MSCs during conditioning (Table 4). After co-transplantation, six patients remained alive between 3 and 25 months. Severe aGVHD (grade III to IV) was not observed in MSC group. Six patients had aGVHD stage 0-I, and one patient exhibited stage II aGVHD. Chronic GVHD was not registered.

bb6e52dab3.jpg

Table 4. Result of usage of MSC after co-transplantation


Additional infusions of MSCs for treatment of GVHD were not required due to the absence of severe GVHD. Two patients of this group died. In first case, graft failure was observed by D+16, complicated with disseminated intravenous coagulation and cerebral stroke. The second patient had disease progression and died at D+186. No treatment-related toxicities could be immediately ascribed to infusions of MSCs. 

Overall 2.5 years relapse-free survival was 71%. No clinical complications were detected that could be attributed to MSC treatment.

Since non-myelоablative conditioning was used for 88% of co-transplanted patients, we have also compared the outcomes in these cases with general group after HSCT with reduced conditioning regimen.  

Overall survival in MSC-treated group proved to be significantly higher, i.e., 71% after co-transplantation versus 34% after HSCT without MSCs (P=0,05). However, these data are rather preliminary and need further confirmation in larger series.

Mean incidence of infections in co-transplanted group was lower (25% against 48% in HSCT group). Two of eight patients developed respiratory, severe CMV and Aspergillus infection.

Result of MSC use for treatment of GVHD

Acute GVHD with involvement of skin was diagnosed in all patients (n=16), isolated involvement of skin (stage II-III) was detectable in eight patients. Combined aGVHD grade II with involvement of skin and liver was registered in one case, liver and gut GVHD, grade II-III was evident in four patients, and gut GVHD grade II-IV was found in three cases. One, two, or three MSC doses were administered, respectively, to ten, five, and one patient. Therefore, a total of twenty-three MSC infusions were performed. In ten patients, MSCs were used for treatment of acute GVHD, and in six cases they were applied for therapy of chronic GVHD.

After isolated infusions of MSCs in steroid-resistant aGVHD, a partial response (PR) was observed in five cases, complete response in two cases, without improvement in three cases. (Tab.5). Hence, after infusion of MSCs in the patients with aGVHD, a detectable response was observed in seven pts of ten (overall response rate 70%). Positive results of MSC administration for treatment of chGVHD were observed in 67%.

b25ff479b8.jpg

Table 5. Result of use MSC for treatment of GVHD


The median MSC dose did not differ for those patients who responded to the therapy, as compared with nonresponder group (2.0 x 10^6/kg b.w.of recipient). Six patients who responded to the first infusion were given a second infusion, to prevent GVHD recurrence upon reduction of immunosuppressive drug treatment. Two patients had complete response but received several (two or three) doses of MSCs because of GVHD recurrence. Four patients had partial responses and were given multiple (two or three) doses. Six of ten patients with involvement of one or two organs in aGVHD did respond to the therapy, as compared to four (of ten) patients with involvement of three organs.

Median time interval from onset of aGVHD to the start of treatment with MSC was 36 days (range 3-116).

Five patients were alive at the time of data analysis (May of 2008), with a median follow-up of 6,3 months (3-14,5 months) after infusion of MSCs.

Three patients had recurrences of their basic diseases, one with NHL, one with acute lymphoblastic leukaemia, and one with acute myeloid leukaemia. Fatal outcome was registered in all these cases. Acute GVHD was the most common cause of death in other cases (six patients of ten), with or without concomitant infection. One patient died with multiorgan failure. Infections in patients who died with acute or chronic GVHD included cytomegalovirus, aspergillosis and an unidentified pathogen.

In more than a half of patients with both acute and chGVHD, a single MSC dose produced a response, whereas in a few patients with partial response or with recurrence of acute or chronic GVHD, several doses were needed to induce a lasting response.

We have analyzed dependence of the response to MSCs infusion of various factors, such as conditioning regimen, GVHD prophylaxis, transplant type, donor and recipient characteristics. However, no significant differences were found, probably because of small and variable group of patients. There was relation between the treatment given before infusion of MSCs and response. In case of MSC infusion in the patients (n=7) after myeloablative HSCT, immunosupression and result of treatment of acute GVHD were better than after non-myeloablative regimen (Figure 2). Usage of ALG (Atgam by Pfizer) in GVHD prophylaxis did worsen the response to GVHD treatment with MSCs (Figure 3). In cases of HLA mismatch, HSCT response to MSCs infusion was more significant than after full-match HSCs. Patients transplanted from donor of opposite sex exhibited a more pronounced response to MSCs. ABO-incompatibility between donor and recipient did not influence response to MSCs. There are no differences in reactions to MSCs after GVHD prophylaxis with cyclosporine A versus tacrolimus.

Efficiency of MSCs therapy of GVHD with depending on:

57c03ae1c5.jpg

Figure 2. Conditioning regimen

e69e593eba.jpg

Figure 3. Usage of ALG

Conclusions

1.   MSCs infusion in patients, who underwent allo-HSCT, is well-tolerated, safe, without immediate infusion-related or late MSC-associated toxicities.
2.   Infusion of MSCs before HSCs transplantation did not influence duration of engraftment.
3.   Infusion of MSCs during conditioning therapy before HSCT may prevent severe acute and chronic GVHD.
4.   Infusion of MSCs for treatment-resistant both acute and chronic GVHD lead to reduction of GVHD grade in some patients.
5.   Usage MSCs before HSC transplantation did not increase frequency of malignancy relapses.
6.   Usage of MSCs seems to be more effective in patients after HSCT with myeloablative regimen and GVHD prophylaxis without ATG.
7.   Large randomized clinical trials are necessary for evaluation of therapeutic effect of MSCs in allo-HSCT patients.

References

1. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow: analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6:230-47.

2. Haynesworth SE, Goshima J, Goldberg VM, Caplan AI. Characterization of cells with osteogenic potential from human marrow. Bone. 1992;13:81-88.

3. Koc ON, Gerson SL, Cooper BW, et al. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol. 2000;18:307-16.

4. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringdén O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol. 2003;57:11-20.

5. Noort WA, Kruisselbrink AB, in’t Anker PS, et al. Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34 (+) cells in NOD/SCID mice. Exp Hematol. 2002;30:870-78.

6. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30:42-48.

7. Le Blanc K, Samuelsson H, Gustafsson B, et al. Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells. Leukemia. 2007;21:1733-38.

8. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815-22.

9. Maitra B, Szekely E, Gjini K, Laughlin MJ, Dennis J, Haynesworth SE, and Koc ON. Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation. Bone Marrow Transplantation. 2004;33:597-604.

10. Eliopoulos N, Stagg J, Lejeune L, Pommey S, and Galipeau J. Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice. Blood. 2005 Dec 15;106(13).

11. Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant. 1995;16:557-64.

12. Fibbe WE and Noort WA. Mesenchymal stem cell and hematopoietic stem cell transplantation. Ann N Y Acad Sci. 2003;996:235-244.

13. Ball LM, Bernardo ME, Roelofs H, et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood. 2007;110:2764-67.

14. Friedenstein AJ, Chailakhyan RK, Gerasimov UV. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet. 1987;20:263-72.

15. Ringden O, Uzunel M, Rasmusson I, et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation. 2006;81:1390-97.

16. Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439-41.

17. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo M, Remberger M, Dini G, Egeler R, Bacigalupo A, Fibbe W, Ringden O. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008 May 10;371.

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Эти клетки улучшают приживление ГСК после аллогенной ТГСК и способствуют репарации тканей мезенхимного происхождения, а также способны модулировать иммунный ответ <em>in vitro</em> и <em>in vivo</em>. В результате, ко-трансплантация аллогенных МСК с аллогенными ГСК гипотетически обладает такими положительными эффектами, как улучшение приживления трансплантата и восстановление баланса внутри иммунной системы. Это обстоятельство может быть использовано как для профилактики РТПХ, так и для лечения острой стероид-резистентной РТПХ или хронической РТПХ. В данном исследовании показано, что на терапию МСК  отвечают более половины пациентов со стероид-резистентной острой РТПХ. </p> <h2>Пациенты и методы</h2> <p class="bodytext"> В исследование включены пациенты от 6 до 53 лет с ОЛЛ (n=9), ОМЛ (n=7), НХЛ (n=3), МДС (n=2) и ХМЛ (n=3), которым в период с октября 2005 по май 2008 была выполнена аллогенная ТГСК от родственного (n=5) или неродственного доноров (n=19). Для приживления ГСК и профилактики острой РТПХ 8 пациентам проведена ко-трансплантация МСК и ГСК. Шестнадцать пациентов получили изолированное введение МСК для лечения стероид-резистентной РТПХ. Десяти пациентам осуществлено одно введение МСК, пять пациентов два введения и один пациент получил три введения МСК. Процесс выделения и культивирования МСК осуществляли в компании «Транс Технологии» (лицензия № 99-01-002224 от 14.07.2005). </p> <h2>Результаты</h2> <p class="bodytext"> В случае выполнения ко-трансплантации приживление лейкоцитов зарегистрировано на 21 день (от 16 до 38), тромбоцитов на 24 день (от 14 до 45). Острую РТПХ 0-I степеней наблюдали в 85,8% ко-трансплантаций, что не требовало дополнительной терапии, острая РТПХ II-IV развилась у 14,2 % пациентов. У всех пациентов хронической РТПХ не было. Инфекционные осложнения зарегистрированы у 2 пациентов (25%). Общая безрецидивная 2,5-летняя выживаемость составила 71%.<br> Результаты применения МСК для терапии РТПХ представлены в таблице 1. </p> <div class="csc-textpic csc-textpic-intext-left-nowrap"> <div class="csc-textpic-imagewrap"> <dl class="csc-textpic-image csc-textpic-firstcol csc-textpic-lastcol" style="width:600px;"> <img width="420" alt="974b56410a.jpg" src="/upload/medialibrary/98f/98f24ae7195f0030c84d9bbad4190557.jpg" height="163" title="974b56410a.jpg"> </dl> </div> </div> <span style="font-size: 17px; font-family: Cuprum, sans-serif; font-weight: bold; line-height: 24px;">Таблица 1. Результаты применения МСК для терапии РТПХ. </span> <h2>Выводы</h2> <p class="bodytext"> 1. Инфузии МСК были безопасны, не сопровождались немедленными реакциями во время введения или отсроченными МСК-ассоциированными токсичностями.<br> 2. Инфузия МСК перед аллоТГСК не влияли на приживление трансплантата ГСК. <br> 3. Инфузия МСК при ко-трансплантации в режиме кондиционирования может предотвратить развитие тяжелых форм острой или хронической РТПХ.<br> 4. Инфузия МСК для лечения резистентной острой РТПХ может быть эффективным у ряда пациентов. <br> 5. Использование МСК перед аллоТГСК не увеличивало частоту рецидивов основного заболевания.<br> 6. Использование МСК более эффективно у пациентов, получивших миелоаблативный режим кондиционирования и профилактику острой РТПХ с применением АЛГ.<br> 7. 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А., Головачева А. А., Бабенко Е. В., Алянский А. Л., Паина О. В., Зубаровская Л. С., Семенова E. В., Полынцев Д. Г., Кругляков П. В., Афанасьев Б. В.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(286) "

Станкевич Ю. А., Головачева А. А., Бабенко Е. В., Алянский А. Л., Паина О. В., Зубаровская Л. С., Семенова E. В., Полынцев Д. Г., Кругляков П. В., Афанасьев Б. В.

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Эти клетки улучшают приживление ГСК после аллогенной ТГСК и способствуют репарации тканей мезенхимного происхождения, а также способны модулировать иммунный ответ <em>in vitro</em> и <em>in vivo</em>. В результате, ко-трансплантация аллогенных МСК с аллогенными ГСК гипотетически обладает такими положительными эффектами, как улучшение приживления трансплантата и восстановление баланса внутри иммунной системы. Это обстоятельство может быть использовано как для профилактики РТПХ, так и для лечения острой стероид-резистентной РТПХ или хронической РТПХ. В данном исследовании показано, что на терапию МСК  отвечают более половины пациентов со стероид-резистентной острой РТПХ. </p> <h2>Пациенты и методы</h2> <p class="bodytext"> В исследование включены пациенты от 6 до 53 лет с ОЛЛ (n=9), ОМЛ (n=7), НХЛ (n=3), МДС (n=2) и ХМЛ (n=3), которым в период с октября 2005 по май 2008 была выполнена аллогенная ТГСК от родственного (n=5) или неродственного доноров (n=19). Для приживления ГСК и профилактики острой РТПХ 8 пациентам проведена ко-трансплантация МСК и ГСК. Шестнадцать пациентов получили изолированное введение МСК для лечения стероид-резистентной РТПХ. Десяти пациентам осуществлено одно введение МСК, пять пациентов два введения и один пациент получил три введения МСК. Процесс выделения и культивирования МСК осуществляли в компании «Транс Технологии» (лицензия № 99-01-002224 от 14.07.2005). </p> <h2>Результаты</h2> <p class="bodytext"> В случае выполнения ко-трансплантации приживление лейкоцитов зарегистрировано на 21 день (от 16 до 38), тромбоцитов на 24 день (от 14 до 45). Острую РТПХ 0-I степеней наблюдали в 85,8% ко-трансплантаций, что не требовало дополнительной терапии, острая РТПХ II-IV развилась у 14,2 % пациентов. У всех пациентов хронической РТПХ не было. Инфекционные осложнения зарегистрированы у 2 пациентов (25%). Общая безрецидивная 2,5-летняя выживаемость составила 71%.<br> Результаты применения МСК для терапии РТПХ представлены в таблице 1. </p> <div class="csc-textpic csc-textpic-intext-left-nowrap"> <div class="csc-textpic-imagewrap"> <dl class="csc-textpic-image csc-textpic-firstcol csc-textpic-lastcol" style="width:600px;"> <img width="420" alt="974b56410a.jpg" src="/upload/medialibrary/98f/98f24ae7195f0030c84d9bbad4190557.jpg" height="163" title="974b56410a.jpg"> </dl> </div> </div> <span style="font-size: 17px; font-family: Cuprum, sans-serif; font-weight: bold; line-height: 24px;">Таблица 1. Результаты применения МСК для терапии РТПХ. </span> <h2>Выводы</h2> <p class="bodytext"> 1. Инфузии МСК были безопасны, не сопровождались немедленными реакциями во время введения или отсроченными МСК-ассоциированными токсичностями.<br> 2. Инфузия МСК перед аллоТГСК не влияли на приживление трансплантата ГСК. <br> 3. Инфузия МСК при ко-трансплантации в режиме кондиционирования может предотвратить развитие тяжелых форм острой или хронической РТПХ.<br> 4. Инфузия МСК для лечения резистентной острой РТПХ может быть эффективным у ряда пациентов. <br> 5. Использование МСК перед аллоТГСК не увеличивало частоту рецидивов основного заболевания.<br> 6. Использование МСК более эффективно у пациентов, получивших миелоаблативный режим кондиционирования и профилактику острой РТПХ с применением АЛГ.<br> 7. Необходимо проведение дальнейших рандомизированных клинических исследований для оценки терапевтического эффекта МСК у пациентов после аллоТГСК и определения факторов, оказывающих влияние на эффективность МСК терапии. </p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6192) "

Резюме

Введение

Костный мозг человека содержит гемопоэтические стволовые клетки (ГСК) и негемопоэтические стволовые клетки, называемые мезенхимными стволовыми клетками (МСК). Эти клетки улучшают приживление ГСК после аллогенной ТГСК и способствуют репарации тканей мезенхимного происхождения, а также способны модулировать иммунный ответ in vitro и in vivo. В результате, ко-трансплантация аллогенных МСК с аллогенными ГСК гипотетически обладает такими положительными эффектами, как улучшение приживления трансплантата и восстановление баланса внутри иммунной системы. Это обстоятельство может быть использовано как для профилактики РТПХ, так и для лечения острой стероид-резистентной РТПХ или хронической РТПХ. В данном исследовании показано, что на терапию МСК  отвечают более половины пациентов со стероид-резистентной острой РТПХ.

Пациенты и методы

В исследование включены пациенты от 6 до 53 лет с ОЛЛ (n=9), ОМЛ (n=7), НХЛ (n=3), МДС (n=2) и ХМЛ (n=3), которым в период с октября 2005 по май 2008 была выполнена аллогенная ТГСК от родственного (n=5) или неродственного доноров (n=19). Для приживления ГСК и профилактики острой РТПХ 8 пациентам проведена ко-трансплантация МСК и ГСК. Шестнадцать пациентов получили изолированное введение МСК для лечения стероид-резистентной РТПХ. Десяти пациентам осуществлено одно введение МСК, пять пациентов два введения и один пациент получил три введения МСК. Процесс выделения и культивирования МСК осуществляли в компании «Транс Технологии» (лицензия № 99-01-002224 от 14.07.2005).

Результаты

В случае выполнения ко-трансплантации приживление лейкоцитов зарегистрировано на 21 день (от 16 до 38), тромбоцитов на 24 день (от 14 до 45). Острую РТПХ 0-I степеней наблюдали в 85,8% ко-трансплантаций, что не требовало дополнительной терапии, острая РТПХ II-IV развилась у 14,2 % пациентов. У всех пациентов хронической РТПХ не было. Инфекционные осложнения зарегистрированы у 2 пациентов (25%). Общая безрецидивная 2,5-летняя выживаемость составила 71%.
Результаты применения МСК для терапии РТПХ представлены в таблице 1.

974b56410a.jpg
Таблица 1. Результаты применения МСК для терапии РТПХ. 

Выводы

1. Инфузии МСК были безопасны, не сопровождались немедленными реакциями во время введения или отсроченными МСК-ассоциированными токсичностями.
2. Инфузия МСК перед аллоТГСК не влияли на приживление трансплантата ГСК.
3. Инфузия МСК при ко-трансплантации в режиме кондиционирования может предотвратить развитие тяжелых форм острой или хронической РТПХ.
4. Инфузия МСК для лечения резистентной острой РТПХ может быть эффективным у ряда пациентов.
5. Использование МСК перед аллоТГСК не увеличивало частоту рецидивов основного заболевания.
6. Использование МСК более эффективно у пациентов, получивших миелоаблативный режим кондиционирования и профилактику острой РТПХ с применением АЛГ.
7. Необходимо проведение дальнейших рандомизированных клинических исследований для оценки терапевтического эффекта МСК у пациентов после аллоТГСК и определения факторов, оказывающих влияние на эффективность МСК терапии.

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Stankevich Y.1, Golovacheva A.1, Babenko E.1, Alyansky A.1, Paina O.1, Zubarovskaya L.1, Semenova E.1, Polintsev D.2,
Kruglyakov P.2, Afanasyev B.1

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1Pavlov State Medical University, St. Petersburg, Russia;
2"TransTechnology" LtD, St. Petersburg, Russia

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Summary

Within bone marrow stroma, there exist subsets of nonhematopoietic cells referred to as mesenchymal stem cells (MSCs), or mesenchymal stromal cells [1]. These cells may not only improve HSC engraftment and regeneration of damaged tissues after allogeneic transplantation [7], but also modulate immune responses in vitro and in vivo [8]. Hence, co-transplantation of allogeneic HSC together with allogeneic MSC hypothetically could provide some beneficial effects, such as enhanced engraftment, acceleration of immune reconstitution [4], GVHD suppression, and it may be used for GVHD prophylaxis, like as for treatment of severe acute or chronic GVHD. This study shows that more than a half of the patients with steroid-refractory acute GVHD responded to treatment with MSCs. However, further randomized clinical trials are necessary for estimation of therapeutic effect of MSCs in allo-HSCT patients and definition of important and significant factors influenced upon MSCs infusion.

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Stankevich Y.1, Golovacheva A.1, Babenko E.1, Alyansky A.1, Paina O.1, Zubarovskaya L.1, Semenova E.1, Polintsev D.2,
Kruglyakov P.2, Afanasyev B.1

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Stankevich Y.1, Golovacheva A.1, Babenko E.1, Alyansky A.1, Paina O.1, Zubarovskaya L.1, Semenova E.1, Polintsev D.2,
Kruglyakov P.2, Afanasyev B.1

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Summary

Within bone marrow stroma, there exist subsets of nonhematopoietic cells referred to as mesenchymal stem cells (MSCs), or mesenchymal stromal cells [1]. These cells may not only improve HSC engraftment and regeneration of damaged tissues after allogeneic transplantation [7], but also modulate immune responses in vitro and in vivo [8]. Hence, co-transplantation of allogeneic HSC together with allogeneic MSC hypothetically could provide some beneficial effects, such as enhanced engraftment, acceleration of immune reconstitution [4], GVHD suppression, and it may be used for GVHD prophylaxis, like as for treatment of severe acute or chronic GVHD. This study shows that more than a half of the patients with steroid-refractory acute GVHD responded to treatment with MSCs. However, further randomized clinical trials are necessary for estimation of therapeutic effect of MSCs in allo-HSCT patients and definition of important and significant factors influenced upon MSCs infusion.

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Summary

Within bone marrow stroma, there exist subsets of nonhematopoietic cells referred to as mesenchymal stem cells (MSCs), or mesenchymal stromal cells [1]. These cells may not only improve HSC engraftment and regeneration of damaged tissues after allogeneic transplantation [7], but also modulate immune responses in vitro and in vivo [8]. Hence, co-transplantation of allogeneic HSC together with allogeneic MSC hypothetically could provide some beneficial effects, such as enhanced engraftment, acceleration of immune reconstitution [4], GVHD suppression, and it may be used for GVHD prophylaxis, like as for treatment of severe acute or chronic GVHD. This study shows that more than a half of the patients with steroid-refractory acute GVHD responded to treatment with MSCs. However, further randomized clinical trials are necessary for estimation of therapeutic effect of MSCs in allo-HSCT patients and definition of important and significant factors influenced upon MSCs infusion.

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1Pavlov State Medical University, St. Petersburg, Russia;
2"TransTechnology" LtD, St. Petersburg, Russia

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1Pavlov State Medical University, St. Petersburg, Russia;
2"TransTechnology" LtD, St. Petersburg, Russia

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Станкевич Ю. А., Головачева А. А., Бабенко Е. В., Алянский А. Л., Паина О. В., Зубаровская Л. С., Семенова E. В., Полынцев Д. Г., Кругляков П. В., Афанасьев Б. В.

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Станкевич Ю. А., Головачева А. А., Бабенко Е. В., Алянский А. Л., Паина О. В., Зубаровская Л. С., Семенова E. В., Полынцев Д. Г., Кругляков П. В., Афанасьев Б. В.

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["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(4) { [0]=> string(5) "10703" [1]=> string(5) "10704" [2]=> string(5) "10705" [3]=> string(5) "10706" } ["VALUE"]=> array(4) { [0]=> string(2) "15" [1]=> string(3) "464" [2]=> string(3) "465" [3]=> string(2) "83" } ["DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(4) { [0]=> string(2) "15" [1]=> string(3) "464" [2]=> string(3) "465" [3]=> string(2) "83" } ["~DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> array(4) { [0]=> string(134) "трансплантация гемопоэтических стволовых клеток" [1]=> string(65) "острая РТПХ" [2]=> string(75) "хроническая РТПХ" [3]=> string(97) "мезенхимные стволовые клетки" } ["LINK_ELEMENT_VALUE"]=> bool(false) } ["CONTACT"]=> array(38) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "5240" ["VALUE"]=> string(3) "459" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(3) "459" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(56) "Stankevich Y." ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "5252" ["VALUE"]=> array(2) { ["TEXT"]=> string(6560) "<h2>Резюме</h2> <h2>Введение </h2> <p class="bodytext"> Костный мозг человека содержит гемопоэтические стволовые клетки (ГСК) и негемопоэтические стволовые клетки, называемые мезенхимными стволовыми клетками (МСК). Эти клетки улучшают приживление ГСК после аллогенной ТГСК и способствуют репарации тканей мезенхимного происхождения, а также способны модулировать иммунный ответ <em>in vitro</em> и <em>in vivo</em>. В результате, ко-трансплантация аллогенных МСК с аллогенными ГСК гипотетически обладает такими положительными эффектами, как улучшение приживления трансплантата и восстановление баланса внутри иммунной системы. Это обстоятельство может быть использовано как для профилактики РТПХ, так и для лечения острой стероид-резистентной РТПХ или хронической РТПХ. В данном исследовании показано, что на терапию МСК  отвечают более половины пациентов со стероид-резистентной острой РТПХ. </p> <h2>Пациенты и методы</h2> <p class="bodytext"> В исследование включены пациенты от 6 до 53 лет с ОЛЛ (n=9), ОМЛ (n=7), НХЛ (n=3), МДС (n=2) и ХМЛ (n=3), которым в период с октября 2005 по май 2008 была выполнена аллогенная ТГСК от родственного (n=5) или неродственного доноров (n=19). Для приживления ГСК и профилактики острой РТПХ 8 пациентам проведена ко-трансплантация МСК и ГСК. Шестнадцать пациентов получили изолированное введение МСК для лечения стероид-резистентной РТПХ. Десяти пациентам осуществлено одно введение МСК, пять пациентов два введения и один пациент получил три введения МСК. Процесс выделения и культивирования МСК осуществляли в компании «Транс Технологии» (лицензия № 99-01-002224 от 14.07.2005). </p> <h2>Результаты</h2> <p class="bodytext"> В случае выполнения ко-трансплантации приживление лейкоцитов зарегистрировано на 21 день (от 16 до 38), тромбоцитов на 24 день (от 14 до 45). Острую РТПХ 0-I степеней наблюдали в 85,8% ко-трансплантаций, что не требовало дополнительной терапии, острая РТПХ II-IV развилась у 14,2 % пациентов. У всех пациентов хронической РТПХ не было. Инфекционные осложнения зарегистрированы у 2 пациентов (25%). Общая безрецидивная 2,5-летняя выживаемость составила 71%.<br> Результаты применения МСК для терапии РТПХ представлены в таблице 1. </p> <div class="csc-textpic csc-textpic-intext-left-nowrap"> <div class="csc-textpic-imagewrap"> <dl class="csc-textpic-image csc-textpic-firstcol csc-textpic-lastcol" style="width:600px;"> <img width="420" alt="974b56410a.jpg" src="/upload/medialibrary/98f/98f24ae7195f0030c84d9bbad4190557.jpg" height="163" title="974b56410a.jpg"> </dl> </div> </div> <span style="font-size: 17px; font-family: Cuprum, sans-serif; font-weight: bold; line-height: 24px;">Таблица 1. Результаты применения МСК для терапии РТПХ. </span> <h2>Выводы</h2> <p class="bodytext"> 1. Инфузии МСК были безопасны, не сопровождались немедленными реакциями во время введения или отсроченными МСК-ассоциированными токсичностями.<br> 2. Инфузия МСК перед аллоТГСК не влияли на приживление трансплантата ГСК. <br> 3. Инфузия МСК при ко-трансплантации в режиме кондиционирования может предотвратить развитие тяжелых форм острой или хронической РТПХ.<br> 4. Инфузия МСК для лечения резистентной острой РТПХ может быть эффективным у ряда пациентов. <br> 5. Использование МСК перед аллоТГСК не увеличивало частоту рецидивов основного заболевания.<br> 6. Использование МСК более эффективно у пациентов, получивших миелоаблативный режим кондиционирования и профилактику острой РТПХ с применением АЛГ.<br> 7. Необходимо проведение дальнейших рандомизированных клинических исследований для оценки терапевтического эффекта МСК у пациентов после аллоТГСК и определения факторов, оказывающих влияние на эффективность МСК терапии. </p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6192) "

Резюме

Введение

Костный мозг человека содержит гемопоэтические стволовые клетки (ГСК) и негемопоэтические стволовые клетки, называемые мезенхимными стволовыми клетками (МСК). Эти клетки улучшают приживление ГСК после аллогенной ТГСК и способствуют репарации тканей мезенхимного происхождения, а также способны модулировать иммунный ответ in vitro и in vivo. В результате, ко-трансплантация аллогенных МСК с аллогенными ГСК гипотетически обладает такими положительными эффектами, как улучшение приживления трансплантата и восстановление баланса внутри иммунной системы. Это обстоятельство может быть использовано как для профилактики РТПХ, так и для лечения острой стероид-резистентной РТПХ или хронической РТПХ. В данном исследовании показано, что на терапию МСК  отвечают более половины пациентов со стероид-резистентной острой РТПХ.

Пациенты и методы

В исследование включены пациенты от 6 до 53 лет с ОЛЛ (n=9), ОМЛ (n=7), НХЛ (n=3), МДС (n=2) и ХМЛ (n=3), которым в период с октября 2005 по май 2008 была выполнена аллогенная ТГСК от родственного (n=5) или неродственного доноров (n=19). Для приживления ГСК и профилактики острой РТПХ 8 пациентам проведена ко-трансплантация МСК и ГСК. Шестнадцать пациентов получили изолированное введение МСК для лечения стероид-резистентной РТПХ. Десяти пациентам осуществлено одно введение МСК, пять пациентов два введения и один пациент получил три введения МСК. Процесс выделения и культивирования МСК осуществляли в компании «Транс Технологии» (лицензия № 99-01-002224 от 14.07.2005).

Результаты

В случае выполнения ко-трансплантации приживление лейкоцитов зарегистрировано на 21 день (от 16 до 38), тромбоцитов на 24 день (от 14 до 45). Острую РТПХ 0-I степеней наблюдали в 85,8% ко-трансплантаций, что не требовало дополнительной терапии, острая РТПХ II-IV развилась у 14,2 % пациентов. У всех пациентов хронической РТПХ не было. Инфекционные осложнения зарегистрированы у 2 пациентов (25%). Общая безрецидивная 2,5-летняя выживаемость составила 71%.
Результаты применения МСК для терапии РТПХ представлены в таблице 1.

974b56410a.jpg
Таблица 1. Результаты применения МСК для терапии РТПХ. 

Выводы

1. Инфузии МСК были безопасны, не сопровождались немедленными реакциями во время введения или отсроченными МСК-ассоциированными токсичностями.
2. Инфузия МСК перед аллоТГСК не влияли на приживление трансплантата ГСК.
3. Инфузия МСК при ко-трансплантации в режиме кондиционирования может предотвратить развитие тяжелых форм острой или хронической РТПХ.
4. Инфузия МСК для лечения резистентной острой РТПХ может быть эффективным у ряда пациентов.
5. Использование МСК перед аллоТГСК не увеличивало частоту рецидивов основного заболевания.
6. Использование МСК более эффективно у пациентов, получивших миелоаблативный режим кондиционирования и профилактику острой РТПХ с применением АЛГ.
7. Необходимо проведение дальнейших рандомизированных клинических исследований для оценки терапевтического эффекта МСК у пациентов после аллоТГСК и определения факторов, оказывающих влияние на эффективность МСК терапии.

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Резюме

Введение

Костный мозг человека содержит гемопоэтические стволовые клетки (ГСК) и негемопоэтические стволовые клетки, называемые мезенхимными стволовыми клетками (МСК). Эти клетки улучшают приживление ГСК после аллогенной ТГСК и способствуют репарации тканей мезенхимного происхождения, а также способны модулировать иммунный ответ in vitro и in vivo. В результате, ко-трансплантация аллогенных МСК с аллогенными ГСК гипотетически обладает такими положительными эффектами, как улучшение приживления трансплантата и восстановление баланса внутри иммунной системы. Это обстоятельство может быть использовано как для профилактики РТПХ, так и для лечения острой стероид-резистентной РТПХ или хронической РТПХ. В данном исследовании показано, что на терапию МСК  отвечают более половины пациентов со стероид-резистентной острой РТПХ.

Пациенты и методы

В исследование включены пациенты от 6 до 53 лет с ОЛЛ (n=9), ОМЛ (n=7), НХЛ (n=3), МДС (n=2) и ХМЛ (n=3), которым в период с октября 2005 по май 2008 была выполнена аллогенная ТГСК от родственного (n=5) или неродственного доноров (n=19). Для приживления ГСК и профилактики острой РТПХ 8 пациентам проведена ко-трансплантация МСК и ГСК. Шестнадцать пациентов получили изолированное введение МСК для лечения стероид-резистентной РТПХ. Десяти пациентам осуществлено одно введение МСК, пять пациентов два введения и один пациент получил три введения МСК. Процесс выделения и культивирования МСК осуществляли в компании «Транс Технологии» (лицензия № 99-01-002224 от 14.07.2005).

Результаты

В случае выполнения ко-трансплантации приживление лейкоцитов зарегистрировано на 21 день (от 16 до 38), тромбоцитов на 24 день (от 14 до 45). Острую РТПХ 0-I степеней наблюдали в 85,8% ко-трансплантаций, что не требовало дополнительной терапии, острая РТПХ II-IV развилась у 14,2 % пациентов. У всех пациентов хронической РТПХ не было. Инфекционные осложнения зарегистрированы у 2 пациентов (25%). Общая безрецидивная 2,5-летняя выживаемость составила 71%.
Результаты применения МСК для терапии РТПХ представлены в таблице 1.

974b56410a.jpg
Таблица 1. Результаты применения МСК для терапии РТПХ. 

Выводы

1. Инфузии МСК были безопасны, не сопровождались немедленными реакциями во время введения или отсроченными МСК-ассоциированными токсичностями.
2. Инфузия МСК перед аллоТГСК не влияли на приживление трансплантата ГСК.
3. Инфузия МСК при ко-трансплантации в режиме кондиционирования может предотвратить развитие тяжелых форм острой или хронической РТПХ.
4. Инфузия МСК для лечения резистентной острой РТПХ может быть эффективным у ряда пациентов.
5. Использование МСК перед аллоТГСК не увеличивало частоту рецидивов основного заболевания.
6. Использование МСК более эффективно у пациентов, получивших миелоаблативный режим кондиционирования и профилактику острой РТПХ с применением АЛГ.
7. Необходимо проведение дальнейших рандомизированных клинических исследований для оценки терапевтического эффекта МСК у пациентов после аллоТГСК и определения факторов, оказывающих влияние на эффективность МСК терапии.

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Introduction

Multiple sclerosis is a chronic inflammatory disorder of the central nervous system (CNS) caused by autoimmune reactivity of T cells towards CNS myelin components. MS progression inevitably leads to the loss of motor function, sensitive disturbances and cognitive impairment because of the immune-mediated demyelination and axon degeneration [1].

MS is one of the most common neurological disorders, which mainly affects young adults, and causes gradual decrease of their quality of life (QoL). The clinical course of the disease is very heterogeneous. However, it typically presents with a relapsing-remitting course (RRMS; 80% of patients), which is followed after 5–15 years in about 70% of patients by a so-called secondary progressive phase (SPMS) [2]. 10–20% of patients have a primary progressive course, which is characterized by a steady progression from the onset with or without any acute exacerbations (progressive relapsing MS or PRMS, and primary progressive MS or PPMS, respectively).

Conventional therapies do not provide satisfactory control of MS due to their inability to eradicate self-specific T cell clones. Recently, HDCT+auto-HSCT was proposed as a new and promising therapy for MS patients [3,4]. HDCT+auto-HSCT leads to the elimination of autoreactive T cells and, subsequently, to the restoration of a normal immune system.

Since 1995, several clinical studies have addressed the issue of feasibility and efficacy of HDCT+auto-HSCT in MS [3-15]. However, the information about long-term effects of HDCT+auto-HSCT in this patient population is scanty. In addition, the majority of patients included in the above-mentioned studies had SPMS, and were severely disabled with an average EDSS score of 6.5. Unfortunately, even complete suppression of autoimmune inflammation does not lead to a significant improvement of QoL in these patients. Therefore, the patient selection criteria for HDCT+auto-HSCT are still unclear and the proper selection of patients for transplantation remains the key issue.

Another important consideration is the selection of appropriate criteria for the assessment of treatment outcomes for MS patients. Both disease-free period and improvement of patient’s QoL are recognized as important outcome parameters. With this in mind, evaluation of both clinical and patient-reported outcomes in MS patients after HDCT+auto-HSCT is worthwhile. However, neurologists traditionally evaluate the clinical response only and rarely use QoL data in the outcome analysis. This may be partly explained by the fact that QoL questionnaires used for MS patients – both generic and specific – are multidimensional, and the interpretation of changes in several QoL scales/domains might be difficult for physicians. Recently, we have developed an approach to obtain an Integral QoL Index (IQLI) for profile questionnaires (both generic and specific). IQLI is a standardized value based on the properties of a geometric profile formed by the scales of a questionnaire, which is assessed by the method of integral profiles; the index has been validated in different patients’ populations [16]. The advantages of IQLI are its ease of use and the possibility of obtaining one index based on several QoL scales. The use of IQLI makes it possible to overcome the difficulties in the interpretation of QoL data and allows the assessment of patient-reported outcomes, namely the QoL response.

To date, some limited information exists on the clinical response of MS patients to HDCT+auto-SCT at long-term follow-up, whereas the data on QoL response is lacking. In addition, the clinical experience in the application of HDCT+auto-HSCT to various types and stages of MS is very limited. Moreover, the timing for transplantation is still unclear.

We report the follow-up results of a prospective Phase II multicenter trial, which was started in 1999 and has since then been conducted by the Russian Cooperative Group for Cellular Therapy. This study is focused on the efficacy of HDCT+auto-HSCT in terms of clinical and quality of life responses in patients with different types and stages of MS.

Patients and Methods

One hundred and nine patients were enrolled in the study. Patient characteristics are shown in Table 1. 

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Table 1. Demographic and clinical profile of the patient population.  All patients were refractory to conventional therapy, which included IFNβ and mitoxantrone, as well as steroids, azathiopine, intravenous immunoglobulin and plasmapheresis in some patients. The mean follow-up was 19 months (range, 6–108 months).

The trial was conducted according to the principles of the Helsinki Declaration, and approved by the IRB and Ethics Committees of all of the participating centers before initiation. All patients gave written informed consent.

The neurological disability of MS patients is quantified according to the Expanded disability status scale (EDSS) [17]. The EDSS scores range from 0 (no disability) to 10 (death related to neurological progression) in 0.5-step increments. EDSS scores from 1.0 to 4.5 refer to the fully ambulatory MS patients, while patients with EDSS scores of 7.0 are essentially restricted to a wheelchair.

Patient Eligibility

Criteria for patient selection were: age between 18 and 55 years; diagnosis of multiple sclerosis verified by clinical and laboratory findings; EDSS score 1.5–8.0; normal mental status; absence of severe concomitant diseases.

The disease activity was determined either by magnetic resonance imaging scans displaying active lesions in the CNS (i.e., gadolinium-enhancing lesions, new or enlarging lesions on serial scans) or by clinical assessment showing rapid neurological deterioration, e.g., 0.5-point increase on the EDSS during the 6-months preceding enrollment.

According to our concept there are 3 strategies of HDCT+auto-HSCT [18]. Early HSCT (in MS patients with EDSS 1.5–3.0) is performed soon after diagnosis in case of primary refractory disease or poor prognosis. Conventional HSCT (EDSS 3.5–6.5) is performed in patients with secondary refractory disease. Salvage HSCT (EDSS 7.0–8.0) is an option in case of high disease activity and rapid neurological deterioration in late stages of the disease. All three strategies were applied in this study (Table 2).

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Table 2. HSCT timing in the studied patient population

Stem Cell Mobilization and Transplant Procedure

Hematopoietic stem cells were mobilized with G-CSF at 10 μg/kg +/- cyclophosphamide at 4 g/m2 according to EBMT/EULAR guidelines [19]. The grafts were not manipulated. BEAM or BEAM-modified conditioning was used. The BEAM conditioning regimen included BCNU (300 mg/m2) on day -6, etoposide (200 mg/m2) from day -5 to day -2, cytarabine (200 mg/m2 bd) from day -5 to day -2 and melphalan (140 mg/m2) on day -1. It was followed by autologous hematopoietic stem cell transplantation (day 0). In vivo T cell-depletion was achieved through infusion of 30 mg/kg of horse anti-thymocyte globulin (ATG) on days 1 and 2. Five μg/kg s.c. of G-CSF were administered from day 3 post-infusion until granulocyte recovery. For infection prophylaxis oral ciprofloxacin, fluconazole, acyclovir, and IV human Ig were given.

Neurological and QoL assessments

Clinical and QoL assessments were performed at baseline, at discharge, at 3, 6, 9, and 12 months after transplantation, every 6 months thereafter up to 48 months, and then at yearly intervals. Neurological assessment included EDSS score and MRI examinations. QoL was assessed by the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) questionnaire and the Functional Assessment of Multiple Sclerosis (FAMS) questionnaire. The FACT-BMT is a self-administered instrument designed to assess multidimensional aspects of QoL in BMT patients [20]. It consists of the 27-item FACT-General and the 23-item Bone Marrow Transplantation Subscale (BMTS). The FAMS is a disease-specific questionnaire for QoL assessment in MS patients [21]. It consists of 58 questions and contains 7 scales: mobility, symptoms, emotional well-being, general contentment, thinking and fatigue, family/social well-being, and additional concerns.

Definition of response to treatment

According to the EBMT criteria of response, patients with either steady EDSS scores representing a halt of disease progression, or with improved EDSS scores representing subsidence of inflammation in the CNS were regarded as responding to treatment [4,8]. Clinical improvement was defined as a ≥0.5 point decrease in EDSS score as compared to the baseline. Progression was defined as an increase of at least 0.5 points. Both had to be confirmed after 6 months. Clinical relapse was defined as the appearance of new symptoms or worsening of old symptoms of at least 24-hour duration, in the absence of fever in a previously (4 weeks) stable patient.

QoL was assessed by calculating the Integral QoL Index (IQLI) value at different time points on the basis of FACT-BMT questionnaire scores, as described previously [14]. Less than 25% improvement in IQLI compared to the baseline value was considered a minimal QoL response; 25–50% improvement a moderate QoL response; 51–75% improvement a good QoL response; and more than 75% improvement a maximal QoL response.

Results

Adverse events

No toxic deaths were reported among the 109 MS patients , irrespective of their clinical condition at the time of transplant. The transplantation procedure was well tolerated by the patients. Mobilization was successful in all cases, with a median number of 2.1 x106/kg (range 1.5–5.5 x106/kg) collected CD34+ cells. and no major clinical adverse events were observed during this phase. Unmanipulated grafts were infused without complications. Engraftment was uneventful, and no signs of an engraftment syndrome were reported. Median days with PMN< 0.5x109 and Plt < 50x109 were 8 (range from 5 to 11) and 10 days (from 2 to 26), respectively.

Common adverse effects following the immunoablative regimen were thrombocytopenia (100%), neutropenia (100%), fatigue (100%), anemia (80%), alopecia (80%), neutropenic fever (51.6%), hepatic toxicity grade I and II (48.1%), transient neurological dysfunction (22.2%), enteropathy (18.5%). Documented sepsis was registered in one patient.

Clinical outcomes

Seventy-nine patients with the follow-up period of at least 9 months or longer were included in the clinical outcome analysis (Table 3).

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Table 3. Efficacy of HDCT+auto-HSCT in MS patients

All patients responded to the treatment. At 6 months post-transplant the following distribution of patients according to clinical response was observed: 42 patients (53%) achieved an objective improvement of neurological symptoms (defined as a ≥0.5 point decrease in the EDSS score as compared to the baseline and confirmed over 3 months): 20 SPMS; 11 RRMS; 4 PRMS, and 7 PPMS. Thirty-seven patients (47%) had disease stabilization (steady EDSS level as compared to the baseline and confirmed over 3 months): 19 SPMS; 8 RRMS; 2 PRMS, and 8 PPMS. Among the patients with improvement there were 25 patients after conventional HDCT+auto-HSCT, 15 after early HDCT+auto-HSCT, and 2 after salvage HDCT+auto-HSCT. Among the patients with stabilization there were 23 patients after conventional HDCT+auto-HSCT, 9 after early HDCT+auto-HSCT, and 5 after salvage HDCT+auto-HSCT. At long-term follow-up, the clinical response in 40 patients (50.6%) was classified as an improvement; 34 patients (43.1%) remained stable. Two patients deteriorated to a worse score after 18 months of stabilization (SPMS and PPMS; conventional auto-HSCT), and one patient after 6 months of stabilization (SPMS, conventional auto-HSCT); 2 others progressed after 12 and 30 months of improvement (RRMS, early auto-HSCT and SPMM, conventional auto-HSCT, respectively). No active, new or enlarging lesions were registered in patients without disease progression.

Remarkably, nine patients improved dramatically (≥1.5 point by EDSS). Patients with different types of MS were observed in this group. As an illustration, in a SPMS patient with the baseline EDSS value of 6.0 we observed a 2.0 point decrease on the EDSS scale at 1 month post-transplant, an additional 1.5 point decrease at 6 months and stabilization with EDSS score of 1.5 at 18 months post-transplant. In another case, a RRMS patient with a base-line EDSS score of 4.5 experienced a decrease in EDSS to 2.0 at 1 month post-transplant with a further decrease to 1.0 at 3 months. The latter EDSS level remained stable throughout the entire follow-up period of 1.5 years. The PRMS patient with baseline EDSS value of 6.0 improved at 3 months to EDSS of 4.5, and then showed further improvement at 30 months post-transplant to the EDSS score of 4.0. The EDSS score at the end of follow-up (6.5 years post-transplant) was 3.5. Finally, the PPMS patient with severe disease (EDSS score of 7.5) had a 1.5-point EDSS decrease and maintained this score during the 3.5 years of follow-up.

The progression-free survival at 6 years after HDCT+auto-HSCT was 72% (Figure 1). Remarkably, all patients who did not have disease progression were off therapy throughout the post-transplant period.

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Figure 1. Progression-free survival after HDCT+auto-HSCT. Probability of progression-free survival in 42 MS patients. Estimated progression-free survival is 72% at 6 years.

QoL outcomes

QoL monitoring and assessment of QoL response were performed in 44 patients. Forty patients exhibited improved QoL at 6 months post-transplant. An increase in QoL parameters was observed according to both FACT-BMT and FAMS questionnaires. Notably, the patient who progressed 18 months after transplantation (SPMS) exhibited no QoL response. Despite clinical disease stabilization, his QoL gradually deteriorated.

In another case, a QoL deterioration was observed in a PPMS patient at 6 months post-transplant in spite of clinical stabilization during the 18 months after transplantation. It is worth mentioning that the patient (RRMS) who experienced relapse at 2.5 years post-transplant experienced a significant QoL decrease 2 years after transplantation.

The distribution of patients according to the grades of QoL response one year after HDCT+auto-HSCT is presented in Table 4.

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Table 4. Distribution of MS patients according to the grades of QoL response at 1 year after HDCT+auto-HSCT(n=44). As is seen in the table, 3 patients exhibited a maximal QoL response, 12 patients a good QoL response, 11 patients a moderate QoL response, 13 patients a minimal QoL response, and 5 patients no QoL response. Remarkably, patients with a longer follow-up experienced further QoL improvement.


Figure 2 demonstrates the QoL profiles of two MS patients (patient A, a 21-year-old female, PRMS, base-line EDSS 6.0; patient B, a 35-year-old female, SPMS, base-line EDSS 5.0) with the long-term follow-up after HDCT+auto-HSCT.

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Figure 2. Quality of life profiles of patient A(a) and patient B (b) at different time points after HDCT+auto-HSCT.

In both patients the QoL parameters improved dramatically at 1 year after HDCT+auto-HSCT.

Improved QoL profiles were preserved throughout the 8-year QoL monitoring of patient A, and the 9-year QoL monitoring of patient B.

Of special interest is the dynamics of QoL profiles of patient A (Figure 2a).

Six months after transplantation an improvement was observed in this patient, which led to the formation of a significantly less compressed and less deformed QoL profile as compared to the baseline.

Further QoL improvement took place at different time points during the 8-year follow-up.

Discussion

Since 1995, HDCT+auto-HSCT has been performed in more than 600 MS patients all over the world. Published clinical results demonstrate that this approach can stop the disease progression in a majority of patients. A comprehensive analysis of the EBMT registry data of 85 patients from 20 centers published by EBMT ADWP in 2002, showed no disease progression for 3 years in 74% of patients [4]. Similar results were obtained in five US studies that included 66 patients in total [6,11]. Remarkably, transplant-related mortality in MS patients does not exceed transplant-related mortality in hematological patients (0–4%).

The results our study have also demonstrated the benefits of HDCT+auto-HSCT in MS. We have included 109 patients with various types of MS from 6 centers affiliated with the Russian Cooperative Group for Cellular Therapy. The transplantation procedure was well tolerated by patients with no transplant-related deaths at all. The efficacy analysis was performed in 79 patients monitored for more than 1 year. All the patients responded to treatment: in 42 patients the EDSS score decreased after HDCT+auto-HSCT as compared to the base-line and was confirmed over 6 months, while disease stabilization (stable EDSS after transplantation confirmed over 6 months) was registered in 37 patients. The majority of patients had either moderate or good QoL responses as well. This data strongly supports the use of HDCT+auto-HSCT as the therapy of choice in autoimmune diseases with imminent patient debilitation, such as MS. 

It is worth mentioning that the issues surrounding the patient selection criteria for HDCT+auto-HSCT are still unclear. The advantage of our study is that we included patients with different types of MS. In spite of some evidence that PPMS patients are less responsive to HDCT+auto-HSCT as compared to both SPMS and RRMS [8], the information about the outcomes of HSCT in patients with various types of MS is limited. The results of our study confirm that transplantation is effective in PPMS patients, and patients with different types of MS might benefit from HDCT+auto-HSCT.

Another advantage of our study is the performance of early, conventional or salvage transplantation, while most patients in the previous studies had late stages of MS.

Our data supports the idea that HDCT+auto-HSCT is more effective in young patients with early stages of rapidly progressing disease. In these patients, autoreactive T cells play a pivotal role in MS pathogenesis. HDCT ablates the patient's immune system and eradicates autoimmune T cells. It is followed by HSCT to restore the immune system, which is expected to become tolerant to autoantigens. Such "resetting" of the immune system is only effective at early stages of MS, particularly in relapsing-remitting MS. Later in the clinical course of the disease, processes of axonal degeneration prevail, and the damage to CNS tissue is too significant to expect a neurological recovery after HDCT+auto-HSCT. Indeed, the failure of HDCT+auto-HSCT to prevent progression of the disease when performed in the late stages has been demonstrated in both animal models [22] and in clinical studies [1,11]. Considering the clinical heterogeneity of MS patients, we propose a classification of transplantation approaches based on the concept of HDCT+auto-HSCT in MS (Table 5). The concept focuses on the goals of MS treatment. There are two goals in the treatment of MS patients. The first is pathogenetic, which is to stop the disease progression and prevent the appearance of new lesions in the nervous tissue. The second is to improve or maintain a patient’s QoL. Since MS is incurable and does not shorten the patient’s life span, the QoL improvement should be considered the ultimate goal of MS treatment. Therefore, QoL assessment is the key criterion for the assessment of efficacy of MS treatment in addition to traditional diagnostic tests, which describe the dynamics of the immunopathological process. It is of special importance in patients with late stages of MS.

1b1701b7dc.jpg

Table 5. Classification of HDCT+auto-HSCT in MS patients


In conclusion, our study has demonstrated that HDCT+auto-HSCT may be an effective treatment for various types of MS in terms of clinical and patient-reported outcomes at long-term follow-up. The data obtained points to the feasibility of early, conventional, and salvage HDCT+auto-HSCT in MS patients. Further studies should be done to investigate clinical and QoL response in MS patients receiving early, conventional, and salvage transplantation to better define treatment success. The concept of HDCT+auto-HSCT opens a new window of opportunities for MS treatment.

Acknowledgements

We would like to acknowledge Sergei V. Shamanski (Moscow), Andrei D. Kulagin (Novosibirsk), Nikolay I. Baziy (Moscow), Nina E. Osipova (St.Petersburg), Andrei E. Zdorov (Petrozavodsk), and Anton V. Kishtovich (St.Petersburg) for their contribution to the study.

References

1. Burt RK, Cohen B, Lobck L, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: importance of disease stage on outcome. Neurology. 2003;40 Suppl:A150.

2. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343:938 -952.

3. Burt RK, Cohen B, Rose J, et al. Hematopoietic stem cell transplantation for multiple sclerosis. Arch Neurol. 2005;62:860-864.

4. Fassas A, Anagnostopoulos A, Kazis A, et al. Autologous stem cell transplantation in progressive multiple sclerosis – an interim analysis of efficacy. J Clin Immunol. 2000;20(1):24-30.

5. Brenner MK. Haematopoietic stem cell transplantation for autoimmune disease: limits and future potential. Best Pract Res Clin Haematol. 2004;17:359-374.

6. Burt RK, Cohen BA, Russell E, et al. Hematopoietic stem cell transplantation for progressive multiple sclerosis; failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores. Blood. 2003;102:2373-2378.

7. Fassas A, Nash R. Multiple sclerosis. Best Pract Res Clin Hematol. 2004;17:247-262.

8. Fassas A, Passweg JR, Anagnostopoulos A, et al. Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol. 2002;249:1088-1097.

9. Kozak T, Havrdova E, Pit’ha J, et al. High-dose immunosuppressive therapy with PBPC support in the treatment of poor risk multiple sclerosis. Bone Marrow Transplant. 2000;25:525-531.

10. Muraro PA, McFarland HF, Martin R. Immunological aspects of multiple sclerosis with emphasis on the potential use of autologous hemopoietic stem cell transplantation. In: Burt RK, Marmont AM, eds. Stem Cell Therapy for Autoimmune Disease. Georgetown, TX: Landes Bioscience. 2004;277-283.

11. Nash RA, Bowen JD, McSweeney PA, et al. High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood. 2003;102:2364-2372.

12. Openshaw H, Lund B, Kashyap A, et al. Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning report of toxicity and immunological monitoring. Biology of Blood and  Marrow Transplant. 2000;25:525-575.

13. Saccardi R, Mancardi GL, Solari A, et al. Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life. Blood. 2005;105:2601-2607.

14. Shevchenko Y, Novik A, Ionova T et al. Clinical and quality of life outcomes in patients with multiple sclerosis after high-dose chemotherapy + autologous stem cell transplantation [abstract no. 1875]. Blood. 2004;104:519a.

15. Shevchenko Y, Novik A, Kuznetsov A et al High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Experimental Hematology. 2008;36(8):922-929.

16. Novik A, Ionova T, Bisaga G, et.al. Clinical and Quality of Life Responses to High-Dose Chemotherapy plus Autologous Stem Cell Transplantation in Patients with Multiple Sclerosis: two case reports. Cytotherapy. 2005;7(4):363–367.

17. Kurtzke JF. Rating neurologic impairment in multiple sclerosis; an expanded disability status scale (EDSS). Neurology. 1983;33:1444-52.

18. Shevchenko YL, Novik AA, Ionova TI, et al. Three strategies of high dose chemotherapy + autologous stem cell transplantation in autoimmune diseases. Bone Marrow Transplant. 2004;33 Suppl 1: 346.

19. Tindall A, Gratwohl A. Blood and marrow stem cell transplants in autoimmune disease: A consensus report written on behalf of the European League against Rheumatism (EULAR) and the European Group for Blood and Marrow transplantation (EBMT). Bone Marrow Transplant. 1997;19:643-645.

20. McQuellon RP, Russell GB, Cella DF, et al. Quality of life measurement in bone marrow transplantation; development of the functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) scale. Bone Marrow Transplant. 1997;19:357-368.

21. Cella DF, Dineen K, Arnason B, et al. Validation of the functional assessment of multiple sclerosis quality of life instrument. Neurology. 1996;47:129-139.

22. Burt RK, Padilla J, Begolka WS, et al. Effect of disease stage on clinical outcome after syngeneic bone marrow transplantation for relapsing experimental autoimmune encephalomyelitis. Blood. 1998;91:2609-2616.

© The Authors. This article is provided under the following license: Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 Unported


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Introduction

Multiple sclerosis is a chronic inflammatory disorder of the central nervous system (CNS) caused by autoimmune reactivity of T cells towards CNS myelin components. MS progression inevitably leads to the loss of motor function, sensitive disturbances and cognitive impairment because of the immune-mediated demyelination and axon degeneration [1].

MS is one of the most common neurological disorders, which mainly affects young adults, and causes gradual decrease of their quality of life (QoL). The clinical course of the disease is very heterogeneous. However, it typically presents with a relapsing-remitting course (RRMS; 80% of patients), which is followed after 5–15 years in about 70% of patients by a so-called secondary progressive phase (SPMS) [2]. 10–20% of patients have a primary progressive course, which is characterized by a steady progression from the onset with or without any acute exacerbations (progressive relapsing MS or PRMS, and primary progressive MS or PPMS, respectively).

Conventional therapies do not provide satisfactory control of MS due to their inability to eradicate self-specific T cell clones. Recently, HDCT+auto-HSCT was proposed as a new and promising therapy for MS patients [3,4]. HDCT+auto-HSCT leads to the elimination of autoreactive T cells and, subsequently, to the restoration of a normal immune system.

Since 1995, several clinical studies have addressed the issue of feasibility and efficacy of HDCT+auto-HSCT in MS [3-15]. However, the information about long-term effects of HDCT+auto-HSCT in this patient population is scanty. In addition, the majority of patients included in the above-mentioned studies had SPMS, and were severely disabled with an average EDSS score of 6.5. Unfortunately, even complete suppression of autoimmune inflammation does not lead to a significant improvement of QoL in these patients. Therefore, the patient selection criteria for HDCT+auto-HSCT are still unclear and the proper selection of patients for transplantation remains the key issue.

Another important consideration is the selection of appropriate criteria for the assessment of treatment outcomes for MS patients. Both disease-free period and improvement of patient’s QoL are recognized as important outcome parameters. With this in mind, evaluation of both clinical and patient-reported outcomes in MS patients after HDCT+auto-HSCT is worthwhile. However, neurologists traditionally evaluate the clinical response only and rarely use QoL data in the outcome analysis. This may be partly explained by the fact that QoL questionnaires used for MS patients – both generic and specific – are multidimensional, and the interpretation of changes in several QoL scales/domains might be difficult for physicians. Recently, we have developed an approach to obtain an Integral QoL Index (IQLI) for profile questionnaires (both generic and specific). IQLI is a standardized value based on the properties of a geometric profile formed by the scales of a questionnaire, which is assessed by the method of integral profiles; the index has been validated in different patients’ populations [16]. The advantages of IQLI are its ease of use and the possibility of obtaining one index based on several QoL scales. The use of IQLI makes it possible to overcome the difficulties in the interpretation of QoL data and allows the assessment of patient-reported outcomes, namely the QoL response.

To date, some limited information exists on the clinical response of MS patients to HDCT+auto-SCT at long-term follow-up, whereas the data on QoL response is lacking. In addition, the clinical experience in the application of HDCT+auto-HSCT to various types and stages of MS is very limited. Moreover, the timing for transplantation is still unclear.

We report the follow-up results of a prospective Phase II multicenter trial, which was started in 1999 and has since then been conducted by the Russian Cooperative Group for Cellular Therapy. This study is focused on the efficacy of HDCT+auto-HSCT in terms of clinical and quality of life responses in patients with different types and stages of MS.

Patients and Methods

One hundred and nine patients were enrolled in the study. Patient characteristics are shown in Table 1. 

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Table 1. Demographic and clinical profile of the patient population.  All patients were refractory to conventional therapy, which included IFNβ and mitoxantrone, as well as steroids, azathiopine, intravenous immunoglobulin and plasmapheresis in some patients. The mean follow-up was 19 months (range, 6–108 months).

The trial was conducted according to the principles of the Helsinki Declaration, and approved by the IRB and Ethics Committees of all of the participating centers before initiation. All patients gave written informed consent.

The neurological disability of MS patients is quantified according to the Expanded disability status scale (EDSS) [17]. The EDSS scores range from 0 (no disability) to 10 (death related to neurological progression) in 0.5-step increments. EDSS scores from 1.0 to 4.5 refer to the fully ambulatory MS patients, while patients with EDSS scores of 7.0 are essentially restricted to a wheelchair.

Patient Eligibility

Criteria for patient selection were: age between 18 and 55 years; diagnosis of multiple sclerosis verified by clinical and laboratory findings; EDSS score 1.5–8.0; normal mental status; absence of severe concomitant diseases.

The disease activity was determined either by magnetic resonance imaging scans displaying active lesions in the CNS (i.e., gadolinium-enhancing lesions, new or enlarging lesions on serial scans) or by clinical assessment showing rapid neurological deterioration, e.g., 0.5-point increase on the EDSS during the 6-months preceding enrollment.

According to our concept there are 3 strategies of HDCT+auto-HSCT [18]. Early HSCT (in MS patients with EDSS 1.5–3.0) is performed soon after diagnosis in case of primary refractory disease or poor prognosis. Conventional HSCT (EDSS 3.5–6.5) is performed in patients with secondary refractory disease. Salvage HSCT (EDSS 7.0–8.0) is an option in case of high disease activity and rapid neurological deterioration in late stages of the disease. All three strategies were applied in this study (Table 2).

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Table 2. HSCT timing in the studied patient population

Stem Cell Mobilization and Transplant Procedure

Hematopoietic stem cells were mobilized with G-CSF at 10 μg/kg +/- cyclophosphamide at 4 g/m2 according to EBMT/EULAR guidelines [19]. The grafts were not manipulated. BEAM or BEAM-modified conditioning was used. The BEAM conditioning regimen included BCNU (300 mg/m2) on day -6, etoposide (200 mg/m2) from day -5 to day -2, cytarabine (200 mg/m2 bd) from day -5 to day -2 and melphalan (140 mg/m2) on day -1. It was followed by autologous hematopoietic stem cell transplantation (day 0). In vivo T cell-depletion was achieved through infusion of 30 mg/kg of horse anti-thymocyte globulin (ATG) on days 1 and 2. Five μg/kg s.c. of G-CSF were administered from day 3 post-infusion until granulocyte recovery. For infection prophylaxis oral ciprofloxacin, fluconazole, acyclovir, and IV human Ig were given.

Neurological and QoL assessments

Clinical and QoL assessments were performed at baseline, at discharge, at 3, 6, 9, and 12 months after transplantation, every 6 months thereafter up to 48 months, and then at yearly intervals. Neurological assessment included EDSS score and MRI examinations. QoL was assessed by the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) questionnaire and the Functional Assessment of Multiple Sclerosis (FAMS) questionnaire. The FACT-BMT is a self-administered instrument designed to assess multidimensional aspects of QoL in BMT patients [20]. It consists of the 27-item FACT-General and the 23-item Bone Marrow Transplantation Subscale (BMTS). The FAMS is a disease-specific questionnaire for QoL assessment in MS patients [21]. It consists of 58 questions and contains 7 scales: mobility, symptoms, emotional well-being, general contentment, thinking and fatigue, family/social well-being, and additional concerns.

Definition of response to treatment

According to the EBMT criteria of response, patients with either steady EDSS scores representing a halt of disease progression, or with improved EDSS scores representing subsidence of inflammation in the CNS were regarded as responding to treatment [4,8]. Clinical improvement was defined as a ≥0.5 point decrease in EDSS score as compared to the baseline. Progression was defined as an increase of at least 0.5 points. Both had to be confirmed after 6 months. Clinical relapse was defined as the appearance of new symptoms or worsening of old symptoms of at least 24-hour duration, in the absence of fever in a previously (4 weeks) stable patient.

QoL was assessed by calculating the Integral QoL Index (IQLI) value at different time points on the basis of FACT-BMT questionnaire scores, as described previously [14]. Less than 25% improvement in IQLI compared to the baseline value was considered a minimal QoL response; 25–50% improvement a moderate QoL response; 51–75% improvement a good QoL response; and more than 75% improvement a maximal QoL response.

Results

Adverse events

No toxic deaths were reported among the 109 MS patients , irrespective of their clinical condition at the time of transplant. The transplantation procedure was well tolerated by the patients. Mobilization was successful in all cases, with a median number of 2.1 x106/kg (range 1.5–5.5 x106/kg) collected CD34+ cells. and no major clinical adverse events were observed during this phase. Unmanipulated grafts were infused without complications. Engraftment was uneventful, and no signs of an engraftment syndrome were reported. Median days with PMN< 0.5x109 and Plt < 50x109 were 8 (range from 5 to 11) and 10 days (from 2 to 26), respectively.

Common adverse effects following the immunoablative regimen were thrombocytopenia (100%), neutropenia (100%), fatigue (100%), anemia (80%), alopecia (80%), neutropenic fever (51.6%), hepatic toxicity grade I and II (48.1%), transient neurological dysfunction (22.2%), enteropathy (18.5%). Documented sepsis was registered in one patient.

Clinical outcomes

Seventy-nine patients with the follow-up period of at least 9 months or longer were included in the clinical outcome analysis (Table 3).

58a709a2e0.jpg

Table 3. Efficacy of HDCT+auto-HSCT in MS patients

All patients responded to the treatment. At 6 months post-transplant the following distribution of patients according to clinical response was observed: 42 patients (53%) achieved an objective improvement of neurological symptoms (defined as a ≥0.5 point decrease in the EDSS score as compared to the baseline and confirmed over 3 months): 20 SPMS; 11 RRMS; 4 PRMS, and 7 PPMS. Thirty-seven patients (47%) had disease stabilization (steady EDSS level as compared to the baseline and confirmed over 3 months): 19 SPMS; 8 RRMS; 2 PRMS, and 8 PPMS. Among the patients with improvement there were 25 patients after conventional HDCT+auto-HSCT, 15 after early HDCT+auto-HSCT, and 2 after salvage HDCT+auto-HSCT. Among the patients with stabilization there were 23 patients after conventional HDCT+auto-HSCT, 9 after early HDCT+auto-HSCT, and 5 after salvage HDCT+auto-HSCT. At long-term follow-up, the clinical response in 40 patients (50.6%) was classified as an improvement; 34 patients (43.1%) remained stable. Two patients deteriorated to a worse score after 18 months of stabilization (SPMS and PPMS; conventional auto-HSCT), and one patient after 6 months of stabilization (SPMS, conventional auto-HSCT); 2 others progressed after 12 and 30 months of improvement (RRMS, early auto-HSCT and SPMM, conventional auto-HSCT, respectively). No active, new or enlarging lesions were registered in patients without disease progression.

Remarkably, nine patients improved dramatically (≥1.5 point by EDSS). Patients with different types of MS were observed in this group. As an illustration, in a SPMS patient with the baseline EDSS value of 6.0 we observed a 2.0 point decrease on the EDSS scale at 1 month post-transplant, an additional 1.5 point decrease at 6 months and stabilization with EDSS score of 1.5 at 18 months post-transplant. In another case, a RRMS patient with a base-line EDSS score of 4.5 experienced a decrease in EDSS to 2.0 at 1 month post-transplant with a further decrease to 1.0 at 3 months. The latter EDSS level remained stable throughout the entire follow-up period of 1.5 years. The PRMS patient with baseline EDSS value of 6.0 improved at 3 months to EDSS of 4.5, and then showed further improvement at 30 months post-transplant to the EDSS score of 4.0. The EDSS score at the end of follow-up (6.5 years post-transplant) was 3.5. Finally, the PPMS patient with severe disease (EDSS score of 7.5) had a 1.5-point EDSS decrease and maintained this score during the 3.5 years of follow-up.

The progression-free survival at 6 years after HDCT+auto-HSCT was 72% (Figure 1). Remarkably, all patients who did not have disease progression were off therapy throughout the post-transplant period.

aa0964d60e.jpg

Figure 1. Progression-free survival after HDCT+auto-HSCT. Probability of progression-free survival in 42 MS patients. Estimated progression-free survival is 72% at 6 years.

QoL outcomes

QoL monitoring and assessment of QoL response were performed in 44 patients. Forty patients exhibited improved QoL at 6 months post-transplant. An increase in QoL parameters was observed according to both FACT-BMT and FAMS questionnaires. Notably, the patient who progressed 18 months after transplantation (SPMS) exhibited no QoL response. Despite clinical disease stabilization, his QoL gradually deteriorated.

In another case, a QoL deterioration was observed in a PPMS patient at 6 months post-transplant in spite of clinical stabilization during the 18 months after transplantation. It is worth mentioning that the patient (RRMS) who experienced relapse at 2.5 years post-transplant experienced a significant QoL decrease 2 years after transplantation.

The distribution of patients according to the grades of QoL response one year after HDCT+auto-HSCT is presented in Table 4.

8df52dbed2.jpg

Table 4. Distribution of MS patients according to the grades of QoL response at 1 year after HDCT+auto-HSCT(n=44). As is seen in the table, 3 patients exhibited a maximal QoL response, 12 patients a good QoL response, 11 patients a moderate QoL response, 13 patients a minimal QoL response, and 5 patients no QoL response. Remarkably, patients with a longer follow-up experienced further QoL improvement.


Figure 2 demonstrates the QoL profiles of two MS patients (patient A, a 21-year-old female, PRMS, base-line EDSS 6.0; patient B, a 35-year-old female, SPMS, base-line EDSS 5.0) with the long-term follow-up after HDCT+auto-HSCT.

f988869359.jpg

b5f718c9a2.jpg

Figure 2. Quality of life profiles of patient A(a) and patient B (b) at different time points after HDCT+auto-HSCT.

In both patients the QoL parameters improved dramatically at 1 year after HDCT+auto-HSCT.

Improved QoL profiles were preserved throughout the 8-year QoL monitoring of patient A, and the 9-year QoL monitoring of patient B.

Of special interest is the dynamics of QoL profiles of patient A (Figure 2a).

Six months after transplantation an improvement was observed in this patient, which led to the formation of a significantly less compressed and less deformed QoL profile as compared to the baseline.

Further QoL improvement took place at different time points during the 8-year follow-up.

Discussion

Since 1995, HDCT+auto-HSCT has been performed in more than 600 MS patients all over the world. Published clinical results demonstrate that this approach can stop the disease progression in a majority of patients. A comprehensive analysis of the EBMT registry data of 85 patients from 20 centers published by EBMT ADWP in 2002, showed no disease progression for 3 years in 74% of patients [4]. Similar results were obtained in five US studies that included 66 patients in total [6,11]. Remarkably, transplant-related mortality in MS patients does not exceed transplant-related mortality in hematological patients (0–4%).

The results our study have also demonstrated the benefits of HDCT+auto-HSCT in MS. We have included 109 patients with various types of MS from 6 centers affiliated with the Russian Cooperative Group for Cellular Therapy. The transplantation procedure was well tolerated by patients with no transplant-related deaths at all. The efficacy analysis was performed in 79 patients monitored for more than 1 year. All the patients responded to treatment: in 42 patients the EDSS score decreased after HDCT+auto-HSCT as compared to the base-line and was confirmed over 6 months, while disease stabilization (stable EDSS after transplantation confirmed over 6 months) was registered in 37 patients. The majority of patients had either moderate or good QoL responses as well. This data strongly supports the use of HDCT+auto-HSCT as the therapy of choice in autoimmune diseases with imminent patient debilitation, such as MS. 

It is worth mentioning that the issues surrounding the patient selection criteria for HDCT+auto-HSCT are still unclear. The advantage of our study is that we included patients with different types of MS. In spite of some evidence that PPMS patients are less responsive to HDCT+auto-HSCT as compared to both SPMS and RRMS [8], the information about the outcomes of HSCT in patients with various types of MS is limited. The results of our study confirm that transplantation is effective in PPMS patients, and patients with different types of MS might benefit from HDCT+auto-HSCT.

Another advantage of our study is the performance of early, conventional or salvage transplantation, while most patients in the previous studies had late stages of MS.

Our data supports the idea that HDCT+auto-HSCT is more effective in young patients with early stages of rapidly progressing disease. In these patients, autoreactive T cells play a pivotal role in MS pathogenesis. HDCT ablates the patient's immune system and eradicates autoimmune T cells. It is followed by HSCT to restore the immune system, which is expected to become tolerant to autoantigens. Such "resetting" of the immune system is only effective at early stages of MS, particularly in relapsing-remitting MS. Later in the clinical course of the disease, processes of axonal degeneration prevail, and the damage to CNS tissue is too significant to expect a neurological recovery after HDCT+auto-HSCT. Indeed, the failure of HDCT+auto-HSCT to prevent progression of the disease when performed in the late stages has been demonstrated in both animal models [22] and in clinical studies [1,11]. Considering the clinical heterogeneity of MS patients, we propose a classification of transplantation approaches based on the concept of HDCT+auto-HSCT in MS (Table 5). The concept focuses on the goals of MS treatment. There are two goals in the treatment of MS patients. The first is pathogenetic, which is to stop the disease progression and prevent the appearance of new lesions in the nervous tissue. The second is to improve or maintain a patient’s QoL. Since MS is incurable and does not shorten the patient’s life span, the QoL improvement should be considered the ultimate goal of MS treatment. Therefore, QoL assessment is the key criterion for the assessment of efficacy of MS treatment in addition to traditional diagnostic tests, which describe the dynamics of the immunopathological process. It is of special importance in patients with late stages of MS.

1b1701b7dc.jpg

Table 5. Classification of HDCT+auto-HSCT in MS patients


In conclusion, our study has demonstrated that HDCT+auto-HSCT may be an effective treatment for various types of MS in terms of clinical and patient-reported outcomes at long-term follow-up. The data obtained points to the feasibility of early, conventional, and salvage HDCT+auto-HSCT in MS patients. Further studies should be done to investigate clinical and QoL response in MS patients receiving early, conventional, and salvage transplantation to better define treatment success. The concept of HDCT+auto-HSCT opens a new window of opportunities for MS treatment.

Acknowledgements

We would like to acknowledge Sergei V. Shamanski (Moscow), Andrei D. Kulagin (Novosibirsk), Nikolay I. Baziy (Moscow), Nina E. Osipova (St.Petersburg), Andrei E. Zdorov (Petrozavodsk), and Anton V. Kishtovich (St.Petersburg) for their contribution to the study.

References

1. Burt RK, Cohen B, Lobck L, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: importance of disease stage on outcome. Neurology. 2003;40 Suppl:A150.

2. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343:938 -952.

3. Burt RK, Cohen B, Rose J, et al. Hematopoietic stem cell transplantation for multiple sclerosis. Arch Neurol. 2005;62:860-864.

4. Fassas A, Anagnostopoulos A, Kazis A, et al. Autologous stem cell transplantation in progressive multiple sclerosis – an interim analysis of efficacy. J Clin Immunol. 2000;20(1):24-30.

5. Brenner MK. Haematopoietic stem cell transplantation for autoimmune disease: limits and future potential. Best Pract Res Clin Haematol. 2004;17:359-374.

6. Burt RK, Cohen BA, Russell E, et al. Hematopoietic stem cell transplantation for progressive multiple sclerosis; failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores. Blood. 2003;102:2373-2378.

7. Fassas A, Nash R. Multiple sclerosis. Best Pract Res Clin Hematol. 2004;17:247-262.

8. Fassas A, Passweg JR, Anagnostopoulos A, et al. Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study. J Neurol. 2002;249:1088-1097.

9. Kozak T, Havrdova E, Pit’ha J, et al. High-dose immunosuppressive therapy with PBPC support in the treatment of poor risk multiple sclerosis. Bone Marrow Transplant. 2000;25:525-531.

10. Muraro PA, McFarland HF, Martin R. Immunological aspects of multiple sclerosis with emphasis on the potential use of autologous hemopoietic stem cell transplantation. In: Burt RK, Marmont AM, eds. Stem Cell Therapy for Autoimmune Disease. Georgetown, TX: Landes Bioscience. 2004;277-283.

11. Nash RA, Bowen JD, McSweeney PA, et al. High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood. 2003;102:2364-2372.

12. Openshaw H, Lund B, Kashyap A, et al. Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning report of toxicity and immunological monitoring. Biology of Blood and  Marrow Transplant. 2000;25:525-575.

13. Saccardi R, Mancardi GL, Solari A, et al. Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life. Blood. 2005;105:2601-2607.

14. Shevchenko Y, Novik A, Ionova T et al. Clinical and quality of life outcomes in patients with multiple sclerosis after high-dose chemotherapy + autologous stem cell transplantation [abstract no. 1875]. Blood. 2004;104:519a.

15. Shevchenko Y, Novik A, Kuznetsov A et al High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Experimental Hematology. 2008;36(8):922-929.

16. Novik A, Ionova T, Bisaga G, et.al. Clinical and Quality of Life Responses to High-Dose Chemotherapy plus Autologous Stem Cell Transplantation in Patients with Multiple Sclerosis: two case reports. Cytotherapy. 2005;7(4):363–367.

17. Kurtzke JF. Rating neurologic impairment in multiple sclerosis; an expanded disability status scale (EDSS). Neurology. 1983;33:1444-52.

18. Shevchenko YL, Novik AA, Ionova TI, et al. Three strategies of high dose chemotherapy + autologous stem cell transplantation in autoimmune diseases. Bone Marrow Transplant. 2004;33 Suppl 1: 346.

19. Tindall A, Gratwohl A. Blood and marrow stem cell transplants in autoimmune disease: A consensus report written on behalf of the European League against Rheumatism (EULAR) and the European Group for Blood and Marrow transplantation (EBMT). Bone Marrow Transplant. 1997;19:643-645.

20. McQuellon RP, Russell GB, Cella DF, et al. Quality of life measurement in bone marrow transplantation; development of the functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) scale. Bone Marrow Transplant. 1997;19:357-368.

21. Cella DF, Dineen K, Arnason B, et al. Validation of the functional assessment of multiple sclerosis quality of life instrument. Neurology. 1996;47:129-139.

22. Burt RK, Padilla J, Begolka WS, et al. Effect of disease stage on clinical outcome after syngeneic bone marrow transplantation for relapsing experimental autoimmune encephalomyelitis. Blood. 1998;91:2609-2616.

© The Authors. This article is provided under the following license: Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 Unported


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Ю. Л. Шевченко, А. А. Новик, А. Н. Кузнецов, Б. В. Афанасьев, И. А. Лисуков, O. А. Рукавицын, А. А. Мясников,
В. Я. Мельниченко, Д. А. Федоренко, T. И. Ионова, Р. А. Иванов, Г. Городокин

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Введение

Рассеянный склероз (РС) – хроническое прогрессирующее заболевание центральной нервной системы, которое клинически проявляется мультисистемной неврологической симптоматикой, а патоморфологически характеризуется образованием множественных очагов демиелинизации в белом веществе головного и спинного мозга. Основным механизмом, приводящим к повреждению миелина, является опосредованная Т-лимфоцитами реакция гиперчувствительности замедленного типа, а непосредственными клетками-эффекторами иммунопатологического процесса – макрофаги.

Существующие методы лечения не позволяют достичь устойчивого терапевтического эффекта при рассеянном склерозе. Выдвигалась гипотеза, основанная на доклинических данных, о высокой эффективности аллогенной транплантации стволовых кроветворных клеток (ТСКК). Однако высокая посттрансплантационная летальность не позволила приступить к клиническим исследованиям данного вида терапии РС. По мнению большинства экспертов одним из наиболее перспективных методов лечения РС на сегодняшний день является высокодозная химиотерапия (ВДТ) с аутологичной трансплантацией стволовых кроветворных клеток (АуТСКК). Начиная с 1995 года, безопасность ВДТ+AyТКСК при РС была изучена в ряде клинических исследований. Тем не менее, объем информации о клинической эффективности данного метода и, особенно, о его влиянии на качество жизни больных РС, остается недостаточным. Кроме того, большинство пациентов, включенных в вышеупомянутые исследования, имели вторично-прогрессирующую форму РС и значительную степень инвалидизации со значением шкалы EDSS 4.5-8.5 баллов. К сожалению, даже полное прекращение активности иммунопатологического процесса у таких больных не может привести к значительному улучшению качества жизни. Поэтому вопрос об оптимальных сроках проведения трансплантации по-прежнему остается открытым.

В статье приведены результаты проспективного многоцентрового исследования безопасности и эффективности ВДТ+АуТКСК при РС, которое было начато в 1999 году и в настоящее время объединяет 5 крупных российских медицинских центров. Изучали влияние ВДТ+АуТКСК на клиническое течение и показатели качества жизни больных с разными формами и стадиями РС.

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Yury L. Shevchenko1, Andrei A. Novik1, Alexey N. Kuznetsov1, Boris V. Afanasiev2, Igor A. Lisukov3, Oleg A. Rykavicin4, Аlexandr A. Myasnikov5, Vladimir Y. Melnichenko1, Denis A. Fedorenko1, Tatyana I. Ionova6, Roman A. Ivanov1, and Gary Gorodokin7 on behalf of the Russian Cooperative Group for Cellular Therapy

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1Pirogov National Medical Surgical Center, Moscow, Russia;
2Pavlov State Medical University, St. Petersburg, Russia;
3Institute of Clinical Immunology, Siberian Branch of Russian Academy of Science, Novosibirsk, Russia;
4Burdenko Central Military Hospital, Moscow, Russia;
5Republic Hospital, Petrozavodsk, Russia;
6Multinational Center of Quality of Life Research, St. Petersburg, Russia;
7New Jersey Center for Quality of Life and Health Outcome Research, NJ, USA

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Although there is no effective cure for this disease, high-dose chemotherapy (HDCT), together with autologous hematopoietic stem cell transplantation (auto-HSCT) offers promising results in the treatment of multiple sclerosis (MS) patients.

Methods

In this paper we present results of a prospective clinical study of safety and efficacy of HDCT+auto-HSCT in MS patients. One hundred and nine patients with various types of MS were included in this study. The patients underwent early, conventional, or salvage/late transplantation.

Results

The transplantation procedure was well tolerated by MS patients, with no transplant-related deaths at all. The efficacy analysis was performed in 79 patients. Forty-two achieved an objective improvement of neurological symptoms (defined as a ≥0.5 point decrease in EDSS score as compared to the baseline and confirmed over 6 months), and 37 patients had disease stabilization (steady EDSS level as compared to the baseline and confirmed over 6 months). Quality of life (QoL) was assessed in 44 patients. Thirty-nine patients exhibited a QoL response 1 year after transplantation.

Conclusions

This study provides ample evidence in support of HDCT+auto-HSCT efficacy in MS patients. The results obtained show that transplantation appears to be effective in patients with various types of MS.

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Значение индекса EDSS до трансплантации колебалось от 1.5 до 8.0 баллов (в среднем было равно 5.0 баллам). Длительность наблюдения составила в среднем 19 месяцев (от 6 до 108 месяцев). Активность заболевания определяли с помощью неврологического осмотра и данных магнитно-резонансной томографии.<br> Больным были выполнены следующие виды ВДТ+АуТКСК:<br> <b> - Ранняя трансплантация</b> проводилась в дебюте заболевания при наличии неблагоприятных прогностических факторов в отношении химиорезистентности или возможности тяжелой инвалидизации больного.<br> <b> - Этапная трансплантация</b> проводилась при выходе заболевания из-под контроля традиционных методов лечения и формировании вторичной химиорезистентности.<br> <b> - Трансплантация спасения</b> проводилась в далеко зашедшей стадии заболевания при высокой активности иммунопатологического процесса и быстром прогрессировании инвалидизации больного.<br> Тридцати двум больным была выполнена ранняя трансплантация (EDSS 1.5-3.0); 70 больным - этапная трансплантация (EDSS 3.5-6.5) и 7 больным - трансплантация спасения (EDSS 7.0-8.0).</p> <p> Оценку клинического ответа и ответа, связанного с качеством жизни, проводили до трансплантации, при выписке из стационара, через 3, 6, 9 и 12 месяцев после трансплантации, затем – каждые 6 месяцев в течение первых 4 лет и ежегодно впоследствии. Изучение неврологического статуса включало определение выраженности неврологического дефицита по шкале EDSS и магнитно-резонансную томографию. Качество жизни больных 16 www.ctt-journal.com 2008;1(2) оценивали с использованием опросников FACT-BMT (функциональная оценка состояния больных после трансплантации костного мозга) и FAMS (функциональная оценка больных с рассеянным склерозом). Клиническим улучшением считали уменьшение выраженности неврологической симптоматики, по меньшей мере, на 0.5 балла по шкале EDSS по сравнению с исходным уровнем, при условии, что это улучшение было подтверждено через 6 месяцев на следующем визите. Любое увеличение выраженности неврологической симптоматики по шкале EDSS считали прогрессированием заболевания. Рецидив констатировали при появлении новых симптомов или нарастании выраженности прежних симптомов, по меньшей мере, в течение 24 часов в отсутствие лихорадки у пациента, который был стабилен в течение 4 предшествующих недель. Ответ, связанный с качеством жизни, характеризовался как минимальный, умеренный, хороший или максимальный. Для определения ответа, связанного с качеством жизни, рассчитывали различия в значении интегрального показателя качества жизни до проведения трансплантации и в различные периоды времени после нее.</p> <h2>Результаты</h2> <p>У всех 79 больных со сроком наблюдения ≥9 месяцев отмечено клиническое улучшение или стабилизация в течении заболевания. Во время проведения трансплантации не было зарегистрировано ни одного смертельного исхода и тяжелых неконтролируемых побочных эффектов. Через 6 месяцев после трансплантации распределение пациентов согласно клиническому ответу было следующим: улучшение – 42 (53%) больных, стабилизация – 37 (47%) больных. Среди больных с улучшением у 20 было вторично-прогрессирующее течение, у 7 – первично-прогрессирующее, у 4 – прогрессирующе-рецидивирующее и у 11 – рецидивирующе-ремиттирующее течение. В этой группе 25 больных проведена этапная трансплантация, 15 – ранняя и 2 – трансплантация спасения. Из 37 больных, у которых зарегистрирована стабилизация заболевания, у 19 было вторично-прогрессирующее течение, у 8 – первично-прогрессирующее, у 2 – прогрессирующе-рецидивирующее и у 8 – рецидивирующе-ремиттирующее течение. В этой группе 23 больным проведена этапная трансплантация, 9 – ранняя и 5 – трансплантация спасения.</p> <p> В более длительные сроки наблюдения у 40 больных (50.6%) сохранялось улучшение, у 34 (43.1%) – стабилизация. У одного больного после 6 месяцев и двух больных после 18 месяцев стабилизации произошло повышение индекса инвалидизации. У двух пациентов прогрессирование заболевания наступило после 12 и 30 месяцев клинического улучшения. По данным МРТ у всех больных без прогрессирования заболевания после трансплантации отсутствовали активные или новые очаги поражения. В целом, 6-летняя выживаемость без прогрессии после ВДТ+АуТКСК составила 72%. Больные, у которых не было зарегистрировано признаков прогрессирования заболевания, не получали иммуномодулирующую или иммуносупрессивную терапию после трансплантации. Мониторинг качества жизни проводился у 44 пациентов, включенных в исследование. У 40 из них наблюдали улучшение показателей качества жизни через 6 месяцев после трансплантации. Улучшение параметров качества жизни установлено с помощью опросников – FACT-BMT и FAMS. Через 1 год после ВДТ+АуТКСК зарегистрировано следующее распределение пациентов в соответствии со степенью ответа, связанного с качеством жизни: у 3 больных наблюдали максимальный ответ (более чем 75% улучшение интегрального показателя качества жизни в сравнении с исходным уровнем); у 12 больных – хороший ответ (улучшение на 50-75%); у 11 больных – умеренный ответ (на 25-50%); у 13 – минимальный ответ (улучшение менее чем на 25%) и у 5 больных ответ, связанный с качеством жизни, отсутствовал. Следует отметить, что у пациентов с более длительным сроком наблюдения было отмечено дальнейшее улучшение показателей качества жизни. В статье представлена классификация типов трансплантации при рассеянном склерозе, основанная на концепции ВДТ+ТКСК при аутоиммунных заболеваниях.</p> <h2>Заключение</h2> <p>Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией кроветворных стволовых клеток является эффективным методом лечения больных рассеянным склерозом: у большинства больных после ВДТ+АуТКСК зарегистрировано клиническое улучшение или стабилизация заболевания; ВДТ+АуТКСК сопровождается существенным улучшением качества жизни больных. Результаты свидетельствуют о целесообразности изучения результатов ранней трансплантации, этапной трансплантации и трансплантации спасения. Необходимы дальнейшие исследования для определения оптимальных сроков проведения трансплан-тации и уточнения режимов кондиционирования. </p>" ["TYPE"]=> string(4) "TEXT" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(11579) "

Материалы и методы

В исследование было включено 109 больных РС (49 мужчин, 60 женщин; средний возраст – 33 года; диапазон – 17-54): 51 с вторично-прогрессирующим течением, 19 с первично-прогрессирующим, 8 с прогрессирующе-рецидивирующим и 31 с рецидивирующе-ремиттирующим течением. Значение индекса EDSS до трансплантации колебалось от 1.5 до 8.0 баллов (в среднем было равно 5.0 баллам). Длительность наблюдения составила в среднем 19 месяцев (от 6 до 108 месяцев). Активность заболевания определяли с помощью неврологического осмотра и данных магнитно-резонансной томографии.
Больным были выполнены следующие виды ВДТ+АуТКСК:
- Ранняя трансплантация проводилась в дебюте заболевания при наличии неблагоприятных прогностических факторов в отношении химиорезистентности или возможности тяжелой инвалидизации больного.
- Этапная трансплантация проводилась при выходе заболевания из-под контроля традиционных методов лечения и формировании вторичной химиорезистентности.
- Трансплантация спасения проводилась в далеко зашедшей стадии заболевания при высокой активности иммунопатологического процесса и быстром прогрессировании инвалидизации больного.
Тридцати двум больным была выполнена ранняя трансплантация (EDSS 1.5-3.0); 70 больным - этапная трансплантация (EDSS 3.5-6.5) и 7 больным - трансплантация спасения (EDSS 7.0-8.0).

Оценку клинического ответа и ответа, связанного с качеством жизни, проводили до трансплантации, при выписке из стационара, через 3, 6, 9 и 12 месяцев после трансплантации, затем – каждые 6 месяцев в течение первых 4 лет и ежегодно впоследствии. Изучение неврологического статуса включало определение выраженности неврологического дефицита по шкале EDSS и магнитно-резонансную томографию. Качество жизни больных 16 www.ctt-journal.com 2008;1(2) оценивали с использованием опросников FACT-BMT (функциональная оценка состояния больных после трансплантации костного мозга) и FAMS (функциональная оценка больных с рассеянным склерозом). Клиническим улучшением считали уменьшение выраженности неврологической симптоматики, по меньшей мере, на 0.5 балла по шкале EDSS по сравнению с исходным уровнем, при условии, что это улучшение было подтверждено через 6 месяцев на следующем визите. Любое увеличение выраженности неврологической симптоматики по шкале EDSS считали прогрессированием заболевания. Рецидив констатировали при появлении новых симптомов или нарастании выраженности прежних симптомов, по меньшей мере, в течение 24 часов в отсутствие лихорадки у пациента, который был стабилен в течение 4 предшествующих недель. Ответ, связанный с качеством жизни, характеризовался как минимальный, умеренный, хороший или максимальный. Для определения ответа, связанного с качеством жизни, рассчитывали различия в значении интегрального показателя качества жизни до проведения трансплантации и в различные периоды времени после нее.

Результаты

У всех 79 больных со сроком наблюдения ≥9 месяцев отмечено клиническое улучшение или стабилизация в течении заболевания. Во время проведения трансплантации не было зарегистрировано ни одного смертельного исхода и тяжелых неконтролируемых побочных эффектов. Через 6 месяцев после трансплантации распределение пациентов согласно клиническому ответу было следующим: улучшение – 42 (53%) больных, стабилизация – 37 (47%) больных. Среди больных с улучшением у 20 было вторично-прогрессирующее течение, у 7 – первично-прогрессирующее, у 4 – прогрессирующе-рецидивирующее и у 11 – рецидивирующе-ремиттирующее течение. В этой группе 25 больных проведена этапная трансплантация, 15 – ранняя и 2 – трансплантация спасения. Из 37 больных, у которых зарегистрирована стабилизация заболевания, у 19 было вторично-прогрессирующее течение, у 8 – первично-прогрессирующее, у 2 – прогрессирующе-рецидивирующее и у 8 – рецидивирующе-ремиттирующее течение. В этой группе 23 больным проведена этапная трансплантация, 9 – ранняя и 5 – трансплантация спасения.

В более длительные сроки наблюдения у 40 больных (50.6%) сохранялось улучшение, у 34 (43.1%) – стабилизация. У одного больного после 6 месяцев и двух больных после 18 месяцев стабилизации произошло повышение индекса инвалидизации. У двух пациентов прогрессирование заболевания наступило после 12 и 30 месяцев клинического улучшения. По данным МРТ у всех больных без прогрессирования заболевания после трансплантации отсутствовали активные или новые очаги поражения. В целом, 6-летняя выживаемость без прогрессии после ВДТ+АуТКСК составила 72%. Больные, у которых не было зарегистрировано признаков прогрессирования заболевания, не получали иммуномодулирующую или иммуносупрессивную терапию после трансплантации. Мониторинг качества жизни проводился у 44 пациентов, включенных в исследование. У 40 из них наблюдали улучшение показателей качества жизни через 6 месяцев после трансплантации. Улучшение параметров качества жизни установлено с помощью опросников – FACT-BMT и FAMS. Через 1 год после ВДТ+АуТКСК зарегистрировано следующее распределение пациентов в соответствии со степенью ответа, связанного с качеством жизни: у 3 больных наблюдали максимальный ответ (более чем 75% улучшение интегрального показателя качества жизни в сравнении с исходным уровнем); у 12 больных – хороший ответ (улучшение на 50-75%); у 11 больных – умеренный ответ (на 25-50%); у 13 – минимальный ответ (улучшение менее чем на 25%) и у 5 больных ответ, связанный с качеством жизни, отсутствовал. Следует отметить, что у пациентов с более длительным сроком наблюдения было отмечено дальнейшее улучшение показателей качества жизни. В статье представлена классификация типов трансплантации при рассеянном склерозе, основанная на концепции ВДТ+ТКСК при аутоиммунных заболеваниях.

Заключение

Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией кроветворных стволовых клеток является эффективным методом лечения больных рассеянным склерозом: у большинства больных после ВДТ+АуТКСК зарегистрировано клиническое улучшение или стабилизация заболевания; ВДТ+АуТКСК сопровождается существенным улучшением качества жизни больных. Результаты свидетельствуют о целесообразности изучения результатов ранней трансплантации, этапной трансплантации и трансплантации спасения. Необходимы дальнейшие исследования для определения оптимальных сроков проведения трансплан-тации и уточнения режимов кондиционирования.

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Shevchenko<sup>1</sup>, Andrei A. Novik<sup>1</sup>, Alexey N. Kuznetsov<sup>1</sup>, Boris V. Afanasiev<sup>2</sup>, Igor A. Lisukov<sup>3</sup>, Oleg A. Rykavicin<sup>4</sup>, Аlexandr A. Myasnikov<sup>5</sup>, Vladimir Y. Melnichenko<sup>1</sup>, Denis A. Fedorenko<sup>1</sup>, Tatyana I. Ionova<sup>6</sup>, Roman A. Ivanov<sup>1</sup>, and Gary Gorodokin<sup>7</sup> on behalf of the Russian Cooperative Group for Cellular Therapy</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(467) "

Yury L. Shevchenko1, Andrei A. Novik1, Alexey N. Kuznetsov1, Boris V. Afanasiev2, Igor A. Lisukov3, Oleg A. Rykavicin4, Аlexandr A. Myasnikov5, Vladimir Y. Melnichenko1, Denis A. Fedorenko1, Tatyana I. Ionova6, Roman A. Ivanov1, and Gary Gorodokin7 on behalf of the Russian Cooperative Group for Cellular Therapy

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Yury L. Shevchenko1, Andrei A. Novik1, Alexey N. Kuznetsov1, Boris V. Afanasiev2, Igor A. Lisukov3, Oleg A. Rykavicin4, Аlexandr A. Myasnikov5, Vladimir Y. Melnichenko1, Denis A. Fedorenko1, Tatyana I. Ionova6, Roman A. Ivanov1, and Gary Gorodokin7 on behalf of the Russian Cooperative Group for Cellular Therapy

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Although there is no effective cure for this disease, high-dose chemotherapy (HDCT), together with autologous hematopoietic stem cell transplantation (auto-HSCT) offers promising results in the treatment of multiple sclerosis (MS) patients.

Methods

In this paper we present results of a prospective clinical study of safety and efficacy of HDCT+auto-HSCT in MS patients. One hundred and nine patients with various types of MS were included in this study. The patients underwent early, conventional, or salvage/late transplantation.

Results

The transplantation procedure was well tolerated by MS patients, with no transplant-related deaths at all. The efficacy analysis was performed in 79 patients. Forty-two achieved an objective improvement of neurological symptoms (defined as a ≥0.5 point decrease in EDSS score as compared to the baseline and confirmed over 6 months), and 37 patients had disease stabilization (steady EDSS level as compared to the baseline and confirmed over 6 months). Quality of life (QoL) was assessed in 44 patients. Thirty-nine patients exhibited a QoL response 1 year after transplantation.

Conclusions

This study provides ample evidence in support of HDCT+auto-HSCT efficacy in MS patients. The results obtained show that transplantation appears to be effective in patients with various types of MS.

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Although there is no effective cure for this disease, high-dose chemotherapy (HDCT), together with autologous hematopoietic stem cell transplantation (auto-HSCT) offers promising results in the treatment of multiple sclerosis (MS) patients.

Methods

In this paper we present results of a prospective clinical study of safety and efficacy of HDCT+auto-HSCT in MS patients. One hundred and nine patients with various types of MS were included in this study. The patients underwent early, conventional, or salvage/late transplantation.

Results

The transplantation procedure was well tolerated by MS patients, with no transplant-related deaths at all. The efficacy analysis was performed in 79 patients. Forty-two achieved an objective improvement of neurological symptoms (defined as a ≥0.5 point decrease in EDSS score as compared to the baseline and confirmed over 6 months), and 37 patients had disease stabilization (steady EDSS level as compared to the baseline and confirmed over 6 months). Quality of life (QoL) was assessed in 44 patients. Thirty-nine patients exhibited a QoL response 1 year after transplantation.

Conclusions

This study provides ample evidence in support of HDCT+auto-HSCT efficacy in MS patients. The results obtained show that transplantation appears to be effective in patients with various types of MS.

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1Pirogov National Medical Surgical Center, Moscow, Russia;
2Pavlov State Medical University, St. Petersburg, Russia;
3Institute of Clinical Immunology, Siberian Branch of Russian Academy of Science, Novosibirsk, Russia;
4Burdenko Central Military Hospital, Moscow, Russia;
5Republic Hospital, Petrozavodsk, Russia;
6Multinational Center of Quality of Life Research, St. Petersburg, Russia;
7New Jersey Center for Quality of Life and Health Outcome Research, NJ, USA

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1Pirogov National Medical Surgical Center, Moscow, Russia;
2Pavlov State Medical University, St. Petersburg, Russia;
3Institute of Clinical Immunology, Siberian Branch of Russian Academy of Science, Novosibirsk, Russia;
4Burdenko Central Military Hospital, Moscow, Russia;
5Republic Hospital, Petrozavodsk, Russia;
6Multinational Center of Quality of Life Research, St. Petersburg, Russia;
7New Jersey Center for Quality of Life and Health Outcome Research, NJ, USA

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Ю. Л. Шевченко, А. А. Новик, А. Н. Кузнецов, Б. В. Афанасьев, И. А. Лисуков, O. А. Рукавицын, А. А. Мясников,
В. Я. Мельниченко, Д. А. Федоренко, T. И. Ионова, Р. А. Иванов, Г. Городокин

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    Ю. Л. Шевченко, А. А. Новик, А. Н. Кузнецов, Б. В. Афанасьев, И. А. Лисуков, O. А. Рукавицын, А. А. Мясников, <br> В. Я. Мельниченко, Д. А. Федоренко, T. И. Ионова, Р. А. Иванов, Г. Городокин
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"L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "4024" ["VALUE"]=> array(2) { ["TEXT"]=> string(4131) " <h3>Введение</h3> <p>Рассеянный склероз (РС) – хроническое прогрессирующее заболевание центральной нервной системы, которое клинически проявляется мультисистемной неврологической симптоматикой, а патоморфологически характеризуется образованием множественных очагов демиелинизации в белом веществе головного и спинного мозга. Основным механизмом, приводящим к повреждению миелина, является опосредованная Т-лимфоцитами реакция гиперчувствительности замедленного типа, а непосредственными клетками-эффекторами иммунопатологического процесса – макрофаги.</p> <p>Существующие методы лечения не позволяют достичь устойчивого терапевтического эффекта при рассеянном склерозе. Выдвигалась гипотеза, основанная на доклинических данных, о высокой эффективности аллогенной транплантации стволовых кроветворных клеток (ТСКК). Однако высокая посттрансплантационная летальность не позволила приступить к клиническим исследованиям данного вида терапии РС. По мнению большинства экспертов одним из наиболее перспективных методов лечения РС на сегодняшний день является высокодозная химиотерапия (ВДТ) с аутологичной трансплантацией стволовых кроветворных клеток (АуТСКК). Начиная с 1995 года, безопасность ВДТ+AyТКСК при РС была изучена в ряде клинических исследований. Тем не менее, объем информации о клинической эффективности данного метода и, особенно, о его влиянии на качество жизни больных РС, остается недостаточным. Кроме того, большинство пациентов, включенных в вышеупомянутые исследования, имели вторично-прогрессирующую форму РС и значительную степень инвалидизации со значением шкалы EDSS 4.5-8.5 баллов. К сожалению, даже полное прекращение активности иммунопатологического процесса у таких больных не может привести к значительному улучшению качества жизни. Поэтому вопрос об оптимальных сроках проведения трансплантации по-прежнему остается открытым.</p> <p>В статье приведены результаты проспективного многоцентрового исследования безопасности и эффективности ВДТ+АуТКСК при РС, которое было начато в 1999 году и в настоящее время объединяет 5 крупных российских медицинских центров. Изучали влияние ВДТ+АуТКСК на клиническое течение и показатели качества жизни больных с разными формами и стадиями РС.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4083) "

Введение

Рассеянный склероз (РС) – хроническое прогрессирующее заболевание центральной нервной системы, которое клинически проявляется мультисистемной неврологической симптоматикой, а патоморфологически характеризуется образованием множественных очагов демиелинизации в белом веществе головного и спинного мозга. Основным механизмом, приводящим к повреждению миелина, является опосредованная Т-лимфоцитами реакция гиперчувствительности замедленного типа, а непосредственными клетками-эффекторами иммунопатологического процесса – макрофаги.

Существующие методы лечения не позволяют достичь устойчивого терапевтического эффекта при рассеянном склерозе. Выдвигалась гипотеза, основанная на доклинических данных, о высокой эффективности аллогенной транплантации стволовых кроветворных клеток (ТСКК). Однако высокая посттрансплантационная летальность не позволила приступить к клиническим исследованиям данного вида терапии РС. По мнению большинства экспертов одним из наиболее перспективных методов лечения РС на сегодняшний день является высокодозная химиотерапия (ВДТ) с аутологичной трансплантацией стволовых кроветворных клеток (АуТСКК). Начиная с 1995 года, безопасность ВДТ+AyТКСК при РС была изучена в ряде клинических исследований. Тем не менее, объем информации о клинической эффективности данного метода и, особенно, о его влиянии на качество жизни больных РС, остается недостаточным. Кроме того, большинство пациентов, включенных в вышеупомянутые исследования, имели вторично-прогрессирующую форму РС и значительную степень инвалидизации со значением шкалы EDSS 4.5-8.5 баллов. К сожалению, даже полное прекращение активности иммунопатологического процесса у таких больных не может привести к значительному улучшению качества жизни. Поэтому вопрос об оптимальных сроках проведения трансплантации по-прежнему остается открытым.

В статье приведены результаты проспективного многоцентрового исследования безопасности и эффективности ВДТ+АуТКСК при РС, которое было начато в 1999 году и в настоящее время объединяет 5 крупных российских медицинских центров. Изучали влияние ВДТ+АуТКСК на клиническое течение и показатели качества жизни больных с разными формами и стадиями РС.

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Введение

Рассеянный склероз (РС) – хроническое прогрессирующее заболевание центральной нервной системы, которое клинически проявляется мультисистемной неврологической симптоматикой, а патоморфологически характеризуется образованием множественных очагов демиелинизации в белом веществе головного и спинного мозга. Основным механизмом, приводящим к повреждению миелина, является опосредованная Т-лимфоцитами реакция гиперчувствительности замедленного типа, а непосредственными клетками-эффекторами иммунопатологического процесса – макрофаги.

Существующие методы лечения не позволяют достичь устойчивого терапевтического эффекта при рассеянном склерозе. Выдвигалась гипотеза, основанная на доклинических данных, о высокой эффективности аллогенной транплантации стволовых кроветворных клеток (ТСКК). Однако высокая посттрансплантационная летальность не позволила приступить к клиническим исследованиям данного вида терапии РС. По мнению большинства экспертов одним из наиболее перспективных методов лечения РС на сегодняшний день является высокодозная химиотерапия (ВДТ) с аутологичной трансплантацией стволовых кроветворных клеток (АуТСКК). Начиная с 1995 года, безопасность ВДТ+AyТКСК при РС была изучена в ряде клинических исследований. Тем не менее, объем информации о клинической эффективности данного метода и, особенно, о его влиянии на качество жизни больных РС, остается недостаточным. Кроме того, большинство пациентов, включенных в вышеупомянутые исследования, имели вторично-прогрессирующую форму РС и значительную степень инвалидизации со значением шкалы EDSS 4.5-8.5 баллов. К сожалению, даже полное прекращение активности иммунопатологического процесса у таких больных не может привести к значительному улучшению качества жизни. Поэтому вопрос об оптимальных сроках проведения трансплантации по-прежнему остается открытым.

В статье приведены результаты проспективного многоцентрового исследования безопасности и эффективности ВДТ+АуТКСК при РС, которое было начато в 1999 году и в настоящее время объединяет 5 крупных российских медицинских центров. Изучали влияние ВДТ+АуТКСК на клиническое течение и показатели качества жизни больных с разными формами и стадиями РС.

" } ["FULL_TEXT_RU"]=> array(37) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(4) "3658" ["VALUE"]=> array(2) { ["TEXT"]=> string(11741) " <h2>Материалы и методы</h2> <p>В исследование было включено 109 больных РС (49 мужчин, 60 женщин; средний возраст – 33 года; диапазон – 17-54): 51 с вторично-прогрессирующим течением, 19 с первично-прогрессирующим, 8 с прогрессирующе-рецидивирующим и 31 с рецидивирующе-ремиттирующим течением. Значение индекса EDSS до трансплантации колебалось от 1.5 до 8.0 баллов (в среднем было равно 5.0 баллам). Длительность наблюдения составила в среднем 19 месяцев (от 6 до 108 месяцев). Активность заболевания определяли с помощью неврологического осмотра и данных магнитно-резонансной томографии.<br> Больным были выполнены следующие виды ВДТ+АуТКСК:<br> <b> - Ранняя трансплантация</b> проводилась в дебюте заболевания при наличии неблагоприятных прогностических факторов в отношении химиорезистентности или возможности тяжелой инвалидизации больного.<br> <b> - Этапная трансплантация</b> проводилась при выходе заболевания из-под контроля традиционных методов лечения и формировании вторичной химиорезистентности.<br> <b> - Трансплантация спасения</b> проводилась в далеко зашедшей стадии заболевания при высокой активности иммунопатологического процесса и быстром прогрессировании инвалидизации больного.<br> Тридцати двум больным была выполнена ранняя трансплантация (EDSS 1.5-3.0); 70 больным - этапная трансплантация (EDSS 3.5-6.5) и 7 больным - трансплантация спасения (EDSS 7.0-8.0).</p> <p> Оценку клинического ответа и ответа, связанного с качеством жизни, проводили до трансплантации, при выписке из стационара, через 3, 6, 9 и 12 месяцев после трансплантации, затем – каждые 6 месяцев в течение первых 4 лет и ежегодно впоследствии. Изучение неврологического статуса включало определение выраженности неврологического дефицита по шкале EDSS и магнитно-резонансную томографию. Качество жизни больных 16 www.ctt-journal.com 2008;1(2) оценивали с использованием опросников FACT-BMT (функциональная оценка состояния больных после трансплантации костного мозга) и FAMS (функциональная оценка больных с рассеянным склерозом). Клиническим улучшением считали уменьшение выраженности неврологической симптоматики, по меньшей мере, на 0.5 балла по шкале EDSS по сравнению с исходным уровнем, при условии, что это улучшение было подтверждено через 6 месяцев на следующем визите. Любое увеличение выраженности неврологической симптоматики по шкале EDSS считали прогрессированием заболевания. Рецидив констатировали при появлении новых симптомов или нарастании выраженности прежних симптомов, по меньшей мере, в течение 24 часов в отсутствие лихорадки у пациента, который был стабилен в течение 4 предшествующих недель. Ответ, связанный с качеством жизни, характеризовался как минимальный, умеренный, хороший или максимальный. Для определения ответа, связанного с качеством жизни, рассчитывали различия в значении интегрального показателя качества жизни до проведения трансплантации и в различные периоды времени после нее.</p> <h2>Результаты</h2> <p>У всех 79 больных со сроком наблюдения ≥9 месяцев отмечено клиническое улучшение или стабилизация в течении заболевания. Во время проведения трансплантации не было зарегистрировано ни одного смертельного исхода и тяжелых неконтролируемых побочных эффектов. Через 6 месяцев после трансплантации распределение пациентов согласно клиническому ответу было следующим: улучшение – 42 (53%) больных, стабилизация – 37 (47%) больных. Среди больных с улучшением у 20 было вторично-прогрессирующее течение, у 7 – первично-прогрессирующее, у 4 – прогрессирующе-рецидивирующее и у 11 – рецидивирующе-ремиттирующее течение. В этой группе 25 больных проведена этапная трансплантация, 15 – ранняя и 2 – трансплантация спасения. Из 37 больных, у которых зарегистрирована стабилизация заболевания, у 19 было вторично-прогрессирующее течение, у 8 – первично-прогрессирующее, у 2 – прогрессирующе-рецидивирующее и у 8 – рецидивирующе-ремиттирующее течение. В этой группе 23 больным проведена этапная трансплантация, 9 – ранняя и 5 – трансплантация спасения.</p> <p> В более длительные сроки наблюдения у 40 больных (50.6%) сохранялось улучшение, у 34 (43.1%) – стабилизация. У одного больного после 6 месяцев и двух больных после 18 месяцев стабилизации произошло повышение индекса инвалидизации. У двух пациентов прогрессирование заболевания наступило после 12 и 30 месяцев клинического улучшения. По данным МРТ у всех больных без прогрессирования заболевания после трансплантации отсутствовали активные или новые очаги поражения. В целом, 6-летняя выживаемость без прогрессии после ВДТ+АуТКСК составила 72%. Больные, у которых не было зарегистрировано признаков прогрессирования заболевания, не получали иммуномодулирующую или иммуносупрессивную терапию после трансплантации. Мониторинг качества жизни проводился у 44 пациентов, включенных в исследование. У 40 из них наблюдали улучшение показателей качества жизни через 6 месяцев после трансплантации. Улучшение параметров качества жизни установлено с помощью опросников – FACT-BMT и FAMS. Через 1 год после ВДТ+АуТКСК зарегистрировано следующее распределение пациентов в соответствии со степенью ответа, связанного с качеством жизни: у 3 больных наблюдали максимальный ответ (более чем 75% улучшение интегрального показателя качества жизни в сравнении с исходным уровнем); у 12 больных – хороший ответ (улучшение на 50-75%); у 11 больных – умеренный ответ (на 25-50%); у 13 – минимальный ответ (улучшение менее чем на 25%) и у 5 больных ответ, связанный с качеством жизни, отсутствовал. Следует отметить, что у пациентов с более длительным сроком наблюдения было отмечено дальнейшее улучшение показателей качества жизни. В статье представлена классификация типов трансплантации при рассеянном склерозе, основанная на концепции ВДТ+ТКСК при аутоиммунных заболеваниях.</p> <h2>Заключение</h2> <p>Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией кроветворных стволовых клеток является эффективным методом лечения больных рассеянным склерозом: у большинства больных после ВДТ+АуТКСК зарегистрировано клиническое улучшение или стабилизация заболевания; ВДТ+АуТКСК сопровождается существенным улучшением качества жизни больных. Результаты свидетельствуют о целесообразности изучения результатов ранней трансплантации, этапной трансплантации и трансплантации спасения. Необходимы дальнейшие исследования для определения оптимальных сроков проведения трансплан-тации и уточнения режимов кондиционирования. </p>" ["TYPE"]=> string(4) "TEXT" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(11579) "

Материалы и методы

В исследование было включено 109 больных РС (49 мужчин, 60 женщин; средний возраст – 33 года; диапазон – 17-54): 51 с вторично-прогрессирующим течением, 19 с первично-прогрессирующим, 8 с прогрессирующе-рецидивирующим и 31 с рецидивирующе-ремиттирующим течением. Значение индекса EDSS до трансплантации колебалось от 1.5 до 8.0 баллов (в среднем было равно 5.0 баллам). Длительность наблюдения составила в среднем 19 месяцев (от 6 до 108 месяцев). Активность заболевания определяли с помощью неврологического осмотра и данных магнитно-резонансной томографии.
Больным были выполнены следующие виды ВДТ+АуТКСК:
- Ранняя трансплантация проводилась в дебюте заболевания при наличии неблагоприятных прогностических факторов в отношении химиорезистентности или возможности тяжелой инвалидизации больного.
- Этапная трансплантация проводилась при выходе заболевания из-под контроля традиционных методов лечения и формировании вторичной химиорезистентности.
- Трансплантация спасения проводилась в далеко зашедшей стадии заболевания при высокой активности иммунопатологического процесса и быстром прогрессировании инвалидизации больного.
Тридцати двум больным была выполнена ранняя трансплантация (EDSS 1.5-3.0); 70 больным - этапная трансплантация (EDSS 3.5-6.5) и 7 больным - трансплантация спасения (EDSS 7.0-8.0).

Оценку клинического ответа и ответа, связанного с качеством жизни, проводили до трансплантации, при выписке из стационара, через 3, 6, 9 и 12 месяцев после трансплантации, затем – каждые 6 месяцев в течение первых 4 лет и ежегодно впоследствии. Изучение неврологического статуса включало определение выраженности неврологического дефицита по шкале EDSS и магнитно-резонансную томографию. Качество жизни больных 16 www.ctt-journal.com 2008;1(2) оценивали с использованием опросников FACT-BMT (функциональная оценка состояния больных после трансплантации костного мозга) и FAMS (функциональная оценка больных с рассеянным склерозом). Клиническим улучшением считали уменьшение выраженности неврологической симптоматики, по меньшей мере, на 0.5 балла по шкале EDSS по сравнению с исходным уровнем, при условии, что это улучшение было подтверждено через 6 месяцев на следующем визите. Любое увеличение выраженности неврологической симптоматики по шкале EDSS считали прогрессированием заболевания. Рецидив констатировали при появлении новых симптомов или нарастании выраженности прежних симптомов, по меньшей мере, в течение 24 часов в отсутствие лихорадки у пациента, который был стабилен в течение 4 предшествующих недель. Ответ, связанный с качеством жизни, характеризовался как минимальный, умеренный, хороший или максимальный. Для определения ответа, связанного с качеством жизни, рассчитывали различия в значении интегрального показателя качества жизни до проведения трансплантации и в различные периоды времени после нее.

Результаты

У всех 79 больных со сроком наблюдения ≥9 месяцев отмечено клиническое улучшение или стабилизация в течении заболевания. Во время проведения трансплантации не было зарегистрировано ни одного смертельного исхода и тяжелых неконтролируемых побочных эффектов. Через 6 месяцев после трансплантации распределение пациентов согласно клиническому ответу было следующим: улучшение – 42 (53%) больных, стабилизация – 37 (47%) больных. Среди больных с улучшением у 20 было вторично-прогрессирующее течение, у 7 – первично-прогрессирующее, у 4 – прогрессирующе-рецидивирующее и у 11 – рецидивирующе-ремиттирующее течение. В этой группе 25 больных проведена этапная трансплантация, 15 – ранняя и 2 – трансплантация спасения. Из 37 больных, у которых зарегистрирована стабилизация заболевания, у 19 было вторично-прогрессирующее течение, у 8 – первично-прогрессирующее, у 2 – прогрессирующе-рецидивирующее и у 8 – рецидивирующе-ремиттирующее течение. В этой группе 23 больным проведена этапная трансплантация, 9 – ранняя и 5 – трансплантация спасения.

В более длительные сроки наблюдения у 40 больных (50.6%) сохранялось улучшение, у 34 (43.1%) – стабилизация. У одного больного после 6 месяцев и двух больных после 18 месяцев стабилизации произошло повышение индекса инвалидизации. У двух пациентов прогрессирование заболевания наступило после 12 и 30 месяцев клинического улучшения. По данным МРТ у всех больных без прогрессирования заболевания после трансплантации отсутствовали активные или новые очаги поражения. В целом, 6-летняя выживаемость без прогрессии после ВДТ+АуТКСК составила 72%. Больные, у которых не было зарегистрировано признаков прогрессирования заболевания, не получали иммуномодулирующую или иммуносупрессивную терапию после трансплантации. Мониторинг качества жизни проводился у 44 пациентов, включенных в исследование. У 40 из них наблюдали улучшение показателей качества жизни через 6 месяцев после трансплантации. Улучшение параметров качества жизни установлено с помощью опросников – FACT-BMT и FAMS. Через 1 год после ВДТ+АуТКСК зарегистрировано следующее распределение пациентов в соответствии со степенью ответа, связанного с качеством жизни: у 3 больных наблюдали максимальный ответ (более чем 75% улучшение интегрального показателя качества жизни в сравнении с исходным уровнем); у 12 больных – хороший ответ (улучшение на 50-75%); у 11 больных – умеренный ответ (на 25-50%); у 13 – минимальный ответ (улучшение менее чем на 25%) и у 5 больных ответ, связанный с качеством жизни, отсутствовал. Следует отметить, что у пациентов с более длительным сроком наблюдения было отмечено дальнейшее улучшение показателей качества жизни. В статье представлена классификация типов трансплантации при рассеянном склерозе, основанная на концепции ВДТ+ТКСК при аутоиммунных заболеваниях.

Заключение

Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией кроветворных стволовых клеток является эффективным методом лечения больных рассеянным склерозом: у большинства больных после ВДТ+АуТКСК зарегистрировано клиническое улучшение или стабилизация заболевания; ВДТ+АуТКСК сопровождается существенным улучшением качества жизни больных. Результаты свидетельствуют о целесообразности изучения результатов ранней трансплантации, этапной трансплантации и трансплантации спасения. Необходимы дальнейшие исследования для определения оптимальных сроков проведения трансплан-тации и уточнения режимов кондиционирования.

" ["TYPE"]=> string(4) "TEXT" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(23) "Полный текст" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(12433) "    <h2>Материалы и методы</h2>
<p>В исследование было включено 109 больных РС (49 мужчин, 60 женщин; средний возраст – 33 года; диапазон – 17-54): 51 с вторично-прогрессирующим течением, 19 с первично-прогрессирующим, 8 с прогрессирующе-рецидивирующим и 31 с рецидивирующе-ремиттирующим течением. Значение индекса EDSS до трансплантации колебалось от 1.5 до 8.0 баллов (в среднем было равно 5.0 баллам). Длительность наблюдения составила в среднем 19 месяцев (от 6 до 108 месяцев). Активность заболевания определяли с помощью неврологического осмотра и данных магнитно-резонансной томографии.<br>
     Больным были выполнены следующие виды ВДТ+АуТКСК:<br>
    <b> - Ранняя трансплантация</b> проводилась в дебюте заболевания при наличии неблагоприятных прогностических факторов в отношении химиорезистентности или возможности тяжелой инвалидизации больного.<br>
    <b> - Этапная трансплантация</b> проводилась при выходе заболевания из-под контроля традиционных методов лечения и формировании вторичной химиорезистентности.<br>
    <b> - Трансплантация спасения</b> проводилась в далеко зашедшей стадии заболевания при высокой активности иммунопатологического процесса и быстром прогрессировании инвалидизации больного.<br>
     Тридцати двум больным была выполнена ранняя трансплантация (EDSS 1.5-3.0); 70 больным - этапная трансплантация (EDSS 3.5-6.5) и 7 больным - трансплантация спасения (EDSS 7.0-8.0).</p>
    <p> Оценку клинического ответа и ответа, связанного с качеством жизни, проводили до трансплантации, при выписке из стационара, через 3, 6, 9 и 12 месяцев после трансплантации, затем – каждые 6 месяцев в течение первых 4 лет и ежегодно впоследствии. Изучение неврологического статуса включало определение выраженности неврологического дефицита по шкале EDSS и магнитно-резонансную томографию. Качество жизни больных
     16 www.ctt-journal.com 2008;1(2)
     оценивали с использованием опросников FACT-BMT (функциональная оценка состояния больных после трансплантации костного мозга) и FAMS (функциональная оценка больных с рассеянным склерозом).
     Клиническим улучшением считали уменьшение выраженности неврологической симптоматики, по меньшей мере, на 0.5 балла по шкале EDSS по сравнению с исходным уровнем, при условии, что это улучшение было подтверждено через 6 месяцев на следующем визите. Любое увеличение выраженности неврологической симптоматики по шкале EDSS считали прогрессированием заболевания. Рецидив констатировали при появлении новых симптомов или нарастании выраженности прежних симптомов, по меньшей мере, в течение 24 часов в отсутствие лихорадки у пациента, который был стабилен в течение 4 предшествующих недель.
     Ответ, связанный с качеством жизни, характеризовался как минимальный, умеренный, хороший или максимальный. Для определения ответа, связанного с качеством жизни, рассчитывали различия в значении интегрального показателя качества жизни до проведения трансплантации и в различные периоды времени после нее.</p>
    <h2>Результаты</h2>
<p>У всех 79 больных со сроком наблюдения ≥9 месяцев отмечено клиническое улучшение или стабилизация в течении заболевания. Во время проведения трансплантации не было зарегистрировано ни одного смертельного исхода и тяжелых неконтролируемых побочных эффектов. Через 6 месяцев после трансплантации распределение пациентов согласно клиническому ответу было следующим: улучшение – 42 (53%) больных, стабилизация – 37 (47%) больных. Среди больных с улучшением у 20 было вторично-прогрессирующее течение, у 7 – первично-прогрессирующее, у 4 – прогрессирующе-рецидивирующее и у 11 – рецидивирующе-ремиттирующее течение. В этой группе 25 больных проведена этапная трансплантация, 15 – ранняя и 2 – трансплантация спасения. Из 37 больных, у которых зарегистрирована стабилизация заболевания, у 19 было вторично-прогрессирующее течение, у 8 – первично-прогрессирующее, у 2 – прогрессирующе-рецидивирующее и у 8 – рецидивирующе-ремиттирующее течение. В этой группе 23 больным проведена этапная трансплантация, 9 – ранняя и 5 – трансплантация спасения.</p>
    <p> В более длительные сроки наблюдения у 40 больных (50.6%) сохранялось улучшение, у 34 (43.1%) – стабилизация. У одного больного после 6 месяцев и двух больных после 18 месяцев стабилизации произошло повышение индекса инвалидизации. У двух пациентов прогрессирование заболевания наступило после 12 и 30 месяцев клинического улучшения.
     По данным МРТ у всех больных без прогрессирования заболевания после трансплантации отсутствовали активные или новые очаги поражения. В целом, 6-летняя выживаемость без прогрессии после ВДТ+АуТКСК составила 72%. Больные, у которых не было зарегистрировано признаков прогрессирования заболевания, не получали иммуномодулирующую или иммуносупрессивную терапию после трансплантации.
     Мониторинг качества жизни проводился у 44 пациентов, включенных в исследование. У 40 из них наблюдали улучшение показателей качества жизни через 6 месяцев после трансплантации. Улучшение параметров качества жизни установлено с помощью опросников – FACT-BMT и FAMS. Через 1 год после ВДТ+АуТКСК зарегистрировано следующее распределение пациентов в соответствии со степенью ответа, связанного с качеством жизни: у 3 больных наблюдали максимальный ответ (более чем 75% улучшение интегрального показателя качества жизни в сравнении с исходным уровнем); у 12 больных – хороший ответ (улучшение на 50-75%); у 11 больных – умеренный ответ (на 25-50%); у 13 – минимальный ответ (улучшение менее чем на 25%) и у 5 больных ответ, связанный с качеством жизни, отсутствовал. Следует отметить, что у пациентов с более длительным сроком наблюдения было отмечено дальнейшее улучшение показателей качества жизни.
     В статье представлена классификация типов трансплантации при рассеянном склерозе, основанная на концепции ВДТ+ТКСК при аутоиммунных заболеваниях.</p>

     <h2>Заключение</h2>
<p>Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией кроветворных стволовых клеток является эффективным методом лечения больных рассеянным склерозом: у большинства больных после ВДТ+АуТКСК зарегистрировано клиническое улучшение или стабилизация заболевания; ВДТ+АуТКСК сопровождается существенным улучшением качества жизни больных. Результаты свидетельствуют о целесообразности изучения результатов ранней трансплантации, этапной трансплантации и трансплантации спасения. Необходимы дальнейшие исследования для определения оптимальных сроков проведения трансплан-тации и уточнения режимов кондиционирования.
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Introduction

Stromal cells of the hematopoietic microenvironment are the progeny of mesenchymal stem cells (MSC). MSC are non-hematopoietic multipotent stem cells able to differentiate into different cells lines, such as osteoblasts, adipocytes, chondrocytes, fibroblasts, and other cell lines [1]. The ability to self-renew has not been proven for human MSC [2]; however, these cells are known to have high proliferative potential when cultured. Murine MSC are able to transfer a hematopoietic microenvironment in vivo at least 9 times, confirming their ability for self-maintenance [3]. Until now, the data about phenotypical markers of MSC has not been developed sufficiently [4], but MSC are able to express the number of non-specific markers [5]. It was shown recently that fibroblast activation protein perfectly identifies mesenchymal stromal cells [6]. The compartment of stromal precursor cells can be characterized by physiological methods according to the first 25 years of hematopoietic stem cells (HSC) research. Explantation of bone marrow cell suspension into culture flasks led to the development of discrete fibroblast-like colonies. Each colony represents a clone produced by single clonogenic precursor cells–colony-forming unit fibroblasts (CFU-F) [7]. CFU-F are of mesenchymal origin and do not develop from HSC [8, 9]. CFU-F are heterogenic cell populations and some of them possess high proliferative potential; their ability to differentiate could be associated with MSC [10]. The transplantation of the pull of colonies into the organism leads to the development of different tissues, including bone and adipose tissues [11, 12]. The comparison of CFU-F with MSC is questionable because CFU-F are able to differentiate inside the diffusion chambers after implantation to the organism, but it is not known whether they are able to transfer the full microenvironment or self-maintain. Recent data suggests that CD146+ CFU-F with high proliferative capacity, are able to transfer the microenvironment, but this can be applied only to rare cells in the bone marrow [13]. Moreover, human multipotent stromal cells readily form single-cell-derived colonies, which are heterogeneous because cells from a colony form new colonies that vary in size and differentiation potential [14]. Several growth factors influence the CFU-F growth, and four of them are necessary for CFU-F development: PDGF, bFGF, TGFβ and EGF [15]. The proliferative potential of CFU-F is not studied in detail, but it is known that most of the CFU-F in the organism are not cycling and remain in the “Go” phase [16]. However, CFU-F start to proliferate when transferred to cultures.

The compartments of MSC and HSC have hierarchical structures. This is well known for HSC, but in the case of MSC it was discovered for the first time in experiments with ectopic foci formation in vivo. At 6 weeks after implantation of the donor bone marrow plug under the renal capsule of the syngeneic recipient, ectopic hematopoietic foci developed at the site of transplantation. In such foci, stromal cells belong to the donor, and hematopoietic cells belong to the recipient. Multiple histological examinations during foci formation have revealed that the hematopoietic microenvironment was built de novo. The method of ectopic foci formation is not only qualitative, but also quantitative. The size of the hematopoietic territory is defined by the number of MSCs transplanted, and restricted accordingly to the number of niches transferred with the bone marrow plug; since the foci size is proportional to the amount of implanted bone marrow. It is possible to transfer the foci under the renal capsule of the secondary recipient. In this case foci again would be built de novo due to the presence of MSC. The foci sustain at least 9 re-transplantations that prove the high capability of MSC to self-renew [3]. The radio-sensitivity of MSC is much lower than that of HSC [17]. In summarizing this data it is possible to conclude that stromal precursor cells that are able to transfer the microenvironment are true stem cells and the method of ectopic foci formation allows the opportunity to estimate their numbers in bone marrow.

In irradiated recipients foci formed after the implantation of bone marrow plugs are enlarged 2-3 fold in comparison with foci developed in non-irradiated mice. However, the re-transplantation of these enlarged foci to non-irradiated recipients led to the formation of foci of normal size. Thus, in the enlarged foci the number of MSC do not increase, and the microenvironment created in the irradiated recipients is enlarged by cells other than MSC inducible precursor cells, which are not able to self-renew [18]. Such stromal multipotent precursor (SMP) cells have the position in the hierarchy of MSC similar to the position of the multipotent precursor in the hierarchy of HSC. The position of CFU-F in the hierarchy of MSC is unknown. It is possible to define it by studying the concentration of CFU-F in ectopic foci formed in non-irradiated and irradiated recipients. There are three possible variants for the irradiated recipients: the concentration of CFU-F could increase, decrease, or remain unchanged. We suppose that CFU-F could be considered to be the progeny of SMP in cases where their concentration in enlarged foci do not change and their numbers increase 2-3 fold according to the foci size. In cases of both decreased concentration and number of CFU-F in enlarged foci, it is possible to assume that these precursor cells with limited proliferative potential are used irreversibly to form SMP, thus CFU-F are located higher than SMP in the hierarchy of MSC and have the position directly before SMP. If the actual number of CFU-F in the enlarged foci do not change, one could conclude that there are precursors that do not take part in the formation of the microenvironment and represent special populations of stromal clonogenic cells.

The measurement of the concentration and number of CFU-F in ectopic foci in irradiated and non-irradiated recipients performed in this study defines the position of CFU-F immediately after MSC and before SMP in the hierarchy of mesenchymal stem cells.

Materials and methods

The hybrid mice (СВАхC57Bl/6) F1 at the age of 12-16 weeks at the beginning of the experiment were used. The animals were irradiated on the IPK 137Cs irradiator with a dose rate of 16 сGy/min.

For CFU-F analysis 106 bone marrow cells were seeded into the T25 flask in 5 ml αМЕМ (ICN) with 20% fetal bovine serum (Hyclone) and 5 ng/ml basic Fibroblast Growth Factor (bFGF) (donated by Gasparian M.E., Lab. of Protein engineering, IBC, RAS). Cells were cultivated for 14 days in 370С and 5% СО2. Formed colonies were stained with 0.1% crystal violet on 20% methanol and counted under the inverted microscope (the colony was counted if it contained no less than 50 cells).

For cloning of individual CFU-F, bone marrow cells were planted into a 96-well plate in concentrations from 30,000 to 50,000 of nucleated cells per well in standard media. In this cultivation system the most convenient concentration turned out to be 30,000 cells per well (Table 1). In this assay the frequency of CFU-F was calculated by means of the Poisson equation:

2008-2-en-Shipounova-et-al-MSC-Equation.jpg

Table 1. Frequency of CFU-F in the bone marrow of mice

2008-2-en-Shipounova-et-al-MSC-Table-1.jpg

Clones from the wells containing single colonies were transferred into 24-well plates, then into 6-well plates, and finally into T25 flasks. For each procedure, the cells were washed with Versen solution and detached with 0.25% tripsin solution. The proliferative potential of CFU-F was estimated by their ability to form a confluent monolayer during sequential transfers from small to large available growth areas. The number of divisions performed by CFU-F progeny was evaluated by the assumption that the number of cells in the confluent monolayer increases proportionally to the growth area. For instance, the bottom square of the well in a 96-well plate is 0.32 cm2; 24-well, 1.88 cm2; 6-well, 9.4 cm2; and a Т25 flask is 25 cm2. If the confluent monolayer is transferred from one well of a 96-well plate into one well of a 24-well plate, the size of available growth area increases 6-fold; from a 24-well plate to a 6-well plate is 5-fold; and from a 6-well plate into a T25 flask is 2.3-fold. One could calculate easily that in order to cover the bottom surface of one well of a 6-well plate the cells should be divided 5 times (counting from confluent monolayer of one well of a 96-well plate) and have to go through one more mitosis to reach the confluent monolayer in flask T25.

The method of ectopic foci formation has been described previously [18]. In brief, the bone marrow plug was implanted under the renal capsule of non-irradited or irradiated with the dose of 6-10 Gy syngeneic recipient mice. Hematopoiesis in animals irradiated with 10 Gy was carried out by the intravenous injection of syngeneic bone marrow cells (no less than 106 bone marrow cells per mouse). Six weeks later, the size of the developed ectopic foci was measured by the calculation of the number of nucleated cells inside the foci. The number of CFU-F in ectopic foci was measured by the standard method described above.

Statistical analysis was performed using Student's t-test.

Results and discussion

CFU-F is a heterogenic group of stromal precursor cells with different proliferative potential. The concentration of CFU-F per 106 bone marrow cells in non-irradiated and irradiated with 6 Gy mice 1.5 to 3 months before the analysis does not differ significantly (68.4 ± 8.3 versus 80.6 ± 7.4 correspondingly). CFU-F derived colonies from the bone marrow of non-irradiated and sub-lethally irradiated mice after cloning (seeding concentration 30,000 cells per well of the 96-well plate) were sequentially re-transplanted to 24- and 6- well plates, and subsequently to a T25 flask (Fig. 1). Cells from only 30% of CFU-F derived colonies from non-irradiated mice and 6.25% from irradiated ones were able to undergo more than six rounds of mitosis. After irradiation, the proliferative potential of CFU-F decreased while their concentration in the bone marrow did not change. Precursor cells that survived the irradiation filled the concentration of CFU-F in the bone marrow that resulted in the exhaustion of precursors with high enough proliferative potential. On the contrary, after treatment of mice with different cytostatic agents the concentration of CFU-F in the bone marrow decreased dramatically, and even at 6 weeks after the end of treatment the concentration was not restored [19]. Taking into consideration that stromal cells are highly radio-resistant, one could suggest that CFU-F regenerate after irradiation much more efficiently than after cytostatics.

2008-2-en-Shipounova-et-al-MSC-Figure-1.jpg


Figure 1. Proportion of CFU-F derived colonies from bone marrow of non-irradiated and irradiated mice which are able to grow to the confluent monolayer in different culture ware.


Data are shown as the means (±SEM).
Axis of abscissa: culture ware
Axis of ordinate: percent of wells that reached confluence

The implantation of confluent monolayers from 9 CFU-F derived colonies, grown in T25 flasks after sequential re-transplantations under the renal capsule of syngeneic recipients, resulted in no foci formation. Therefore, CFU-F derived cells are not able to transfer the hematopoietic microenvironment. Probably only the very rare CD146 positive CFU-F are able to proliferate and differentiate in vivo forming bone marrow hematopoietic microenvironment [13].

CFU-F in ectopic foci has not been characterized yet. The concentration of CFU-F in the ectopic foci turned out to be lower than in the bone marrow (Fig. 2А). The concentration of CFU-F in ectopic foci formed in irradiated recipients was reduced 20-fold in comparison with foci formed in non-irradiated recipients. As the size of the foci in irradiated recipients is enlarged significantly (Fig. 2B), the actual number of CFU-F in such foci is only 3-fold lower than in foci formed in non-irradiated recipients (Fig. 2C).

2008-2-en-Shipounova-et-al-MSC-Figure-2A.jpg


Figure 2. CFU-F in the ectopic foci formed in non-irradiated and irradiated recipients.

А. Concentration of CFU-F in the ectopic foci and bone marrow of non-irradiated mice.om bone marrow of non-irradiated and irradiated mice which are able to grow to the confluent monolayer in different culture ware.


Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of CFU-F per 106 cells

2008-2-en-Shipounova-et-al-MSC-Figure-2B.jpg


B. The size of ectopic foci formed in non-irradiated and irradiated recipients.


Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of nucleated cells in the foci, х 106

2008-2-en-Shipounova-et-al-MSC-Figure-2C.jpg

C. CFU-F number in the ectopic foci.

Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of CFU-F per foci


Thus, it is possible to suggest that the position of CFU-F in the hierarchy of MSC is higher than the position of SMP, but lower than MSC.

Stromal growth factor produced by bones of irradiated recipients induces the formation of enlarged foci and has been shown to persist in blood [20]. Addition of murine sera to CFU-F cultivation media increased their number [21]. However, addition of 2.5% of sera from irradiated mice to cultivation media for CFU-F decreased their number dramatically (Fig. 3). A high number of separate cells that were not producing clones could be seen on the flask bottom, which is atypical for the method and the mode of CFU-F growth. One could suggest several causes for the decreasing CFU-F number in the presence of sera from irradiated mice. It is impossible to neglect the difficulties in CFU-F against the background of a multitude of separate cells revealed after the addition of sera from irradiated mice. On the other hand, stromal growth factor from this serum obviously stimulated the differentiation of CFU-F progeny, as if inducing hematopoietic territory as it happens in vivo during the development of hematopoietic ectopic foci in irradiated recipients. The in vitro decrease of CFU-F concentration in this case is also analogous to the results obtained in vivo. Therefore, the data concerning the effect of the addition of sera from irradiated mice on CFU-F growth also supports the proposed positions of SMP and CFU-F in the hierarchy of MSC.

2008-2-en-Shipounova-et-al-MSC-Figure-3.jpg


Figure 3. Effect of sera from non-irradiated and irradiated mice on the number of CFU-F.


Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of CFU-F per 106 cell

Analysis of the total data positioned CFU-F in the hierarchy of stromal precursor cells (Fig. 4). These heterogenic groups are not able to self-renew, but their high proliferative potential is the result of being the progeny of MSC. SMP, stimulated by stromal growth factor, enlarges the hematopoietic territory in irradiated recipients and takes place at a lower position than CFU-F. There is still a lot of research that needs to be done regarding the hierarchy of MSC.

Figure 4. Hierarchy of MSC

2008-2-en-Shipounova-et-al-MSC-Figure-4.jpg

Acknowledgements

This study was supported by Grant 07-04-00183-а of Russian Fund of Fundamental science.

References

1. Caplan AI. The mesengenic process. Clin Plast Surg. 1994;21:429-435.

2. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, and Keating A. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy. 2005;7:393-395.

3. Chertkov JL and Gurevitch OA. Self-maintenance ability and kinetics of haemopoietic stroma precursors. Cell Tissue Kinet. 1980;13:535-541.

4. Short B, Brouard N, Occhiodoro-Scott T, Ramakrishnan A, and Simmons PJ. Mesenchymal stem cells. Arch Med Res. 2003;34:565-571.

5. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, and Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315-317.

6. Bae S, Park CW, Son HK, Ju HK, Paik D, Jeon CJ, Koh GY, Kim J, and Kim H. Fibroblast activation protein alpha identifies mesenchymal stromal cells from human bone marrow. Br J Haematol. 2008;142:827-830.

7. Friedenstein AJ, Chailakhjan RK, and Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 1970;3:393-403.

8. Castro-Malaspina H, Gay RE, Jhanwar SC, Hamilton JA, Chiarieri DR, Meyers PA, Gay S, and Moore MA. Characteristics of bone marrow fibroblast colony-forming cells (CFU-F) and their progeny in patients with myeloproliferative disorders. Blood. 1982;59:1046-1054.

9. Koide Y, Morikawa S, Mabuchi Y, Muguruma Y, Hiratsu E, Hasegawa K, Kobayashi M, Ando K, Kinjo K, Okano H, and Matsuzaki Y. Two distinct stem cell lineages in murine bone marrow. Stem Cells. 2007;25:1213-1221.

10. Owen M and Friedenstein AJ. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found Symp. 1988;136:42-60.

11. Friedenstein AJ, Chailakhyan RK, and Gerasimov UV. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet. 1987;20:263-272.

12. Bennett JH, Joyner CJ, Triffitt JT, and Owen ME.  Adipocytic cells cultured from marrow have osteogenic potential. J Cell Sci. 1991;99(Pt 1): 131-139.

13. Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, Tagliafico E, Ferrari S, Robey PG, Riminucci M, and Bianco P. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell. 2007;131:324-336.

14. Ylostalo J, Bazhanov N, and Prockop DJ. Reversible commitment to differentiation by human multipotent stromal cells in single-cell-derived colonies. Exp Hematol. 2008.

15. Kuznetsov SA, Friedenstein AJ, and Robey PG. Factors required for bone marrow stromal fibroblast colony formation in vitro. Br J Haematol. 1997;97:561-570.

16. Kaneko S, Motomura S, and Ibayashi H. Differentiation of human bone marrow-derived fibroblastoid colony forming cells (CFU-F) and their roles in haemopoiesis in vitro. Br J Haematol. 1982;51:217-225.

17. Chertkov JL and Gurevitch OA. Radiosencitivity of precursors of hematopoietic microenvironment. Radiat Res. 1979;79:177-186.

18. Chertkov JL and Gurevitch OA. Hematopoietic stem cell and its microenvironment. Moscow: Meditzina; 1984.

19. Nifontova I, Svinareva D, Petrova T, and Drize N. Sensitivity of Mesenchymal Stem Cells and Their Progeny to Medicines Used for the Treatment of Hematoproliferative Diseases. Acta Haematol. 2008;119:98-103.

20. Drize NI, Ershler MA, and Chertkov IL. Radiation-induced hemopoietic cell growth factor: detection in a culture. Bull Exp Biol Med. 2001;132:1213-1215.

21. Abe R, Donnelly SC, Peng T, Bucala R, and Metz CN. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol. 2001;166:7556-7562.


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Introduction

Stromal cells of the hematopoietic microenvironment are the progeny of mesenchymal stem cells (MSC). MSC are non-hematopoietic multipotent stem cells able to differentiate into different cells lines, such as osteoblasts, adipocytes, chondrocytes, fibroblasts, and other cell lines [1]. The ability to self-renew has not been proven for human MSC [2]; however, these cells are known to have high proliferative potential when cultured. Murine MSC are able to transfer a hematopoietic microenvironment in vivo at least 9 times, confirming their ability for self-maintenance [3]. Until now, the data about phenotypical markers of MSC has not been developed sufficiently [4], but MSC are able to express the number of non-specific markers [5]. It was shown recently that fibroblast activation protein perfectly identifies mesenchymal stromal cells [6]. The compartment of stromal precursor cells can be characterized by physiological methods according to the first 25 years of hematopoietic stem cells (HSC) research. Explantation of bone marrow cell suspension into culture flasks led to the development of discrete fibroblast-like colonies. Each colony represents a clone produced by single clonogenic precursor cells–colony-forming unit fibroblasts (CFU-F) [7]. CFU-F are of mesenchymal origin and do not develop from HSC [8, 9]. CFU-F are heterogenic cell populations and some of them possess high proliferative potential; their ability to differentiate could be associated with MSC [10]. The transplantation of the pull of colonies into the organism leads to the development of different tissues, including bone and adipose tissues [11, 12]. The comparison of CFU-F with MSC is questionable because CFU-F are able to differentiate inside the diffusion chambers after implantation to the organism, but it is not known whether they are able to transfer the full microenvironment or self-maintain. Recent data suggests that CD146+ CFU-F with high proliferative capacity, are able to transfer the microenvironment, but this can be applied only to rare cells in the bone marrow [13]. Moreover, human multipotent stromal cells readily form single-cell-derived colonies, which are heterogeneous because cells from a colony form new colonies that vary in size and differentiation potential [14]. Several growth factors influence the CFU-F growth, and four of them are necessary for CFU-F development: PDGF, bFGF, TGFβ and EGF [15]. The proliferative potential of CFU-F is not studied in detail, but it is known that most of the CFU-F in the organism are not cycling and remain in the “Go” phase [16]. However, CFU-F start to proliferate when transferred to cultures.

The compartments of MSC and HSC have hierarchical structures. This is well known for HSC, but in the case of MSC it was discovered for the first time in experiments with ectopic foci formation in vivo. At 6 weeks after implantation of the donor bone marrow plug under the renal capsule of the syngeneic recipient, ectopic hematopoietic foci developed at the site of transplantation. In such foci, stromal cells belong to the donor, and hematopoietic cells belong to the recipient. Multiple histological examinations during foci formation have revealed that the hematopoietic microenvironment was built de novo. The method of ectopic foci formation is not only qualitative, but also quantitative. The size of the hematopoietic territory is defined by the number of MSCs transplanted, and restricted accordingly to the number of niches transferred with the bone marrow plug; since the foci size is proportional to the amount of implanted bone marrow. It is possible to transfer the foci under the renal capsule of the secondary recipient. In this case foci again would be built de novo due to the presence of MSC. The foci sustain at least 9 re-transplantations that prove the high capability of MSC to self-renew [3]. The radio-sensitivity of MSC is much lower than that of HSC [17]. In summarizing this data it is possible to conclude that stromal precursor cells that are able to transfer the microenvironment are true stem cells and the method of ectopic foci formation allows the opportunity to estimate their numbers in bone marrow.

In irradiated recipients foci formed after the implantation of bone marrow plugs are enlarged 2-3 fold in comparison with foci developed in non-irradiated mice. However, the re-transplantation of these enlarged foci to non-irradiated recipients led to the formation of foci of normal size. Thus, in the enlarged foci the number of MSC do not increase, and the microenvironment created in the irradiated recipients is enlarged by cells other than MSC inducible precursor cells, which are not able to self-renew [18]. Such stromal multipotent precursor (SMP) cells have the position in the hierarchy of MSC similar to the position of the multipotent precursor in the hierarchy of HSC. The position of CFU-F in the hierarchy of MSC is unknown. It is possible to define it by studying the concentration of CFU-F in ectopic foci formed in non-irradiated and irradiated recipients. There are three possible variants for the irradiated recipients: the concentration of CFU-F could increase, decrease, or remain unchanged. We suppose that CFU-F could be considered to be the progeny of SMP in cases where their concentration in enlarged foci do not change and their numbers increase 2-3 fold according to the foci size. In cases of both decreased concentration and number of CFU-F in enlarged foci, it is possible to assume that these precursor cells with limited proliferative potential are used irreversibly to form SMP, thus CFU-F are located higher than SMP in the hierarchy of MSC and have the position directly before SMP. If the actual number of CFU-F in the enlarged foci do not change, one could conclude that there are precursors that do not take part in the formation of the microenvironment and represent special populations of stromal clonogenic cells.

The measurement of the concentration and number of CFU-F in ectopic foci in irradiated and non-irradiated recipients performed in this study defines the position of CFU-F immediately after MSC and before SMP in the hierarchy of mesenchymal stem cells.

Materials and methods

The hybrid mice (СВАхC57Bl/6) F1 at the age of 12-16 weeks at the beginning of the experiment were used. The animals were irradiated on the IPK 137Cs irradiator with a dose rate of 16 сGy/min.

For CFU-F analysis 106 bone marrow cells were seeded into the T25 flask in 5 ml αМЕМ (ICN) with 20% fetal bovine serum (Hyclone) and 5 ng/ml basic Fibroblast Growth Factor (bFGF) (donated by Gasparian M.E., Lab. of Protein engineering, IBC, RAS). Cells were cultivated for 14 days in 370С and 5% СО2. Formed colonies were stained with 0.1% crystal violet on 20% methanol and counted under the inverted microscope (the colony was counted if it contained no less than 50 cells).

For cloning of individual CFU-F, bone marrow cells were planted into a 96-well plate in concentrations from 30,000 to 50,000 of nucleated cells per well in standard media. In this cultivation system the most convenient concentration turned out to be 30,000 cells per well (Table 1). In this assay the frequency of CFU-F was calculated by means of the Poisson equation:

2008-2-en-Shipounova-et-al-MSC-Equation.jpg

Table 1. Frequency of CFU-F in the bone marrow of mice

2008-2-en-Shipounova-et-al-MSC-Table-1.jpg

Clones from the wells containing single colonies were transferred into 24-well plates, then into 6-well plates, and finally into T25 flasks. For each procedure, the cells were washed with Versen solution and detached with 0.25% tripsin solution. The proliferative potential of CFU-F was estimated by their ability to form a confluent monolayer during sequential transfers from small to large available growth areas. The number of divisions performed by CFU-F progeny was evaluated by the assumption that the number of cells in the confluent monolayer increases proportionally to the growth area. For instance, the bottom square of the well in a 96-well plate is 0.32 cm2; 24-well, 1.88 cm2; 6-well, 9.4 cm2; and a Т25 flask is 25 cm2. If the confluent monolayer is transferred from one well of a 96-well plate into one well of a 24-well plate, the size of available growth area increases 6-fold; from a 24-well plate to a 6-well plate is 5-fold; and from a 6-well plate into a T25 flask is 2.3-fold. One could calculate easily that in order to cover the bottom surface of one well of a 6-well plate the cells should be divided 5 times (counting from confluent monolayer of one well of a 96-well plate) and have to go through one more mitosis to reach the confluent monolayer in flask T25.

The method of ectopic foci formation has been described previously [18]. In brief, the bone marrow plug was implanted under the renal capsule of non-irradited or irradiated with the dose of 6-10 Gy syngeneic recipient mice. Hematopoiesis in animals irradiated with 10 Gy was carried out by the intravenous injection of syngeneic bone marrow cells (no less than 106 bone marrow cells per mouse). Six weeks later, the size of the developed ectopic foci was measured by the calculation of the number of nucleated cells inside the foci. The number of CFU-F in ectopic foci was measured by the standard method described above.

Statistical analysis was performed using Student's t-test.

Results and discussion

CFU-F is a heterogenic group of stromal precursor cells with different proliferative potential. The concentration of CFU-F per 106 bone marrow cells in non-irradiated and irradiated with 6 Gy mice 1.5 to 3 months before the analysis does not differ significantly (68.4 ± 8.3 versus 80.6 ± 7.4 correspondingly). CFU-F derived colonies from the bone marrow of non-irradiated and sub-lethally irradiated mice after cloning (seeding concentration 30,000 cells per well of the 96-well plate) were sequentially re-transplanted to 24- and 6- well plates, and subsequently to a T25 flask (Fig. 1). Cells from only 30% of CFU-F derived colonies from non-irradiated mice and 6.25% from irradiated ones were able to undergo more than six rounds of mitosis. After irradiation, the proliferative potential of CFU-F decreased while their concentration in the bone marrow did not change. Precursor cells that survived the irradiation filled the concentration of CFU-F in the bone marrow that resulted in the exhaustion of precursors with high enough proliferative potential. On the contrary, after treatment of mice with different cytostatic agents the concentration of CFU-F in the bone marrow decreased dramatically, and even at 6 weeks after the end of treatment the concentration was not restored [19]. Taking into consideration that stromal cells are highly radio-resistant, one could suggest that CFU-F regenerate after irradiation much more efficiently than after cytostatics.

2008-2-en-Shipounova-et-al-MSC-Figure-1.jpg


Figure 1. Proportion of CFU-F derived colonies from bone marrow of non-irradiated and irradiated mice which are able to grow to the confluent monolayer in different culture ware.


Data are shown as the means (±SEM).
Axis of abscissa: culture ware
Axis of ordinate: percent of wells that reached confluence

The implantation of confluent monolayers from 9 CFU-F derived colonies, grown in T25 flasks after sequential re-transplantations under the renal capsule of syngeneic recipients, resulted in no foci formation. Therefore, CFU-F derived cells are not able to transfer the hematopoietic microenvironment. Probably only the very rare CD146 positive CFU-F are able to proliferate and differentiate in vivo forming bone marrow hematopoietic microenvironment [13].

CFU-F in ectopic foci has not been characterized yet. The concentration of CFU-F in the ectopic foci turned out to be lower than in the bone marrow (Fig. 2А). The concentration of CFU-F in ectopic foci formed in irradiated recipients was reduced 20-fold in comparison with foci formed in non-irradiated recipients. As the size of the foci in irradiated recipients is enlarged significantly (Fig. 2B), the actual number of CFU-F in such foci is only 3-fold lower than in foci formed in non-irradiated recipients (Fig. 2C).

2008-2-en-Shipounova-et-al-MSC-Figure-2A.jpg


Figure 2. CFU-F in the ectopic foci formed in non-irradiated and irradiated recipients.

А. Concentration of CFU-F in the ectopic foci and bone marrow of non-irradiated mice.om bone marrow of non-irradiated and irradiated mice which are able to grow to the confluent monolayer in different culture ware.


Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of CFU-F per 106 cells

2008-2-en-Shipounova-et-al-MSC-Figure-2B.jpg


B. The size of ectopic foci formed in non-irradiated and irradiated recipients.


Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of nucleated cells in the foci, х 106

2008-2-en-Shipounova-et-al-MSC-Figure-2C.jpg

C. CFU-F number in the ectopic foci.

Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of CFU-F per foci


Thus, it is possible to suggest that the position of CFU-F in the hierarchy of MSC is higher than the position of SMP, but lower than MSC.

Stromal growth factor produced by bones of irradiated recipients induces the formation of enlarged foci and has been shown to persist in blood [20]. Addition of murine sera to CFU-F cultivation media increased their number [21]. However, addition of 2.5% of sera from irradiated mice to cultivation media for CFU-F decreased their number dramatically (Fig. 3). A high number of separate cells that were not producing clones could be seen on the flask bottom, which is atypical for the method and the mode of CFU-F growth. One could suggest several causes for the decreasing CFU-F number in the presence of sera from irradiated mice. It is impossible to neglect the difficulties in CFU-F against the background of a multitude of separate cells revealed after the addition of sera from irradiated mice. On the other hand, stromal growth factor from this serum obviously stimulated the differentiation of CFU-F progeny, as if inducing hematopoietic territory as it happens in vivo during the development of hematopoietic ectopic foci in irradiated recipients. The in vitro decrease of CFU-F concentration in this case is also analogous to the results obtained in vivo. Therefore, the data concerning the effect of the addition of sera from irradiated mice on CFU-F growth also supports the proposed positions of SMP and CFU-F in the hierarchy of MSC.

2008-2-en-Shipounova-et-al-MSC-Figure-3.jpg


Figure 3. Effect of sera from non-irradiated and irradiated mice on the number of CFU-F.


Data are shown as the means (±SEM).
Axis of abscissa: group
Axis of ordinate: number of CFU-F per 106 cell

Analysis of the total data positioned CFU-F in the hierarchy of stromal precursor cells (Fig. 4). These heterogenic groups are not able to self-renew, but their high proliferative potential is the result of being the progeny of MSC. SMP, stimulated by stromal growth factor, enlarges the hematopoietic territory in irradiated recipients and takes place at a lower position than CFU-F. There is still a lot of research that needs to be done regarding the hierarchy of MSC.

Figure 4. Hierarchy of MSC

2008-2-en-Shipounova-et-al-MSC-Figure-4.jpg

Acknowledgements

This study was supported by Grant 07-04-00183-а of Russian Fund of Fundamental science.

References

1. Caplan AI. The mesengenic process. Clin Plast Surg. 1994;21:429-435.

2. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, and Keating A. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy. 2005;7:393-395.

3. Chertkov JL and Gurevitch OA. Self-maintenance ability and kinetics of haemopoietic stroma precursors. Cell Tissue Kinet. 1980;13:535-541.

4. Short B, Brouard N, Occhiodoro-Scott T, Ramakrishnan A, and Simmons PJ. Mesenchymal stem cells. Arch Med Res. 2003;34:565-571.

5. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, and Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315-317.

6. Bae S, Park CW, Son HK, Ju HK, Paik D, Jeon CJ, Koh GY, Kim J, and Kim H. Fibroblast activation protein alpha identifies mesenchymal stromal cells from human bone marrow. Br J Haematol. 2008;142:827-830.

7. Friedenstein AJ, Chailakhjan RK, and Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 1970;3:393-403.

8. Castro-Malaspina H, Gay RE, Jhanwar SC, Hamilton JA, Chiarieri DR, Meyers PA, Gay S, and Moore MA. Characteristics of bone marrow fibroblast colony-forming cells (CFU-F) and their progeny in patients with myeloproliferative disorders. Blood. 1982;59:1046-1054.

9. Koide Y, Morikawa S, Mabuchi Y, Muguruma Y, Hiratsu E, Hasegawa K, Kobayashi M, Ando K, Kinjo K, Okano H, and Matsuzaki Y. Two distinct stem cell lineages in murine bone marrow. Stem Cells. 2007;25:1213-1221.

10. Owen M and Friedenstein AJ. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found Symp. 1988;136:42-60.

11. Friedenstein AJ, Chailakhyan RK, and Gerasimov UV. Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet. 1987;20:263-272.

12. Bennett JH, Joyner CJ, Triffitt JT, and Owen ME.  Adipocytic cells cultured from marrow have osteogenic potential. J Cell Sci. 1991;99(Pt 1): 131-139.

13. Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, Tagliafico E, Ferrari S, Robey PG, Riminucci M, and Bianco P. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell. 2007;131:324-336.

14. Ylostalo J, Bazhanov N, and Prockop DJ. Reversible commitment to differentiation by human multipotent stromal cells in single-cell-derived colonies. Exp Hematol. 2008.

15. Kuznetsov SA, Friedenstein AJ, and Robey PG. Factors required for bone marrow stromal fibroblast colony formation in vitro. Br J Haematol. 1997;97:561-570.

16. Kaneko S, Motomura S, and Ibayashi H. Differentiation of human bone marrow-derived fibroblastoid colony forming cells (CFU-F) and their roles in haemopoiesis in vitro. Br J Haematol. 1982;51:217-225.

17. Chertkov JL and Gurevitch OA. Radiosencitivity of precursors of hematopoietic microenvironment. Radiat Res. 1979;79:177-186.

18. Chertkov JL and Gurevitch OA. Hematopoietic stem cell and its microenvironment. Moscow: Meditzina; 1984.

19. Nifontova I, Svinareva D, Petrova T, and Drize N. Sensitivity of Mesenchymal Stem Cells and Their Progeny to Medicines Used for the Treatment of Hematoproliferative Diseases. Acta Haematol. 2008;119:98-103.

20. Drize NI, Ershler MA, and Chertkov IL. Radiation-induced hemopoietic cell growth factor: detection in a culture. Bull Exp Biol Med. 2001;132:1213-1215.

21. Abe R, Donnelly SC, Peng T, Bucala R, and Metz CN. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol. 2001;166:7556-7562.


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Известно, что при переносе костномозгового цилиндра под капсулу почки сингенных мышей очаг эктопического кроветворения образуется за счет мезенхимных стволовых клеток (МСК) донора. <br>У облученных реципиентов образуется очаг в 2-3 раза большего размера за счет «индуцибельных» предшественников, более дифференцированных по сравнению с МСК. Наряду с упомянутыми тестами in vivo, широко применяется метод оценки концентрации клоногенных стромальных предшественников в культуре (колониеобразующих единиц фибробластных, КОЕф). Однако, взаимное расположение описанных клеток-предшественников в иерархии стромальных стволовых клеток неясно. В работе было проанализировано изменение количества указанных предшественников в очагах, образующихся у облученных реципиентов. Показано, что КОЕф являются самыми близкими из известных на сегодняшний день потомками МСК, а «индуцибельные» предшественники – мультипотентные стромальные предшественники находятся ниже в иерархии и являются клетками, непосредственно увеличивающими размер кроветворной территории в облученных реципиентах.</p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(71) "Иерархия мезенхимных стволовых клеток" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(71) "Иерархия мезенхимных стволовых клеток" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(71) "Иерархия мезенхимных стволовых клеток" ["SECTION_META_TITLE"]=> string(71) "Иерархия мезенхимных стволовых клеток" ["SECTION_META_KEYWORDS"]=> string(71) "Иерархия мезенхимных стволовых клеток" ["SECTION_META_DESCRIPTION"]=> string(71) "Иерархия мезенхимных стволовых клеток" ["SECTION_PICTURE_FILE_ALT"]=> string(71) "Иерархия мезенхимных стволовых клеток" ["SECTION_PICTURE_FILE_TITLE"]=> string(71) "Иерархия мезенхимных стволовых клеток" 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["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(5) { [0]=> string(5) "11470" [1]=> string(5) "11471" [2]=> string(5) "11472" [3]=> string(5) "11473" [4]=> string(5) "11474" } ["VALUE"]=> array(5) { [0]=> string(2) "83" [1]=> string(3) "738" [2]=> string(3) "834" [3]=> string(3) "835" [4]=> string(3) "836" } ["DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(5) { [0]=> string(2) "83" [1]=> string(3) "738" [2]=> string(3) "834" [3]=> string(3) "835" [4]=> string(3) "836" } ["~DESCRIPTION"]=> array(5) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" } ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11400" ["VALUE"]=> string(10) "14.10.2008" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "14.10.2008" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11401" ["VALUE"]=> string(10) "21.11.2008" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "21.11.2008" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" 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"Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) 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["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> array(4) { [0]=> string(5) "11475" [1]=> string(5) "11476" [2]=> string(5) "11477" [3]=> string(5) "11478" } ["VALUE"]=> array(4) { [0]=> string(3) "830" [1]=> string(3) "831" [2]=> string(3) "832" [3]=> string(3) "833" } ["DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(4) { [0]=> string(3) "830" [1]=> string(3) "831" [2]=> string(3) "832" [3]=> string(3) "833" } ["~DESCRIPTION"]=> array(4) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11419" ["VALUE"]=> array(2) { ["TEXT"]=> string(160) "<p class="Autor">Шипунова (Нифонтова) И. Н., Свинарева Д. А., Чертков И. Л., Дризе Н. И.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(138) "

Шипунова (Нифонтова) И. Н., Свинарева Д. А., Чертков И. Л., Дризе Н. И.

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В работе изучали иерархию стромальных предшественников. Известно, что при переносе костномозгового цилиндра под капсулу почки сингенных мышей очаг эктопического кроветворения образуется за счет мезенхимных стволовых клеток (МСК) донора.
У облученных реципиентов образуется очаг в 2-3 раза большего размера за счет «индуцибельных» предшественников, более дифференцированных по сравнению с МСК. Наряду с упомянутыми тестами in vivo, широко применяется метод оценки концентрации клоногенных стромальных предшественников в культуре (колониеобразующих единиц фибробластных, КОЕф). Однако, взаимное расположение описанных клеток-предшественников в иерархии стромальных стволовых клеток неясно. В работе было проанализировано изменение количества указанных предшественников в очагах, образующихся у облученных реципиентов. Показано, что КОЕф являются самыми близкими из известных на сегодняшний день потомками МСК, а «индуцибельные» предшественники – мультипотентные стромальные предшественники находятся ниже в иерархии и являются клетками, непосредственно увеличивающими размер кроветворной территории в облученных реципиентах.

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Irina Shipounova (Nifontova), Daria Svinareva, Josef Chertkov, Nina Drize

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The hierarchy of stromal precursors is the focus of this research. It has been previously shown that transplantation of the bone marrow plug under the renal capsule of the syngeneic animal leads to the formation of the foci of ectopic hematopoiesis, where a stromal microenvironment is formed by the donor's mesenchymal stem cells (MSC). In the irradiated recipients such foci are 2-3 times larger than in non-irradiated foci due to "inducible" precursors that are more differentiated than MSC. Along with the in vivo tests, the method of in vitro estimation of concentration of clonogenic stromal precursors (CFU-F) is widely used. However, the hierarchical arrangement of the described precursors is still unclear. This study describes the alterations in the number of mentioned precursors in the ectopic hematopoietic foci formed in the irradiated recipients. CFU-F was shown to be the closest MSC progeny thus far, while "inducible" precursor cells – stromal multipotent precursors – are at a lower position in the hierarchy and possibly enlarge the hematopoietic territory in the irradiated recipients directly.

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Irina Shipounova (Nifontova), Daria Svinareva, Josef Chertkov, Nina Drize

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Irina Shipounova (Nifontova), Daria Svinareva, Josef Chertkov, Nina Drize

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The hierarchy of stromal precursors is the focus of this research. It has been previously shown that transplantation of the bone marrow plug under the renal capsule of the syngeneic animal leads to the formation of the foci of ectopic hematopoiesis, where a stromal microenvironment is formed by the donor's mesenchymal stem cells (MSC). In the irradiated recipients such foci are 2-3 times larger than in non-irradiated foci due to "inducible" precursors that are more differentiated than MSC. Along with the in vivo tests, the method of in vitro estimation of concentration of clonogenic stromal precursors (CFU-F) is widely used. However, the hierarchical arrangement of the described precursors is still unclear. This study describes the alterations in the number of mentioned precursors in the ectopic hematopoietic foci formed in the irradiated recipients. CFU-F was shown to be the closest MSC progeny thus far, while "inducible" precursor cells – stromal multipotent precursors – are at a lower position in the hierarchy and possibly enlarge the hematopoietic territory in the irradiated recipients directly.

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The hierarchy of stromal precursors is the focus of this research. It has been previously shown that transplantation of the bone marrow plug under the renal capsule of the syngeneic animal leads to the formation of the foci of ectopic hematopoiesis, where a stromal microenvironment is formed by the donor's mesenchymal stem cells (MSC). In the irradiated recipients such foci are 2-3 times larger than in non-irradiated foci due to "inducible" precursors that are more differentiated than MSC. Along with the in vivo tests, the method of in vitro estimation of concentration of clonogenic stromal precursors (CFU-F) is widely used. However, the hierarchical arrangement of the described precursors is still unclear. This study describes the alterations in the number of mentioned precursors in the ectopic hematopoietic foci formed in the irradiated recipients. CFU-F was shown to be the closest MSC progeny thus far, while "inducible" precursor cells – stromal multipotent precursors – are at a lower position in the hierarchy and possibly enlarge the hematopoietic territory in the irradiated recipients directly.

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Н., Свинарева Д. А., Чертков И. Л., Дризе Н. И.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(138) "

Шипунова (Нифонтова) И. Н., Свинарева Д. А., Чертков И. Л., Дризе Н. И.

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Шипунова (Нифонтова) И. Н., Свинарева Д. А., Чертков И. Л., Дризе Н. И.

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Известно, что при переносе костномозгового цилиндра под капсулу почки сингенных мышей очаг эктопического кроветворения образуется за счет мезенхимных стволовых клеток (МСК) донора. <br>У облученных реципиентов образуется очаг в 2-3 раза большего размера за счет «индуцибельных» предшественников, более дифференцированных по сравнению с МСК. Наряду с упомянутыми тестами in vivo, широко применяется метод оценки концентрации клоногенных стромальных предшественников в культуре (колониеобразующих единиц фибробластных, КОЕф). Однако, взаимное расположение описанных клеток-предшественников в иерархии стромальных стволовых клеток неясно. В работе было проанализировано изменение количества указанных предшественников в очагах, образующихся у облученных реципиентов. Показано, что КОЕф являются самыми близкими из известных на сегодняшний день потомками МСК, а «индуцибельные» предшественники – мультипотентные стромальные предшественники находятся ниже в иерархии и являются клетками, непосредственно увеличивающими размер кроветворной территории в облученных реципиентах.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2116) "

В работе изучали иерархию стромальных предшественников. Известно, что при переносе костномозгового цилиндра под капсулу почки сингенных мышей очаг эктопического кроветворения образуется за счет мезенхимных стволовых клеток (МСК) донора.
У облученных реципиентов образуется очаг в 2-3 раза большего размера за счет «индуцибельных» предшественников, более дифференцированных по сравнению с МСК. Наряду с упомянутыми тестами in vivo, широко применяется метод оценки концентрации клоногенных стромальных предшественников в культуре (колониеобразующих единиц фибробластных, КОЕф). Однако, взаимное расположение описанных клеток-предшественников в иерархии стромальных стволовых клеток неясно. В работе было проанализировано изменение количества указанных предшественников в очагах, образующихся у облученных реципиентов. Показано, что КОЕф являются самыми близкими из известных на сегодняшний день потомками МСК, а «индуцибельные» предшественники – мультипотентные стромальные предшественники находятся ниже в иерархии и являются клетками, непосредственно увеличивающими размер кроветворной территории в облученных реципиентах.

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В работе изучали иерархию стромальных предшественников. Известно, что при переносе костномозгового цилиндра под капсулу почки сингенных мышей очаг эктопического кроветворения образуется за счет мезенхимных стволовых клеток (МСК) донора.
У облученных реципиентов образуется очаг в 2-3 раза большего размера за счет «индуцибельных» предшественников, более дифференцированных по сравнению с МСК. Наряду с упомянутыми тестами in vivo, широко применяется метод оценки концентрации клоногенных стромальных предшественников в культуре (колониеобразующих единиц фибробластных, КОЕф). Однако, взаимное расположение описанных клеток-предшественников в иерархии стромальных стволовых клеток неясно. В работе было проанализировано изменение количества указанных предшественников в очагах, образующихся у облученных реципиентов. Показано, что КОЕф являются самыми близкими из известных на сегодняшний день потомками МСК, а «индуцибельные» предшественники – мультипотентные стромальные предшественники находятся ниже в иерархии и являются клетками, непосредственно увеличивающими размер кроветворной территории в облученных реципиентах.

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Introduction

Multipotent mesenchymal stromal cells (MSC), also named mesenchymal stem cells, are characterized by adherence to plastic when maintained in standard cultures in vitro, by expression of surface antigens CD105 and CD90 but lack of hematopoietic markers CD34 and CD45, and by differentiation into osteoblasts, adipocytes and chondroblasts in vitro [1]. Since their first description [2], a multitude of work has been carried out to show their properties and functionality in vitro and in vivo [3, 4, 5]. MSC have been shown to display a considerable therapeutic potential in pre-clinical [6-11] and clinical [12-16] studies for the treatment/regeneration of neuronal degeneration, osteogenesis imperfecta, graft-versus-host disease, support of hematopoietic engraftment, metabolic diseases, and bone and cartilage tissues, as well as renal and myocardial infarction. To date, all reported clinical trials are employing hMSC generated in medium supplemented with fetal calf serum (FCS). FCS, however, is a source of undesirable xenogeneic antigens, and carries the risk of transmitting animal viral, prion and zoonose contaminations. Additionally, FCS has been implicated with anaphylactic or arthus-like immune reactions in patients who received cells generated in FCS-supplemented medium [17], even leading to arrhythmias after cellular cardioplasty [18]. Uptake of FCS components is an active process [19]. Although up to 99.99% of FCS can be removed by sequential cultivation of MSC first in FCS, followed by autologous or heterologous serum [20], a residual risk still remains.

Very recently, human platelet lysates (PL) have been shown to serve as a safe substitute for animal serum for hMSC expansion [21-23], but the resulting hMSC are still not fully characterized. We have extensively analyzed animal-serum free culture conditions for hMSC expansion using platelet lysate as a substitute for FCS. Compared to FCS-supplemented culture conditions, we found a significant increase of both CFU-F as well as cumulative cell numbers after expansion. Our optimized protocol uses 5% of PL as growth supplement. Cells obtained by this protocol meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. MSC retained their immune-privileged potential by suppressing the allogeneic reaction of T-cells. Additionally, gene expression profiles showed decreased mRNA levels of MHC II components. Taken together, our GMP-compatible protocol allows for safe and accelerated expansion of hMSC, which could be of interest for cell and tissue therapies.

Results and discussion

In comparing the additives FCS and PL, the media used consisted of α-MEM containing glutamax, the stable form of glutamine, supplemented either with + 10% preselected fetal calf serum (FCS; BioWhittaker, Apen, Germany) + 1% glutamine or 5% freshly thawed platelet lysate (PL) + 10 IU Heparin (Roche, Grenzach-Wylen, Germany; 5000 IU/ml) per 5 ml medium. The isolation of hMSC already revealed a higher number of CFU-F in PL-containing medium (Table 1) as well as larger colonies (Figure 1). In line with the CFU-F numbers, the expansion capabilities of hMSC grown in PL were considerably higher (Figure 2), reaching twice as many cells after only 40 days. With regard to morphology, a more elongated cell appearance has been observed in PL-cultures, resulting in significantly higher cell numbers per growth area.

Table 1. Isolation of hMSC with FCS- or PL-supplemented media.
Values are shown for 107 plated cells.

2008-2-en-Lange-et-al-Table-1.jpg

Figure 1. Isolation of hMSC by plating 5 x 105 mononuclear cells/well in 3 ml.
Shown are crystal violet-stained CFU-F in FCS- or PL-supplemented media 14 days after seeding.

2008-2-en-Lange-et-al-Figure-1.jpg

Figure 2. Accelerated expansion of MSC in PL- compared to FCS-containing medium αMEM.
Shown are cumulative cell numbers of one example out of 11 experiments. Each symbol respresents a single time point of trypsinization.

2008-2-en-Lange-et-al-Figure-2.jpg


PL contains 7 fundamental growth factors actively secreted by platelets: PDGF-αα (platelet derived growth factor), -ββ, -αβ, TGF-β1 (transforming growth factor) and -β2, VEGF (vascular endothelial growth factor) and EGF (epidermal growth factor) [24, 25]. The growth factors PDGF, TGF, EGF and FGF (fibroblast growth factor) have been described as mitogens for MSC [4]. Thrombocyte concentrates are regularly produced and applied in everyday clinical life, and meet all criteria for a safe and well-controlled growth factor source. The main reason for the superiority of PL therefore may originate in the release of these factors. We thoroughly analyzed PL with either Human 27-plex (BIO-RAD) or ELISA and showed that inflammatory and anti-inflammatory cytokines as well as a variety of mitogenic factors are contained in PL (Table 2). Previously, it has been shown that thrombocytes release certain amounts of mitogenic cytokines, varying for PDGF-αβ for example, between 35-133 ng/ml [25]. For effective expansion of MSC, an optimized preparation of PL is needed. It consists of pooled PL from at least 10 donors (to equalize for differences in cytokine concentrations) with a minimum concentration of 3 x 109 thrombocytes/ml. Beside this, the accelerated growth under the influence of PL is supported by differential gene expression profile showing an upregulation of cycle-promoting proteins and downregulation of genes for differentiation, attachment, and apoptosis [26].

Table 2. Determination of factor-concentrations in PL. Anti-inflammatory cytokines are shown in bold, inflammatory in italic.
The human-plex method presents the concentration in [pg/ml] from undiluted PL, while in the ELISA PL was diluted to a thrombocyte concentration of 1 x 109/ml and used as 5% in medium (the values therefore have to be multiplied by at least 20). < : below the detection limit.

2008-2-en-Lange-et-al-Table-2.jpg


Evaluation of the surface antigens CD34, CD45, CD59, CD90 and CD105 by flow cytometry revealed a similar phenotype as with FCS-medium, i.e. a lack of the hematopoietic markers CD34 and CD45 and expression of CD59, CD90 and CD105 (not shown). Additionally, both expansion media enabled a subsequent differentiation of hMSC into osteo-, adipo- and chondrogenic lineages. An exception in the quantity of differentiating cells was found for adipogenic differentiation. The formation of adipocytes was delayed and required longer induction times. This result is supported by the downregulation of genes involved in fatty acid metabolism [26]. We assess this decreased adipogenic/lipogenic ability as a favorable property, because in mice the intra-arterial injection of MSC for treatment of chronic kidney injury has revealed formation of adipocytes [27].

MSC have been described as immunomodulatory by impairing T-cell activation without inducing anergy. We tested the immunomodulatory properties of PL-expanded hMSC in vitro in the mixed lymphocyte reaction (MLR). MLRs were carried out with different combinations of allogeneic human peripheral blood mononuclear cells (hPBMC) used as effectors (E) and irradiated stimulators/activators (A) at ratios of 1:1. Human MSC (M) added to the MLR were from unrelated healthy donors. In all 6 experiments, hMSC added at effector/stimulator/MSC ratio of 1:1:1 suppressed T cell proliferation efficiently (p=0.000004). The average inhibition at this ratio was 84.8 ± 9.7% (Figure 3). In contrast to FCS-generated hMSC, no dilution effect of the MSC-effect with decreasing numbers [28] was observed. This result is supported by differential gene expression showing a downregulation of MHC II compounds in hMSC (Figure 4). Addition of PL-generated hMSC leads to significantly decreased immunostimulation of allogeneic T cells caused by MSC. Expanded hMSC express MHC I but not II complexes although MHC II is present intracellularly, and can be induced by addition of interferon gamma (IFN-γ) [29]. The lack of MHC II on hMSC has been interpreted so far as evidence for their non-stimulating properties, so that MSC are transplantable between MHC-incompatible individuals. The downregulation of MHC II in hMSC expanded in PL-supplemented medium makes the cell preparations even more safe and useful for application in cell-replacement therapies. It has been shown that both autologous and allogeneic MSC can be used without significant immune reactions [30, 31, 32] and PL-MSC could make the allogeneic use even safer. We expect, according to the results of decreased allo-stimulation under the influence of PL-MSC, a broader applicability of these MSC.

2008-2-en-Lange-et-al-Figure-3.jpg


Figure 3. Immunomodulatory properties of hMSC are preserved after cultivation in PL-supplemented medium. Bar graph shows the relative percentage of Ki-67+ CD3+ cells in the presence of effector (E), irradiated activator (A), and PL-generated MSCs (M) in various ratios. Data represent relative mean values ± SD of proliferating Ki-67 positive T-cells from 6 experiments.









2008-2-en-Lange-et-al-Figure-4.jpg

Figure 4. Differential gene expression profile reveals the downregulation of MHC II compounds in MSCs cultured in PL- compared to FCS-supplemented media.
Gene expression values are shown as log2 of raw fluorescence for MHC II genes involved in antigen presentation.


Additional gene expression data shows that PL-generated MSCs might be particularly good candidates for regenerative therapy in CNS damage. They express the gene Prickle1, which is involved in neuro-regeneration, to an eight-fold higher degree when compared to MSCs cultured in FCS-supplemented media. Mouse Prickle1 and Prickle2 are expressed in postmitotic neurons and promote neurite outgrowth [33]. Furthermore, MAG (Myelin-associated glycoprotein) is expressed at 13-fold lower amount. MAG is a cell membrane glycoprotein, and may be involved in myelination during nerve regereneration. The lack of recovery after central nervous system injury is caused, in part, by myelin inhibitors including MAG. MAG acts as a neurite outgrowth inhibitor for most neurons tested, but stimulates neurite outgrowth in immature dorsal root ganglion neurons [34]. These differentially regulated genes would favor the use of PL-cultured hMSC for regeneration of neuronal injury. Additionally, the 12-fold higher expression of RAR (retinoid acid receptor) -responsive 1 gene (TIG1) [35], 9-fold higher expression of Keratin 18 [36], 5.7-fold higher expression of the cellular retinol binding protein 1 CRBP1 [37], and Prickle 1 suggest a less tumorigenic phenotype of the MSCs after cultivation in PL-supplemented media.

Conclusions

Isolation and expansion of hMSC using PL as medium supplement allows for rapid generation of high cell amounts within short time. MSC expanded under these conditions fulfill all criteria stated for hMSC. Differential gene expressions support the findings of delayed adipogenesis and favorable immunological properties. Thus, PL-generated hMSC are prime candidates for transplantation as well as regenerative approaches.

Acknowledgement

The work was supported by the Federal Ministry of Education and Research, Contract grant number 13N8904 (HyCelex).

References

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2. Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luria EA, Ruadkow IA. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol. 1974;2:83-92.

3. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143-147.

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6. Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A. 1999;96:10711-10716.

7. Mahmood A, Lu D, Chopp M. Marrow stromal cell transplantation after traumatic brain injury promotes cellular proliferation within the brain. Neurosurgery. 2004;55:1185-1193.

8. Petite H, Viateau V, Bensaid W, Meunier A, de Pollak C, Bourguignon M, Oudina K, Sedel L, Guillemin G. Tissue-engineered bone regeneration. Nat Biotechnol. 2000;18:959-963.

9. Lange C, Togel F, Ittrich H, Clayton F, Nolte-Ernsting C, Zander AR, Westenfelder C.  Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney Int. 2005;68:1613-7.

10. Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 2005;289:F31-42.

11. Jaquet K, Krause KT, Denschel J, Faessler P, Nauerz M, Geidel S, Boczor S, Lange C, Stute N, Zander A, Kuck KH. Reduction of myocardial scar size after implantation of mesenchymal stem cells in rats: what is the mechanism? Stem Cells Dev. 2005;14:299-309.

12. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE, Brenner MK. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med. 1999;5: 309-313.

13. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439-1441.

14. Koc ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE, Caplan AI, Lazarus HM. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol. 2000;18:307-316.

15. Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant. 2002;30:215-222.

16. Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, Zhang JJ, Chunhua RZ, Liao LM, Lin S, Sun JP. Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol. 2004;94:92-95.

17. Selvaggi TA, Walker RE, Fleisher TA. Development of antibodies to fetal calf serum with arthus-like reactions in human immunodeficiency virus-infected patients given syngeneic lymphocyte infusions. Blood. 1997;89:776-779.

18. Chachques JC, Herreros J, Trainini J, Juffe A, Rendal E, Prosper F, Genovese J. Life-threatening arrhythmias after cellular cardioplasty. Autologous human serum for cell culture avoids the implantation of cardioverter-defibrillators in cellular cardiomyoplasty. Int J Cardiol. 2004;95, Suppl 1:S29-33.

19. Gregory CA, Reyes E, Whitney MJ, Spees JL. Enhanced engraftment of mesenchymal stem cells in a cutaneous wound model by culture in allogenic species-specific serum and administration in fibrin constructs. Stem Cells. 2006;24:2232-2243.

20. Spees JL, Gregory CA, Singh H, Tucker HA, Peister A, Lynch PJ, Hsu SC, Smith J, Prockop DJ. Internalized antigens must be removed to prepare hypoimmunogenic mesenchymal stem cells for cell and gene therapy. Mol Ther. 2004;9:747-756.

21. Yamada Y, Ueda M, Hibi H, Nagasaka T. Translational Research for Injectable Tissue-Engineered Bone Regeneration Using Mesenchymal Stem Cells and Platelet-Rich Plasma: From Basic Research to Clinical Case Study. Cell Transplantation. 2004;13:343-355.

22. Doucet C, Ernou I, Zhang Y, Llense JR, Begot L, Holy X, Lataillade JJ. Platelet lysates promote mesenchymal stem cell expansion: a safety substitute for animal serum in cell-based therapy applications. J Cell Physiol. 2005;205:228-236.

23. Muller I, Kordowich S, Holzwarth C, Spano C, Isensee G, Staiber A, Viebahn S, Gieseke F, Langer H, Gawaz MP, Horwitz EM, Conte P, Handgretinger R, Dominici M. Animal serum-free culture conditions for isolation and expansion of multipotent mesenchymal stromal cells from human BM. Cytotherapy. 2006;8:437-444.

24. Marx RE, Carlson ER, Eichstaedt RM, Schimmele SR, Strauss JE, Georgeff KR. Platelet-rich plasma: Growth factor enhancement for bone grafts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1998;85:638-646.

25. Marx RE. Platelet-rich plasma: evidence to support its use. J Oral Maxillofac Surg. 2004;62:489-496.

26. Lange C, Cakiroglu F, Spiess AN, Cappallo-Obermann H, Dierlamm J, Zander AR. Accelerated and safe expansion of human mesenchymal stromal cells in animal serum-free medium for transplantation and regenerative medicine. J Cell Physiol. 2007;25:18-26.

27. Kunter U, Rong S, Boor P, et al. Mesenchymal stem cells prevent progressive experimental renal failure but maldifferentiate into glomerular adipocytes. J Am Soc Nephrol. 2007 Jun;18(6):1754-64).

28. Fang L, Lange C, Engel M, Zander AR, Fehse B. Sensitive Balance of Suppressing and Activating Effects of MSC on T Cell Proliferation. Transplantation. 2006;82:1370-1373.

29. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003;31:890-896.

30. Poh KK, Sperry E, Young RG, Freyman T, Barringhaus KG, Thompson CA. Repeated direct endomyocardial transplantation of allogeneic mesenchymal stem cells: Safety of a high dose, "off-the-shelf", cellular cardiomyoplasty strategy. Int J Cardiol Aug. 2006;2; [Epub ahead of print]

31. Ringden O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lonnies H, Marschall HU, Dlugosz A, Szakos A, Hassan Z, Omazic B, Aschan J, Barkholt L, Le Blanc K.  Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation. 2006;81:1390-1397.

32. Dai W, Hale SL, Martin BJ, Kuang JQ, Dow JS, Wold LE, Kloner RA. Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short- and long-term effects. Circulation. 2005;112:214-223.

33. Okuda H, Miyata S, Mori Y, Tohyama M. FEBS Lett. 2007;581:4754-60.

34. Vyas AA, Patel HV, Fromholt SE, Heffer-Lauc M, Vyas KA, Dang J, Schachner M, Schnaar RL. Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration. Proc Natl Acad Sci U S A. 2002;99:8412-7.

35. Liang Y, Jansen Mi, Aronow B, Geiger H, Van Zant G. The quantitative trait gene latexin influences the size of the hematopoietic stromal cell population in mice. Nature Genetics. 2007;39:178-188.

36. Bühler H, Schaller G. Transfection of keratin 18 gene in human breast cancer cells causes induction of adhesion proteins and dramatic regression of malignancy in vitro and in vivo. Mol Cancer Res. 2005;3:365-71.

37. Roberts D, Williams SJ, Cvetkovic D, Weinstein JK, Godwin AK, Johnson SW, Hamilton TC. Decreased expression of retinol-binding proteins is associated with malignant transformation of the ovarian surface epithelium. DNA Cell Biol. 2002;21:11-9.

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Introduction

Multipotent mesenchymal stromal cells (MSC), also named mesenchymal stem cells, are characterized by adherence to plastic when maintained in standard cultures in vitro, by expression of surface antigens CD105 and CD90 but lack of hematopoietic markers CD34 and CD45, and by differentiation into osteoblasts, adipocytes and chondroblasts in vitro [1]. Since their first description [2], a multitude of work has been carried out to show their properties and functionality in vitro and in vivo [3, 4, 5]. MSC have been shown to display a considerable therapeutic potential in pre-clinical [6-11] and clinical [12-16] studies for the treatment/regeneration of neuronal degeneration, osteogenesis imperfecta, graft-versus-host disease, support of hematopoietic engraftment, metabolic diseases, and bone and cartilage tissues, as well as renal and myocardial infarction. To date, all reported clinical trials are employing hMSC generated in medium supplemented with fetal calf serum (FCS). FCS, however, is a source of undesirable xenogeneic antigens, and carries the risk of transmitting animal viral, prion and zoonose contaminations. Additionally, FCS has been implicated with anaphylactic or arthus-like immune reactions in patients who received cells generated in FCS-supplemented medium [17], even leading to arrhythmias after cellular cardioplasty [18]. Uptake of FCS components is an active process [19]. Although up to 99.99% of FCS can be removed by sequential cultivation of MSC first in FCS, followed by autologous or heterologous serum [20], a residual risk still remains.

Very recently, human platelet lysates (PL) have been shown to serve as a safe substitute for animal serum for hMSC expansion [21-23], but the resulting hMSC are still not fully characterized. We have extensively analyzed animal-serum free culture conditions for hMSC expansion using platelet lysate as a substitute for FCS. Compared to FCS-supplemented culture conditions, we found a significant increase of both CFU-F as well as cumulative cell numbers after expansion. Our optimized protocol uses 5% of PL as growth supplement. Cells obtained by this protocol meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. MSC retained their immune-privileged potential by suppressing the allogeneic reaction of T-cells. Additionally, gene expression profiles showed decreased mRNA levels of MHC II components. Taken together, our GMP-compatible protocol allows for safe and accelerated expansion of hMSC, which could be of interest for cell and tissue therapies.

Results and discussion

In comparing the additives FCS and PL, the media used consisted of α-MEM containing glutamax, the stable form of glutamine, supplemented either with + 10% preselected fetal calf serum (FCS; BioWhittaker, Apen, Germany) + 1% glutamine or 5% freshly thawed platelet lysate (PL) + 10 IU Heparin (Roche, Grenzach-Wylen, Germany; 5000 IU/ml) per 5 ml medium. The isolation of hMSC already revealed a higher number of CFU-F in PL-containing medium (Table 1) as well as larger colonies (Figure 1). In line with the CFU-F numbers, the expansion capabilities of hMSC grown in PL were considerably higher (Figure 2), reaching twice as many cells after only 40 days. With regard to morphology, a more elongated cell appearance has been observed in PL-cultures, resulting in significantly higher cell numbers per growth area.

Table 1. Isolation of hMSC with FCS- or PL-supplemented media.
Values are shown for 107 plated cells.

2008-2-en-Lange-et-al-Table-1.jpg

Figure 1. Isolation of hMSC by plating 5 x 105 mononuclear cells/well in 3 ml.
Shown are crystal violet-stained CFU-F in FCS- or PL-supplemented media 14 days after seeding.

2008-2-en-Lange-et-al-Figure-1.jpg

Figure 2. Accelerated expansion of MSC in PL- compared to FCS-containing medium αMEM.
Shown are cumulative cell numbers of one example out of 11 experiments. Each symbol respresents a single time point of trypsinization.

2008-2-en-Lange-et-al-Figure-2.jpg


PL contains 7 fundamental growth factors actively secreted by platelets: PDGF-αα (platelet derived growth factor), -ββ, -αβ, TGF-β1 (transforming growth factor) and -β2, VEGF (vascular endothelial growth factor) and EGF (epidermal growth factor) [24, 25]. The growth factors PDGF, TGF, EGF and FGF (fibroblast growth factor) have been described as mitogens for MSC [4]. Thrombocyte concentrates are regularly produced and applied in everyday clinical life, and meet all criteria for a safe and well-controlled growth factor source. The main reason for the superiority of PL therefore may originate in the release of these factors. We thoroughly analyzed PL with either Human 27-plex (BIO-RAD) or ELISA and showed that inflammatory and anti-inflammatory cytokines as well as a variety of mitogenic factors are contained in PL (Table 2). Previously, it has been shown that thrombocytes release certain amounts of mitogenic cytokines, varying for PDGF-αβ for example, between 35-133 ng/ml [25]. For effective expansion of MSC, an optimized preparation of PL is needed. It consists of pooled PL from at least 10 donors (to equalize for differences in cytokine concentrations) with a minimum concentration of 3 x 109 thrombocytes/ml. Beside this, the accelerated growth under the influence of PL is supported by differential gene expression profile showing an upregulation of cycle-promoting proteins and downregulation of genes for differentiation, attachment, and apoptosis [26].

Table 2. Determination of factor-concentrations in PL. Anti-inflammatory cytokines are shown in bold, inflammatory in italic.
The human-plex method presents the concentration in [pg/ml] from undiluted PL, while in the ELISA PL was diluted to a thrombocyte concentration of 1 x 109/ml and used as 5% in medium (the values therefore have to be multiplied by at least 20). < : below the detection limit.

2008-2-en-Lange-et-al-Table-2.jpg


Evaluation of the surface antigens CD34, CD45, CD59, CD90 and CD105 by flow cytometry revealed a similar phenotype as with FCS-medium, i.e. a lack of the hematopoietic markers CD34 and CD45 and expression of CD59, CD90 and CD105 (not shown). Additionally, both expansion media enabled a subsequent differentiation of hMSC into osteo-, adipo- and chondrogenic lineages. An exception in the quantity of differentiating cells was found for adipogenic differentiation. The formation of adipocytes was delayed and required longer induction times. This result is supported by the downregulation of genes involved in fatty acid metabolism [26]. We assess this decreased adipogenic/lipogenic ability as a favorable property, because in mice the intra-arterial injection of MSC for treatment of chronic kidney injury has revealed formation of adipocytes [27].

MSC have been described as immunomodulatory by impairing T-cell activation without inducing anergy. We tested the immunomodulatory properties of PL-expanded hMSC in vitro in the mixed lymphocyte reaction (MLR). MLRs were carried out with different combinations of allogeneic human peripheral blood mononuclear cells (hPBMC) used as effectors (E) and irradiated stimulators/activators (A) at ratios of 1:1. Human MSC (M) added to the MLR were from unrelated healthy donors. In all 6 experiments, hMSC added at effector/stimulator/MSC ratio of 1:1:1 suppressed T cell proliferation efficiently (p=0.000004). The average inhibition at this ratio was 84.8 ± 9.7% (Figure 3). In contrast to FCS-generated hMSC, no dilution effect of the MSC-effect with decreasing numbers [28] was observed. This result is supported by differential gene expression showing a downregulation of MHC II compounds in hMSC (Figure 4). Addition of PL-generated hMSC leads to significantly decreased immunostimulation of allogeneic T cells caused by MSC. Expanded hMSC express MHC I but not II complexes although MHC II is present intracellularly, and can be induced by addition of interferon gamma (IFN-γ) [29]. The lack of MHC II on hMSC has been interpreted so far as evidence for their non-stimulating properties, so that MSC are transplantable between MHC-incompatible individuals. The downregulation of MHC II in hMSC expanded in PL-supplemented medium makes the cell preparations even more safe and useful for application in cell-replacement therapies. It has been shown that both autologous and allogeneic MSC can be used without significant immune reactions [30, 31, 32] and PL-MSC could make the allogeneic use even safer. We expect, according to the results of decreased allo-stimulation under the influence of PL-MSC, a broader applicability of these MSC.

2008-2-en-Lange-et-al-Figure-3.jpg


Figure 3. Immunomodulatory properties of hMSC are preserved after cultivation in PL-supplemented medium. Bar graph shows the relative percentage of Ki-67+ CD3+ cells in the presence of effector (E), irradiated activator (A), and PL-generated MSCs (M) in various ratios. Data represent relative mean values ± SD of proliferating Ki-67 positive T-cells from 6 experiments.









2008-2-en-Lange-et-al-Figure-4.jpg

Figure 4. Differential gene expression profile reveals the downregulation of MHC II compounds in MSCs cultured in PL- compared to FCS-supplemented media.
Gene expression values are shown as log2 of raw fluorescence for MHC II genes involved in antigen presentation.


Additional gene expression data shows that PL-generated MSCs might be particularly good candidates for regenerative therapy in CNS damage. They express the gene Prickle1, which is involved in neuro-regeneration, to an eight-fold higher degree when compared to MSCs cultured in FCS-supplemented media. Mouse Prickle1 and Prickle2 are expressed in postmitotic neurons and promote neurite outgrowth [33]. Furthermore, MAG (Myelin-associated glycoprotein) is expressed at 13-fold lower amount. MAG is a cell membrane glycoprotein, and may be involved in myelination during nerve regereneration. The lack of recovery after central nervous system injury is caused, in part, by myelin inhibitors including MAG. MAG acts as a neurite outgrowth inhibitor for most neurons tested, but stimulates neurite outgrowth in immature dorsal root ganglion neurons [34]. These differentially regulated genes would favor the use of PL-cultured hMSC for regeneration of neuronal injury. Additionally, the 12-fold higher expression of RAR (retinoid acid receptor) -responsive 1 gene (TIG1) [35], 9-fold higher expression of Keratin 18 [36], 5.7-fold higher expression of the cellular retinol binding protein 1 CRBP1 [37], and Prickle 1 suggest a less tumorigenic phenotype of the MSCs after cultivation in PL-supplemented media.

Conclusions

Isolation and expansion of hMSC using PL as medium supplement allows for rapid generation of high cell amounts within short time. MSC expanded under these conditions fulfill all criteria stated for hMSC. Differential gene expressions support the findings of delayed adipogenesis and favorable immunological properties. Thus, PL-generated hMSC are prime candidates for transplantation as well as regenerative approaches.

Acknowledgement

The work was supported by the Federal Ministry of Education and Research, Contract grant number 13N8904 (HyCelex).

References

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Р.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(136) "

Ланге К., Чакироглу Ф., Шписс А., Каппалло-Оберманн Х., Цандер А. Р.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11583" ["VALUE"]=> array(2) { ["TEXT"]=> string(3672) "<p class="bodytext">Мезенхимные стромальные клетки (МСК) из костного мозга человека являются перспективными кандидатами для новых способов лечения в трансплантационной и регенеративной медицине. Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3650) "

Мезенхимные стромальные клетки (МСК) из костного мозга человека являются перспективными кандидатами для новых способов лечения в трансплантационной и регенеративной медицине. Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.

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Claudia Lange, Figen Cakiroglu, Andrej Spiess, Heike Cappallo-Obermann, Axel R. Zander

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Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

Correspondence:
Claudia Lange, Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany,
E-mail: cllange@spam is baduke.uni-hamburg.de

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Human bone marrow mesenchymal stromal cells (hMSC) are promising candidates for new treatment options in transplant and regenerative medicine. However, most expansion protocols still use fetal calf serum (FCS) as growth factor supplement, which is a potential source of undesirable xenogeneic pathogens. We established an easy and reproducible expansion protocol for hMSC based on the addition of platelet lysate (PL) obtained from human thrombocyte concentrates. Both CFU-F and cumulative cell numbers were significantly increased compared to the conventional FCS-based medium. The generated cells meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. Human MSC expanded with PL revealed favorable immunological properties in vitro. Gene expression profiles showed upregulation of cell cycle and DNA replication genes and downregulation of developmental, differentiation, adipogenic and MHC II genes. Thus, PL provides a safe component for accelerated and safe hMSC expansion.

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Human bone marrow mesenchymal stromal cells (hMSC) are promising candidates for new treatment options in transplant and regenerative medicine. However, most expansion protocols still use fetal calf serum (FCS) as growth factor supplement, which is a potential source of undesirable xenogeneic pathogens. We established an easy and reproducible expansion protocol for hMSC based on the addition of platelet lysate (PL) obtained from human thrombocyte concentrates. Both CFU-F and cumulative cell numbers were significantly increased compared to the conventional FCS-based medium. The generated cells meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. Human MSC expanded with PL revealed favorable immunological properties in vitro. Gene expression profiles showed upregulation of cell cycle and DNA replication genes and downregulation of developmental, differentiation, adipogenic and MHC II genes. Thus, PL provides a safe component for accelerated and safe hMSC expansion.

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Human bone marrow mesenchymal stromal cells (hMSC) are promising candidates for new treatment options in transplant and regenerative medicine. However, most expansion protocols still use fetal calf serum (FCS) as growth factor supplement, which is a potential source of undesirable xenogeneic pathogens. We established an easy and reproducible expansion protocol for hMSC based on the addition of platelet lysate (PL) obtained from human thrombocyte concentrates. Both CFU-F and cumulative cell numbers were significantly increased compared to the conventional FCS-based medium. The generated cells meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. Human MSC expanded with PL revealed favorable immunological properties in vitro. Gene expression profiles showed upregulation of cell cycle and DNA replication genes and downregulation of developmental, differentiation, adipogenic and MHC II genes. Thus, PL provides a safe component for accelerated and safe hMSC expansion.

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Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

Correspondence:
Claudia Lange, Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany,
E-mail: cllange@spam is baduke.uni-hamburg.de

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Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

Correspondence:
Claudia Lange, Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany,
E-mail: cllange@spam is baduke.uni-hamburg.de

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Ланге К., Чакироглу Ф., Шписс А., Каппалло-Оберманн Х., Цандер А. Р.

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Ланге К., Чакироглу Ф., Шписс А., Каппалло-Оберманн Х., Цандер А. Р.

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Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3650) "

Мезенхимные стромальные клетки (МСК) из костного мозга человека являются перспективными кандидатами для новых способов лечения в трансплантационной и регенеративной медицине. Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.

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Мезенхимные стромальные клетки (МСК) из костного мозга человека являются перспективными кандидатами для новых способов лечения в трансплантационной и регенеративной медицине. Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.

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Introduction

Fungal infections with Aspergillus or Candida, mainly of the lung, are a major cause of treatment-related mortality in allogeneic stem cell transplantation (SCT) [1, 2]. Invasive Aspergillosis (IA) in hematopoietic stem cell transplant (HSCT) recipients was associated with case-fatality rates of 87% [3], and an overall 1-year survival rate of only 20% [4]. Patients with a history of systemic or invasive fungal infection (IFI) who undergo allogeneic transplantation are considered to be at high risk of disease reactivation or progression leading to a high mortality. More recently, leukemias and other malignancies have been treated with more intensive induction therapies up front, resulting in a higher incidence of fungal infections before receiving a stem cell transplant. 

Primary antifungal prophylaxis is given routinely in patients with no prior IFI who undergo allogeneic stem cell transplantation [5-9], whereas secondary prophylaxis is given in patients with prior IFI. Up to now, for those patients with a history of IFI who undergo allogeneic SCT, no prospective study of secondary antifungal prophylaxis in a larger series of these high-risk patients exists. More recently, several retrospective studies indicate that bone marrow transplantation (BMT) in patients with a history of IA is feasible [10-12]. Apart from that, the only case reports that can be found in the literature concern patients with fungal disease who underwent SCT and were successfully treated with fluconazole, itraconazole, surgical resection, amphotericin B, and voriconazole [13-15].

We therefore conducted a prospective single-center study to evaluate the efficacy and safety of caspofungin as secondary prophylaxis or therapy, in order to prevent recurrence or progression of systemic or invasive fungal infections in patients with a history of IFI who underwent allogeneic SCT. 
Caspofungin is an echinocandin, which interferes with fungal cell wall assembly by inhibition of  β(1,3)-D-glucan synthase, an enzyme not present in mammalian cells [16]. It shows no signs of nephrotoxicity and has only modest side effects, such as chills and fever, in very few patients (1-3 %). Caspofungin has proven to be effective and well-tolerated in the treatment of infections caused by Aspergillus and Candida species in clinical trials [17-24].

Patients and methods

Study design
Patients included in our study had a history of proven or probable IFI according to modified EORTC criteria for diagnosis of invasive fungal infection. Proven IFI requires histo- or cytopathology positive for hyphae with evidence of associated tissue damage or a positive culture for mold species from a normally sterile site consistent with infection. Probable IFI included cases with one host criterion plus one microbial criterion and one major or two minor clinical criteria, or a patient with recent neutropenia or an allogeneic SCT patient with a chest CT scan positive for "halo" or "air crescent" signs [25-28]. The patients included were scheduled to undergo an allogeneic bone marrow or stem cell transplantation and needed to have sufficient organ function.

The primary efficacy endpoint was the incidence of clinically manifest mycoses under the prophylactic use of caspofungin (development of breakthrough IFI) or response thereof, in case of florid infections at start of conditioning. The secondary endpoints were the evaluation of toxicity and overall survival until day +365. Failure was defined as suspected or documented fungal infection (failure to prevent a new IFI), or a progressive fungal infection in case of prior florid activity (failure to improve a partially treated IFI). Secondary endpoints were evaluated descriptively. All patients included were evaluated on an intent-to-treat basis.

Modified EORTC criteria for diagnosis of IFI are more clinically oriented than the strict EORTC-IFICG/MSG criteria (European Organization for Research and Treatment of Cancer - IFI Cooperative Group & Mycoses Study Group). These criteria were specifically developed for use in large clinical trials on the efficacy of antifungals and should not be used to guide clinical decisions [25]. This approach is reflected by the clinical practice in BMT, where proven and even probable IFI with direct microbiological evidence are diagnosed in only a minority of high risk patients, and diagnosis of fungal infection is often made on clinical and radiological grounds alone.

Prior to study entry, we performed a chest CT scan, a bronchoalveolar lavage (BAL), and an abdominal ultrasound. We also carried out a high-resolution chest CT scan at the end of the caspofungin prophylaxis or in case of fever. Weekly controls of circulating Aspergillus galactomannan antigen (Platelia® Aspergillus EIA, index used for cut-off was 1.0, BioRad Laboratories, Hercules, CA, USA) and Candida antibody titer (Cand-Tec® latex agglutination test for heat-labile antigen, Ramco Laboratories, Stafford, TX, USA) were performed in all patients. To measure potential side effects we conducted daily blood counts and clinical chemistry analyses.

Patients
Successive patients with a history of systemic or invasive fungal infection in the past who underwent allogeneic BMT were included in this prospective study. 
Conditioning was performed with myeloablative regimens. In unrelated donors and mismatched family donors, we added anti-thymocyte globulin (ATG Fresenius, 30-90 mg/kg intravenously (i.v.)) to the conditioning in order to minimize the risk of graft-versus-host disease (GvHD). Cyclosporin A (CSA) for immunosuppression was given to all patients post-transplant with a target level of 200-300 µg/L. The local ethics committee approved the study and all patients gave prior written informed consent.

Treatment plan & response assessment
Patients were given 50 mg caspofungin i.v. daily over one hour, following a 70 mg loading dose from start of conditioning until stable engraftment. No other systemic antifungal was given. All patients were nursed in reversed isolation in conventional or laminar airflow rooms. Antibiotic prophylaxis consisted of ciprofloxacin, local antifungals, and acyclovir. Prophylaxis against pneumocystis carinii was carried out with cotrimoxazole (or pentamidine inhalation). CMV-negative patients received only CMV-negative blood products. All blood products were irradiated at 25 Gy. CMV-positive patients were monitored weekly for CMV infection by PCR and/or antigenemia-assay for pp65. Preemptive therapy was started with 10 mg/kg gancyclovir after two consecutive positive PCR or one positive antigenemia-assay. In the case of neutropenic fever during transplantation, ceftazidime and vancomycin were given; if fever or signs of infection persisted, tobramycin was added after two days. In patients without signs of fungal infection after engraftment, antimycotic prophylaxis was switched to itraconazole 200 mg twice daily until day +100.An experienced clinician and radiologist performed the mycological response assessment according to EORTC criteria. Radiographic criteria for complete response (CR) required a > 90% clearing of CT scan abnormalities associated with active fungal infection or persistent residual scarring only. Partial response (PR) required a > 50% improvement in radiographic abnormalities on relevant scans, as compared to baseline. Stable response was diagnosed if minor or no improvement occurred and there was no worsening of attributable radiographic signs of the IFI. Failure included worsening CT scan abnormalities consistent with progressive infection or, clinically, an increase in the number and/or severity of clinical signs and symptoms attributable to the IFI.

Results

Patients' characteristics
Twenty-eight successive patients from one center, all of whom happened to have acute leukemias, were included in this prospective study from July 2001 to September 2003 (details of patients are given in Table 1). Patients included in this study had a history of probable (n=26) or proven (n=2) systemic or invasive fungal infection in the past according to modified EORTC criteria, which include typical signs of fungal infection on a CT scan closely related to neutropenia. 
Prior fungal infection was diagnosed by a CT scan of the lungs (n=27) and liver, spleen or kidneys (n=9) at a median of 3 months before transplant (range 1 week – 3 years).

Table 1. Patients' characteristics

2008-2-en-Stute-Table-1.png

At the beginning of transplantation, 12 patients (often unexpectedly) had florid infections by CT scan criteria, 10 had residuals and 6 were in CR. A bronchoscopy (BAL) and an abdominal ultrasound were performed prior to conditioning in most patients, but were not as informative as high resolution CT scans. However, in two patients with residual disease, we isolated Candida albicans via BAL in one, and Candida glabrata in the other.

Conditioning was performed with myeloablative regimens. Median duration of neutropenia was 18 days (range 7-47). Transplants were from unrelated (n=19) and related (n=9) donors, 6 of whom had a mismatch.

Side effects and toxicity of caspofungin
Caspofungin was given over a median duration of 27 days (range 15-47), which was similar in patients with and without active signs of IFI at the start of caspofungin. It was not necessary to discontinue caspofungin due to side effects in any patient. Median toxicity of conditioning, immunosuppression and supportive therapy according to Bearman was comparable to historic controls: mouth: grade 2, liver: grade 1, kidney: grade 0, and gut: grade 0. Maximal laboratory values (median and range) for liver and renal toxicity during caspofungin prophylaxis or therapy were: total bilirubin 2.7 mg/dL (range 1.2-22.2, normal ≤ 1.0), AST 36 U/L (range 6-215, normal ≤ 18), ALT 46 U/L (range 9-299, normal ≤ 22), and creatinine 1.1 mg/dL (range 0.7-3.0, normal ≤ 1.2). When maximal bilirubin was > 6 (n=4) mg/dL it was either due to liver toxicity (n=3), not related to any particular drug, or suspected hepatic veno-occlusive disease (n=1). When maximal creatinine was > 2 mg/dL (n=6) it was usually due to the nephrotoxic side effects of antibiotics given for fever and CSA. It is noteworthy that caspofungin was well tolerated in all 28 patients who received CSA for immunosuppression post-transplant without any associated renal or hepatic problems. No CSA dosage adaptation was required due to liver toxicity potentially related to caspofungin. Ten out of 28 patients experienced acute GvHD ≥ grade 2 after engraftment and prior to day +100 and needed additional immunosuppression.

Response to caspofungin
Importantly, in 10 out of 12 cases (83%) a florid fungal infection with a positive CT scan at start of transplantation responded to caspofungin alone, with 4 CR and 6 PR despite severe immunosuppression (Table 2).

2008-2-en-Stute-Table-2.png

Table 2. Response to caspofungin after engraftment by CT scan criteria.

NOTE. CR = complete response, PR = partial response (for definition see Methods)


Two case reports are shown for illustration (Figure 1). Four out of 12 patients received additional granulocyte transfusions during aplasia, and one patient with prolonged aplasia of 29 days nevertheless developed a fungal infection. In 14 out of 16 patients (88 %) without active signs of infection at start of transplantation, no fungal disease was observed after prophylaxis with caspofungin. Only 2 out of 16 patients developed a fungal infection under caspofungin despite additional granulocyte transfusions. Both patients had prolonged aplasia for 40 and 47 days, respectively.

Figure 1. Case reports of responses to caspofungin. Shown are chest CT scans of patients undergoing stem cell transplantation prior conditioning and after engraftment.

2008-2-en-Stute-Figure-1.png

A Partial response of prior florid fungal infection: 29-year-old woman with AML, FAB M6, complex cytogenetics. She received a mismatched unrelated PBSCT and had 23 days of aplasia.

2008-2-en-Stute-Figure-1B.jpg

B Complete response of prior florid fungal infection: 26-year-old man with early relapse c-ALL. He was given a matched unrelated BMT and had 22 days of aplasia.



Treatment failure was defined as documented or suspected progressive fungal infection.

In 4 out of 28 patients (1 CR, 1 residual and 2 florid states prior to transplantation) anti-mycotic treatment was, therefore, changed from caspofungin to second-line agents such as voriconazole, amphotericin B or AmBisome® i.v. (= 14% failure rate). Three out of four patients who developed a fungal infection following HSCT despite prophylaxis or therapy with caspofungin had delayed engraftment or primary graft failure with 29, 40 and 47 days of aplasia with leucocytes <1000 /µl.

The four patients who failed on caspofungin had suspected or documented progressive fungal infection until engraftment. All four had a positive chest CT scan with worsening of radiographic signs and only one had positive antigen tests for IFI. Patient 1 had increasing CRP, a positive test for Aspergillus antigen, and 40 days of aplasia due to primary graft failure. She received granulocytes and her autologous backup, responded to voriconazole and amphotericin B (PR), but still had residuals at day +100 and developed new infiltrates later. Patient 2 was BAL negative. She responded to voriconazole initially (PR) but died before day +100 from alveolar hemorrhage with pancytopenia and suspected fungal pneumonia. Patient 3 had a fever, Aspergillus fumigatus in BAL, and a normal antifungal serology (failure of secondary prophylaxis with fungal breakthrough infection). He had 47 days of aplasia, received granulocytes, and had grade 2 toxicity of mouth, liver, and kidney. He was treated with amphotericin B and had a CR from his fungal disease by day +100. However, he later died from a relapse of his leukemia. Patient 4 had 29 days of aplasia. She was given AmBisome®, responded with a CR, but died of multi-organ failure prior to day +100.

One patient with florid nodular infiltrates responded to caspofungin initially (PR), but received high dose steroids because of severe acute skin GvHD after engraftment, and later died of systemic Scedosporium prolificans resistant to caspofungin.

1 Year outcome
Overall mortality at one year was as high as expected. 11 out of 28 patients (39%) had died with overall survival of 61%. Causes of death were: pneumonia with sepsis (n=3) with suspected fungal pneumonia in two cases, systemic fungal sepsis with Scedosporium (n=1), sepsis of unknown etiology (n=1), alveolar hemorrhage (n=1), multi-organ failure (n=2), and relapse of leukemia (n=3). Five deaths were associated with pancytopenia or secondary graft failure and five fatalities with severe GvHD. Transplant-related mortality (TRM) was 8 out of 28 patients (29%) and no death was attributed to caspofungin. Six out of 8 patients who died due to TRM within the first year had signs of pulmonary infiltrates at time of death, and in 2 cases these were indicative of active IFI (patients A and B, see below). Only 1 out of 17 patients still alive at 1 year had signs of residual fungal disease (patient C, see below).

Relapse IFI of the lung in the first year post transplant after the initial phase of caspofungin prophylaxis or therapy was suspected in 3 patients (patients who had a relapse of their leukemia prior to developing signs of IFI are not included): At 1.5 months after transplant, patient A, after being treated with steroids for skin and gut GvHD, still under itraconazole prophylaxis, developed atypical infiltrates on chest CT scan. He was treated with antibiotics and voriconazole, and died of pneumonia shortly thereafter. Eight months after transplant, patient B, after a cholecystitis and colitis, showed a positive chest X-ray and voriconazole treatment was initiated; he developed an ileus and died shortly thereafter of multi-organ failure. After 8 and 10 months, patient C (caspofungin-failure patient 1), after a relapse of her leukemia and another SCT with primary graft failure, developed new round infiltrates on chest CT scan, which regressed under therapy with voriconazole.

Six out of 28 patients (21%) experienced a relapse of their leukemia in the first year after transplant. Three patients underwent a second SCT and achieved a complete remission of their leukemia. One patient progressed despite reinduction therapy and two patients received palliative therapy only. At one year, all 17 patients alive were in complete remission with regard to their underlying disease.

Discussion

This is the first prospective, non-controlled, single-center study of secondary antifungal prophylaxis or therapy in allogeneic SCT in high-risk patients with prior systemic or invasive fungal infections. Caspofungin is effective for secondary prophylaxis and in those patients with an active infection at time of SCT. In 88% of patients (n=16) without active signs of infection at start of transplantation, secondary prophylaxis with caspofungin was successful, and in 83% of patients (n=12), a florid fungal infection at the time of transplantation responded to caspofungin despite aplasia and additional immunosuppression. Scheduled transplantations were not delayed until fungal infections resolved, for this may have had major implications for prognosis.

Six patients received 1 to 6 granulocyte transfusions (median 3) before engraftment, which could also attribute to the resolution of fungal infection. Three patients failed on caspofungin despite receiving granulocytes. Each of these patients had prolonged aplasia >4 weeks (one had signs of florid infection, one had residuals, and one was in CR at the start of transplantation).

Retrospective studies had indicated that BMT in patients with a history of IA is feasible. Offner et al. performed a multicenter retrospective analysis of 48 patients with documented or probable IA prior to BMT using various antifungals for secondary prophylaxis. The overall incidence of relapse IA was lower than expected (33%), but the mortality rate among relapsed patients was 88% [10]. Fukuda et al. described a 10-year experience at a single transplant center and included 45 patients with a known history of IA before HSCT. Post-transplantation IA occurred in 13 of these patients, 9 infections were considered recurrent. Compared with other patients who received allogeneic HSCT during the same period, patients with histories of IA had a lower overall survival of 56% and a higher TRM of 38% at 100 days after BMT [11].

Post-transplantation IA occurred more frequently in patients who received < 1 month of antifungal therapy prior to BMT. Patients receiving >1 month of antifungal therapy and who had a resolution of radiographic abnormalities did better. Recently, Cordonnier et al. have shown that voriconazole may be useful to prevent reactivation of prior fungal disease in a retrospective study of 9 patients undergoing allogeneic HSCT [12]. These included 5 proven and 4 probable cases of IA according to EORTC criteria and at time of transplant, 3 patients had residual fungal disease. Voriconazole 400 mg/day i.v. or p.o. was given from start of conditioning until end of immunosuppression. None of the patients experienced fungal relapse or new fungal disease and scheduled treatment was not delayed. Voriconazole was well tolerated, except in one patient who had abnormal liver tests secondary to GvHD, and one who had transient visual disturbances.

Caspofungin was chosen in our prospective study as secondary prophylaxis or therapy because of its high efficacy in Aspergillus and Candida infections and its low side effects [22]. Caspofungin is active in vitro against Candida spp., including C. krusei, C. glabrata and C. tropicalis, as well as Aspergillus spp., such as A. fumigatus, A. flavus and A. niger. Caspofungin is resistant, however, against Fusarium, Rhizopus, Cryptococcus and Scedosporium prolificans [22]. Caspofungin has shown high efficacy in clinical trials in esophageal candidiasis, refractory invasive aspergillosis, candidemia, and empiric antifungal therapy. It has been approved for first-line therapy of candidemia and second-line therapy of aspergillosis [17-23].

Sable et al. analyzed the safety and tolerability of caspofungin, which was generally well tolerated; caspofungin was discontinued only in 2% of patients due to adverse events [24]. Drug-related adverse events were fever, local phlebitis at the infusion-site, headache and nausea. Renal tolerability was excellent and transient mild-to-moderate elevations in ALT, AST and alkaline phosphatase levels were observed. In our study, caspofungin was well tolerated and did not have to be discontinued due to side effects in a single patient. It is of note that caspofungin was safe in all 28 patients who received cyclosporin A (CSA) for immunosuppression post-transplant without any liver or renal problems due to CSA. Similar results have been found by Sanz-Rodriguez et al. recently in 13 patients who received CSA concomitantly [29]. The incidence of liver and renal toxicity and acute GvHD ≥ grade 2 was comparable to historic controls without caspofungin.

Long-term aplasia is a high risk factor for fungal (breakthrough) infection. Chest CT scans prior to transplantation and frequently thereafter, e.g. once weekly, are likely to benefit this high-risk group of patients. In our study, in 12 out of 28 cases chest CT scans revealed a florid infection at start of transplantation despite a lack of clinical signs and symptoms.

A limitation of our study was that no control group existed; therefore conclusions about toxicity and efficacy are based on clinical experience and should be handled with caution. There also was a tendency to declare failure in neutropenic patients who had increasing infiltrates on CT scan, and to discontinue caspofungin early despite the lack of concrete evidence of IFI (this was possibly relevant in 3 out of 4 patients).

In conclusion, the use of caspofungin as secondary prophylaxis or therapy in high-risk patients with a history or persistence of IFI undergoing allogeneic SCT is safe and effective. It does not result in a high toxicity and shows a low incidence of breakthrough infections. This allows SCT to proceed as scheduled, even if signs of florid fungal disease are still evident at time of transplant.

Acknowledgements

We thank the staff of the BMT unit for providing excellent care of our patients, the radiologists for their cooperation, and the medical technicians for their excellent work in the BMT laboratory.

References

1. Fukuda T, Boeckh M, Carter RA, Sandmaier BM, Maris MB, Maloney DG, et al. Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning. Blood. 2003;102(3):827-833.

2. Wingard JR. Antifungal chemoprophylaxis after blood and marrow transplantation. Clin Infect Dis. 2002;34(10):1386-1390.

3. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32(3):358-366.

4. Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34(7):909-917.

5. Hamza NS, Ghannoum MA, Lazarus HM. Choices aplenty: antifungal prophylaxis in hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2004;34(5):377-389.

6. Goodman JL, Winston DJ, Greenfield RA, Chandrasekar PH, Fox B, Kaizer H, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992;326(13):845-851.

7. Slavin MA, Osborne B, Adams R, Levenstein MJ, Schoch HG, Feldman AR, et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation - a prospective, randomized, double-blind study. J Infect Dis. 1995;171(6):1545-1552.

8. Marr KA, Seidel K, Slavin MA, Bowden RA, Schoch HG, Flowers ME, et al. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial. Blood. 2000;96(6):2055-2061.

9. Dykewicz CA. Summary of the Guidelines for Preventing Opportunistic Infections among Hematopoietic Stem Cell Transplant Recipients. Clin Infect Dis. 2001;33(2):139-144.

10. Offner F, Cordonnier C, Ljungman P, Prentice HG, Engelhard D, De Bacquer D, et al. Impact of previous aspergillosis on the outcome of bone marrow transplantation. Clin Infect Dis. 1998;26(5):1098-1103.

11. Fukuda T, Boeckh M, Guthrie KA, Mattson DK, Owens S, Wald A, et al. Invasive aspergillosis before allogeneic hematopoietic stem cell transplantation: 10-year experience at a single transplant center. Biol Blood Marrow Transplant. 2004;10(7):494-503.

12. Cordonnier C, Maury S, Pautas C, Bastie JN, Chehata S, Castaigne S, et al. Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients. Bone Marrow Transplant. 2004;33(9):943-948.

13. Martino R, Nomdedeu J, Altes A, Sureda A, Brunet S, Martinez C, et al. Successful bone marrow transplantation in patients with previous invasive fungal infections: report of four cases. Bone Marrow Transplant. 1994;13(3):265-269.

14. Richard C, Romon I, Baro J, Insunza A, Loyola I, Zurbano F, et al. Invasive pulmonary aspergillosis prior to BMT in acute leukemia patients does not predict a poor outcome. Bone Marrow Transplant. 1993;12(3):237-241.

15. Mattei D, Mordini N, Lo NC, Ghirardo D, Ferrua MT, Osenda M, et al. Voriconazole in the management of invasive aspergillosis in two patients with acute myeloid leukemia undergoing stem cell transplantation. Bone Marrow Transplant. 2002;30(12):967-970.

16. Denning DW. Echinocandin antifungal drugs. Lancet. 2003;362(9390):1142-1151.

17. Villanueva A, Arathoon EG, Gotuzzo E, Berman RS, DiNubile MJ, Sable CA. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis. 2001;33(9):1529-1535.

18. Villanueva A, Gotuzzo E, Arathoon EG, Noriega LM, Kartsonis NA, Lupinacci RJ, et al. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med. 2002;113(4):294-299.

19. Arathoon EG, Gotuzzo E, Noriega LM, Berman RS, DiNubile MJ, Sable CA. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases. Antimicrob Agents Chemother. 2002;46(2):451-457.

20. Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347(25):2020-2029.

21. Maertens J, Boogaerts M. Caspofungin in the treatment of candidosis and aspergillosis. Int J Infect Dis. 2003;7(2):94-101.

22. Letscher-Bru V, Herbrecht R. Caspofungin: the first representative of a new antifungal class. J Antimicrob Chemother. 2003;51(3):513-521.

23. Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004;351(14):1391-1402.

24. Sable CA, Nguyen BY, Chodakewitz JA, DiNubile MJ. Safety and tolerability of caspofungin acetate in the treatment of fungal infections. Transpl Infect Dis. 2002;4(1):25-30.

25. Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2002;34(1):7-14.

26. Caillot D, Couaillier JF, Bernard A, Casasnovas O, Denning DW, Mannone L, et al. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol. 2001;19(1):253-259.

27. Kuhlman JE, Fishman EK, Burch PA, Karp JE, Zerhouni EA, Siegelman SS. Invasive pulmonary aspergillosis in acute leukemia. The contribution of CT to early diagnosis and aggressive management. Chest. 1987;92(1):95-99.

28. Kuhlman JE, Fishman EK, Siegelman SS. Invasive pulmonary aspergillosis in acute leukemia: characteristic findings on CT, the CT halo sign, and the role of CT in early diagnosis. Radiology. 1985;157(3):611-614.

29. Sanz-Rodriguez C, Lopez-Duarte M, Jurado M, Lopez J, Arranz R, Cisneros JM, et al. Safety of the concomitant use of caspofungin and cyclosporin A in patients with invasive fungal infections. Bone Marrow Transplant. 2004.

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Introduction

Fungal infections with Aspergillus or Candida, mainly of the lung, are a major cause of treatment-related mortality in allogeneic stem cell transplantation (SCT) [1, 2]. Invasive Aspergillosis (IA) in hematopoietic stem cell transplant (HSCT) recipients was associated with case-fatality rates of 87% [3], and an overall 1-year survival rate of only 20% [4]. Patients with a history of systemic or invasive fungal infection (IFI) who undergo allogeneic transplantation are considered to be at high risk of disease reactivation or progression leading to a high mortality. More recently, leukemias and other malignancies have been treated with more intensive induction therapies up front, resulting in a higher incidence of fungal infections before receiving a stem cell transplant. 

Primary antifungal prophylaxis is given routinely in patients with no prior IFI who undergo allogeneic stem cell transplantation [5-9], whereas secondary prophylaxis is given in patients with prior IFI. Up to now, for those patients with a history of IFI who undergo allogeneic SCT, no prospective study of secondary antifungal prophylaxis in a larger series of these high-risk patients exists. More recently, several retrospective studies indicate that bone marrow transplantation (BMT) in patients with a history of IA is feasible [10-12]. Apart from that, the only case reports that can be found in the literature concern patients with fungal disease who underwent SCT and were successfully treated with fluconazole, itraconazole, surgical resection, amphotericin B, and voriconazole [13-15].

We therefore conducted a prospective single-center study to evaluate the efficacy and safety of caspofungin as secondary prophylaxis or therapy, in order to prevent recurrence or progression of systemic or invasive fungal infections in patients with a history of IFI who underwent allogeneic SCT. 
Caspofungin is an echinocandin, which interferes with fungal cell wall assembly by inhibition of  β(1,3)-D-glucan synthase, an enzyme not present in mammalian cells [16]. It shows no signs of nephrotoxicity and has only modest side effects, such as chills and fever, in very few patients (1-3 %). Caspofungin has proven to be effective and well-tolerated in the treatment of infections caused by Aspergillus and Candida species in clinical trials [17-24].

Patients and methods

Study design
Patients included in our study had a history of proven or probable IFI according to modified EORTC criteria for diagnosis of invasive fungal infection. Proven IFI requires histo- or cytopathology positive for hyphae with evidence of associated tissue damage or a positive culture for mold species from a normally sterile site consistent with infection. Probable IFI included cases with one host criterion plus one microbial criterion and one major or two minor clinical criteria, or a patient with recent neutropenia or an allogeneic SCT patient with a chest CT scan positive for "halo" or "air crescent" signs [25-28]. The patients included were scheduled to undergo an allogeneic bone marrow or stem cell transplantation and needed to have sufficient organ function.

The primary efficacy endpoint was the incidence of clinically manifest mycoses under the prophylactic use of caspofungin (development of breakthrough IFI) or response thereof, in case of florid infections at start of conditioning. The secondary endpoints were the evaluation of toxicity and overall survival until day +365. Failure was defined as suspected or documented fungal infection (failure to prevent a new IFI), or a progressive fungal infection in case of prior florid activity (failure to improve a partially treated IFI). Secondary endpoints were evaluated descriptively. All patients included were evaluated on an intent-to-treat basis.

Modified EORTC criteria for diagnosis of IFI are more clinically oriented than the strict EORTC-IFICG/MSG criteria (European Organization for Research and Treatment of Cancer - IFI Cooperative Group & Mycoses Study Group). These criteria were specifically developed for use in large clinical trials on the efficacy of antifungals and should not be used to guide clinical decisions [25]. This approach is reflected by the clinical practice in BMT, where proven and even probable IFI with direct microbiological evidence are diagnosed in only a minority of high risk patients, and diagnosis of fungal infection is often made on clinical and radiological grounds alone.

Prior to study entry, we performed a chest CT scan, a bronchoalveolar lavage (BAL), and an abdominal ultrasound. We also carried out a high-resolution chest CT scan at the end of the caspofungin prophylaxis or in case of fever. Weekly controls of circulating Aspergillus galactomannan antigen (Platelia® Aspergillus EIA, index used for cut-off was 1.0, BioRad Laboratories, Hercules, CA, USA) and Candida antibody titer (Cand-Tec® latex agglutination test for heat-labile antigen, Ramco Laboratories, Stafford, TX, USA) were performed in all patients. To measure potential side effects we conducted daily blood counts and clinical chemistry analyses.

Patients
Successive patients with a history of systemic or invasive fungal infection in the past who underwent allogeneic BMT were included in this prospective study. 
Conditioning was performed with myeloablative regimens. In unrelated donors and mismatched family donors, we added anti-thymocyte globulin (ATG Fresenius, 30-90 mg/kg intravenously (i.v.)) to the conditioning in order to minimize the risk of graft-versus-host disease (GvHD). Cyclosporin A (CSA) for immunosuppression was given to all patients post-transplant with a target level of 200-300 µg/L. The local ethics committee approved the study and all patients gave prior written informed consent.

Treatment plan & response assessment
Patients were given 50 mg caspofungin i.v. daily over one hour, following a 70 mg loading dose from start of conditioning until stable engraftment. No other systemic antifungal was given. All patients were nursed in reversed isolation in conventional or laminar airflow rooms. Antibiotic prophylaxis consisted of ciprofloxacin, local antifungals, and acyclovir. Prophylaxis against pneumocystis carinii was carried out with cotrimoxazole (or pentamidine inhalation). CMV-negative patients received only CMV-negative blood products. All blood products were irradiated at 25 Gy. CMV-positive patients were monitored weekly for CMV infection by PCR and/or antigenemia-assay for pp65. Preemptive therapy was started with 10 mg/kg gancyclovir after two consecutive positive PCR or one positive antigenemia-assay. In the case of neutropenic fever during transplantation, ceftazidime and vancomycin were given; if fever or signs of infection persisted, tobramycin was added after two days. In patients without signs of fungal infection after engraftment, antimycotic prophylaxis was switched to itraconazole 200 mg twice daily until day +100.An experienced clinician and radiologist performed the mycological response assessment according to EORTC criteria. Radiographic criteria for complete response (CR) required a > 90% clearing of CT scan abnormalities associated with active fungal infection or persistent residual scarring only. Partial response (PR) required a > 50% improvement in radiographic abnormalities on relevant scans, as compared to baseline. Stable response was diagnosed if minor or no improvement occurred and there was no worsening of attributable radiographic signs of the IFI. Failure included worsening CT scan abnormalities consistent with progressive infection or, clinically, an increase in the number and/or severity of clinical signs and symptoms attributable to the IFI.

Results

Patients' characteristics
Twenty-eight successive patients from one center, all of whom happened to have acute leukemias, were included in this prospective study from July 2001 to September 2003 (details of patients are given in Table 1). Patients included in this study had a history of probable (n=26) or proven (n=2) systemic or invasive fungal infection in the past according to modified EORTC criteria, which include typical signs of fungal infection on a CT scan closely related to neutropenia. 
Prior fungal infection was diagnosed by a CT scan of the lungs (n=27) and liver, spleen or kidneys (n=9) at a median of 3 months before transplant (range 1 week – 3 years).

Table 1. Patients' characteristics

2008-2-en-Stute-Table-1.png

At the beginning of transplantation, 12 patients (often unexpectedly) had florid infections by CT scan criteria, 10 had residuals and 6 were in CR. A bronchoscopy (BAL) and an abdominal ultrasound were performed prior to conditioning in most patients, but were not as informative as high resolution CT scans. However, in two patients with residual disease, we isolated Candida albicans via BAL in one, and Candida glabrata in the other.

Conditioning was performed with myeloablative regimens. Median duration of neutropenia was 18 days (range 7-47). Transplants were from unrelated (n=19) and related (n=9) donors, 6 of whom had a mismatch.

Side effects and toxicity of caspofungin
Caspofungin was given over a median duration of 27 days (range 15-47), which was similar in patients with and without active signs of IFI at the start of caspofungin. It was not necessary to discontinue caspofungin due to side effects in any patient. Median toxicity of conditioning, immunosuppression and supportive therapy according to Bearman was comparable to historic controls: mouth: grade 2, liver: grade 1, kidney: grade 0, and gut: grade 0. Maximal laboratory values (median and range) for liver and renal toxicity during caspofungin prophylaxis or therapy were: total bilirubin 2.7 mg/dL (range 1.2-22.2, normal ≤ 1.0), AST 36 U/L (range 6-215, normal ≤ 18), ALT 46 U/L (range 9-299, normal ≤ 22), and creatinine 1.1 mg/dL (range 0.7-3.0, normal ≤ 1.2). When maximal bilirubin was > 6 (n=4) mg/dL it was either due to liver toxicity (n=3), not related to any particular drug, or suspected hepatic veno-occlusive disease (n=1). When maximal creatinine was > 2 mg/dL (n=6) it was usually due to the nephrotoxic side effects of antibiotics given for fever and CSA. It is noteworthy that caspofungin was well tolerated in all 28 patients who received CSA for immunosuppression post-transplant without any associated renal or hepatic problems. No CSA dosage adaptation was required due to liver toxicity potentially related to caspofungin. Ten out of 28 patients experienced acute GvHD ≥ grade 2 after engraftment and prior to day +100 and needed additional immunosuppression.

Response to caspofungin
Importantly, in 10 out of 12 cases (83%) a florid fungal infection with a positive CT scan at start of transplantation responded to caspofungin alone, with 4 CR and 6 PR despite severe immunosuppression (Table 2).

2008-2-en-Stute-Table-2.png

Table 2. Response to caspofungin after engraftment by CT scan criteria.

NOTE. CR = complete response, PR = partial response (for definition see Methods)


Two case reports are shown for illustration (Figure 1). Four out of 12 patients received additional granulocyte transfusions during aplasia, and one patient with prolonged aplasia of 29 days nevertheless developed a fungal infection. In 14 out of 16 patients (88 %) without active signs of infection at start of transplantation, no fungal disease was observed after prophylaxis with caspofungin. Only 2 out of 16 patients developed a fungal infection under caspofungin despite additional granulocyte transfusions. Both patients had prolonged aplasia for 40 and 47 days, respectively.

Figure 1. Case reports of responses to caspofungin. Shown are chest CT scans of patients undergoing stem cell transplantation prior conditioning and after engraftment.

2008-2-en-Stute-Figure-1.png

A Partial response of prior florid fungal infection: 29-year-old woman with AML, FAB M6, complex cytogenetics. She received a mismatched unrelated PBSCT and had 23 days of aplasia.

2008-2-en-Stute-Figure-1B.jpg

B Complete response of prior florid fungal infection: 26-year-old man with early relapse c-ALL. He was given a matched unrelated BMT and had 22 days of aplasia.



Treatment failure was defined as documented or suspected progressive fungal infection.

In 4 out of 28 patients (1 CR, 1 residual and 2 florid states prior to transplantation) anti-mycotic treatment was, therefore, changed from caspofungin to second-line agents such as voriconazole, amphotericin B or AmBisome® i.v. (= 14% failure rate). Three out of four patients who developed a fungal infection following HSCT despite prophylaxis or therapy with caspofungin had delayed engraftment or primary graft failure with 29, 40 and 47 days of aplasia with leucocytes <1000 /µl.

The four patients who failed on caspofungin had suspected or documented progressive fungal infection until engraftment. All four had a positive chest CT scan with worsening of radiographic signs and only one had positive antigen tests for IFI. Patient 1 had increasing CRP, a positive test for Aspergillus antigen, and 40 days of aplasia due to primary graft failure. She received granulocytes and her autologous backup, responded to voriconazole and amphotericin B (PR), but still had residuals at day +100 and developed new infiltrates later. Patient 2 was BAL negative. She responded to voriconazole initially (PR) but died before day +100 from alveolar hemorrhage with pancytopenia and suspected fungal pneumonia. Patient 3 had a fever, Aspergillus fumigatus in BAL, and a normal antifungal serology (failure of secondary prophylaxis with fungal breakthrough infection). He had 47 days of aplasia, received granulocytes, and had grade 2 toxicity of mouth, liver, and kidney. He was treated with amphotericin B and had a CR from his fungal disease by day +100. However, he later died from a relapse of his leukemia. Patient 4 had 29 days of aplasia. She was given AmBisome®, responded with a CR, but died of multi-organ failure prior to day +100.

One patient with florid nodular infiltrates responded to caspofungin initially (PR), but received high dose steroids because of severe acute skin GvHD after engraftment, and later died of systemic Scedosporium prolificans resistant to caspofungin.

1 Year outcome
Overall mortality at one year was as high as expected. 11 out of 28 patients (39%) had died with overall survival of 61%. Causes of death were: pneumonia with sepsis (n=3) with suspected fungal pneumonia in two cases, systemic fungal sepsis with Scedosporium (n=1), sepsis of unknown etiology (n=1), alveolar hemorrhage (n=1), multi-organ failure (n=2), and relapse of leukemia (n=3). Five deaths were associated with pancytopenia or secondary graft failure and five fatalities with severe GvHD. Transplant-related mortality (TRM) was 8 out of 28 patients (29%) and no death was attributed to caspofungin. Six out of 8 patients who died due to TRM within the first year had signs of pulmonary infiltrates at time of death, and in 2 cases these were indicative of active IFI (patients A and B, see below). Only 1 out of 17 patients still alive at 1 year had signs of residual fungal disease (patient C, see below).

Relapse IFI of the lung in the first year post transplant after the initial phase of caspofungin prophylaxis or therapy was suspected in 3 patients (patients who had a relapse of their leukemia prior to developing signs of IFI are not included): At 1.5 months after transplant, patient A, after being treated with steroids for skin and gut GvHD, still under itraconazole prophylaxis, developed atypical infiltrates on chest CT scan. He was treated with antibiotics and voriconazole, and died of pneumonia shortly thereafter. Eight months after transplant, patient B, after a cholecystitis and colitis, showed a positive chest X-ray and voriconazole treatment was initiated; he developed an ileus and died shortly thereafter of multi-organ failure. After 8 and 10 months, patient C (caspofungin-failure patient 1), after a relapse of her leukemia and another SCT with primary graft failure, developed new round infiltrates on chest CT scan, which regressed under therapy with voriconazole.

Six out of 28 patients (21%) experienced a relapse of their leukemia in the first year after transplant. Three patients underwent a second SCT and achieved a complete remission of their leukemia. One patient progressed despite reinduction therapy and two patients received palliative therapy only. At one year, all 17 patients alive were in complete remission with regard to their underlying disease.

Discussion

This is the first prospective, non-controlled, single-center study of secondary antifungal prophylaxis or therapy in allogeneic SCT in high-risk patients with prior systemic or invasive fungal infections. Caspofungin is effective for secondary prophylaxis and in those patients with an active infection at time of SCT. In 88% of patients (n=16) without active signs of infection at start of transplantation, secondary prophylaxis with caspofungin was successful, and in 83% of patients (n=12), a florid fungal infection at the time of transplantation responded to caspofungin despite aplasia and additional immunosuppression. Scheduled transplantations were not delayed until fungal infections resolved, for this may have had major implications for prognosis.

Six patients received 1 to 6 granulocyte transfusions (median 3) before engraftment, which could also attribute to the resolution of fungal infection. Three patients failed on caspofungin despite receiving granulocytes. Each of these patients had prolonged aplasia >4 weeks (one had signs of florid infection, one had residuals, and one was in CR at the start of transplantation).

Retrospective studies had indicated that BMT in patients with a history of IA is feasible. Offner et al. performed a multicenter retrospective analysis of 48 patients with documented or probable IA prior to BMT using various antifungals for secondary prophylaxis. The overall incidence of relapse IA was lower than expected (33%), but the mortality rate among relapsed patients was 88% [10]. Fukuda et al. described a 10-year experience at a single transplant center and included 45 patients with a known history of IA before HSCT. Post-transplantation IA occurred in 13 of these patients, 9 infections were considered recurrent. Compared with other patients who received allogeneic HSCT during the same period, patients with histories of IA had a lower overall survival of 56% and a higher TRM of 38% at 100 days after BMT [11].

Post-transplantation IA occurred more frequently in patients who received < 1 month of antifungal therapy prior to BMT. Patients receiving >1 month of antifungal therapy and who had a resolution of radiographic abnormalities did better. Recently, Cordonnier et al. have shown that voriconazole may be useful to prevent reactivation of prior fungal disease in a retrospective study of 9 patients undergoing allogeneic HSCT [12]. These included 5 proven and 4 probable cases of IA according to EORTC criteria and at time of transplant, 3 patients had residual fungal disease. Voriconazole 400 mg/day i.v. or p.o. was given from start of conditioning until end of immunosuppression. None of the patients experienced fungal relapse or new fungal disease and scheduled treatment was not delayed. Voriconazole was well tolerated, except in one patient who had abnormal liver tests secondary to GvHD, and one who had transient visual disturbances.

Caspofungin was chosen in our prospective study as secondary prophylaxis or therapy because of its high efficacy in Aspergillus and Candida infections and its low side effects [22]. Caspofungin is active in vitro against Candida spp., including C. krusei, C. glabrata and C. tropicalis, as well as Aspergillus spp., such as A. fumigatus, A. flavus and A. niger. Caspofungin is resistant, however, against Fusarium, Rhizopus, Cryptococcus and Scedosporium prolificans [22]. Caspofungin has shown high efficacy in clinical trials in esophageal candidiasis, refractory invasive aspergillosis, candidemia, and empiric antifungal therapy. It has been approved for first-line therapy of candidemia and second-line therapy of aspergillosis [17-23].

Sable et al. analyzed the safety and tolerability of caspofungin, which was generally well tolerated; caspofungin was discontinued only in 2% of patients due to adverse events [24]. Drug-related adverse events were fever, local phlebitis at the infusion-site, headache and nausea. Renal tolerability was excellent and transient mild-to-moderate elevations in ALT, AST and alkaline phosphatase levels were observed. In our study, caspofungin was well tolerated and did not have to be discontinued due to side effects in a single patient. It is of note that caspofungin was safe in all 28 patients who received cyclosporin A (CSA) for immunosuppression post-transplant without any liver or renal problems due to CSA. Similar results have been found by Sanz-Rodriguez et al. recently in 13 patients who received CSA concomitantly [29]. The incidence of liver and renal toxicity and acute GvHD ≥ grade 2 was comparable to historic controls without caspofungin.

Long-term aplasia is a high risk factor for fungal (breakthrough) infection. Chest CT scans prior to transplantation and frequently thereafter, e.g. once weekly, are likely to benefit this high-risk group of patients. In our study, in 12 out of 28 cases chest CT scans revealed a florid infection at start of transplantation despite a lack of clinical signs and symptoms.

A limitation of our study was that no control group existed; therefore conclusions about toxicity and efficacy are based on clinical experience and should be handled with caution. There also was a tendency to declare failure in neutropenic patients who had increasing infiltrates on CT scan, and to discontinue caspofungin early despite the lack of concrete evidence of IFI (this was possibly relevant in 3 out of 4 patients).

In conclusion, the use of caspofungin as secondary prophylaxis or therapy in high-risk patients with a history or persistence of IFI undergoing allogeneic SCT is safe and effective. It does not result in a high toxicity and shows a low incidence of breakthrough infections. This allows SCT to proceed as scheduled, even if signs of florid fungal disease are still evident at time of transplant.

Acknowledgements

We thank the staff of the BMT unit for providing excellent care of our patients, the radiologists for their cooperation, and the medical technicians for their excellent work in the BMT laboratory.

References

1. Fukuda T, Boeckh M, Carter RA, Sandmaier BM, Maris MB, Maloney DG, et al. Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning. Blood. 2003;102(3):827-833.

2. Wingard JR. Antifungal chemoprophylaxis after blood and marrow transplantation. Clin Infect Dis. 2002;34(10):1386-1390.

3. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001;32(3):358-366.

4. Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34(7):909-917.

5. Hamza NS, Ghannoum MA, Lazarus HM. Choices aplenty: antifungal prophylaxis in hematopoietic stem cell transplant recipients. Bone Marrow Transplant. 2004;34(5):377-389.

6. Goodman JL, Winston DJ, Greenfield RA, Chandrasekar PH, Fox B, Kaizer H, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992;326(13):845-851.

7. Slavin MA, Osborne B, Adams R, Levenstein MJ, Schoch HG, Feldman AR, et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation - a prospective, randomized, double-blind study. J Infect Dis. 1995;171(6):1545-1552.

8. Marr KA, Seidel K, Slavin MA, Bowden RA, Schoch HG, Flowers ME, et al. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial. Blood. 2000;96(6):2055-2061.

9. Dykewicz CA. Summary of the Guidelines for Preventing Opportunistic Infections among Hematopoietic Stem Cell Transplant Recipients. Clin Infect Dis. 2001;33(2):139-144.

10. Offner F, Cordonnier C, Ljungman P, Prentice HG, Engelhard D, De Bacquer D, et al. Impact of previous aspergillosis on the outcome of bone marrow transplantation. Clin Infect Dis. 1998;26(5):1098-1103.

11. Fukuda T, Boeckh M, Guthrie KA, Mattson DK, Owens S, Wald A, et al. Invasive aspergillosis before allogeneic hematopoietic stem cell transplantation: 10-year experience at a single transplant center. Biol Blood Marrow Transplant. 2004;10(7):494-503.

12. Cordonnier C, Maury S, Pautas C, Bastie JN, Chehata S, Castaigne S, et al. Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients. Bone Marrow Transplant. 2004;33(9):943-948.

13. Martino R, Nomdedeu J, Altes A, Sureda A, Brunet S, Martinez C, et al. Successful bone marrow transplantation in patients with previous invasive fungal infections: report of four cases. Bone Marrow Transplant. 1994;13(3):265-269.

14. Richard C, Romon I, Baro J, Insunza A, Loyola I, Zurbano F, et al. Invasive pulmonary aspergillosis prior to BMT in acute leukemia patients does not predict a poor outcome. Bone Marrow Transplant. 1993;12(3):237-241.

15. Mattei D, Mordini N, Lo NC, Ghirardo D, Ferrua MT, Osenda M, et al. Voriconazole in the management of invasive aspergillosis in two patients with acute myeloid leukemia undergoing stem cell transplantation. Bone Marrow Transplant. 2002;30(12):967-970.

16. Denning DW. Echinocandin antifungal drugs. Lancet. 2003;362(9390):1142-1151.

17. Villanueva A, Arathoon EG, Gotuzzo E, Berman RS, DiNubile MJ, Sable CA. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis. 2001;33(9):1529-1535.

18. Villanueva A, Gotuzzo E, Arathoon EG, Noriega LM, Kartsonis NA, Lupinacci RJ, et al. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med. 2002;113(4):294-299.

19. Arathoon EG, Gotuzzo E, Noriega LM, Berman RS, DiNubile MJ, Sable CA. Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases. Antimicrob Agents Chemother. 2002;46(2):451-457.

20. Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347(25):2020-2029.

21. Maertens J, Boogaerts M. Caspofungin in the treatment of candidosis and aspergillosis. Int J Infect Dis. 2003;7(2):94-101.

22. Letscher-Bru V, Herbrecht R. Caspofungin: the first representative of a new antifungal class. J Antimicrob Chemother. 2003;51(3):513-521.

23. Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004;351(14):1391-1402.

24. Sable CA, Nguyen BY, Chodakewitz JA, DiNubile MJ. Safety and tolerability of caspofungin acetate in the treatment of fungal infections. Transpl Infect Dis. 2002;4(1):25-30.

25. Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2002;34(1):7-14.

26. Caillot D, Couaillier JF, Bernard A, Casasnovas O, Denning DW, Mannone L, et al. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol. 2001;19(1):253-259.

27. Kuhlman JE, Fishman EK, Burch PA, Karp JE, Zerhouni EA, Siegelman SS. Invasive pulmonary aspergillosis in acute leukemia. The contribution of CT to early diagnosis and aggressive management. Chest. 1987;92(1):95-99.

28. Kuhlman JE, Fishman EK, Siegelman SS. Invasive pulmonary aspergillosis in acute leukemia: characteristic findings on CT, the CT halo sign, and the role of CT in early diagnosis. Radiology. 1985;157(3):611-614.

29. Sanz-Rodriguez C, Lopez-Duarte M, Jurado M, Lopez J, Arranz R, Cisneros JM, et al. Safety of the concomitant use of caspofungin and cyclosporin A in patients with invasive fungal infections. Bone Marrow Transplant. 2004.

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Больные с анамнезом или риском развития инвазивных грибковых инфекций (ИГИ), при аллогенной трансплантации стволовых клеток имеют высокий риск реактивации или прогрессии этих инфекций. В проспективном исследовании мы оценивали эффективность и безопасность каспофунгина в качестве вторичной профилактики или лечения персистирующего заболеванимя. Каспофунгин - это эхинокандин, нарушающий сборку клеточной стенки грибка посредством ингибирования β(1,3)-D-глюкансинтазы. </p> <h3>Методы</h3> <p>Двадцать восемь больных были включены в это исследование, все они были с острым лейкозом. В период ТСК, 16 больных не имели симптомов инфекции, тогда как в 12 случаях (с помощью компьютерной томографии) были отмечены признаки цветущих грибковых инфекций. До начала исследования проводился бронхоальвеолярный лаваж и УЗИ абдоминальной области. Контрольные определения галактоманнана <em>Aspergillus</em> и антител к <em>Candida</em> проводили еженедельно. 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Штуте Н., Забелина Т., Фезе Б., Хассенпфлюг В., Панзе Й., Вольшке К., Айюк Ф., Шидер Х., Ренгес Х., Кратохвилл А.,
фон Хинюбер Р., Эрттманн Р., Цандер А.Р., Крегер Н.

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Состояние вопроса

Грибковые инфекции, вызванные Aspergillus or Candida, поражают, главным образом, легкие и являются основной причиной смертности при трансплантации стволовых клеток (ТСК). Больные с анамнезом или риском развития инвазивных грибковых инфекций (ИГИ), при аллогенной трансплантации стволовых клеток имеют высокий риск реактивации или прогрессии этих инфекций. В проспективном исследовании мы оценивали эффективность и безопасность каспофунгина в качестве вторичной профилактики или лечения персистирующего заболеванимя. Каспофунгин - это эхинокандин, нарушающий сборку клеточной стенки грибка посредством ингибирования β(1,3)-D-глюкансинтазы.

Методы

Двадцать восемь больных были включены в это исследование, все они были с острым лейкозом. В период ТСК, 16 больных не имели симптомов инфекции, тогда как в 12 случаях (с помощью компьютерной томографии) были отмечены признаки цветущих грибковых инфекций. До начала исследования проводился бронхоальвеолярный лаваж и УЗИ абдоминальной области. Контрольные определения галактоманнана Aspergillus и антител к Candida проводили еженедельно. Каспофунгин (по 50 мг вдень вводили внутривенно от начала кондиционирования до стабильного приживления трансплантата.

Результаты

Ни у одного из больных не проявлялось побочных эффектов, ведущих к прерыванию лечения каспофунгином. У 14 из 16 больных (88%) без признаков активной инфекции в начале трансплантации не наблюдалось грибковой инфекции после профилактики каспофунгином. В 10 из 12 случаев (83%) с радиологическими признаками активной грибковой инфекции, наблюдаемыми до трансплантации, были получены полные (n=4) или частичные (n=6) ответы после лечения каспофунгином.

Выводы

Применение каспофунгина безопасно и эффективно у больных высокого риска с ИГИ в анамнезе.

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N. Stute, T. Zabelina, N. Fehse, W. Hassenpflug, J. Panse, C. Wolschke, F. Ayuk, H. Schieder, H. Renges, A. Kratochwille, R. von Hinüber, R. Erttmann, A.R. Zander, N. Kröger

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Dept of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany


Correspondence:
Prof.  Dr. med. Nicolaus Kröger, Bone Marrow Transplant Center, University Hospital Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany, Tel.: +49-40-42803 5864, Fax: +49-40-42803 3795, E-mail: nkroeger@spam is baduke.uni-hamburg.de

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Background

Patients with a history of or ongoing invasive fungal infection (IFI) who undergo allogeneic stem cell transplantation (SCT) have a high risk of reactivation or progression. In a prospective study we evaluated the efficacy and safety of caspofungin as secondary prophylaxis or as therapy for persistent disease.

Methods

Twenty-eight adult patients were included in this study, all of whom had acute leukemia. At the time of SCT 16 patients had no signs of infection, while in 12 cases radiographic signs (CT scan) of florid fungal infections were noted. Caspofungin 50 mg intravenously was given daily from start of conditioning until stable engraftment. 

Results

No patient experienced side effects leading to the discontinuation of caspofungin. In 14 out of 16 patients (88%) without active signs of infection at start of transplantation, no fungal disease was observed after prophylaxis with caspofungin. In 10 out of 12 cases (83%) with radiographic signs of florid fungal infection pre-transplantation, complete (n=4) or partial (n=6) responses after caspofungin treatment were achieved. 

Conclusions

The use of caspofungin is safe and effective in high-risk patients with a history of IFI when undergoing allogeneic SCT.

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Stute, T. Zabelina, N. Fehse, W. Hassenpflug, J. Panse, C. Wolschke, F. Ayuk, H. Schieder, H. Renges, A. Kratochwille, R. von Hinüber, R. Erttmann, A.R. Zander, N. Kröger</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(196) "

N. Stute, T. Zabelina, N. Fehse, W. Hassenpflug, J. Panse, C. Wolschke, F. Ayuk, H. Schieder, H. Renges, A. Kratochwille, R. von Hinüber, R. Erttmann, A.R. Zander, N. Kröger

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N. Stute, T. Zabelina, N. Fehse, W. Hassenpflug, J. Panse, C. Wolschke, F. Ayuk, H. Schieder, H. Renges, A. Kratochwille, R. von Hinüber, R. Erttmann, A.R. Zander, N. Kröger

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Background

Patients with a history of or ongoing invasive fungal infection (IFI) who undergo allogeneic stem cell transplantation (SCT) have a high risk of reactivation or progression. In a prospective study we evaluated the efficacy and safety of caspofungin as secondary prophylaxis or as therapy for persistent disease.

Methods

Twenty-eight adult patients were included in this study, all of whom had acute leukemia. At the time of SCT 16 patients had no signs of infection, while in 12 cases radiographic signs (CT scan) of florid fungal infections were noted. Caspofungin 50 mg intravenously was given daily from start of conditioning until stable engraftment. 

Results

No patient experienced side effects leading to the discontinuation of caspofungin. In 14 out of 16 patients (88%) without active signs of infection at start of transplantation, no fungal disease was observed after prophylaxis with caspofungin. In 10 out of 12 cases (83%) with radiographic signs of florid fungal infection pre-transplantation, complete (n=4) or partial (n=6) responses after caspofungin treatment were achieved. 

Conclusions

The use of caspofungin is safe and effective in high-risk patients with a history of IFI when undergoing allogeneic SCT.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1322) "

Background

Patients with a history of or ongoing invasive fungal infection (IFI) who undergo allogeneic stem cell transplantation (SCT) have a high risk of reactivation or progression. In a prospective study we evaluated the efficacy and safety of caspofungin as secondary prophylaxis or as therapy for persistent disease.

Methods

Twenty-eight adult patients were included in this study, all of whom had acute leukemia. At the time of SCT 16 patients had no signs of infection, while in 12 cases radiographic signs (CT scan) of florid fungal infections were noted. Caspofungin 50 mg intravenously was given daily from start of conditioning until stable engraftment. 

Results

No patient experienced side effects leading to the discontinuation of caspofungin. In 14 out of 16 patients (88%) without active signs of infection at start of transplantation, no fungal disease was observed after prophylaxis with caspofungin. In 10 out of 12 cases (83%) with radiographic signs of florid fungal infection pre-transplantation, complete (n=4) or partial (n=6) responses after caspofungin treatment were achieved. 

Conclusions

The use of caspofungin is safe and effective in high-risk patients with a history of IFI when undergoing allogeneic SCT.

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Dept of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany


Correspondence:
Prof.  Dr. med. Nicolaus Kröger, Bone Marrow Transplant Center, University Hospital Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany, Tel.: +49-40-42803 5864, Fax: +49-40-42803 3795, E-mail: nkroeger@spam is baduke.uni-hamburg.de

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Dept of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany


Correspondence:
Prof.  Dr. med. Nicolaus Kröger, Bone Marrow Transplant Center, University Hospital Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany, Tel.: +49-40-42803 5864, Fax: +49-40-42803 3795, E-mail: nkroeger@spam is baduke.uni-hamburg.de

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Штуте Н., Забелина Т., Фезе Б., Хассенпфлюг В., Панзе Й., Вольшке К., Айюк Ф., Шидер Х., Ренгес Х., Кратохвилл А.,
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фон Хинюбер Р., Эрттманн Р., Цандер А.Р., Крегер Н.

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Больные с анамнезом или риском развития инвазивных грибковых инфекций (ИГИ), при аллогенной трансплантации стволовых клеток имеют высокий риск реактивации или прогрессии этих инфекций. В проспективном исследовании мы оценивали эффективность и безопасность каспофунгина в качестве вторичной профилактики или лечения персистирующего заболеванимя. Каспофунгин - это эхинокандин, нарушающий сборку клеточной стенки грибка посредством ингибирования β(1,3)-D-глюкансинтазы. </p> <h3>Методы</h3> <p>Двадцать восемь больных были включены в это исследование, все они были с острым лейкозом. В период ТСК, 16 больных не имели симптомов инфекции, тогда как в 12 случаях (с помощью компьютерной томографии) были отмечены признаки цветущих грибковых инфекций. До начала исследования проводился бронхоальвеолярный лаваж и УЗИ абдоминальной области. Контрольные определения галактоманнана <em>Aspergillus</em> и антител к <em>Candida</em> проводили еженедельно. Каспофунгин (по 50 мг вдень вводили внутривенно от начала кондиционирования до стабильного приживления трансплантата. </p> <h3>Результаты</h3> <p>Ни у одного из больных не проявлялось побочных эффектов, ведущих к прерыванию лечения каспофунгином. У 14 из 16 больных (88%) без признаков активной инфекции в начале трансплантации не наблюдалось грибковой инфекции после профилактики каспофунгином. В 10 из 12 случаев (83%) с радиологическими признаками активной грибковой инфекции, наблюдаемыми до трансплантации, были получены полные (n=4) или частичные (n=6) ответы после лечения каспофунгином. </p> <h3>Выводы</h3> <p>Применение каспофунгина безопасно и эффективно у больных высокого риска с ИГИ в анамнезе.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3327) "

Состояние вопроса

Грибковые инфекции, вызванные Aspergillus or Candida, поражают, главным образом, легкие и являются основной причиной смертности при трансплантации стволовых клеток (ТСК). Больные с анамнезом или риском развития инвазивных грибковых инфекций (ИГИ), при аллогенной трансплантации стволовых клеток имеют высокий риск реактивации или прогрессии этих инфекций. В проспективном исследовании мы оценивали эффективность и безопасность каспофунгина в качестве вторичной профилактики или лечения персистирующего заболеванимя. Каспофунгин - это эхинокандин, нарушающий сборку клеточной стенки грибка посредством ингибирования β(1,3)-D-глюкансинтазы.

Методы

Двадцать восемь больных были включены в это исследование, все они были с острым лейкозом. В период ТСК, 16 больных не имели симптомов инфекции, тогда как в 12 случаях (с помощью компьютерной томографии) были отмечены признаки цветущих грибковых инфекций. До начала исследования проводился бронхоальвеолярный лаваж и УЗИ абдоминальной области. Контрольные определения галактоманнана Aspergillus и антител к Candida проводили еженедельно. Каспофунгин (по 50 мг вдень вводили внутривенно от начала кондиционирования до стабильного приживления трансплантата.

Результаты

Ни у одного из больных не проявлялось побочных эффектов, ведущих к прерыванию лечения каспофунгином. У 14 из 16 больных (88%) без признаков активной инфекции в начале трансплантации не наблюдалось грибковой инфекции после профилактики каспофунгином. В 10 из 12 случаев (83%) с радиологическими признаками активной грибковой инфекции, наблюдаемыми до трансплантации, были получены полные (n=4) или частичные (n=6) ответы после лечения каспофунгином.

Выводы

Применение каспофунгина безопасно и эффективно у больных высокого риска с ИГИ в анамнезе.

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Состояние вопроса

Грибковые инфекции, вызванные Aspergillus or Candida, поражают, главным образом, легкие и являются основной причиной смертности при трансплантации стволовых клеток (ТСК). Больные с анамнезом или риском развития инвазивных грибковых инфекций (ИГИ), при аллогенной трансплантации стволовых клеток имеют высокий риск реактивации или прогрессии этих инфекций. В проспективном исследовании мы оценивали эффективность и безопасность каспофунгина в качестве вторичной профилактики или лечения персистирующего заболеванимя. Каспофунгин - это эхинокандин, нарушающий сборку клеточной стенки грибка посредством ингибирования β(1,3)-D-глюкансинтазы.

Методы

Двадцать восемь больных были включены в это исследование, все они были с острым лейкозом. В период ТСК, 16 больных не имели симптомов инфекции, тогда как в 12 случаях (с помощью компьютерной томографии) были отмечены признаки цветущих грибковых инфекций. До начала исследования проводился бронхоальвеолярный лаваж и УЗИ абдоминальной области. Контрольные определения галактоманнана Aspergillus и антител к Candida проводили еженедельно. Каспофунгин (по 50 мг вдень вводили внутривенно от начала кондиционирования до стабильного приживления трансплантата.

Результаты

Ни у одного из больных не проявлялось побочных эффектов, ведущих к прерыванию лечения каспофунгином. У 14 из 16 больных (88%) без признаков активной инфекции в начале трансплантации не наблюдалось грибковой инфекции после профилактики каспофунгином. В 10 из 12 случаев (83%) с радиологическими признаками активной грибковой инфекции, наблюдаемыми до трансплантации, были получены полные (n=4) или частичные (n=6) ответы после лечения каспофунгином.

Выводы

Применение каспофунгина безопасно и эффективно у больных высокого риска с ИГИ в анамнезе.

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Introduction

Chronic myeloid leukaemia (CML) has an annual worldwide incidence of 1/100,000, with a male: female ratio of 1.5:1. The incidence rises slowly with age to reach a median of about 60 years [1]. The median age of patients with CML in Nigeria and other African countries with a similar demographic pattern is 38 years [2, 3]. Fleming and Menendez reported that more native African patients under age 40 years suffer from CML than any other group in the world; this differential age incidence pattern of CML is believed to be due to the age distribution of African populations rather than any inherent biological characteristic [4]. In the USA however, the incidence of CML in the age group under 70 years is higher among the African-Americans than among any other racial/ethnic groups [5]. It is probable that a combination of environment and as yet unknown biological factors may account for the differential age incidence pattern of CML between the Blacks and the other races in USA.  

The advent of Imatinib, an orally available, small molecule signal transduction inhibitor (STI) that specifically targets protein tyrosine kinases (TKIs), in particular, the CML-related bcr-abl, has led to radical changes in the management of CML following the publication of several studies that confirmed superior clinical, haematologic and cytogenetic remissions when the drug was compared to IFN-α and ara-C in all phases of the disease [6-9]. Imatinib has become the first-line therapy for CML in the world,  allogeneic stem cell transplantation now being reserved mainly for younger patients with poor-risk disease or for those who are resistant to Imatinib and/ or second generation TKIs [8, 9]. With the availability of free Imatinib Mesylate in resource-poor countries (through donation from the Glivec international patient-assistance program [GIPAP]; www.maxaid.org), this drug has also become the first-line therapy for CML in Nigeria; a great relief for patients in resource-limited countries.

This report describes the results for patients with newly diagnosed CML in diverse phases of the disease that were treated with Imatinib.

Patients and Methods

Between August 2003 and August 2007, a total of 98 consenting adults and children, who had been diagnosed with CML, were commenced on Imatinib as part of the ongoing GIPAP treatment programme at the Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Nigeria. Eighty-four patients had been exposed to previous single-agent chemotherapy comprising: hydroxyurea (n = 79), busulphan (n = 5) and IFN-alfa (n = 5). Five patients had previously received concurrent multiple chemotherapeutic agents, including Cyclophosphamide, Oncovin, ara-C and prednisolone (COAP; n = 4) and Doxorubicin and ara-c (DA; n = 1). Participants were drawn from all parts of Nigeria. The diagnosis of CML was made according to the WHO standard clinical, haematologic and cytogenetic criteria [10], which has also been applied to the staging of the diseases in Imatinib era [11].

Chromosome analysis was done using cultured bone marrow aspirate samples; Philadelphia chromosome was estimated from at least 20 metaphases and the proportion of Ph+ cells was noted for each patient.

Patients in chronic phase received oral Imatinib: 400mg daily. Those in the accelerated or blastic phase received 600mg daily. Imatinib was continued for as long as there was evidence of continued benefit from therapy. Allopurinol (300 mg daily) was given until leucocyte count fell below 20 x 109/L. Patients with hyperleucocytosis (leucocyte count > 100 x 109/L), and on hydroxyurea, were continued on the latter for another 1-3 weeks, with monitoring of the full blood count before final withdrawal of the drug, when the white cell count fell to less than 100 x 109/L.

In individuals with severe Imatinib-induced myelosuppression, the drug was withheld until the neutrophils rose to 1.5 x 109/L and the platelets to at least 75 x 109/L. Patients with recurrent, therapy-induced myelosuppression had the Imatinib dose reduced to 300mg daily until blood counts normalised (minimum dose for therapeutic blood levels in adults). However, if the myelosuppression was related to blastic transformation, Imatinib was continued with appropriate supportive therapy being given.

Response to therapy was assessed by clinical, haematologic and cytogenetic parameters as recommended by the expert panel of the European LeukemiaNet [12]. Clinical examination and full blood count monitoring were performed every 1-2 weeks for the first three months, until the blood count became stable, or until remission was achieved. Thereafter, patients were monitored every three months. Serum chemistry and cytogenetic analyses were evaluated every six months.

Previously published definitions of CP, AP and BP were used [10, 11]. Overall survival (OS) was the primary end-point and was defined as the interval between the date of commencement of Imatinib and the date of death or loss to follow-up. Secondary end-points were time to complete haematologic remission (CHR) and/or complete cytogenetic remission (CCR). CHR was defined as restoration of a normal blood count, with absence of blasts or promyelocytes, extramedullary deposits, or other signs of the disease. Cytogenetic response was checked every 6 months, by counting proportions of Ph+ cells from among not less than 20 metaphases, whilst definitions of complete, major, minor and no cytogenetic response (CCR (0% Ph+), MCR (1-34% Ph+),  mnCR (35-90 Ph+), and NCR (> 90% Ph+) and those for complete or major molecular response (CMR, MMR) were as previously described [12].

2008-Durosinmi_Fig01.png

Figure 1. Overall survival of patients according to attainment of complete cytogenetic remission (CCR) at 6 months 



This study was conducted according to the declaration of Helsinki concerning patients' rights and confidentiality. Approval for the study was obtained from the OAUTHC ethical committee. All patients or their parents (in the case of minors) gave written informed consent.

The study is ongoing but for the purpose of this analysis, August 31st 2007 was taken as the cut-off, this being the date on which the first patient has been followed-up for 48 months. Analyses of OS and PFS were performed using the Kaplan-Meier method, by "intention-to-treat". Differences between subgroups of patients receiving Imatinib were analysed using the Log-rank test. SPSS for Windows 11 (SPSS Inc. 1981-2001, USA) and Microsoft Excel were used for all statistical calculations. The following pre-treatment variables were analysed for correlations with achievement of response, OS and PFS: age, gender, time of starting treatment and platelet count prior chemotherapy.

Results

This study was based on 98 patients, their ages ranging from 11 to 65 years (median = 36). There were 56 males and 42 females. The median time from diagnosis to treatment was 14.3 weeks (range 0-239 weeks). Seventy-eight (80%) and 40 (41%) of 98 patients presented with splenomegaly and/ or hepatomegaly, with a median size of 12cm and 7cm below the costal margin, respectively; 85 (86.7%) patients were in CP and 13 (13.2%) in AP/BP (12 and 1 respectively, Table 1).

Table 1. Patients’ characteristics at diagnosis

2008-2-en-Durosinmi-et-al-Table-1.png


With a median follow-up of 25 months, 51 patients had repeat chromosome analysis at least 6 months into Glivec therapy; 30 (59%) and 18 (35%) achieved CCR and a MCR, respectively. 

Also notable was the fact that on completion of one and three months of Imatinib therapy, 53/83 (64%) and 58/70 (83%) of patients respectively were in complete haematologic remission (CHR).

Kaplan-Meier analysis of the relevant pre- and post-recruitment variables shows that commencement of Imatinib within 60 days of diagnosis,  and achievement of CHR within one month of commencing therapy were  predictive for achieving a CCR (p = 0.039 and 0.019 respectively; Table 2).

Table 2. Univariate analysis of patients characteristics, survival and cytogenetic remission.

2008-2-en-Durosinmi-et-al-Table-2.png

p-Values in bold type are significant, those in regular type are close to significance. *The variables with the better outcomes are written first. Abbreviations: OS, overall survival; PFS, progression-free survival; SE, standard error; BCM, below the costal margin; LFU, last follow-up; ns, not significant; NA, not applicable; CHR, complete haematologic remission; CCR: complete cytogenetic remission; MCR: major cytogenetic remission; mCR: minor cytogenetic remission.

Kaplan-Meier estimates for OS and PFS at one year were 96% and 91%, respectively. At 40 months, the OS and PFS had dropped to 68% and 61%, respectively. Eighty-seven of the 98 patients overall (88.8%) remain alive, and are tolerating the drug well.

Also, achievement of CHR within 3 months or CCR within 6 months of commencing therapy predicted for better OS and PFS (CHR: p = 0.027, 0.011 respectively; CCR: p = 0.043, 0.045 respectively; Table 2). A statistically insignificant trend (p = 0.06) was observed for better OS in patients who did not experience myelosuppression (requiring cessation of the drug for ≥ 2 weeks) during the first 6 months of treatment. Eleven of the 44 patients (25%) who were in MCR/mnCR at six months had improved to CCR at the last follow-up.

Discussion

With a median follow-up of 25 months, these results demonstrate a CCR rate of 59%, which is the same as that reported by Kantarjian et al in a previous study with 18 months' follow-up [13]. The latter group of patients had however previously received IFN-α, whereas most of the Nigerian patients had been treated with hydroxyurea as first-line therapy. Overall, 80% of newly diagnosed patients with CML in chronic phase would be expected to achieve CCR with Imatinib [14]. In this study, relatively shorter survival was to be expected, since 21 patients were not in chronic phase at the time of starting treatment, and responses are known to be less durable in AP and almost always transient in BP [8, 15, 16].

The median time from diagnosis to commencement of Imatinib was relatively long, at 14.3 weeks (range 0-239 weeks) and it is known that this can worsen the prognosis and reduce the probability of response. Nonetheless, the relatively high survival (96%, SE = 0.022) at one year is impressive for an African population of patients, although obviously, this value will fall with longer follow-up, with 68.3% at 40 months. The extended IRIS study has recently reported a 5-year overall survival estimate of 89% [17] and several studies have demonstrated significant survival differences based on the Sokal and/or Hasford risk groups at diagnosis [14, 15, 18-20]. However, these parameters could not be evaluated since initial data (at diagnosis) on the majority of our patients were unavailable.

The survival advantage observed for patients in whom CCR was achieved by six months is an important finding since it confirms the efficacy of Imatinib, an observation that has not been reported in native sub-Saharan Africans before. This pioneering work has shown that outcome of Imatinib therapy for Ph+ CML in native Nigerians is no different from reports in the Western populations.

We conclude that Imatinib in Nigerian patients with CML is very promising with the additional advantages of oral availability and tolerability, both of which make the drug highly acceptable.

Acknowledgements

We are grateful to Novartis for providing Imatinib mesylate (Glivec), to the Max Foundation and Axios International for facilitating the delivery of the drug, to the Federal Government and NAFDAC for facilitating customs clearance of the drug. We are also indebted to all the faculty and staff of the Department of Haematology, Obafemi Awolowo University (OAU) and OAU Teaching Hospitals Complex, Ile-Ife for the care of the patients involved in this study. We are especially grateful to the nursing staff. Professor Ama Rohatiner of the St. Baths Hospital, London, kindly reviewed the manuscript.

References

1. Deninger MWN, Druker BJ. Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib. Pharmacol Rev. 2003;55:401-423.

2. Boma PO, Durosinmi MA, Adediran IA, Akinola NO, Salawu L. Clinical and prognostic features of Nigerians with chronic myeloid leukemia. Niger Postgrad Med J. 2006;13:47-52.

3. Okanny CC, Akinyanju OO. Chronic leukaemia: an African experience. Med Oncol Tumor Pharmacother. 1989;6:189-194.

4. Fleming AF, Menendez C. Blood. In: Parry E, Godfrey R, Mabey D, Gill G, eds. Principles of Medicine in Africa. Vol. 78. Cambridge, United Kingdom; 2004:961.

5. Groves FD, Linet MS, Devesa SS. Patterns of occurrence of the leukaemias. Eur J Cancer. 1995;31A:941-994.

6. Deininger MWN, O'Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving Imatinib. J Clin Oncol. 2003;21:1637-1647.

7. Melo JV, Hughes TP, Apperley JF. Chronic myeloid leukemia. ASH Hematology. 2003:132-152.

8. Shah NP. Loss of Response to Imatinib: Mechanisms and Management. Hematology. 2005;2005:183-187.

9. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding Imatinib Resistance with a Novel ABL Kinase Inhibitor. Science. 2004;305:399-401.

10. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292–2302.

11. Cortes JE, Talpaz M, O’Brien S, et al. Staging of Chronic Myeloid Leukemia in the Imatinib Era: An Evaluation of the World Health Organization Proposal. Cancer. 2006;106:1306–1315.

12. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809–1820.

13. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346:645-652.

14. Deininger MWN. Chronic myeloid leukemia: Management of Early Stage Disease. ASH Hematology. 2005:174-182.

15. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876-880.

16. O'Brien S, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1008.

17. Talpaz M, Silver RT, Druker BJ, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood. 2002;99:1928-1937.

18. Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst. 1998;90:850-858.

19. Sneed TB, Kantarjian HM, Talpaz M, et al. The Significance of Myelosuppression during Therapy with Imatinib Mesylate in Patients with Chronic Myelogenous Leukemia in Chronic Phase. Cancer. 2004;100:116–121.

20. Sokal JE, Cox EB, Baccarani M, et al. Prognostic Discrimination in “Good Risk” Chronic Granulocytic Leukemia. Blood. 1984;63:789-799.

" ["~DETAIL_TEXT"]=> string(17545) "

Introduction

Chronic myeloid leukaemia (CML) has an annual worldwide incidence of 1/100,000, with a male: female ratio of 1.5:1. The incidence rises slowly with age to reach a median of about 60 years [1]. The median age of patients with CML in Nigeria and other African countries with a similar demographic pattern is 38 years [2, 3]. Fleming and Menendez reported that more native African patients under age 40 years suffer from CML than any other group in the world; this differential age incidence pattern of CML is believed to be due to the age distribution of African populations rather than any inherent biological characteristic [4]. In the USA however, the incidence of CML in the age group under 70 years is higher among the African-Americans than among any other racial/ethnic groups [5]. It is probable that a combination of environment and as yet unknown biological factors may account for the differential age incidence pattern of CML between the Blacks and the other races in USA.  

The advent of Imatinib, an orally available, small molecule signal transduction inhibitor (STI) that specifically targets protein tyrosine kinases (TKIs), in particular, the CML-related bcr-abl, has led to radical changes in the management of CML following the publication of several studies that confirmed superior clinical, haematologic and cytogenetic remissions when the drug was compared to IFN-α and ara-C in all phases of the disease [6-9]. Imatinib has become the first-line therapy for CML in the world,  allogeneic stem cell transplantation now being reserved mainly for younger patients with poor-risk disease or for those who are resistant to Imatinib and/ or second generation TKIs [8, 9]. With the availability of free Imatinib Mesylate in resource-poor countries (through donation from the Glivec international patient-assistance program [GIPAP]; www.maxaid.org), this drug has also become the first-line therapy for CML in Nigeria; a great relief for patients in resource-limited countries.

This report describes the results for patients with newly diagnosed CML in diverse phases of the disease that were treated with Imatinib.

Patients and Methods

Between August 2003 and August 2007, a total of 98 consenting adults and children, who had been diagnosed with CML, were commenced on Imatinib as part of the ongoing GIPAP treatment programme at the Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile-Ife, Nigeria. Eighty-four patients had been exposed to previous single-agent chemotherapy comprising: hydroxyurea (n = 79), busulphan (n = 5) and IFN-alfa (n = 5). Five patients had previously received concurrent multiple chemotherapeutic agents, including Cyclophosphamide, Oncovin, ara-C and prednisolone (COAP; n = 4) and Doxorubicin and ara-c (DA; n = 1). Participants were drawn from all parts of Nigeria. The diagnosis of CML was made according to the WHO standard clinical, haematologic and cytogenetic criteria [10], which has also been applied to the staging of the diseases in Imatinib era [11].

Chromosome analysis was done using cultured bone marrow aspirate samples; Philadelphia chromosome was estimated from at least 20 metaphases and the proportion of Ph+ cells was noted for each patient.

Patients in chronic phase received oral Imatinib: 400mg daily. Those in the accelerated or blastic phase received 600mg daily. Imatinib was continued for as long as there was evidence of continued benefit from therapy. Allopurinol (300 mg daily) was given until leucocyte count fell below 20 x 109/L. Patients with hyperleucocytosis (leucocyte count > 100 x 109/L), and on hydroxyurea, were continued on the latter for another 1-3 weeks, with monitoring of the full blood count before final withdrawal of the drug, when the white cell count fell to less than 100 x 109/L.

In individuals with severe Imatinib-induced myelosuppression, the drug was withheld until the neutrophils rose to 1.5 x 109/L and the platelets to at least 75 x 109/L. Patients with recurrent, therapy-induced myelosuppression had the Imatinib dose reduced to 300mg daily until blood counts normalised (minimum dose for therapeutic blood levels in adults). However, if the myelosuppression was related to blastic transformation, Imatinib was continued with appropriate supportive therapy being given.

Response to therapy was assessed by clinical, haematologic and cytogenetic parameters as recommended by the expert panel of the European LeukemiaNet [12]. Clinical examination and full blood count monitoring were performed every 1-2 weeks for the first three months, until the blood count became stable, or until remission was achieved. Thereafter, patients were monitored every three months. Serum chemistry and cytogenetic analyses were evaluated every six months.

Previously published definitions of CP, AP and BP were used [10, 11]. Overall survival (OS) was the primary end-point and was defined as the interval between the date of commencement of Imatinib and the date of death or loss to follow-up. Secondary end-points were time to complete haematologic remission (CHR) and/or complete cytogenetic remission (CCR). CHR was defined as restoration of a normal blood count, with absence of blasts or promyelocytes, extramedullary deposits, or other signs of the disease. Cytogenetic response was checked every 6 months, by counting proportions of Ph+ cells from among not less than 20 metaphases, whilst definitions of complete, major, minor and no cytogenetic response (CCR (0% Ph+), MCR (1-34% Ph+),  mnCR (35-90 Ph+), and NCR (> 90% Ph+) and those for complete or major molecular response (CMR, MMR) were as previously described [12].

2008-Durosinmi_Fig01.png

Figure 1. Overall survival of patients according to attainment of complete cytogenetic remission (CCR) at 6 months 



This study was conducted according to the declaration of Helsinki concerning patients' rights and confidentiality. Approval for the study was obtained from the OAUTHC ethical committee. All patients or their parents (in the case of minors) gave written informed consent.

The study is ongoing but for the purpose of this analysis, August 31st 2007 was taken as the cut-off, this being the date on which the first patient has been followed-up for 48 months. Analyses of OS and PFS were performed using the Kaplan-Meier method, by "intention-to-treat". Differences between subgroups of patients receiving Imatinib were analysed using the Log-rank test. SPSS for Windows 11 (SPSS Inc. 1981-2001, USA) and Microsoft Excel were used for all statistical calculations. The following pre-treatment variables were analysed for correlations with achievement of response, OS and PFS: age, gender, time of starting treatment and platelet count prior chemotherapy.

Results

This study was based on 98 patients, their ages ranging from 11 to 65 years (median = 36). There were 56 males and 42 females. The median time from diagnosis to treatment was 14.3 weeks (range 0-239 weeks). Seventy-eight (80%) and 40 (41%) of 98 patients presented with splenomegaly and/ or hepatomegaly, with a median size of 12cm and 7cm below the costal margin, respectively; 85 (86.7%) patients were in CP and 13 (13.2%) in AP/BP (12 and 1 respectively, Table 1).

Table 1. Patients’ characteristics at diagnosis

2008-2-en-Durosinmi-et-al-Table-1.png


With a median follow-up of 25 months, 51 patients had repeat chromosome analysis at least 6 months into Glivec therapy; 30 (59%) and 18 (35%) achieved CCR and a MCR, respectively. 

Also notable was the fact that on completion of one and three months of Imatinib therapy, 53/83 (64%) and 58/70 (83%) of patients respectively were in complete haematologic remission (CHR).

Kaplan-Meier analysis of the relevant pre- and post-recruitment variables shows that commencement of Imatinib within 60 days of diagnosis,  and achievement of CHR within one month of commencing therapy were  predictive for achieving a CCR (p = 0.039 and 0.019 respectively; Table 2).

Table 2. Univariate analysis of patients characteristics, survival and cytogenetic remission.

2008-2-en-Durosinmi-et-al-Table-2.png

p-Values in bold type are significant, those in regular type are close to significance. *The variables with the better outcomes are written first. Abbreviations: OS, overall survival; PFS, progression-free survival; SE, standard error; BCM, below the costal margin; LFU, last follow-up; ns, not significant; NA, not applicable; CHR, complete haematologic remission; CCR: complete cytogenetic remission; MCR: major cytogenetic remission; mCR: minor cytogenetic remission.

Kaplan-Meier estimates for OS and PFS at one year were 96% and 91%, respectively. At 40 months, the OS and PFS had dropped to 68% and 61%, respectively. Eighty-seven of the 98 patients overall (88.8%) remain alive, and are tolerating the drug well.

Also, achievement of CHR within 3 months or CCR within 6 months of commencing therapy predicted for better OS and PFS (CHR: p = 0.027, 0.011 respectively; CCR: p = 0.043, 0.045 respectively; Table 2). A statistically insignificant trend (p = 0.06) was observed for better OS in patients who did not experience myelosuppression (requiring cessation of the drug for ≥ 2 weeks) during the first 6 months of treatment. Eleven of the 44 patients (25%) who were in MCR/mnCR at six months had improved to CCR at the last follow-up.

Discussion

With a median follow-up of 25 months, these results demonstrate a CCR rate of 59%, which is the same as that reported by Kantarjian et al in a previous study with 18 months' follow-up [13]. The latter group of patients had however previously received IFN-α, whereas most of the Nigerian patients had been treated with hydroxyurea as first-line therapy. Overall, 80% of newly diagnosed patients with CML in chronic phase would be expected to achieve CCR with Imatinib [14]. In this study, relatively shorter survival was to be expected, since 21 patients were not in chronic phase at the time of starting treatment, and responses are known to be less durable in AP and almost always transient in BP [8, 15, 16].

The median time from diagnosis to commencement of Imatinib was relatively long, at 14.3 weeks (range 0-239 weeks) and it is known that this can worsen the prognosis and reduce the probability of response. Nonetheless, the relatively high survival (96%, SE = 0.022) at one year is impressive for an African population of patients, although obviously, this value will fall with longer follow-up, with 68.3% at 40 months. The extended IRIS study has recently reported a 5-year overall survival estimate of 89% [17] and several studies have demonstrated significant survival differences based on the Sokal and/or Hasford risk groups at diagnosis [14, 15, 18-20]. However, these parameters could not be evaluated since initial data (at diagnosis) on the majority of our patients were unavailable.

The survival advantage observed for patients in whom CCR was achieved by six months is an important finding since it confirms the efficacy of Imatinib, an observation that has not been reported in native sub-Saharan Africans before. This pioneering work has shown that outcome of Imatinib therapy for Ph+ CML in native Nigerians is no different from reports in the Western populations.

We conclude that Imatinib in Nigerian patients with CML is very promising with the additional advantages of oral availability and tolerability, both of which make the drug highly acceptable.

Acknowledgements

We are grateful to Novartis for providing Imatinib mesylate (Glivec), to the Max Foundation and Axios International for facilitating the delivery of the drug, to the Federal Government and NAFDAC for facilitating customs clearance of the drug. We are also indebted to all the faculty and staff of the Department of Haematology, Obafemi Awolowo University (OAU) and OAU Teaching Hospitals Complex, Ile-Ife for the care of the patients involved in this study. We are especially grateful to the nursing staff. Professor Ama Rohatiner of the St. Baths Hospital, London, kindly reviewed the manuscript.

References

1. Deninger MWN, Druker BJ. Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib. Pharmacol Rev. 2003;55:401-423.

2. Boma PO, Durosinmi MA, Adediran IA, Akinola NO, Salawu L. Clinical and prognostic features of Nigerians with chronic myeloid leukemia. Niger Postgrad Med J. 2006;13:47-52.

3. Okanny CC, Akinyanju OO. Chronic leukaemia: an African experience. Med Oncol Tumor Pharmacother. 1989;6:189-194.

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А., Фалуйи Дж. О., Ойекунле А. А. и соавт.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(112) "

Дуросинми М. А., Фалуйи Дж. О., Ойекунле А. А. и соавт.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11759" ["VALUE"]=> array(2) { ["TEXT"]=> string(3404) "<h3>Цель работы</h3> <p>Оценить клинический ответ и токсичность иматиниба мезилата (Гливека) у нигерийских больных хроническим миелолейкозом (ХМЛ).</p> <h3> Методы и клинический материал</h3> <p> С августа 2003 г. по август 2007 г. под наблюдением находились 98 больных с диагнозом ХМЛ (средний возраст 36 лет – от 11 до 65 лет), позитивных по Ph/bcr-abl, давших согласие на терапию, в том числе 56 мужчин и 42 женщины. Независимо от фазы заболевания, лечение Иматинибом проводилось в дозах 300-600 мг в день в госпитале OAU (Нигерия). Ответ на лечение оценивался по клиническим, гематологическим, цитогенетическим и/или молекулярным параметрам. Число клеток в крови проверяли каждые 2 недели в течение первых трех месяцев терапии. Кариотипирование повторяли каждые 6 месяцев. Регистрировали общую выживаемость и частоту полной гематологической ремиссии (ПГР) или большой цитогенетической ремиссии (БЦР, 1-34% Ph+ клеток). <br /> <h3>Результаты</h3> <p> После 1 и 3 месяцев лечения полная гематологическая ремиссия была достигнута, соответственно, у 64% и 83% больных. При среднем сроке наблюдения 25 месяцев, частота ПГР и БЦР составляла 59% и 35%, соответственно. Спленомегалия и/или гепатомегалия менее 7 см от края ребер были прогностическими признаками в отношении ПГР (соответственно, p = 0.0006 и 0.034). После 12 месяцев наблюдения, общая выживаемость и выживаемость без прогрессии (ВБП) составляла, соответственно, 96% и 91%. Число бластных форм на периферии ниже 5% на момент диагноза и достижение ПГР через 6 мес. были ассоциированы со значительно лучшим выживанием (уровни p были, соответственно, 0.037 and 0.043). <br /><h3>Выводы</h3> <p>В сравнении с обычной химиотерапией и применением альфа-интерферона, как было ранее показано в Нигерии, иматиниб может индуцировать раннюю цитогенетическую ремиссию у Ph/bcr-abl- позитивных больных ХМЛ, при минимальных (побочных) заболеваниях. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3308) "

Цель работы

Оценить клинический ответ и токсичность иматиниба мезилата (Гливека) у нигерийских больных хроническим миелолейкозом (ХМЛ).

Методы и клинический материал

С августа 2003 г. по август 2007 г. под наблюдением находились 98 больных с диагнозом ХМЛ (средний возраст 36 лет – от 11 до 65 лет), позитивных по Ph/bcr-abl, давших согласие на терапию, в том числе 56 мужчин и 42 женщины. Независимо от фазы заболевания, лечение Иматинибом проводилось в дозах 300-600 мг в день в госпитале OAU (Нигерия). Ответ на лечение оценивался по клиническим, гематологическим, цитогенетическим и/или молекулярным параметрам. Число клеток в крови проверяли каждые 2 недели в течение первых трех месяцев терапии. Кариотипирование повторяли каждые 6 месяцев. Регистрировали общую выживаемость и частоту полной гематологической ремиссии (ПГР) или большой цитогенетической ремиссии (БЦР, 1-34% Ph+ клеток).

Результаты

После 1 и 3 месяцев лечения полная гематологическая ремиссия была достигнута, соответственно, у 64% и 83% больных. При среднем сроке наблюдения 25 месяцев, частота ПГР и БЦР составляла 59% и 35%, соответственно. Спленомегалия и/или гепатомегалия менее 7 см от края ребер были прогностическими признаками в отношении ПГР (соответственно, p = 0.0006 и 0.034). После 12 месяцев наблюдения, общая выживаемость и выживаемость без прогрессии (ВБП) составляла, соответственно, 96% и 91%. Число бластных форм на периферии ниже 5% на момент диагноза и достижение ПГР через 6 мес. были ассоциированы со значительно лучшим выживанием (уровни p были, соответственно, 0.037 and 0.043).

Выводы

В сравнении с обычной химиотерапией и применением альфа-интерферона, как было ранее показано в Нигерии, иматиниб может индуцировать раннюю цитогенетическую ремиссию у Ph/bcr-abl- позитивных больных ХМЛ, при минимальных (побочных) заболеваниях.

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Prof. Muheez A. Durosinmi1, Prof. Julius O. Faluyi2, Dr. Anthony A. Oyekunle1, Dr. Lateef Salawu1, Dr. Ismail A. Adediran1, Dr. Norah O. Akinola1, Oluwakemi O. Bamgbade3, Dr. Charles C. Okanny4, Dr. Sulaiman Akanmu4, Dr. Oche P. Ogbe5, Dr. Tambi T. Wakama5, Dr. Chijoke A. Nwauche6, Dr. Matthew E. Enosolease7, Dr. Daye N.K. Halim7, Dr. Godwin N. Bazuaye7, Dr. Chide E. Okocha8, Dr. J. A. Olaniyi9, Dr. Titi S. Akingbola9, Dr. Victor O. Mabayoje10, Dr. Ajani A. Raji10, Dr. Aisha Mamman11, Dr. Aisha Kuliya-Gwarzo12, Dr. Obike G. Ibegbulam13, Dr. Sunday Ocheni13, Dr. Yohanna Tanko14, Dr. Oladimeji P. Arewa1, Dr. Rahman A.A. Bolarinwa1, Dr. Davidson O. Kassim1, Dr. Mohammed A. Ndakotsu1, Dr. Omotilewa A. Amusu15, Prof. O. O. Akinyanju16

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1Department of Haematology, Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, Nigeria; 2Department of Botany, Obafemi Awolowo University, Ile-Ife, Nigeria; 3Department of Pharmacy, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria; 4Department of Haematology, University of Lagos, Nigeria; 5Department of Haematology, National Hospital, Abuja, Nigeria; 6Department of Haematology, University of Port-Harcourt, Port-Harcourt, Nigeria; 7Department of Haematology, University of Benin, Nigeria; 8Department of Haematology, Nnamdi Azikiwe University, Nnewi, Nigeria; 9Department of Haematology, University College Hospital, Ibadan, Nigeria; 10Department of Haematology, Ladoke Akintola University of Technology, Osogbo, Nigeria; 11Department of Haematology, Ahmadu Bello University, Zaria, Nigeria, 12Department of Haematology, Bayero University,  Kano, Nigeria; 13Department of Haematology, University of Nigeria, Enugu, Nigeria; 14Department of Haematology, Gwagwalada Specialist Hospital, Abuja, Nigeria; 15Department of Haematology, Army Reference Hospital, Lagos, Nigeria; 16Asaju Medical Clinic, Victoria Island, Lagos, Nigeria

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Objectives

To assess response and toxicity to Imatinib mesylate (Glivec) in Nigerian Patients with chronic myeloid leukemia.

Methods

From August 2003 to August 2007, 98 consecutive, consenting patients, 56 (57%) males and 42 (43%) females, median age 36 years (range, 11-65 years) diagnosed with  CML, irrespective of disease phase received Imatinib at a dose of 300-600mg/day at the OAU Teaching Hospitals, Nigeria. Response to therapy was assessed by clinical, haematological and cytogenetic parameters. Blood counts were checked every two weeks in the first three months of therapy. Chromosome analysis was repeated sixth monthly. Overall survival (OS) and frequency of complete or major cytogenetic remission (CCR/MCR) were evaluated.  

Results

Complete haematologic remission was achieved in 64% and 83% of patients at one and three months, respectively. With a median follow-up of 25 months, the rates of CCR and MCR were 59% and 35% respectively. At 12 months of follow-up, OS and progression- free survival (PFS) were 96% and 91%, respectively. Achievement of CR at six months was associated with significantly better survival (p = 0.043).

Conclusions

Compared to treatment outcome with conventional chemotherapy and alpha interferon, as previously used in Nigeria, the results obtained with this regimen has established Imatinib as the first-line treatment strategy in patients with CML, as it is in other populations, with minimal morbidity.

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Durosinmi<sup>1</sup>, Prof. Julius O. Faluyi<sup>2</sup>, Dr. Anthony A. Oyekunle<sup>1</sup>, Dr. Lateef Salawu<sup>1</sup>, Dr. Ismail A. Adediran<sup>1</sup>, Dr. Norah O. Akinola<sup>1</sup>, Oluwakemi O. Bamgbade<sup>3</sup>, Dr. Charles C. Okanny<sup>4</sup>, Dr. Sulaiman Akanmu<sup>4</sup>, Dr. Oche P. Ogbe<sup>5</sup>, Dr. Tambi T. Wakama<sup>5</sup>, Dr. Chijoke A. Nwauche<sup>6</sup>, Dr. Matthew E. Enosolease<sup>7</sup>, Dr. Daye N.K. Halim<sup>7</sup>, Dr. Godwin N. Bazuaye<sup>7</sup>, Dr. Chide E. Okocha<sup>8</sup>, Dr. J. A. Olaniyi<sup>9</sup>, Dr. Titi S. Akingbola<sup>9</sup>, Dr. Victor O. Mabayoje<sup>10</sup>, Dr. Ajani A. Raji<sup>10</sup>, Dr. Aisha Mamman<sup>11</sup>, Dr. Aisha Kuliya-Gwarzo<sup>12</sup>, Dr. Obike G. Ibegbulam<sup>13</sup>, Dr. Sunday Ocheni<sup>13</sup>, Dr. Yohanna Tanko<sup>14</sup>, Dr. Oladimeji P. Arewa<sup>1</sup>, Dr. Rahman A.A. Bolarinwa<sup>1</sup>, Dr. Davidson O. Kassim<sup>1</sup>, Dr. Mohammed A. Ndakotsu<sup>1</sup>, Dr. Omotilewa A. Amusu<sup>15</sup>, Prof. O. O. Akinyanju<sup>16</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1101) "

Prof. Muheez A. Durosinmi1, Prof. Julius O. Faluyi2, Dr. Anthony A. Oyekunle1, Dr. Lateef Salawu1, Dr. Ismail A. Adediran1, Dr. Norah O. Akinola1, Oluwakemi O. Bamgbade3, Dr. Charles C. Okanny4, Dr. Sulaiman Akanmu4, Dr. Oche P. Ogbe5, Dr. Tambi T. Wakama5, Dr. Chijoke A. Nwauche6, Dr. Matthew E. Enosolease7, Dr. Daye N.K. Halim7, Dr. Godwin N. Bazuaye7, Dr. Chide E. Okocha8, Dr. J. A. Olaniyi9, Dr. Titi S. Akingbola9, Dr. Victor O. Mabayoje10, Dr. Ajani A. Raji10, Dr. Aisha Mamman11, Dr. Aisha Kuliya-Gwarzo12, Dr. Obike G. Ibegbulam13, Dr. Sunday Ocheni13, Dr. Yohanna Tanko14, Dr. Oladimeji P. Arewa1, Dr. Rahman A.A. Bolarinwa1, Dr. Davidson O. Kassim1, Dr. Mohammed A. Ndakotsu1, Dr. Omotilewa A. Amusu15, Prof. O. O. Akinyanju16

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Prof. Muheez A. Durosinmi1, Prof. Julius O. Faluyi2, Dr. Anthony A. Oyekunle1, Dr. Lateef Salawu1, Dr. Ismail A. Adediran1, Dr. Norah O. Akinola1, Oluwakemi O. Bamgbade3, Dr. Charles C. Okanny4, Dr. Sulaiman Akanmu4, Dr. Oche P. Ogbe5, Dr. Tambi T. Wakama5, Dr. Chijoke A. Nwauche6, Dr. Matthew E. Enosolease7, Dr. Daye N.K. Halim7, Dr. Godwin N. Bazuaye7, Dr. Chide E. Okocha8, Dr. J. A. Olaniyi9, Dr. Titi S. Akingbola9, Dr. Victor O. Mabayoje10, Dr. Ajani A. Raji10, Dr. Aisha Mamman11, Dr. Aisha Kuliya-Gwarzo12, Dr. Obike G. Ibegbulam13, Dr. Sunday Ocheni13, Dr. Yohanna Tanko14, Dr. Oladimeji P. Arewa1, Dr. Rahman A.A. Bolarinwa1, Dr. Davidson O. Kassim1, Dr. Mohammed A. Ndakotsu1, Dr. Omotilewa A. Amusu15, Prof. O. O. Akinyanju16

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Objectives

To assess response and toxicity to Imatinib mesylate (Glivec) in Nigerian Patients with chronic myeloid leukemia.

Methods

From August 2003 to August 2007, 98 consecutive, consenting patients, 56 (57%) males and 42 (43%) females, median age 36 years (range, 11-65 years) diagnosed with  CML, irrespective of disease phase received Imatinib at a dose of 300-600mg/day at the OAU Teaching Hospitals, Nigeria. Response to therapy was assessed by clinical, haematological and cytogenetic parameters. Blood counts were checked every two weeks in the first three months of therapy. Chromosome analysis was repeated sixth monthly. Overall survival (OS) and frequency of complete or major cytogenetic remission (CCR/MCR) were evaluated.  

Results

Complete haematologic remission was achieved in 64% and 83% of patients at one and three months, respectively. With a median follow-up of 25 months, the rates of CCR and MCR were 59% and 35% respectively. At 12 months of follow-up, OS and progression- free survival (PFS) were 96% and 91%, respectively. Achievement of CR at six months was associated with significantly better survival (p = 0.043).

Conclusions

Compared to treatment outcome with conventional chemotherapy and alpha interferon, as previously used in Nigeria, the results obtained with this regimen has established Imatinib as the first-line treatment strategy in patients with CML, as it is in other populations, with minimal morbidity.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1540) "

Objectives

To assess response and toxicity to Imatinib mesylate (Glivec) in Nigerian Patients with chronic myeloid leukemia.

Methods

From August 2003 to August 2007, 98 consecutive, consenting patients, 56 (57%) males and 42 (43%) females, median age 36 years (range, 11-65 years) diagnosed with  CML, irrespective of disease phase received Imatinib at a dose of 300-600mg/day at the OAU Teaching Hospitals, Nigeria. Response to therapy was assessed by clinical, haematological and cytogenetic parameters. Blood counts were checked every two weeks in the first three months of therapy. Chromosome analysis was repeated sixth monthly. Overall survival (OS) and frequency of complete or major cytogenetic remission (CCR/MCR) were evaluated.  

Results

Complete haematologic remission was achieved in 64% and 83% of patients at one and three months, respectively. With a median follow-up of 25 months, the rates of CCR and MCR were 59% and 35% respectively. At 12 months of follow-up, OS and progression- free survival (PFS) were 96% and 91%, respectively. Achievement of CR at six months was associated with significantly better survival (p = 0.043).

Conclusions

Compared to treatment outcome with conventional chemotherapy and alpha interferon, as previously used in Nigeria, the results obtained with this regimen has established Imatinib as the first-line treatment strategy in patients with CML, as it is in other populations, with minimal morbidity.

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<sup>2</sup>Department of Botany, Obafemi Awolowo University, Ile-Ife, Nigeria; <sup>3</sup>Department of Pharmacy, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria; <sup>4</sup>Department of Haematology, University of Lagos, Nigeria; <sup>5</sup>Department of Haematology, National Hospital, Abuja, Nigeria; <sup>6</sup>Department of Haematology, University of Port-Harcourt, Port-Harcourt, Nigeria; <sup>7</sup>Department of Haematology, University of Benin, Nigeria; <sup>8</sup>Department of Haematology, Nnamdi Azikiwe University, Nnewi, Nigeria; <sup>9</sup>Department of Haematology, University College Hospital, Ibadan, Nigeria; <sup>10</sup>Department of Haematology, Ladoke Akintola University of Technology, Osogbo, Nigeria; <sup>11</sup>Department of Haematology, Ahmadu Bello University, Zaria, Nigeria, <sup>12</sup>Department of Haematology, Bayero University,  Kano, Nigeria; <sup>13</sup>Department of Haematology, University of Nigeria, Enugu, Nigeria; <sup>14</sup>Department of Haematology, Gwagwalada Specialist Hospital, Abuja, Nigeria; <sup>15</sup>Department of Haematology, Army Reference Hospital, Lagos, Nigeria; <sup>16</sup>Asaju Medical Clinic, Victoria Island, Lagos, Nigeria</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1369) "

1Department of Haematology, Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, Nigeria; 2Department of Botany, Obafemi Awolowo University, Ile-Ife, Nigeria; 3Department of Pharmacy, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria; 4Department of Haematology, University of Lagos, Nigeria; 5Department of Haematology, National Hospital, Abuja, Nigeria; 6Department of Haematology, University of Port-Harcourt, Port-Harcourt, Nigeria; 7Department of Haematology, University of Benin, Nigeria; 8Department of Haematology, Nnamdi Azikiwe University, Nnewi, Nigeria; 9Department of Haematology, University College Hospital, Ibadan, Nigeria; 10Department of Haematology, Ladoke Akintola University of Technology, Osogbo, Nigeria; 11Department of Haematology, Ahmadu Bello University, Zaria, Nigeria, 12Department of Haematology, Bayero University,  Kano, Nigeria; 13Department of Haematology, University of Nigeria, Enugu, Nigeria; 14Department of Haematology, Gwagwalada Specialist Hospital, Abuja, Nigeria; 15Department of Haematology, Army Reference Hospital, Lagos, Nigeria; 16Asaju Medical Clinic, Victoria Island, Lagos, Nigeria

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1Department of Haematology, Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, Nigeria; 2Department of Botany, Obafemi Awolowo University, Ile-Ife, Nigeria; 3Department of Pharmacy, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria; 4Department of Haematology, University of Lagos, Nigeria; 5Department of Haematology, National Hospital, Abuja, Nigeria; 6Department of Haematology, University of Port-Harcourt, Port-Harcourt, Nigeria; 7Department of Haematology, University of Benin, Nigeria; 8Department of Haematology, Nnamdi Azikiwe University, Nnewi, Nigeria; 9Department of Haematology, University College Hospital, Ibadan, Nigeria; 10Department of Haematology, Ladoke Akintola University of Technology, Osogbo, Nigeria; 11Department of Haematology, Ahmadu Bello University, Zaria, Nigeria, 12Department of Haematology, Bayero University,  Kano, Nigeria; 13Department of Haematology, University of Nigeria, Enugu, Nigeria; 14Department of Haematology, Gwagwalada Specialist Hospital, Abuja, Nigeria; 15Department of Haematology, Army Reference Hospital, Lagos, Nigeria; 16Asaju Medical Clinic, Victoria Island, Lagos, Nigeria

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Дуросинми М. А., Фалуйи Дж. О., Ойекунле А. А. и соавт.

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Дуросинми М. А., Фалуйи Дж. О., Ойекунле А. А. и соавт.

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Durosinmi" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11759" ["VALUE"]=> array(2) { ["TEXT"]=> string(3404) "<h3>Цель работы</h3> <p>Оценить клинический ответ и токсичность иматиниба мезилата (Гливека) у нигерийских больных хроническим миелолейкозом (ХМЛ).</p> <h3> Методы и клинический материал</h3> <p> С августа 2003 г. по август 2007 г. под наблюдением находились 98 больных с диагнозом ХМЛ (средний возраст 36 лет – от 11 до 65 лет), позитивных по Ph/bcr-abl, давших согласие на терапию, в том числе 56 мужчин и 42 женщины. Независимо от фазы заболевания, лечение Иматинибом проводилось в дозах 300-600 мг в день в госпитале OAU (Нигерия). Ответ на лечение оценивался по клиническим, гематологическим, цитогенетическим и/или молекулярным параметрам. Число клеток в крови проверяли каждые 2 недели в течение первых трех месяцев терапии. Кариотипирование повторяли каждые 6 месяцев. Регистрировали общую выживаемость и частоту полной гематологической ремиссии (ПГР) или большой цитогенетической ремиссии (БЦР, 1-34% Ph+ клеток). <br /> <h3>Результаты</h3> <p> После 1 и 3 месяцев лечения полная гематологическая ремиссия была достигнута, соответственно, у 64% и 83% больных. При среднем сроке наблюдения 25 месяцев, частота ПГР и БЦР составляла 59% и 35%, соответственно. Спленомегалия и/или гепатомегалия менее 7 см от края ребер были прогностическими признаками в отношении ПГР (соответственно, p = 0.0006 и 0.034). После 12 месяцев наблюдения, общая выживаемость и выживаемость без прогрессии (ВБП) составляла, соответственно, 96% и 91%. Число бластных форм на периферии ниже 5% на момент диагноза и достижение ПГР через 6 мес. были ассоциированы со значительно лучшим выживанием (уровни p были, соответственно, 0.037 and 0.043). <br /><h3>Выводы</h3> <p>В сравнении с обычной химиотерапией и применением альфа-интерферона, как было ранее показано в Нигерии, иматиниб может индуцировать раннюю цитогенетическую ремиссию у Ph/bcr-abl- позитивных больных ХМЛ, при минимальных (побочных) заболеваниях. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3308) "

Цель работы

Оценить клинический ответ и токсичность иматиниба мезилата (Гливека) у нигерийских больных хроническим миелолейкозом (ХМЛ).

Методы и клинический материал

С августа 2003 г. по август 2007 г. под наблюдением находились 98 больных с диагнозом ХМЛ (средний возраст 36 лет – от 11 до 65 лет), позитивных по Ph/bcr-abl, давших согласие на терапию, в том числе 56 мужчин и 42 женщины. Независимо от фазы заболевания, лечение Иматинибом проводилось в дозах 300-600 мг в день в госпитале OAU (Нигерия). Ответ на лечение оценивался по клиническим, гематологическим, цитогенетическим и/или молекулярным параметрам. Число клеток в крови проверяли каждые 2 недели в течение первых трех месяцев терапии. Кариотипирование повторяли каждые 6 месяцев. Регистрировали общую выживаемость и частоту полной гематологической ремиссии (ПГР) или большой цитогенетической ремиссии (БЦР, 1-34% Ph+ клеток).

Результаты

После 1 и 3 месяцев лечения полная гематологическая ремиссия была достигнута, соответственно, у 64% и 83% больных. При среднем сроке наблюдения 25 месяцев, частота ПГР и БЦР составляла 59% и 35%, соответственно. Спленомегалия и/или гепатомегалия менее 7 см от края ребер были прогностическими признаками в отношении ПГР (соответственно, p = 0.0006 и 0.034). После 12 месяцев наблюдения, общая выживаемость и выживаемость без прогрессии (ВБП) составляла, соответственно, 96% и 91%. Число бластных форм на периферии ниже 5% на момент диагноза и достижение ПГР через 6 мес. были ассоциированы со значительно лучшим выживанием (уровни p были, соответственно, 0.037 and 0.043).

Выводы

В сравнении с обычной химиотерапией и применением альфа-интерферона, как было ранее показано в Нигерии, иматиниб может индуцировать раннюю цитогенетическую ремиссию у Ph/bcr-abl- позитивных больных ХМЛ, при минимальных (побочных) заболеваниях.

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Цель работы

Оценить клинический ответ и токсичность иматиниба мезилата (Гливека) у нигерийских больных хроническим миелолейкозом (ХМЛ).

Методы и клинический материал

С августа 2003 г. по август 2007 г. под наблюдением находились 98 больных с диагнозом ХМЛ (средний возраст 36 лет – от 11 до 65 лет), позитивных по Ph/bcr-abl, давших согласие на терапию, в том числе 56 мужчин и 42 женщины. Независимо от фазы заболевания, лечение Иматинибом проводилось в дозах 300-600 мг в день в госпитале OAU (Нигерия). Ответ на лечение оценивался по клиническим, гематологическим, цитогенетическим и/или молекулярным параметрам. Число клеток в крови проверяли каждые 2 недели в течение первых трех месяцев терапии. Кариотипирование повторяли каждые 6 месяцев. Регистрировали общую выживаемость и частоту полной гематологической ремиссии (ПГР) или большой цитогенетической ремиссии (БЦР, 1-34% Ph+ клеток).

Результаты

После 1 и 3 месяцев лечения полная гематологическая ремиссия была достигнута, соответственно, у 64% и 83% больных. При среднем сроке наблюдения 25 месяцев, частота ПГР и БЦР составляла 59% и 35%, соответственно. Спленомегалия и/или гепатомегалия менее 7 см от края ребер были прогностическими признаками в отношении ПГР (соответственно, p = 0.0006 и 0.034). После 12 месяцев наблюдения, общая выживаемость и выживаемость без прогрессии (ВБП) составляла, соответственно, 96% и 91%. Число бластных форм на периферии ниже 5% на момент диагноза и достижение ПГР через 6 мес. были ассоциированы со значительно лучшим выживанием (уровни p были, соответственно, 0.037 and 0.043).

Выводы

В сравнении с обычной химиотерапией и применением альфа-интерферона, как было ранее показано в Нигерии, иматиниб может индуцировать раннюю цитогенетическую ремиссию у Ph/bcr-abl- позитивных больных ХМЛ, при минимальных (побочных) заболеваниях.

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Introduction

The hematopoietic system is one of the most dynamic and stable systems in the organism. Hematopoiesis originates in single, pluripotent, hematopoietic stem cells (HSCs) that are capable of differentiation and self-renewal. The ability of HSCs to differentiate into all eight hematopoietic lineages has been confirmed in previous research [1], but further studies are needed to measure the upper limit of the self-renewal potential of HSCs. Prior research shows that hematopoiesis in mice reconstituted with retrovirally-marked HSC is caused by multiple mainly short-lived clones.  These results were obtained by the analysis of the retroviral insertion sites of individual colonies derived from the spleen colony-forming unit (CFU-S) [2]. Polyclonal hematopoiesis was also observed in other animals [3, 4]. The developmental fate of individual, marked clones was studied during the lifespan of several animals. The results revealed that 1) hematopoiesis is mainly the product of the small clones of hematopoietic cells; 2) the lifespan of the majority of clones is only 1 to 2 months; 3) the clones usually function locally; and 4) the vast majority of the clones replace one another sequentially. Primitive HSCs, capable of producing long-lived clones that exist during the entire lifespan of a mouse (constituting approximately 10% of all clones), were detected by the radiation-marker technique [5]. Such clonal kinetics suggests the exhaustion of hematopoietic clones followed by subsequent recruiting of new clones via proliferation (clonal succession).  This also suggests the ability of the HSCs to proliferate and then return to a quiescent status.

Granulocyte colony-stimulating factor (G-CSF) induces the separation of the HSCs from their stromal niches, resulting in their mobilization into the circulation of the body [6]. Repeated injections of G-CSF may induce the proliferation of clones, leading to increased exhaustion of the hematopoietic system. At the same time, mobilized HSCs that have dissociated with their niche might not return to a quiescent state efficiently. Analysis of the influence of G-CSF on the clonal composition in chimeras could validate the stability of the hematopoietic system after such treatment and clarify the mechanisms of clonal hematopoiesis.

In this study, clonal hematopoiesis was demonstrated by using mice that were reconstituted with bone marrow cells expressing the human adenosine deaminase (hADA) gene while undergoing repeated G-CSF treatment. The dosage of 25 μg/kg is considered insufficient for HSC mobilization in mice [7], although it is approximately five times greater than the dosage used for the mobilization of HSCs in humans [6].

Materials and methods

Mice
Twelve to thirty-week-old male and female CBF1 (C57Bl/6xCBA) F1 mice were used as donors and recipients, respectively. Recipient mice were exposed to 1000 cGy 137Cs irradiation divided into two sessions, each exposure three hours apart. Donor mice were injected intravenously with 5-Fluorouracil (5-FU, Sigma, USA, 150 mg/kg body weight) two days before bone marrow (BM) aspiration. For the CFU-S assay [8], irradiated female mice were injected i.v. with 1-3x105 bone marrow cells from reconstituted animals and 10-day-old spleen colonies were isolated for DNA analysis.

Transduction of hematopoietic cells with recombinant virus
Donor bone marrow cells from male mice were pre-stimulated for two days by placing the cells on the irradiated (40 Gy) stroma of three-week-old long-term bone marrow cultures, incubated at 37oC in Fisher medium (ICN, USA), and supplemented with 20% fetal calf serum (Hyclone, USA). Pre-stimulated bone marrow cells were transferred onto the irradiated (40 Gy) monolayer of PGK-hADA cells that produce a retrovirus containing the human ADA gene [9].  The bone marrow cells were incubated in the full media containing 4 μg/ml polybrene (Sigma, USA) for 48 hours, as described [2]. Immediately after, infected cells were injected into irradiated female recipients (1.2 x 106 cells/mouse) for the long-term reconstitution assay. To determine gene transfer efficiency, a small aliquot of cells was injected for CFU-S assay. Transduction efficiency was 90 % (30 CFU-S were analyzed).

Analysis of the recipient animals
Bone marrow samples were collected under light anesthesia from the femurs of individual reconstituted mice before G-CSF treatment. At the same moment the peripheral blood of each mouse was analyzed. The procedure was carried out monthly, ranging from three to eight months after transplantation [2]. In brief, bone marrow was aspirated repeatedly from the left and the right femurs alternatively by puncturing through the knee joint with a 22-gauge needle. Aliquots of bone marrow from each mouse (1-3 x 105 cells) were injected into seven irradiated female recipients for CFU-S (day 10) analysis and the rest of the bone marrow cells were used for DNA isolation. For identification of CFU-S origin, PCR analysis of Smc gene located both on X and Y chromosomes had been used:
5’- CTGAACTATTTGGATCAGATTGC-3’(exon 3) (sense) and 5’-CACCGACGGTCCTTGCAGAT-3’ (exon 4) (antisense) (Surin V.L., unpublished). By using these primers it is possible to synthesize the  391 bp fragment from the gene copy localized on the Y chromosome, and to synthesize the 429 bp fragment from the gene copy localized on the X chromosome. The difference in the fragment length reflects the difference in the intron length on different chromosomes. Thirty-two cycles of PCR were performed: denaturation 940С – 1 min, annealing 620С – 1 min, synthesis 720С – 2 min. Fragments were analyzed in a 2% agarose gel.

PCR and Southern blot analysis of CFU-S-derived colonies
DNA from total bone marrow and individual spleen colonies was extracted and the PGK-hADA provirus was detected by PCR [2]. DNA samples proven to be positive for hADA underwent the standard Southern blotting technique [10]. The samples were digested with the restriction enzyme EcoRI, then analyzed by electrophoresis using a 1% agarose gel. Subsequently, they were transferred to the Hybond N+ filter and hybridized with an hADA cDNA probe, prepared from a 418 bp fragment of hADA gene amplified by PCR [10]. Digestion with EcoRI permits analysis of individual clones, since only one EcoRI restriction site is present within the vector used. The alignment of bands was based on molecular weight standards (phage λ DNA digested with HindIII).

G-CSF treatment
G-CSF (Neupogen 48 Mio U, F.Hoffmann-La Roche) was dissolved in 0.85% NaCl solution with 0,1% bovine serum albumin (Sigma) and injected subcutaneously according to the dosage of 25 μg/kg in 0.2 ml for 4 days per course. The mice received six courses of G-CSF monthly, starting from three months after reconstitution. The last course was performed eight months after reconstitution.
The scheme of the experiments is represented in Fig. 1.

2008-2-en-Shipounova-et-al-clones-Figure-1.jpg

Figure 1. Methodology.
Reconstituted mice were divided into 2 groups. One group was injected with G-CSF; the control group was injected with the placebo. G-CSF was injected for 4 days in a row, once a month. Before each course of G-CSF, peripheral blood was analyzed and a bone marrow aspiration was performed. Bone marrow cells from each mouse were transplanted to secondary irradiated recipients (7 animals per reconstituted mouse) for CFU-S analysis. After the end of each G-CSF course, a peripheral blood analysis was performed. Six G-SCF rounds of injections were given altogether. The last analysis was performed 15 months after the reconstitution.


Statistics

Statistical analysis was done using Student's t-test.

Results and discussion

The number of leukocytes and the proportion of granulocytes in the peripheral blood of the reconstituted mice did not change significantly after repeated G-CSF treatment (Fig. 2 A, B). The fluctuation of leukocytes numbers was due to seasonal variations rather than constrained by G-CSF treatment; the frequency of fluctuations was the same for the animals treated with G-CSF as with the placebo animals. There was no influence of the low dose of G-CSF on the mature blood cells, thus supporting the data obtained from non-irradiated mice [11, 12].

2008-2-en-Shipounova-et-al-Clones-Fig-2A.jpg

Figure 2. Peripheral blood analyses

A. Number of leukocytes in chimeras. Data are shown as the means (±SEM).

Axis of abscissa: time after reconstitution, months
Axis of ordinate: number of leukocytes per mkl of blood, х 103


2008-2-en-Shipounova-et-al-Clones-Fig-2B.jpg

B. Proportion of granulocytes in chimeras. Data are shown as the means (±SEM).

Axis of abscissa: time after reconstituion, months
Axis of ordinate: proportion of granulocytes, %


The concentration of CFU-S in the bone marrow of the reconstituted mice did not change after G-CSF treatment (Fig. 3 A). Only once after the second course of G-CSF did the concentration of CFU-S increase in the bone marrow of treated mice. Later on such changes were not observed in the bone marrow of those animals.

2008-2-en-Shipounova-et-al-Clones-Fig-3A.jpg

Figure 3. CFU-S in the bone marrow of chimeras

А. Concentration of CFU-S.
Data are shown as the means (±SEM).

Axis of abscissa: time after reconstitution, months
Axis of ordinate: CFU-S number per 100,000 bone marrow cells


Among reconstituted mice, 100% donor chimerism is rare; a partial reversal to the hematopoiesis recipient marrow is usually observed. This occurs because of the survival of the recipients’ HSCs even after high doses of irradiation. The ratio of donor and recipient CFU-S were analyzed in the bone marrow of all experimental animals. The dynamics of the changes in donor CFU-S concentration is shown on Fig. 3 B. The proportion of donor CFU-S varied from month to month from 35 to 88%. In the group of reconstituted mice that were not treated with G-CSF, the proportion of donor CFU-S was significantly higher than in the groups that were treated (71.2±6.9% versus 56.5±5.3%, р<0.05). Such differences could be explained by the dual influence of G-CSF on hematopoiesis in chimeras. G-CSF can activate quiescent recipient HSCs that survived after irradiation. Perhaps without G-CSF stimulation such cells would have entered the cycle much later. The reversion to recipients’ hematopoiesis also increased in the old animals [13]. On the other hand, G-CSF could have induced the donor pre-stimulated early HSCs to proliferate and differentiate, thus exhausting CFU-S with their high proliferative potential.

2008-2-en-Shipounova-et-al-Clones-Fig-3B.jpg

B. Proportion of donors’ CFU-S. Data are shown as the means (±SEM).

Axis of abscissa: time after reconstitution, months.
Axis of ordinate: proportion of Y-positive CFU-S, %


Significant differences (р<0.05) were observed in the proportion of marked CFU-S in reconstituted mice (Fig. 3 С). The proportion of transdused CFU-S in the G-CSF treated group was lower and more stable than the non-treated ones (20.6±7.1% versus 45.7±6.3%). Cells were marked due to their proliferation at the moment of viral infection so they had divided at least once more than the non–marked ones, thereby diminishing their proportion two-fold. Such precursor cells could be more sensitive to G-CSF treatment and exhausted by differentiation sooner than similar cells in non-treated animals. This data suggest that G-CSF can selectively affect different hematopoietic precursor cells, changing their developmental fate and, as a consequence, inducing significant disturbance in the hematopoietic system.

2008-2-en-Shipounova-et-al-Clones-Fig-3C.jpg

С. Proportion of genetically marked CFU-S. Data are shown as the means (±SEM).

Axis of abscissa: time after reconstitution, months
Axis of ordinate: proportion of ADA-positive CFU-S, %


Analysis of individual clones in untreated and treated animals did not reveal significant differences in their average number (Fig. 4 А). It was shown earlier that the number of clones observed depends on the frequency of analysis and the method of pre-stimulation of HSCs before marking them with the retroviral vector [2, 5, 14]. This work revealed that the clonal composition of hematopoietic tissue is not sensitive to extrinsic factors and probably depends on intrinsic regulation.  The tissue is not connected with local stromal or distantly regulated by hematopoietic growth factors [15]. Thus, the hematopoietic system is one of the most stable systems in the organism and also very well protected from external actions (i.e., bleeding and other stresses).

2008-2-en-Shipounova-et-al-Clones-Fig-4A.jpg

Figure 4. Clonal composition of CFU-S in chimeras

А. Average number of clones per mouse.
Data are shown as the means (±SEM).

Axis of abscissa: group
Axis of ordinate: number of detected clones


However, G-CSF treatment affects the size of the clones (measured by the number of colonies representing one clone) and their longevity in the bone marrow. The size of the clones significantly decreased upon treatment, as clones were represented by fewer colonies (Fig. 4 B). The period through which those clones were detected was also noticeably shortened (Fig. 4 C). Relatively long-lived clones (detected for more than 3 months) were not observed after G-CSF treatment. Even relatively low doses of G-CSF treatment led to the disconnection of HSCs with the hematopoietic stroma [16]. It was shown previously that the dissociation of HSCs from the stromal microenvironment resulted in the very rare detection of long-living marked clones that function during the lifespan of the organism. Long-living clones were produced only in experiments not involving bone marrow transplantation – the procedure was based on the dissociation of bone marrow cells toward single-cell suspension [5]. Mobilized HSCs differ from their non-mobilized analogues in the bone marrow. The comparison of the mobilized non-differentiated HSC CD34+Lin- or CD34+CD38- from the peripheral blood, along with the bone marrow of donors in xenogeneic (NOD/SCID mice and sheep, revealed that the ability of the mobilized HSCs to maintain hematopoiesis was worse than that of the HSCs from the bone marrow [17, 18]. The proportion of non-dividing cells is higher in the mobilized population [19], however, it was suggested that only cells after mitosis are able mobilize [20]. Each course of mobilization triggers the divided HSCs to leave the niche thus impairing their proliferative potential and shifting their early stem cells’ status toward more mature progenitors. The proliferative potential of HSCs returning to their niches after rounds of G-CSF injections decreased and, as a consequence, they formed clones of diminished numbers of CFU-S and shortened periods of detection in the bone marrow.

Thus, repeated injections of G-CSF in pharmacological concentrations lead to the destabilization of the hematopoietic system. Long-term consequences of HSCs mobilization by means of G-CSF need to be carefully monitored in donors.

2008-2-en-Shipounova-et-al-Clones-Fig-4B.jpg

B. Proportion of clones, presented with different number of colonies.

Axis of abscissa: group
Axis of ordinate: proportion of clones with given number of colonies


2008-2-en-Shipounova-et-al-Clones-Fig-4C.jpg

C. Life span of clones. Data are shown as the means (±SEM).

Axis of abscissa: life span of clones, months
Axis of ordinate: % of all clones


Acknowledgements

This study was supported by grants from the Russian Fund of Fundamental Investigation 07-04-00290-а and President of RF МК-3265.2007.4.

References

1. Dick JE, Magli MC, Huszar D, Phillips RA, and Bernstein A. Introduction of a selectable gene into primitive stem cells capable of long-term reconstitution of the hemopoietic system of W/Wv mice. Cell. 1985;42:71-79.

2. Drize NJ, Keller JR, and Chertkov JL. Local clonal analysis of the hematopoietic system shows that multiple small short-living clones maintain life-long hematopoiesis in reconstituted mice. Blood. 1996;88:2927-2938.

3. Kuramoto K, Follmann DA, Hematti P, Sellers S, Agricola BA, Metzger ME, Donahue RE, von Kalle C, and Dunbar CE. Effect of chronic cytokine therapy on clonal dynamics in nonhuman primates. Blood. 2004;103:4070-4077.

4. Abkowitz JL, Golinelli D, Harrison DE, and Guttorp P. In vivo kinetics of murine hemopoietic stem cells [In Process Citation]. Blood. 2000;96:3399-3405.

5. Drize NJ., Olshanskaya YV, Gerasimova LP, Manakova TE, Samoylina NL, Todria TV, and Chertkov JL. Lifelong hematopoiesis in both reconstituted and sublethally irradiated mice is provided by multiple sequentially recruited stem cells. Exp Hematol. 2001;29:786-794.

6. Morstyn G, Foote MA, Walker T, and Molineux G. Filgrastim (r-metHuG-CSF) in the 21st century: SD/01. Acta Haematol. 2001;105:151-155.

7. Molineux G, Pojda Z, Hampson IN, Lord, BI, and Dexter TM. Transplantation potential of peripheral blood stem cells induced by granulocyte colony-stimulating factor. Blood. 1990;76:2153-2158.

8. Till JEMEA. A direct measurement of radiation sencitivity of normal mouse bone marrow. Radiation Research. 1961;14:213-221.

9. Luskey BD, Rosenblatt M, Zsebo K, and Williams DA. Stem cell factor, interleukin-3, and interleukin-6 promote retroviral- mediated gene transfer into murine hematopoietic stem cells. Blood. 1992;80:396-402.

10. Maniatis T, Fritsch EF, and Sambrook J. Molecular Cloning, A Laboratory Manual. Cold Spring Harbor Laboratory). 1982.

11. Drize N, Chertkov J, Samoilina N, and Zander A. Effect of cytokine treatment (granulocyte colony-stimulating factor and stem cell factor) on hematopoiesis and the circulating pool of hematopoietic stem cells in mice. Exp Hematol. 1996;24:816-822.

12. Nifontova I, Svinareva D, Chertkov JL, Drize N, and Savchenko V. Late consequence of long-term treatment of mice with G-CSF. Bull Exp Biol Med. 2008;145:568-573.

13. Drize N, Chertkov J, Sadovnikova E, Tiessen S, and Zander A. Long-term maintenance of hematopoiesis in irradiated mice by retrovirally transduced peripheral blood stem cells. Blood. 1997;89:1811-1817.

14. Drize NI and Chertkov IL. Clone-Forming Activity of Embryonal Stem Hemopoietic Cells after Transplantation to Newborn or Adult Sublethally Irradiated Mice. Biull Eksp Biol. Med. 2000;130:110-112.

15. Metcalf D. Lineage commitment and maturation in hematopoietic cells: the case for extrinsic regulation. Blood. 1998;92:345-347.

16. Drize N, Gan O, and Zander A. Effect of recombinant human granulocyte colony-stimulating factor treatment of mice on spleen colony-forming unit number and self-renewal capacity. Exp Hematol. 1993;21:1289-1293.

17. Verfaillie CM. Hematopoietic stem cells for transplantation. Nat Immunol. 2002;3:314-317.

18. Korbling M, Anderlini P, and Hematology TA. Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter? Blood. 2001;98:2900-2908.

19. Uchida N, He D, Friera AM, Reitsma M, Sasaki D, Chen B, and Tsukamoto A. The unexpected G0/G1 cell cycle status of mobilized hematopoietic stem cells from peripheral blood. Blood. 1997;89:465-472.

20. Wright DE, Cheshier SH, Wagers AJ, Randall TD, Christensen JL, and Weissman IL. Cyclophosphamide/granulocyte colony-stimulating factor causes selective mobilization of bone marrow hematopoietic stem cells into the blood after M phase of the cell cycle. Blood. 2001;97:2278-2285.


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Introduction

The hematopoietic system is one of the most dynamic and stable systems in the organism. Hematopoiesis originates in single, pluripotent, hematopoietic stem cells (HSCs) that are capable of differentiation and self-renewal. The ability of HSCs to differentiate into all eight hematopoietic lineages has been confirmed in previous research [1], but further studies are needed to measure the upper limit of the self-renewal potential of HSCs. Prior research shows that hematopoiesis in mice reconstituted with retrovirally-marked HSC is caused by multiple mainly short-lived clones.  These results were obtained by the analysis of the retroviral insertion sites of individual colonies derived from the spleen colony-forming unit (CFU-S) [2]. Polyclonal hematopoiesis was also observed in other animals [3, 4]. The developmental fate of individual, marked clones was studied during the lifespan of several animals. The results revealed that 1) hematopoiesis is mainly the product of the small clones of hematopoietic cells; 2) the lifespan of the majority of clones is only 1 to 2 months; 3) the clones usually function locally; and 4) the vast majority of the clones replace one another sequentially. Primitive HSCs, capable of producing long-lived clones that exist during the entire lifespan of a mouse (constituting approximately 10% of all clones), were detected by the radiation-marker technique [5]. Such clonal kinetics suggests the exhaustion of hematopoietic clones followed by subsequent recruiting of new clones via proliferation (clonal succession).  This also suggests the ability of the HSCs to proliferate and then return to a quiescent status.

Granulocyte colony-stimulating factor (G-CSF) induces the separation of the HSCs from their stromal niches, resulting in their mobilization into the circulation of the body [6]. Repeated injections of G-CSF may induce the proliferation of clones, leading to increased exhaustion of the hematopoietic system. At the same time, mobilized HSCs that have dissociated with their niche might not return to a quiescent state efficiently. Analysis of the influence of G-CSF on the clonal composition in chimeras could validate the stability of the hematopoietic system after such treatment and clarify the mechanisms of clonal hematopoiesis.

In this study, clonal hematopoiesis was demonstrated by using mice that were reconstituted with bone marrow cells expressing the human adenosine deaminase (hADA) gene while undergoing repeated G-CSF treatment. The dosage of 25 μg/kg is considered insufficient for HSC mobilization in mice [7], although it is approximately five times greater than the dosage used for the mobilization of HSCs in humans [6].

Materials and methods

Mice
Twelve to thirty-week-old male and female CBF1 (C57Bl/6xCBA) F1 mice were used as donors and recipients, respectively. Recipient mice were exposed to 1000 cGy 137Cs irradiation divided into two sessions, each exposure three hours apart. Donor mice were injected intravenously with 5-Fluorouracil (5-FU, Sigma, USA, 150 mg/kg body weight) two days before bone marrow (BM) aspiration. For the CFU-S assay [8], irradiated female mice were injected i.v. with 1-3x105 bone marrow cells from reconstituted animals and 10-day-old spleen colonies were isolated for DNA analysis.

Transduction of hematopoietic cells with recombinant virus
Donor bone marrow cells from male mice were pre-stimulated for two days by placing the cells on the irradiated (40 Gy) stroma of three-week-old long-term bone marrow cultures, incubated at 37oC in Fisher medium (ICN, USA), and supplemented with 20% fetal calf serum (Hyclone, USA). Pre-stimulated bone marrow cells were transferred onto the irradiated (40 Gy) monolayer of PGK-hADA cells that produce a retrovirus containing the human ADA gene [9].  The bone marrow cells were incubated in the full media containing 4 μg/ml polybrene (Sigma, USA) for 48 hours, as described [2]. Immediately after, infected cells were injected into irradiated female recipients (1.2 x 106 cells/mouse) for the long-term reconstitution assay. To determine gene transfer efficiency, a small aliquot of cells was injected for CFU-S assay. Transduction efficiency was 90 % (30 CFU-S were analyzed).

Analysis of the recipient animals
Bone marrow samples were collected under light anesthesia from the femurs of individual reconstituted mice before G-CSF treatment. At the same moment the peripheral blood of each mouse was analyzed. The procedure was carried out monthly, ranging from three to eight months after transplantation [2]. In brief, bone marrow was aspirated repeatedly from the left and the right femurs alternatively by puncturing through the knee joint with a 22-gauge needle. Aliquots of bone marrow from each mouse (1-3 x 105 cells) were injected into seven irradiated female recipients for CFU-S (day 10) analysis and the rest of the bone marrow cells were used for DNA isolation. For identification of CFU-S origin, PCR analysis of Smc gene located both on X and Y chromosomes had been used:
5’- CTGAACTATTTGGATCAGATTGC-3’(exon 3) (sense) and 5’-CACCGACGGTCCTTGCAGAT-3’ (exon 4) (antisense) (Surin V.L., unpublished). By using these primers it is possible to synthesize the  391 bp fragment from the gene copy localized on the Y chromosome, and to synthesize the 429 bp fragment from the gene copy localized on the X chromosome. The difference in the fragment length reflects the difference in the intron length on different chromosomes. Thirty-two cycles of PCR were performed: denaturation 940С – 1 min, annealing 620С – 1 min, synthesis 720С – 2 min. Fragments were analyzed in a 2% agarose gel.

PCR and Southern blot analysis of CFU-S-derived colonies
DNA from total bone marrow and individual spleen colonies was extracted and the PGK-hADA provirus was detected by PCR [2]. DNA samples proven to be positive for hADA underwent the standard Southern blotting technique [10]. The samples were digested with the restriction enzyme EcoRI, then analyzed by electrophoresis using a 1% agarose gel. Subsequently, they were transferred to the Hybond N+ filter and hybridized with an hADA cDNA probe, prepared from a 418 bp fragment of hADA gene amplified by PCR [10]. Digestion with EcoRI permits analysis of individual clones, since only one EcoRI restriction site is present within the vector used. The alignment of bands was based on molecular weight standards (phage λ DNA digested with HindIII).

G-CSF treatment
G-CSF (Neupogen 48 Mio U, F.Hoffmann-La Roche) was dissolved in 0.85% NaCl solution with 0,1% bovine serum albumin (Sigma) and injected subcutaneously according to the dosage of 25 μg/kg in 0.2 ml for 4 days per course. The mice received six courses of G-CSF monthly, starting from three months after reconstitution. The last course was performed eight months after reconstitution.
The scheme of the experiments is represented in Fig. 1.

2008-2-en-Shipounova-et-al-clones-Figure-1.jpg

Figure 1. Methodology.
Reconstituted mice were divided into 2 groups. One group was injected with G-CSF; the control group was injected with the placebo. G-CSF was injected for 4 days in a row, once a month. Before each course of G-CSF, peripheral blood was analyzed and a bone marrow aspiration was performed. Bone marrow cells from each mouse were transplanted to secondary irradiated recipients (7 animals per reconstituted mouse) for CFU-S analysis. After the end of each G-CSF course, a peripheral blood analysis was performed. Six G-SCF rounds of injections were given altogether. The last analysis was performed 15 months after the reconstitution.


Statistics

Statistical analysis was done using Student's t-test.

Results and discussion

The number of leukocytes and the proportion of granulocytes in the peripheral blood of the reconstituted mice did not change significantly after repeated G-CSF treatment (Fig. 2 A, B). The fluctuation of leukocytes numbers was due to seasonal variations rather than constrained by G-CSF treatment; the frequency of fluctuations was the same for the animals treated with G-CSF as with the placebo animals. There was no influence of the low dose of G-CSF on the mature blood cells, thus supporting the data obtained from non-irradiated mice [11, 12].

2008-2-en-Shipounova-et-al-Clones-Fig-2A.jpg

Figure 2. Peripheral blood analyses

A. Number of leukocytes in chimeras. Data are shown as the means (±SEM).

Axis of abscissa: time after reconstitution, months
Axis of ordinate: number of leukocytes per mkl of blood, х 103


2008-2-en-Shipounova-et-al-Clones-Fig-2B.jpg

B. Proportion of granulocytes in chimeras. Data are shown as the means (±SEM).

Axis of abscissa: time after reconstituion, months
Axis of ordinate: proportion of granulocytes, %


The concentration of CFU-S in the bone marrow of the reconstituted mice did not change after G-CSF treatment (Fig. 3 A). Only once after the second course of G-CSF did the concentration of CFU-S increase in the bone marrow of treated mice. Later on such changes were not observed in the bone marrow of those animals.

2008-2-en-Shipounova-et-al-Clones-Fig-3A.jpg

Figure 3. CFU-S in the bone marrow of chimeras

А. Concentration of CFU-S.
Data are shown as the means (±SEM).

Axis of abscissa: time after reconstitution, months
Axis of ordinate: CFU-S number per 100,000 bone marrow cells


Among reconstituted mice, 100% donor chimerism is rare; a partial reversal to the hematopoiesis recipient marrow is usually observed. This occurs because of the survival of the recipients’ HSCs even after high doses of irradiation. The ratio of donor and recipient CFU-S were analyzed in the bone marrow of all experimental animals. The dynamics of the changes in donor CFU-S concentration is shown on Fig. 3 B. The proportion of donor CFU-S varied from month to month from 35 to 88%. In the group of reconstituted mice that were not treated with G-CSF, the proportion of donor CFU-S was significantly higher than in the groups that were treated (71.2±6.9% versus 56.5±5.3%, р<0.05). Such differences could be explained by the dual influence of G-CSF on hematopoiesis in chimeras. G-CSF can activate quiescent recipient HSCs that survived after irradiation. Perhaps without G-CSF stimulation such cells would have entered the cycle much later. The reversion to recipients’ hematopoiesis also increased in the old animals [13]. On the other hand, G-CSF could have induced the donor pre-stimulated early HSCs to proliferate and differentiate, thus exhausting CFU-S with their high proliferative potential.

2008-2-en-Shipounova-et-al-Clones-Fig-3B.jpg

B. Proportion of donors’ CFU-S. Data are shown as the means (±SEM).

Axis of abscissa: time after reconstitution, months.
Axis of ordinate: proportion of Y-positive CFU-S, %


Significant differences (р<0.05) were observed in the proportion of marked CFU-S in reconstituted mice (Fig. 3 С). The proportion of transdused CFU-S in the G-CSF treated group was lower and more stable than the non-treated ones (20.6±7.1% versus 45.7±6.3%). Cells were marked due to their proliferation at the moment of viral infection so they had divided at least once more than the non–marked ones, thereby diminishing their proportion two-fold. Such precursor cells could be more sensitive to G-CSF treatment and exhausted by differentiation sooner than similar cells in non-treated animals. This data suggest that G-CSF can selectively affect different hematopoietic precursor cells, changing their developmental fate and, as a consequence, inducing significant disturbance in the hematopoietic system.

2008-2-en-Shipounova-et-al-Clones-Fig-3C.jpg

С. Proportion of genetically marked CFU-S. Data are shown as the means (±SEM).

Axis of abscissa: time after reconstitution, months
Axis of ordinate: proportion of ADA-positive CFU-S, %


Analysis of individual clones in untreated and treated animals did not reveal significant differences in their average number (Fig. 4 А). It was shown earlier that the number of clones observed depends on the frequency of analysis and the method of pre-stimulation of HSCs before marking them with the retroviral vector [2, 5, 14]. This work revealed that the clonal composition of hematopoietic tissue is not sensitive to extrinsic factors and probably depends on intrinsic regulation.  The tissue is not connected with local stromal or distantly regulated by hematopoietic growth factors [15]. Thus, the hematopoietic system is one of the most stable systems in the organism and also very well protected from external actions (i.e., bleeding and other stresses).

2008-2-en-Shipounova-et-al-Clones-Fig-4A.jpg

Figure 4. Clonal composition of CFU-S in chimeras

А. Average number of clones per mouse.
Data are shown as the means (±SEM).

Axis of abscissa: group
Axis of ordinate: number of detected clones


However, G-CSF treatment affects the size of the clones (measured by the number of colonies representing one clone) and their longevity in the bone marrow. The size of the clones significantly decreased upon treatment, as clones were represented by fewer colonies (Fig. 4 B). The period through which those clones were detected was also noticeably shortened (Fig. 4 C). Relatively long-lived clones (detected for more than 3 months) were not observed after G-CSF treatment. Even relatively low doses of G-CSF treatment led to the disconnection of HSCs with the hematopoietic stroma [16]. It was shown previously that the dissociation of HSCs from the stromal microenvironment resulted in the very rare detection of long-living marked clones that function during the lifespan of the organism. Long-living clones were produced only in experiments not involving bone marrow transplantation – the procedure was based on the dissociation of bone marrow cells toward single-cell suspension [5]. Mobilized HSCs differ from their non-mobilized analogues in the bone marrow. The comparison of the mobilized non-differentiated HSC CD34+Lin- or CD34+CD38- from the peripheral blood, along with the bone marrow of donors in xenogeneic (NOD/SCID mice and sheep, revealed that the ability of the mobilized HSCs to maintain hematopoiesis was worse than that of the HSCs from the bone marrow [17, 18]. The proportion of non-dividing cells is higher in the mobilized population [19], however, it was suggested that only cells after mitosis are able mobilize [20]. Each course of mobilization triggers the divided HSCs to leave the niche thus impairing their proliferative potential and shifting their early stem cells’ status toward more mature progenitors. The proliferative potential of HSCs returning to their niches after rounds of G-CSF injections decreased and, as a consequence, they formed clones of diminished numbers of CFU-S and shortened periods of detection in the bone marrow.

Thus, repeated injections of G-CSF in pharmacological concentrations lead to the destabilization of the hematopoietic system. Long-term consequences of HSCs mobilization by means of G-CSF need to be carefully monitored in donors.

2008-2-en-Shipounova-et-al-Clones-Fig-4B.jpg

B. Proportion of clones, presented with different number of colonies.

Axis of abscissa: group
Axis of ordinate: proportion of clones with given number of colonies


2008-2-en-Shipounova-et-al-Clones-Fig-4C.jpg

C. Life span of clones. Data are shown as the means (±SEM).

Axis of abscissa: life span of clones, months
Axis of ordinate: % of all clones


Acknowledgements

This study was supported by grants from the Russian Fund of Fundamental Investigation 07-04-00290-а and President of RF МК-3265.2007.4.

References

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"11912" [5]=> string(5) "11913" } ["VALUE"]=> array(6) { [0]=> string(3) "830" [1]=> string(3) "860" [2]=> string(3) "831" [3]=> string(3) "861" [4]=> string(3) "833" [5]=> string(3) "862" } ["DESCRIPTION"]=> array(6) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" [5]=> string(0) "" } ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(6) { [0]=> string(3) "830" [1]=> string(3) "860" [2]=> string(3) "831" [3]=> string(3) "861" [4]=> string(3) "833" [5]=> string(3) "862" } ["~DESCRIPTION"]=> array(6) { [0]=> string(0) "" [1]=> string(0) "" [2]=> string(0) "" [3]=> string(0) "" [4]=> string(0) "" [5]=> string(0) "" } ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11847" ["VALUE"]=> array(2) { ["TEXT"]=> string(202) "<p class="Autor">Шипунова (Нифонтова) И. Н., Сац Н. В., Свинарева Д. А., Петрова Т. В., Дризе Н. И., Савченко В. Г.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(180) "

Шипунова (Нифонтова) И. Н., Сац Н. В., Свинарева Д. А., Петрова Т. В., Дризе Н. И., Савченко В. Г.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11848" ["VALUE"]=> array(2) { ["TEXT"]=> string(4613) "<h3>Введение</h3> <p>Предыдущие исследования показали, что кроветворение у мышей, которым пересаживали гемопоэтические стволовые клетки (ГСК), маркированными ретровирусным материалом, восстанавливается за счет множества короткоживущих клонов. Такая клональная кинетика предполагает истощение гемопоэтических клонов с последующим рекрутированием новых клонов путем их пролиферации (клональная сукцессия).</p> <h3>Материалы и методы</h3> <p> В данном исследовании, клональный гемопоэз изучали в модельных опытах на мышах, причем восстановление гемопоэза исследовали, вводя вирус-инфицированные клетки костного мозга (КМ), экспрессирующие ген АДА человека, или ГСК от донора другого пола. Экспериментальные животные подвергались облучению в летальной дозе и трансплантации маркированных ГСК от мышей-доноров. Определение селезеночных колоний (КОЕ-с) у мышей-реципиентов (самок) проводили по Тиллу и Мак-Каллоху. Происхождение КОЕ-с у мышей после трансплантации отслеживали по гену <em>smc</em>, сцепленному с полом, или по маркеру <em>hADA</em>, трансдуцированному в донорские клетки. Введение Г-КСФ после трансплантации проводили ежемесячно в течение полугода.  <br /></p> <h3>Результаты</h3> <p>Повторное введение Г-КСФ не влияло на число лейкоцитов и долю гранулоцитов в периферической крови после трансплантации. Концентрация КОЕ-с в костном мозге трансплантированных мышей не изменялась после введения Г-КСФ. Полный донорский химеризм развивался редко, обычно наблюдалось частичное возвращение к кроветворению реципиента. Доля донорских КОЕ-с от месяца к месяцу колебалась между 35 и 88%. У трансплантированных мышей, не получавших Г-КСФ, доля донорских КОЕ-с была значительно выше, чем в группе, леченной Г-КСФ (71.2±6.9% против 56.5±5.3%, р&lt;0.05). Доля донорских КОЕ-с, маркированных hADA, в группе, получавшей Г-КСФ, была более низкой и более стабильной, чем у «нелеченых» животных (20.6±7.1% versus 45.7±6.3%). Анализ отдельных клонов у «леченых» и «нелеченых» животных не выявил достоверных различий по их среднему содержанию. Однако величина клонов существенно снижалась при введении Г-КСФ, так как клоны были представлены меньшим числом колоний. Долгоживущие клоны (выявляемые после 3 мес.) не наблюдались после длительного введения Г-КСФ. <br /></p><h3>Заключение</h3> <p>Повторные инъекции Г-КСФ в фармакологических дозах вызывают дисбаланс в кроветворной системе. Долгосрочные последствия мобилизации ГСК посредством Г-КСФ следует внимательно отслеживать у потенциальных доноров.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4477) "

Введение

Предыдущие исследования показали, что кроветворение у мышей, которым пересаживали гемопоэтические стволовые клетки (ГСК), маркированными ретровирусным материалом, восстанавливается за счет множества короткоживущих клонов. Такая клональная кинетика предполагает истощение гемопоэтических клонов с последующим рекрутированием новых клонов путем их пролиферации (клональная сукцессия).

Материалы и методы

В данном исследовании, клональный гемопоэз изучали в модельных опытах на мышах, причем восстановление гемопоэза исследовали, вводя вирус-инфицированные клетки костного мозга (КМ), экспрессирующие ген АДА человека, или ГСК от донора другого пола. Экспериментальные животные подвергались облучению в летальной дозе и трансплантации маркированных ГСК от мышей-доноров. Определение селезеночных колоний (КОЕ-с) у мышей-реципиентов (самок) проводили по Тиллу и Мак-Каллоху. Происхождение КОЕ-с у мышей после трансплантации отслеживали по гену smc, сцепленному с полом, или по маркеру hADA, трансдуцированному в донорские клетки. Введение Г-КСФ после трансплантации проводили ежемесячно в течение полугода. 

Результаты

Повторное введение Г-КСФ не влияло на число лейкоцитов и долю гранулоцитов в периферической крови после трансплантации. Концентрация КОЕ-с в костном мозге трансплантированных мышей не изменялась после введения Г-КСФ. Полный донорский химеризм развивался редко, обычно наблюдалось частичное возвращение к кроветворению реципиента. Доля донорских КОЕ-с от месяца к месяцу колебалась между 35 и 88%. У трансплантированных мышей, не получавших Г-КСФ, доля донорских КОЕ-с была значительно выше, чем в группе, леченной Г-КСФ (71.2±6.9% против 56.5±5.3%, р<0.05). Доля донорских КОЕ-с, маркированных hADA, в группе, получавшей Г-КСФ, была более низкой и более стабильной, чем у «нелеченых» животных (20.6±7.1% versus 45.7±6.3%). Анализ отдельных клонов у «леченых» и «нелеченых» животных не выявил достоверных различий по их среднему содержанию. Однако величина клонов существенно снижалась при введении Г-КСФ, так как клоны были представлены меньшим числом колоний. Долгоживущие клоны (выявляемые после 3 мес.) не наблюдались после длительного введения Г-КСФ.

Заключение

Повторные инъекции Г-КСФ в фармакологических дозах вызывают дисбаланс в кроветворной системе. Долгосрочные последствия мобилизации ГСК посредством Г-КСФ следует внимательно отслеживать у потенциальных доноров.

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Irina Shipounova (Nifontova), Natalia Sats, Daria Svinareva, Tatiana Petrova, Nina Drize, Valeriy Savchenko

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National Hematology Research Center, Russian Academy of Medical Science, Moscow, Russia

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The clonal composition of hematopoietic tissue was studied in chimeras reconstituted with bone marrow cells expressing the human adenosine deaminase gene after repeated rounds of G-CSF treatment. Six courses
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The clonal composition of hematopoietic tissue was studied in chimeras reconstituted with bone marrow cells expressing the human adenosine deaminase gene after repeated rounds of G-CSF treatment. Six courses
of G-CSF treatment led to an insignificant decrease of clone numbers and a considerable reduction in clone size and lifespan. The data suggest that the dissociation of the hematopoietic stem cells from their microenvironment after G-CSF treatment resulted in the exhaustion of clone size, and a decrease in the proliferative potential of the hematopoietic stem cells. Repeated G-CSF treatment adversely affects the hematopoietic system.

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National Hematology Research Center, Russian Academy of Medical Science, Moscow, Russia

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National Hematology Research Center, Russian Academy of Medical Science, Moscow, Russia

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Шипунова (Нифонтова) И. Н., Сац Н. В., Свинарева Д. А., Петрова Т. В., Дризе Н. И., Савченко В. Г.

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["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11848" ["VALUE"]=> array(2) { ["TEXT"]=> string(4613) "<h3>Введение</h3> <p>Предыдущие исследования показали, что кроветворение у мышей, которым пересаживали гемопоэтические стволовые клетки (ГСК), маркированными ретровирусным материалом, восстанавливается за счет множества короткоживущих клонов. Такая клональная кинетика предполагает истощение гемопоэтических клонов с последующим рекрутированием новых клонов путем их пролиферации (клональная сукцессия).</p> <h3>Материалы и методы</h3> <p> В данном исследовании, клональный гемопоэз изучали в модельных опытах на мышах, причем восстановление гемопоэза исследовали, вводя вирус-инфицированные клетки костного мозга (КМ), экспрессирующие ген АДА человека, или ГСК от донора другого пола. Экспериментальные животные подвергались облучению в летальной дозе и трансплантации маркированных ГСК от мышей-доноров. Определение селезеночных колоний (КОЕ-с) у мышей-реципиентов (самок) проводили по Тиллу и Мак-Каллоху. Происхождение КОЕ-с у мышей после трансплантации отслеживали по гену <em>smc</em>, сцепленному с полом, или по маркеру <em>hADA</em>, трансдуцированному в донорские клетки. Введение Г-КСФ после трансплантации проводили ежемесячно в течение полугода.  <br /></p> <h3>Результаты</h3> <p>Повторное введение Г-КСФ не влияло на число лейкоцитов и долю гранулоцитов в периферической крови после трансплантации. Концентрация КОЕ-с в костном мозге трансплантированных мышей не изменялась после введения Г-КСФ. Полный донорский химеризм развивался редко, обычно наблюдалось частичное возвращение к кроветворению реципиента. Доля донорских КОЕ-с от месяца к месяцу колебалась между 35 и 88%. У трансплантированных мышей, не получавших Г-КСФ, доля донорских КОЕ-с была значительно выше, чем в группе, леченной Г-КСФ (71.2±6.9% против 56.5±5.3%, р&lt;0.05). Доля донорских КОЕ-с, маркированных hADA, в группе, получавшей Г-КСФ, была более низкой и более стабильной, чем у «нелеченых» животных (20.6±7.1% versus 45.7±6.3%). Анализ отдельных клонов у «леченых» и «нелеченых» животных не выявил достоверных различий по их среднему содержанию. Однако величина клонов существенно снижалась при введении Г-КСФ, так как клоны были представлены меньшим числом колоний. Долгоживущие клоны (выявляемые после 3 мес.) не наблюдались после длительного введения Г-КСФ. <br /></p><h3>Заключение</h3> <p>Повторные инъекции Г-КСФ в фармакологических дозах вызывают дисбаланс в кроветворной системе. Долгосрочные последствия мобилизации ГСК посредством Г-КСФ следует внимательно отслеживать у потенциальных доноров.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4477) "

Введение

Предыдущие исследования показали, что кроветворение у мышей, которым пересаживали гемопоэтические стволовые клетки (ГСК), маркированными ретровирусным материалом, восстанавливается за счет множества короткоживущих клонов. Такая клональная кинетика предполагает истощение гемопоэтических клонов с последующим рекрутированием новых клонов путем их пролиферации (клональная сукцессия).

Материалы и методы

В данном исследовании, клональный гемопоэз изучали в модельных опытах на мышах, причем восстановление гемопоэза исследовали, вводя вирус-инфицированные клетки костного мозга (КМ), экспрессирующие ген АДА человека, или ГСК от донора другого пола. Экспериментальные животные подвергались облучению в летальной дозе и трансплантации маркированных ГСК от мышей-доноров. Определение селезеночных колоний (КОЕ-с) у мышей-реципиентов (самок) проводили по Тиллу и Мак-Каллоху. Происхождение КОЕ-с у мышей после трансплантации отслеживали по гену smc, сцепленному с полом, или по маркеру hADA, трансдуцированному в донорские клетки. Введение Г-КСФ после трансплантации проводили ежемесячно в течение полугода. 

Результаты

Повторное введение Г-КСФ не влияло на число лейкоцитов и долю гранулоцитов в периферической крови после трансплантации. Концентрация КОЕ-с в костном мозге трансплантированных мышей не изменялась после введения Г-КСФ. Полный донорский химеризм развивался редко, обычно наблюдалось частичное возвращение к кроветворению реципиента. Доля донорских КОЕ-с от месяца к месяцу колебалась между 35 и 88%. У трансплантированных мышей, не получавших Г-КСФ, доля донорских КОЕ-с была значительно выше, чем в группе, леченной Г-КСФ (71.2±6.9% против 56.5±5.3%, р<0.05). Доля донорских КОЕ-с, маркированных hADA, в группе, получавшей Г-КСФ, была более низкой и более стабильной, чем у «нелеченых» животных (20.6±7.1% versus 45.7±6.3%). Анализ отдельных клонов у «леченых» и «нелеченых» животных не выявил достоверных различий по их среднему содержанию. Однако величина клонов существенно снижалась при введении Г-КСФ, так как клоны были представлены меньшим числом колоний. Долгоживущие клоны (выявляемые после 3 мес.) не наблюдались после длительного введения Г-КСФ.

Заключение

Повторные инъекции Г-КСФ в фармакологических дозах вызывают дисбаланс в кроветворной системе. Долгосрочные последствия мобилизации ГСК посредством Г-КСФ следует внимательно отслеживать у потенциальных доноров.

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Введение

Предыдущие исследования показали, что кроветворение у мышей, которым пересаживали гемопоэтические стволовые клетки (ГСК), маркированными ретровирусным материалом, восстанавливается за счет множества короткоживущих клонов. Такая клональная кинетика предполагает истощение гемопоэтических клонов с последующим рекрутированием новых клонов путем их пролиферации (клональная сукцессия).

Материалы и методы

В данном исследовании, клональный гемопоэз изучали в модельных опытах на мышах, причем восстановление гемопоэза исследовали, вводя вирус-инфицированные клетки костного мозга (КМ), экспрессирующие ген АДА человека, или ГСК от донора другого пола. Экспериментальные животные подвергались облучению в летальной дозе и трансплантации маркированных ГСК от мышей-доноров. Определение селезеночных колоний (КОЕ-с) у мышей-реципиентов (самок) проводили по Тиллу и Мак-Каллоху. Происхождение КОЕ-с у мышей после трансплантации отслеживали по гену smc, сцепленному с полом, или по маркеру hADA, трансдуцированному в донорские клетки. Введение Г-КСФ после трансплантации проводили ежемесячно в течение полугода. 

Результаты

Повторное введение Г-КСФ не влияло на число лейкоцитов и долю гранулоцитов в периферической крови после трансплантации. Концентрация КОЕ-с в костном мозге трансплантированных мышей не изменялась после введения Г-КСФ. Полный донорский химеризм развивался редко, обычно наблюдалось частичное возвращение к кроветворению реципиента. Доля донорских КОЕ-с от месяца к месяцу колебалась между 35 и 88%. У трансплантированных мышей, не получавших Г-КСФ, доля донорских КОЕ-с была значительно выше, чем в группе, леченной Г-КСФ (71.2±6.9% против 56.5±5.3%, р<0.05). Доля донорских КОЕ-с, маркированных hADA, в группе, получавшей Г-КСФ, была более низкой и более стабильной, чем у «нелеченых» животных (20.6±7.1% versus 45.7±6.3%). Анализ отдельных клонов у «леченых» и «нелеченых» животных не выявил достоверных различий по их среднему содержанию. Однако величина клонов существенно снижалась при введении Г-КСФ, так как клоны были представлены меньшим числом колоний. Долгоживущие клоны (выявляемые после 3 мес.) не наблюдались после длительного введения Г-КСФ.

Заключение

Повторные инъекции Г-КСФ в фармакологических дозах вызывают дисбаланс в кроветворной системе. Долгосрочные последствия мобилизации ГСК посредством Г-КСФ следует внимательно отслеживать у потенциальных доноров.

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Introduction

Myeloproliferative disorders (MPDs) comprise a group of hematopoietic malignancies that are characterized by enhanced proliferation and survival of one or more myeloid line cells [1]. According to the World Health Organization classification, MPDs include polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF) and chronic myeloid leukemia (CML), plus rarer subtypes, such as chronic neutrophilic leukemia, hypereosinophilic syndrome and chronic eosinophilic leukemia [8]. The clinical picture of these disorders has many features: all malignant cells originate from a single, multipotent hematopoietic stem cell that predominates over nontransformed progenitors; hypercellularity of the bone marrow, with apparently unstimulated overproduction of one or more of the blood corpuscles; and increased risk of thrombosis and bleeding, spontaneous transformation into acute leukemia and marrow fibrosis [3]. Until very recently MPDs continued to be separated and diagnosed on the basis of their clinical and laboratory findings [4]. The identification of new genetic markers represents a major advance in the understanding of the molecular pathogenesis of MPDs, which will likely result in new classifications and the development of novel therapeutic strategies for these diseases.

The most extensively studied mutation is BCR/ABL, the pathogenetic mutation in CML [5]. CML was the first leukemia to be described and associated with a consistent cytogenetic abnormality, the Philadelphia chromosome (Ph1). Since then new approaches, based on detection of different mutations, have been effectively developed.

The discovery of the JAK2V617F mutation has already greatly influenced the diagnostic approach for MPDs, as well as research strategies in terms of both molecular pathogenesis and drug development [6].

JAK2V617F, a somatic gain-of-function mutation involving the JAK2 tyrosine kinase gene, could be found in nearly all patients with polycythemia vera (PV), in approximately 50% in both essential thrombocythemia (ET) and myelofibrosis (MF) patients, up to 20% of the time in certain subcategories of atypical MPD, in less than 3% in de novo MDS or acute myeloid leukemia patients, and 0% of cases of CML [7].

The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway plays a central role in initiating signal transduction from hematopoietic growth factor receptors. Non-receptor tyrosine kinases JAK2 are normally responsible for signaling from various growth factor receptors, including those for erythropoietin and thrombopoietin. Each JAK protein has two active tyrosine kinase domains and a catalytically inactive pseudokinase domain. Under normal physiological circumstances, the pseudokinase domain prevents the closure of the two tyrosine kinase domains and auto-activation. When a ligand (for example erythropoietin) binds with a receptor, a conformational change occurs. The JAK2 protein then contacts the cytoplasmic domain of the receptor, where it catalyses tyrosine phosphorylation. This primarily leads to the recruitment of STAT (signal transducer and activator of transcription) molecules, which are then phosphorylated, homodimerize and translocate to the nucleus, where they act as transcription factors [8]. These processes are key events in the modification of regulatory pathways for cell proliferation and survival.

The specific genetic mutation G1849T observed in exon 14 results in the substitution of phenylalanine by valine, both hydrophobic nonpolar amino acids, at position 617 of the JAK2 protein within the JH2 pseudokinase domain [9]. Loss of JAK2 auto-inhibition results in constitutive activation of the kinase. It results in deregulation of intracellular signaling and disturbance of cell proliferation, which becomes independent of normal growth factor control. Since the mutation has a high specificity for clonal myeloid diseases, the presence of JAK2 V617F can definitively confirm an MPD diagnosis [10].

The main aim of this study was to develop a routine detection technique for the V617F mutation of the JAK2 gene that will be useful both for primary diagnostics and for semiquantative estimation during treatment.

Patients, materials, and methods

Patient characteristics
Fifty-eight patients from hematological clinics of the Saint Petersburg Pavlov State Medical University were included in the study: 8 patients with PV, 7 with ET, 2 with MF and 35 with primary diagnosed MPD. The median age was 55 years (range 20–86 years). All patients did not receive any specific therapy. The control group included 20 standard blood donors.

Cell line
As a positive control we used cell line UKE1 [11], donated by Professor B. Fehse (Germany). The UKE1 cell line is homozygous for the V617F mutation in the Jak2 gene (G1849T substitution in exon 14) [12].

DNA samples
DNA was isolated from 200 µl of bone marrow or 1 ml whole blood using sorbate methods (DNA Technology, Russia). This procedure regularly results in 3 µg to 8 µg DNA in a final volume of 100 µl. After isolation from blood samples, DNA was stored at -20 °C until analysis.

PCR analysis
PCR was performed on an amplificator “Terzik” (DNA Technology, Russia) with standard PCR mix. The program for PCR includes initial denaturation (3 minutes at 95°C) and 40 cycles at 94°C for 20 seconds; 61°C for 30 seconds and 72°C for 60 seconds. The following primers were used: Jak2-F (forward): 5'-GGGTTTCCTCAGAACGTTGA-3'; Jak2-RW (reverse wild type): 5'-TTTACTTACTCTCGTCTCCACATAC-3'; Jak2-RM (reverse mutated): 5'-TTTACTTACTCTCGTCTCCACATAA-3'. After amplification PCR products were visualized in 2% agarose gel and photographed by means of a "Gel Imager, 08-111" (DNA Technology, Russia).
Real-time PCR was performed on a DT-96 amplificator (DNA Technology, Russia), with standard PCR real time mix SYBR GREEN and the same primers. After initial denaturation (3 minutes at 95°C), PCR was carried out for 40 cycles at standard conditions (94°C for 15 seconds; 61°C for 40 seconds). The estimation of "threshold" was performed automatically; "melting curve" analysis was used for discrimination of the nonspecific results.

Results assessment
To assess the specificity of the method we used the UKE1 cell line and 20 donor samples as negative control.

A)    Quality assessment

Each sample was assessed on two lines: line 1 – PCR specific for the wild- type of the Jak2 gene, and line 2 – specific for the mutated gene. If the mutation-specific signal in line 2 was detected, such samples were considered positive for the V617F mutation in the Jak2 gene (see Figure 1).

2008-2-en-Saburova-et-al-Figure-1.jpg

Panel А: Jak2 "wild" type; panel B: Jak2 mutated type.
Samples: 1 – donor, 2 and 3 – patients, 4 – cell line (UKE1). Samples 1 and 2 are homozygous for Jak2 wild-type, sample 3 is heterozygous, and sample 4 is homozygous for the Jak2 mutant type.



B) Semi quantitative assessment

A semi-quantitative assessment was performed by means of the GelPro Analyzer 3.1 computer program. This program allows the quantitative valuation of luminescence levels and assesses those in Relative Units of Luminescence (RU). The sum of RU from two lines (wild and mutated type of gene) was assessed as 100%. Relative intensity of mutant type gene signals thus indicates the number of mutated cells.

Results and discussion

Screening for the JAK2V617F mutation in MPD diagnostics is a predictive and specific approach [13]. In most cases the JAK2 V617F mutation was examined using polymerase chain reaction (PCR)-amplified genomic DNA with two primers (for mutant and wild type gene) [12]. Concerning the results of this study such a method is appropriate for screening the mutation.

As a positive control we used cell line UKE1, which is homozygous for the V617F JAK2 mutation. For negative control we used samples from 20 healthy donors who do not carry this mutation after informed consent. The correlation analysis showed high-level convergence between real time and standard PCR dates. “Melting curve” analysis showed high level specificity and sensitivity.

Prospective evaluation of the V617F JAK2 mutation was implemented at Saint Petersburg Pavlov State Medical University. Fifty-eight patients with a preliminary diagnosis of MPD were examined. The overall mutation frequency was 29.3%. The incidence of different diseases is shown in Table 1.

Table 1. Overall frequency of the V617F JAK2 mutation in 58 patients with different myeloproliferative disorders at the Saint Petersburg Pavlov State Medical University.

2008-2-en-Saburova-et-al-Table-1.jpg


Detection of V617F mutation of JAK2 gene in patients with chronic myeloproliferative disorders is a common criterion for diagnosis. For primary diagnostics, screening methods are widely used. Such methods should be quick in performance, rather cheap and reproducible in laboratories with technical equipment of middle level.

For screening methods, qualitative detection of the JAK2 gene mutation without its quantitative assessment is sufficient. Detection of this mutation helps not only in diagnostics, but also in determining the treatment strategy for a concrete patient.

After specific therapy (standard chemotherapy and particularly hematopoietic stem cells transplantation) it is rather important to assess dynamics of reduction of the tumor clone that bears the mutation in the JAK2 gene. Another substantial goal is to follow minimal amounts of tumor cells (“minimal residual disease”) to predict potential recurrence of the disease. For this purpose both semiquantitative and quantitative methods are appropriate. Quantitative methods need verified controls (e.g. cell line or plasmid dilutions) for establishing a calibration curve.

Concerning the abovementioned protocol we have developed a screening method for the detection of the V617F mutation in the JAK2 gene. This method is based on common allele-specific amplification with further detection in agarose gel. Specificity and sensitivity of this method were tested on the cell line UКE1 (data are not presented). Using this protocol we retrospectively investigated 23 patients with clinically verified diagnoses (see Table 1), and performed prospective trial on 35 outpatients with suspected myeloproliferative disorders.

Comparing our results with data from literature we indicated similarity of incidence rates for V617F mutation in JAK2 gene in patients with idiopathic myelofibrosis and essential thrombocythemia. Discrepancy between incidence rates in patients with polycythemia vera and unspecified myeloproliferative disorders and data from literature could be referred to small sample and/or and shortage of clinical criteria for diagnosis verification. Besides specificity we assessed reproducibility of this method on different types of amplificators – «GeneAmp»-9600 (USA), DT-96 (Russia), «Tercic» (Russia). We showed identity of data obtained on different amplificators, which confirms high reproducibility of the proposed method. All samples positive for V617F mutation in JAK2 gene were analyzed with computer program “GelPrо” to determine percentage ratio of tumor and normal cells.

At the second phase of our study we developed a uniform qualitative method for detection of the JAK2V617F mutation using real-time PCR. Therefore we used the same samples as for the standard PCR analysis. Preliminary data of qPCR analysis were in full agreement with those of standard PCR (not shown). Further refinement may be carried out in order to develop a simple quantitative method to assess minimal residual disease after standard treatment and transplantation.

In conclusion the proposed PCR method for the detection of the JAK2 mutation seems to be suitable for the initial evaluation of patients with myeloproliferative disorders.

References

1. Steensma DP. JAK2 V617F in Myeloid Disorders: Molecular Diagnostic Techniques and Their Clinical Utility. JMD. 2006;8(4):397-410.

2. Tefferi А, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008;22:14-22.

3. Yamaoka K, Saharinen P, Pesu M, Holt VE 3rd, Silvennoinen O, O’Shea JJ. The Janus kinases (Jaks). Genome Biology. 2004;5:253.

4. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951;6:372-375.

5. Wilson-Rawls J, Xie S, Liu J, Laneuville P, Arlinghaus RB. P210 Bcr-Abl interacts with the interleukin 3 receptor beta(c) subunit and constitutively induces its tyrosine phosphorylation. Cancer Res. 1996;56:3426-3430.

6. Spivak JL, Barosi G, Tognoni G, Barbui T, Finazzi G, Marchioli R, Marchetti M. Chronic myeloproliferative disorders. Hematology: American Society of Hematology Education Program Book. 2003:200-224.

7. McLornan D, Percy M, McMullin MF. JAK2 V617F: A Single Mutation in the Myeloproliferative Group of Disorders. Ulster Med J. 2006;75(2):112-119.

8. Tefferi А. Classification, Diagnosis and Management of Myeloproliferative Disorders in the JAK2V617F Era. Hematology. 2006;240-245.

9. Wolanskyj AP, Lasho TL, Schwager SM, McClure RF, Wadleigh M, Lee SJ, et al. JAK2V617F mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance. Br J Haematol. 2005;131(2):208-13.

10. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247:824-830.

11. Fiedler W, Henke RP, Ergün S, Schumacher U, Gehling UM, Vohwinkel G, Kilic N, Hossfeld DK. Derivation of a new hematopoietic cell line with endothelial features from a patient with transformed myeloproliferative syndrome: a case report. Cancer. 2000 Jan 15;88(2):344-51.

12. Lippert E, Girodon F, Hammond E, et al. Concordance of assays designed for the quantification of JAK2V617F: a multicenter study. Haematologica. 2008 Nov 10. Epub ahead of print.

13. Levine RL, Wernig G. Role of JAK-STAT Signaling in the Pathogenesis of Myeloproliferative Disorders. Hematology. 2006:233-239.

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Introduction

Myeloproliferative disorders (MPDs) comprise a group of hematopoietic malignancies that are characterized by enhanced proliferation and survival of one or more myeloid line cells [1]. According to the World Health Organization classification, MPDs include polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF) and chronic myeloid leukemia (CML), plus rarer subtypes, such as chronic neutrophilic leukemia, hypereosinophilic syndrome and chronic eosinophilic leukemia [8]. The clinical picture of these disorders has many features: all malignant cells originate from a single, multipotent hematopoietic stem cell that predominates over nontransformed progenitors; hypercellularity of the bone marrow, with apparently unstimulated overproduction of one or more of the blood corpuscles; and increased risk of thrombosis and bleeding, spontaneous transformation into acute leukemia and marrow fibrosis [3]. Until very recently MPDs continued to be separated and diagnosed on the basis of their clinical and laboratory findings [4]. The identification of new genetic markers represents a major advance in the understanding of the molecular pathogenesis of MPDs, which will likely result in new classifications and the development of novel therapeutic strategies for these diseases.

The most extensively studied mutation is BCR/ABL, the pathogenetic mutation in CML [5]. CML was the first leukemia to be described and associated with a consistent cytogenetic abnormality, the Philadelphia chromosome (Ph1). Since then new approaches, based on detection of different mutations, have been effectively developed.

The discovery of the JAK2V617F mutation has already greatly influenced the diagnostic approach for MPDs, as well as research strategies in terms of both molecular pathogenesis and drug development [6].

JAK2V617F, a somatic gain-of-function mutation involving the JAK2 tyrosine kinase gene, could be found in nearly all patients with polycythemia vera (PV), in approximately 50% in both essential thrombocythemia (ET) and myelofibrosis (MF) patients, up to 20% of the time in certain subcategories of atypical MPD, in less than 3% in de novo MDS or acute myeloid leukemia patients, and 0% of cases of CML [7].

The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway plays a central role in initiating signal transduction from hematopoietic growth factor receptors. Non-receptor tyrosine kinases JAK2 are normally responsible for signaling from various growth factor receptors, including those for erythropoietin and thrombopoietin. Each JAK protein has two active tyrosine kinase domains and a catalytically inactive pseudokinase domain. Under normal physiological circumstances, the pseudokinase domain prevents the closure of the two tyrosine kinase domains and auto-activation. When a ligand (for example erythropoietin) binds with a receptor, a conformational change occurs. The JAK2 protein then contacts the cytoplasmic domain of the receptor, where it catalyses tyrosine phosphorylation. This primarily leads to the recruitment of STAT (signal transducer and activator of transcription) molecules, which are then phosphorylated, homodimerize and translocate to the nucleus, where they act as transcription factors [8]. These processes are key events in the modification of regulatory pathways for cell proliferation and survival.

The specific genetic mutation G1849T observed in exon 14 results in the substitution of phenylalanine by valine, both hydrophobic nonpolar amino acids, at position 617 of the JAK2 protein within the JH2 pseudokinase domain [9]. Loss of JAK2 auto-inhibition results in constitutive activation of the kinase. It results in deregulation of intracellular signaling and disturbance of cell proliferation, which becomes independent of normal growth factor control. Since the mutation has a high specificity for clonal myeloid diseases, the presence of JAK2 V617F can definitively confirm an MPD diagnosis [10].

The main aim of this study was to develop a routine detection technique for the V617F mutation of the JAK2 gene that will be useful both for primary diagnostics and for semiquantative estimation during treatment.

Patients, materials, and methods

Patient characteristics
Fifty-eight patients from hematological clinics of the Saint Petersburg Pavlov State Medical University were included in the study: 8 patients with PV, 7 with ET, 2 with MF and 35 with primary diagnosed MPD. The median age was 55 years (range 20–86 years). All patients did not receive any specific therapy. The control group included 20 standard blood donors.

Cell line
As a positive control we used cell line UKE1 [11], donated by Professor B. Fehse (Germany). The UKE1 cell line is homozygous for the V617F mutation in the Jak2 gene (G1849T substitution in exon 14) [12].

DNA samples
DNA was isolated from 200 µl of bone marrow or 1 ml whole blood using sorbate methods (DNA Technology, Russia). This procedure regularly results in 3 µg to 8 µg DNA in a final volume of 100 µl. After isolation from blood samples, DNA was stored at -20 °C until analysis.

PCR analysis
PCR was performed on an amplificator “Terzik” (DNA Technology, Russia) with standard PCR mix. The program for PCR includes initial denaturation (3 minutes at 95°C) and 40 cycles at 94°C for 20 seconds; 61°C for 30 seconds and 72°C for 60 seconds. The following primers were used: Jak2-F (forward): 5'-GGGTTTCCTCAGAACGTTGA-3'; Jak2-RW (reverse wild type): 5'-TTTACTTACTCTCGTCTCCACATAC-3'; Jak2-RM (reverse mutated): 5'-TTTACTTACTCTCGTCTCCACATAA-3'. After amplification PCR products were visualized in 2% agarose gel and photographed by means of a "Gel Imager, 08-111" (DNA Technology, Russia).
Real-time PCR was performed on a DT-96 amplificator (DNA Technology, Russia), with standard PCR real time mix SYBR GREEN and the same primers. After initial denaturation (3 minutes at 95°C), PCR was carried out for 40 cycles at standard conditions (94°C for 15 seconds; 61°C for 40 seconds). The estimation of "threshold" was performed automatically; "melting curve" analysis was used for discrimination of the nonspecific results.

Results assessment
To assess the specificity of the method we used the UKE1 cell line and 20 donor samples as negative control.

A)    Quality assessment

Each sample was assessed on two lines: line 1 – PCR specific for the wild- type of the Jak2 gene, and line 2 – specific for the mutated gene. If the mutation-specific signal in line 2 was detected, such samples were considered positive for the V617F mutation in the Jak2 gene (see Figure 1).

2008-2-en-Saburova-et-al-Figure-1.jpg

Panel А: Jak2 "wild" type; panel B: Jak2 mutated type.
Samples: 1 – donor, 2 and 3 – patients, 4 – cell line (UKE1). Samples 1 and 2 are homozygous for Jak2 wild-type, sample 3 is heterozygous, and sample 4 is homozygous for the Jak2 mutant type.



B) Semi quantitative assessment

A semi-quantitative assessment was performed by means of the GelPro Analyzer 3.1 computer program. This program allows the quantitative valuation of luminescence levels and assesses those in Relative Units of Luminescence (RU). The sum of RU from two lines (wild and mutated type of gene) was assessed as 100%. Relative intensity of mutant type gene signals thus indicates the number of mutated cells.

Results and discussion

Screening for the JAK2V617F mutation in MPD diagnostics is a predictive and specific approach [13]. In most cases the JAK2 V617F mutation was examined using polymerase chain reaction (PCR)-amplified genomic DNA with two primers (for mutant and wild type gene) [12]. Concerning the results of this study such a method is appropriate for screening the mutation.

As a positive control we used cell line UKE1, which is homozygous for the V617F JAK2 mutation. For negative control we used samples from 20 healthy donors who do not carry this mutation after informed consent. The correlation analysis showed high-level convergence between real time and standard PCR dates. “Melting curve” analysis showed high level specificity and sensitivity.

Prospective evaluation of the V617F JAK2 mutation was implemented at Saint Petersburg Pavlov State Medical University. Fifty-eight patients with a preliminary diagnosis of MPD were examined. The overall mutation frequency was 29.3%. The incidence of different diseases is shown in Table 1.

Table 1. Overall frequency of the V617F JAK2 mutation in 58 patients with different myeloproliferative disorders at the Saint Petersburg Pavlov State Medical University.

2008-2-en-Saburova-et-al-Table-1.jpg


Detection of V617F mutation of JAK2 gene in patients with chronic myeloproliferative disorders is a common criterion for diagnosis. For primary diagnostics, screening methods are widely used. Such methods should be quick in performance, rather cheap and reproducible in laboratories with technical equipment of middle level.

For screening methods, qualitative detection of the JAK2 gene mutation without its quantitative assessment is sufficient. Detection of this mutation helps not only in diagnostics, but also in determining the treatment strategy for a concrete patient.

After specific therapy (standard chemotherapy and particularly hematopoietic stem cells transplantation) it is rather important to assess dynamics of reduction of the tumor clone that bears the mutation in the JAK2 gene. Another substantial goal is to follow minimal amounts of tumor cells (“minimal residual disease”) to predict potential recurrence of the disease. For this purpose both semiquantitative and quantitative methods are appropriate. Quantitative methods need verified controls (e.g. cell line or plasmid dilutions) for establishing a calibration curve.

Concerning the abovementioned protocol we have developed a screening method for the detection of the V617F mutation in the JAK2 gene. This method is based on common allele-specific amplification with further detection in agarose gel. Specificity and sensitivity of this method were tested on the cell line UКE1 (data are not presented). Using this protocol we retrospectively investigated 23 patients with clinically verified diagnoses (see Table 1), and performed prospective trial on 35 outpatients with suspected myeloproliferative disorders.

Comparing our results with data from literature we indicated similarity of incidence rates for V617F mutation in JAK2 gene in patients with idiopathic myelofibrosis and essential thrombocythemia. Discrepancy between incidence rates in patients with polycythemia vera and unspecified myeloproliferative disorders and data from literature could be referred to small sample and/or and shortage of clinical criteria for diagnosis verification. Besides specificity we assessed reproducibility of this method on different types of amplificators – «GeneAmp»-9600 (USA), DT-96 (Russia), «Tercic» (Russia). We showed identity of data obtained on different amplificators, which confirms high reproducibility of the proposed method. All samples positive for V617F mutation in JAK2 gene were analyzed with computer program “GelPrо” to determine percentage ratio of tumor and normal cells.

At the second phase of our study we developed a uniform qualitative method for detection of the JAK2V617F mutation using real-time PCR. Therefore we used the same samples as for the standard PCR analysis. Preliminary data of qPCR analysis were in full agreement with those of standard PCR (not shown). Further refinement may be carried out in order to develop a simple quantitative method to assess minimal residual disease after standard treatment and transplantation.

In conclusion the proposed PCR method for the detection of the JAK2 mutation seems to be suitable for the initial evaluation of patients with myeloproliferative disorders.

References

1. Steensma DP. JAK2 V617F in Myeloid Disorders: Molecular Diagnostic Techniques and Their Clinical Utility. JMD. 2006;8(4):397-410.

2. Tefferi А, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2008;22:14-22.

3. Yamaoka K, Saharinen P, Pesu M, Holt VE 3rd, Silvennoinen O, O’Shea JJ. The Janus kinases (Jaks). Genome Biology. 2004;5:253.

4. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951;6:372-375.

5. Wilson-Rawls J, Xie S, Liu J, Laneuville P, Arlinghaus RB. P210 Bcr-Abl interacts with the interleukin 3 receptor beta(c) subunit and constitutively induces its tyrosine phosphorylation. Cancer Res. 1996;56:3426-3430.

6. Spivak JL, Barosi G, Tognoni G, Barbui T, Finazzi G, Marchioli R, Marchetti M. Chronic myeloproliferative disorders. Hematology: American Society of Hematology Education Program Book. 2003:200-224.

7. McLornan D, Percy M, McMullin MF. JAK2 V617F: A Single Mutation in the Myeloproliferative Group of Disorders. Ulster Med J. 2006;75(2):112-119.

8. Tefferi А. Classification, Diagnosis and Management of Myeloproliferative Disorders in the JAK2V617F Era. Hematology. 2006;240-245.

9. Wolanskyj AP, Lasho TL, Schwager SM, McClure RF, Wadleigh M, Lee SJ, et al. JAK2V617F mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance. Br J Haematol. 2005;131(2):208-13.

10. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247:824-830.

11. Fiedler W, Henke RP, Ergün S, Schumacher U, Gehling UM, Vohwinkel G, Kilic N, Hossfeld DK. Derivation of a new hematopoietic cell line with endothelial features from a patient with transformed myeloproliferative syndrome: a case report. Cancer. 2000 Jan 15;88(2):344-51.

12. Lippert E, Girodon F, Hammond E, et al. Concordance of assays designed for the quantification of JAK2V617F: a multicenter study. Haematologica. 2008 Nov 10. Epub ahead of print.

13. Levine RL, Wernig G. Role of JAK-STAT Signaling in the Pathogenesis of Myeloproliferative Disorders. Hematology. 2006:233-239.

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Их диагностика сложна и часто основывается на критериях исключения. Одним из наиболее диагностически значимых критериев для МПЗ является наличие мутации V617F в гене JAK2. Основная цель данной статьи – описание скринингового метода детекции V617F в гене JAK2, пригодного для первичной диагностики. Геномная ДНК от 58 пациентов с неверифицированным миелопролиферативным заболеванием выделялась по стандартной технологии. Детекция наличия мутации V617F в гене JAK2 проводилась с использованием двух пар праймеров, специфичных для мутантного и дикого типов генов JAK2. Использовалась клеточная линия UKE1 (Б. Фезе, Германия). Установлено, что представляемая методика выявляет наличие мутации V617F в гене JAK2 с диагностически значимой чувствительностью и специфичностью. Частота мутации в общей группе составила 29,3%. Процент встречаемости мутации V617F в гене JAK2 в группе первичных пациентов с неверифицированным диагнозом МПЗ составил 25,7%. 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Ю., Оникийчук Я. С., Зотова И. И., Сологуб Г. Н., Зарайский М. И.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(147) "

Сабурова И. Ю., Оникийчук Я. С., Зотова И. И., Сологуб Г. Н., Зарайский М. И.

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Миелопролиферативные заболевания (МПЗ) представляют собой гетерогенную группу нарушений гемопоэза, сопровождающихся множественной гиперплазией клеток костного мозга. Их диагностика сложна и часто основывается на критериях исключения. Одним из наиболее диагностически значимых критериев для МПЗ является наличие мутации V617F в гене JAK2. Основная цель данной статьи – описание скринингового метода детекции V617F в гене JAK2, пригодного для первичной диагностики. Геномная ДНК от 58 пациентов с неверифицированным миелопролиферативным заболеванием выделялась по стандартной технологии. Детекция наличия мутации V617F в гене JAK2 проводилась с использованием двух пар праймеров, специфичных для мутантного и дикого типов генов JAK2. Использовалась клеточная линия UKE1 (Б. Фезе, Германия). Установлено, что представляемая методика выявляет наличие мутации V617F в гене JAK2 с диагностически значимой чувствительностью и специфичностью. Частота мутации в общей группе составила 29,3%. Процент встречаемости мутации V617F в гене JAK2 в группе первичных пациентов с неверифицированным диагнозом МПЗ составил 25,7%. Таким образом, разработанный нами метод определения мутации V617F в гене JAK2 может быть использован в качестве скрининговой диагностики у пациентов с неверифицированными хроническими миелопролиферативными заболеваниями.

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Irina Y. Saburova, Yana S. Onikiychuk, Irina I. Zotova, Galina N. Sologub, Mikhail I. Zarayskiy

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Saint-Petersburg Pavlov State Medical University, Russia

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Myeloproliferative disorders (MPD) are a heterogeneous group of hematopoietic diseases accompanied by multiple hyperplasia of bone marrow cells. They are rather difficult for diagnostics and often only revealed by excluding other conditions. One of the most valuable diagnostic criteria for MPD is the V617F mutation of the JAK2 gene. The main subject of this study was to develop a routine detection technique for the JAK2V617F mutation that will be useful for primary diagnostics. To do so, we developed two pairs of primers specific for mutated and wild-type JAK2. To ensure high sensitivity and specificity in JAK2V617F detection we first adjusted the novel PCR technique on the UKE1 cell line previously shown to be homozygous for the JAK2V617F mutation. Next we isolated genomic DNA from 58 MPD patients with different diagnoses using standard techniques. The overall mutation rate in this group was found to be 29.3%. The frequency of the JAK2V617F mutation in newly diagnosed patients with non-verified MPD was 25.7%. We conclude that the detection technique for the JAK2V617F mutation developed in our laboratory represents a useful tool as a diagnostic screening method in patients with myeloproliferative disorders.

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Irina Y. Saburova, Yana S. Onikiychuk, Irina I. Zotova, Galina N. Sologub, Mikhail I. Zarayskiy

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Myeloproliferative disorders (MPD) are a heterogeneous group of hematopoietic diseases accompanied by multiple hyperplasia of bone marrow cells. They are rather difficult for diagnostics and often only revealed by excluding other conditions. One of the most valuable diagnostic criteria for MPD is the V617F mutation of the JAK2 gene. The main subject of this study was to develop a routine detection technique for the JAK2V617F mutation that will be useful for primary diagnostics. To do so, we developed two pairs of primers specific for mutated and wild-type JAK2. To ensure high sensitivity and specificity in JAK2V617F detection we first adjusted the novel PCR technique on the UKE1 cell line previously shown to be homozygous for the JAK2V617F mutation. Next we isolated genomic DNA from 58 MPD patients with different diagnoses using standard techniques. The overall mutation rate in this group was found to be 29.3%. The frequency of the JAK2V617F mutation in newly diagnosed patients with non-verified MPD was 25.7%. We conclude that the detection technique for the JAK2V617F mutation developed in our laboratory represents a useful tool as a diagnostic screening method in patients with myeloproliferative disorders.

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Myeloproliferative disorders (MPD) are a heterogeneous group of hematopoietic diseases accompanied by multiple hyperplasia of bone marrow cells. They are rather difficult for diagnostics and often only revealed by excluding other conditions. One of the most valuable diagnostic criteria for MPD is the V617F mutation of the JAK2 gene. The main subject of this study was to develop a routine detection technique for the JAK2V617F mutation that will be useful for primary diagnostics. To do so, we developed two pairs of primers specific for mutated and wild-type JAK2. To ensure high sensitivity and specificity in JAK2V617F detection we first adjusted the novel PCR technique on the UKE1 cell line previously shown to be homozygous for the JAK2V617F mutation. Next we isolated genomic DNA from 58 MPD patients with different diagnoses using standard techniques. The overall mutation rate in this group was found to be 29.3%. The frequency of the JAK2V617F mutation in newly diagnosed patients with non-verified MPD was 25.7%. We conclude that the detection technique for the JAK2V617F mutation developed in our laboratory represents a useful tool as a diagnostic screening method in patients with myeloproliferative disorders.

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Saint-Petersburg Pavlov State Medical University, Russia

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Сабурова И. Ю., Оникийчук Я. С., Зотова И. И., Сологуб Г. Н., Зарайский М. И.

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Сабурова И. Ю., Оникийчук Я. С., Зотова И. И., Сологуб Г. Н., Зарайский М. И.

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Их диагностика сложна и часто основывается на критериях исключения. Одним из наиболее диагностически значимых критериев для МПЗ является наличие мутации V617F в гене JAK2. Основная цель данной статьи – описание скринингового метода детекции V617F в гене JAK2, пригодного для первичной диагностики. Геномная ДНК от 58 пациентов с неверифицированным миелопролиферативным заболеванием выделялась по стандартной технологии. Детекция наличия мутации V617F в гене JAK2 проводилась с использованием двух пар праймеров, специфичных для мутантного и дикого типов генов JAK2. Использовалась клеточная линия UKE1 (Б. Фезе, Германия). Установлено, что представляемая методика выявляет наличие мутации V617F в гене JAK2 с диагностически значимой чувствительностью и специфичностью. Частота мутации в общей группе составила 29,3%. Процент встречаемости мутации V617F в гене JAK2 в группе первичных пациентов с неверифицированным диагнозом МПЗ составил 25,7%. Таким образом, разработанный нами метод определения мутации V617F в гене JAK2 может быть использован в качестве скрининговой диагностики у пациентов с неверифицированными хроническими миелопролиферативными заболеваниями.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2429) "

Миелопролиферативные заболевания (МПЗ) представляют собой гетерогенную группу нарушений гемопоэза, сопровождающихся множественной гиперплазией клеток костного мозга. Их диагностика сложна и часто основывается на критериях исключения. Одним из наиболее диагностически значимых критериев для МПЗ является наличие мутации V617F в гене JAK2. Основная цель данной статьи – описание скринингового метода детекции V617F в гене JAK2, пригодного для первичной диагностики. Геномная ДНК от 58 пациентов с неверифицированным миелопролиферативным заболеванием выделялась по стандартной технологии. Детекция наличия мутации V617F в гене JAK2 проводилась с использованием двух пар праймеров, специфичных для мутантного и дикого типов генов JAK2. Использовалась клеточная линия UKE1 (Б. Фезе, Германия). Установлено, что представляемая методика выявляет наличие мутации V617F в гене JAK2 с диагностически значимой чувствительностью и специфичностью. Частота мутации в общей группе составила 29,3%. Процент встречаемости мутации V617F в гене JAK2 в группе первичных пациентов с неверифицированным диагнозом МПЗ составил 25,7%. Таким образом, разработанный нами метод определения мутации V617F в гене JAK2 может быть использован в качестве скрининговой диагностики у пациентов с неверифицированными хроническими миелопролиферативными заболеваниями.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2429) "

Миелопролиферативные заболевания (МПЗ) представляют собой гетерогенную группу нарушений гемопоэза, сопровождающихся множественной гиперплазией клеток костного мозга. Их диагностика сложна и часто основывается на критериях исключения. Одним из наиболее диагностически значимых критериев для МПЗ является наличие мутации V617F в гене JAK2. Основная цель данной статьи – описание скринингового метода детекции V617F в гене JAK2, пригодного для первичной диагностики. Геномная ДНК от 58 пациентов с неверифицированным миелопролиферативным заболеванием выделялась по стандартной технологии. Детекция наличия мутации V617F в гене JAK2 проводилась с использованием двух пар праймеров, специфичных для мутантного и дикого типов генов JAK2. Использовалась клеточная линия UKE1 (Б. Фезе, Германия). Установлено, что представляемая методика выявляет наличие мутации V617F в гене JAK2 с диагностически значимой чувствительностью и специфичностью. Частота мутации в общей группе составила 29,3%. Процент встречаемости мутации V617F в гене JAK2 в группе первичных пациентов с неверифицированным диагнозом МПЗ составил 25,7%. Таким образом, разработанный нами метод определения мутации V617F в гене JAK2 может быть использован в качестве скрининговой диагностики у пациентов с неверифицированными хроническими миелопролиферативными заболеваниями.

" } } } [12]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(2) "35" ["~IBLOCK_SECTION_ID"]=> string(2) "35" ["ID"]=> string(3) "890" ["~ID"]=> string(3) "890" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(142) "Генерация регуляторных Т-клеток посредством переноса Т-клеточных рецепторов" ["~NAME"]=> string(142) "Генерация регуляторных Т-клеток посредством переноса Т-клеточных рецепторов" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "15.06.2017 14:32:16" ["~TIMESTAMP_X"]=> string(19) "15.06.2017 14:32:16" ["DETAIL_PAGE_URL"]=> string(119) "/ru/archive/Volume-1/obzornye-stati/generatsiya-regulyatornykh-t-kletok-posredstvom-perenosa-t-kletochnykh-retseptorov/" ["~DETAIL_PAGE_URL"]=> string(119) "/ru/archive/Volume-1/obzornye-stati/generatsiya-regulyatornykh-t-kletok-posredstvom-perenosa-t-kletochnykh-retseptorov/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(27414) "

Introduction

Tregs play a crucial role in maintaining immune tolerance during normal homeostasis as well as controlling and resolving active immune responses [1]. Several different groups of regulatory T cells have been identified, which play varying roles in the maintenance of physiological immune tolerance [2]. The most intensely studied of these are the FoxP3+ Tregs, which will be the focus of the remainder of this review. Until recently it was thought that FoxP3+ Tregs were generated exclusively in the thymus, hence their common description as natural Tregs. However, it has now been demonstrated that a proportion of FoxP3+ Tregs are generated in the periphery from conventional CD4+ T cells, termed adaptive Tregs [3]. FoxP3+ Tregs exert regulation via a number of different mechanisms, which at present remain poorly defined. The known mediators of these mechanisms can broadly be split into the contact-dependent mechanisms, including membrane-bound TGFβ [4], CTLA-4 [5, 6] and intra-cellular/peri-cellular adenosine compound generation [7, 8]; and the contact-independent cytokine mediated mechanisms, which include the effects of IL-10 [9] and TGFβ [10].

TCR gene transfer into Tregs

Like conventional T cells, Tregs require stimulation via TCR interaction with a cognate peptide: MHC complex in order to exert suppression [11]; therefore they would be malleable to specificity re-direction by TCR gene transfer. Tregs are capable of potently suppressing T cell responses at naïve, effector and memory stages. In addition they have also been demonstrated to act on various other immune cells, including B cells [12], DCs [5], and monocytes [13]. Many aspects of Treg-mediated suppression make them ideal candidates for Ag targeted therapy of immuno-pathology. Firstly, although Tregs require Ag specific stimulation via the TCR, they suppress in an Ag non-specific manner [11]. This phenomenon, termed linked suppression, means that a Treg of one specificity can suppress a conventional T cell of an unrelated specificity provided the cognate Ag for both is expressed on the same antigen-presenting cell (APC). Utilizing this phenomenon of linked suppression along with an intelligent Ag targeting, it would be possible to direct suppression toward the organ or tissue which is affected regardless of whether the causative epitope, or indeed any of the epitopes additionally involved by antigenic spreading, have been identified. Secondly, Treg-mediated tolerance against one peptide specificity can be transferred to other related specificities [14]. This process, referred to as infectious tolerance, is mediated by modulation of dendritic cells (DC) and de novo induction of adaptive Tregs, and would allow for the generation of long lasting multi-epitope mediated tolerance regardless of the limits of the Ag specificity and persistence of the transferred Tregs. Thirdly, Tregs are an endogenous immune control mechanism, present in all healthy individuals. It is clear that all normal inflammatory protective immune responses are elicited in the presence of Tregs, indicating that re-establishing tolerance via Treg adoptive transfer would not preclude future protective immune responses. This is supported by skin graft models, in which Treg-induced tolerance to allo-grafted skin on the flank was not affected by the rejection of a distinct skin allograft on the contra-lateral flank [15]. If these properties of Tregs could be effectively harnessed they could provide the therapeutic panacea for clinical immune pathology, namely a long lasting Ag-specific control without the complications of a general immune suppression.

2008-2-en-Wright-et-al-Figure-1_01.jpg

Figure 1. Linked suppression and infectious tolerance. Two important concepts of Treg function are linked suppression and infectious tolerance. Linked suppression allows that a Treg of specificity A can suppress a conventional T cell of specificity B provided the cognate antigen for both is expressed on the same antigen presenting cell. This suppression can occur either via the intermediary of the antigen-presenting cell or directly by soluble mediators or Treg to T cell interaction. Infectious tolerance is the process whereby the tolerogenic state of the Treg is transferred to a previously non-tolerogenic T cell. Again, this phenomenon can occur indirectly, via the generation of a tolerogenic DC or directly via interactions between the Treg and conventional T cell.

Tregs in autoimmunity

There are numerous examples of the use of Tregs to prevent murine models of autoimmunity. However, to the best of our knowledge there are only three examples of reversion of ongoing autoimmunity using Tregs. Intriguingly, two of those studies were carried out using Ag specific Tregs [16, 17]. The third was carried out in a model where the Treg niche was empty before adoptive transfer of the Tregs [18]. It is postulated that the reconstitution of this niche may have created a situation whereby Ag-specific expansion of the Tregs was favored – hence providing the level of Ag specificity required to reverse the ongoing disease. It is compelling that in the former study non-obese diabetic mice were reverted from ongoing autoimmunity using a Treg population specific for a single pancreatic Ag [17]. In this elegant study the authors demonstrated that a transgenic monoclonal Treg population was capable of reverting disease by controlling a multiple epitope T cell responses against peptides derived from an entire organ. This work is a clear indication that Ag specificity is required to revert ongoing autoimmunity, and that Tregs specific to a single disease-related Ag may be sufficient to control a complex and advanced immune response. The importance of Ag specificity in autoimmunity, therefore, is of clear importance: autoimmunity is rarely a predictable disease and typically presents after the establishment of a strong immune response and considerable damage.

Tregs in transplantation

Hematopoietic stem cell transplantation is an effective treatment for a number of hematological diseases, but is accompanied by the potential for development of graft versus host disease (GvHD). Several murine studies have demonstrated the efficacy of adoptive Treg transfer in curing GvHD. In addition to this, whilst the adoptive transfer of Tregs in murine models could prevent GvHD, they did not impact on the advantageous graft versus leukemia (GvL) response. The need for Ag-specific targeting in the prevention of GvHD is less clear than is seen in an autoimmune setting. This is probably due to two factors. Firstly, the Tregs are being adoptively transferred into irradiated and hence lymphopenic hosts, and the subsequent expansion of the Tregs to fill their niche may allow for the preferential expansion of allo-Ag specific Tregs. Secondly, and directly related to the first point, there is likely to be a larger proportion of allo-Ag specific Tregs than auto-Ag specific Tregs in the autoimmune situation. Interestingly in GvHD, Ag-specific Tregs offer only marginal improvement in protection upon adoptive transfer when compared with polyclonal Tregs [19, 20]. These promising pre-clinical studies using polyclonal Tregs have encouraged two separate groups to begin early clinical trials in adoptive Treg transfer in the treatment of human GvHD. However, the potential efficacy of polyclonal Tregs in the treatment of GvHD does not negate the need to examine the potential of Ag-targeted Tregs to treat this disease. Indeed, it should be noted that in all three of the murine studies quoted here, very high number of Tregs were transferred to induce tolerance (around 1:1 Treg:conventional T cell). It is likely that if these Tregs were Ag-specific the number could be reduced substantially. In addition, work is ongoing to identify the distinguishing factors between the development of GvHD and GvL; any advancement in our understanding of this difference will likely allow for targeted Treg therapy to prevent GvHD without impacting on GvL.

There is a clear correlation in the clinical setting between solid organ transplant tolerance and Treg levels. In contrast to autoimmune and GvHD settings, prevention of solid organ rejection by polyclonal Treg transfer in murine models has not been demonstrated. However, numerous studies have demonstrated that the transfer of Tregs from previously tolerized mice is sufficient to prevent rejection of solid organs [21]. More recently, it has been additionally demonstrated that Tregs expanded in vitro against allo-antigen are capable of mediating prevention of rejection [15, 22]. These latter studies also highlighted the importance of Tregs directed against indirect allo-Ag in preventing chronic rejection. Both strategies demonstrate the need for Ag specificity targeted against the most appropriate Ag to induce Treg-mediated tolerance.

FoxP3+ Tregs: Potential for antigen specific therapy

It is clear that Ag specificity will be an important factor in successfully translating the promising pre-clinical data into a clinical setting. There are many obstacles to generating Ag-specific Tregs, mainly related to the physiological nature of Tregs as a small population of poorly responsive (in vitro) T cells. Whilst in vitro protocols to expand Ag specific Tregs have advanced in recent years [23] they still represent at present a labor intensive, expensive, and flawed process. Identification of a functional Treg population is at present an imperfect process. Whilst the transcription FoxP3 is generally considered as the only reliable Treg marker, as an intracellular protein it is of no use in identifying functional Tregs. For this reason Tregs are generally identified by a constellation of surface markers, mainly CD4 and CD25. However, CD4+CD25+ population also includes a contaminating fraction of activated conventional T cells. Expansion of this bulk population—whether Ag-specific or polyclonal—leads to an outgrowth of this contaminating conventional T cells population [24]. The more expansion required, the more outgrowth of these cells is seen. The numerous rounds of stimulation required to achieve a sufficient numbers of Ag-specific Tregs for effective treatment in a human setting, if at all possible, would undoubtedly lead to substantial outgrowth of this contaminating population. This contamination population of conventional T cells could potentially be a risk in exacerbating disease. Numerous surface markers have been added to CD4+CD25+ in identifying Tregs (GITR, CD127, CD39, FR4, HLA-DR CD45RA) [25-29] and although many of them allow for higher purity Treg sorting, each additional parameter leads to a decrease in the proportion of Tregs obtained. This is a practical problem when dealing with a population of cells already limited by their paucity.

We are currently examining TCR gene transfer into bead-sorted CD4+CD25+ Tregs. We have been consistently able to express a TCR of known specificity in 60-90% of polyclonally activated Tregs after a single round of activation and transduction. These Tregs demonstrate in vitro Ag-dependent linked suppression of a naïve TCR transgenic CD8+ T cells up-to 30 fold greater than that seen in absence of Ag. With appropriate modifications, including exploration of alternative Treg sorting strategies and optimizing (i.e., reducing) proliferation and transduction protocols, this approach could be used to generate large populations of Ag-specific highly pure Tregs. Other advantages of this approach include the ability to select TCR from outside the normal Treg TCR repertoire. It may be possible to use higher affinity TCR generated in the conventional T cell repertoire or indeed generate high affinity TCR using the allo-restricted strategy [30]. However, it is also important to acknowledge that safety issues must be addressed before the routine use of TCR gene transfer into Tregs. Briefly, those risks primarily involve the danger of development of malignancy caused by insertional mutagenesis and the potential for the creation of unknown specificity TCR from mis-pairing of the endogenous and introduced TCR. The risk of insertional mutagenesis is greatly decreased in mature T cells compared to hematopoietic stem cells, but it remains an important consideration before proceeding with any form of stable gene insertion. The second issue is the generation of novel specificity TCR through mis-pairing of the introduced TCR alpha or beta chains with the corresponding alpha and beta chains endogenously expressed in each T cell. These novel TCR have not been thymically educated and may potentially be strongly self-reactive. It is unclear what the effect of any self-reactive TCR generated through mis-pairing might have in Tregs. It is possible that TCR mis-pairing may be less of an issue in Tregs which are proposed to have a bias in TCR selection towards self specific Ag:MHC complexes. However, it cannot be ruled out that Tregs with a TCR affinity greater than that normally selected during Treg TCR selection may mediate inappropriate suppression. There is considerable effort being employed in addressing these issues in conventional T cells and any advance in TCR gene therapy in that setting will almost certainly be applicable Tregs (see King et al. in this issue for more in-depth review of these issues).

Genetically induced Treg-like T cells

As well as the use of naturally occurring Tregs to treat immune-pathology, there have also been a number of studies using genetically modified “Treg-like” cells. It is well documented that ectopic expression of the regulatory transcription factor FoxP3 induces Treg-like function in conventional murine T cells [31]. Similar to the study described earlier in NOD mice, two studies demonstrated the transduction of FoxP3 into pancreatic islet specific transgenic CD4+ and CD8+ T cells was capable of ameliorating diabetes in NOD mice [32, 33]. FoxP3 expression in polyclonal T cells had no affect in these models. Similar findings have been demonstrated in GvHD settings [34] and solid organ transplantation [35]. Transfer of this concept into a human setting is hindered by subtle differences in the expression and function of FoxP3 in human T cells. Human conventional T cells have been shown to transiently up-regulate FoxP3 subsequent to activation, without the acquisition of any regulatory function. In addition, the ectopic expression of FoxP3 does not consistently instill the same level of regulatory function in human T cells [36]. However, a recent study has demonstrated that lenti-viral mediated expression of FoxP3 in human T cells under a constitutive (i.e., activation state independent) promoter produces consistently efficient regulatory like phenotype [37].

We are currently examining the potential of co-transfer of TCR genes along with the FoxP3 transcription factor using a single tri-cistronic vector to generate functionally suppressive T cells. Subsequent to transduction these cells show limited proliferation and little or no IFNγ and IL-2 secretion. Whilst in our hands the level of Ag-dependent suppression elicited by these T cells is less marked than TCR expressing CD4+CD25+ Tregs, it has proven a reliable method of generating large numbers of homogenous TCR expressing Treg-like T cells. It should also be noted that although the in vitro linked suppression assay is a useful indicator of suppressive ability it is not always completely predictive of the level of suppression in vivo. It will be interesting to compare these two types of regulatory T cells in vivo.

2008-2-en-Wright-et-al-Figure-2_01.jpg

Figure 2. Generating antigen specific Tregs using TCR gene transfer; two approaches. Using lenti or retro viral gene transfer it is possible to generate antigen-specific suppressive T cells. Two strategies have been utilized to achieve this: (A) Gene transfer of TCR alpha and beta chains of a TCR of known specificity into a poly-clonally activated population of sorted Tregs, and (B) Co-transfer of the genes encoding TCR alpha/beta chains and the regulatory transcription factor FoxP3 into a poly-clonally activated population of conventional CD4+ T cells.

Conclusion

There is now a substantial body of evidence in pre-clinical models for the efficacy of Tregs in the treatment of immuno-pathology. However, as yet there are only two ongoing human clinical trials, both in a GvHD setting. Many unanswered questions and obstacles stand in the way of utilizing Tregs to their maximal effect. Not least amongst these is the question of how to generate sufficiently large populations of Ag-specific regulatory T cells. Here we have highlighted the importance of Ag specificity and proposed that TCR gene transfer into polyclonally expanded Tregs as well as artificially generating FoxP3+ TCR expressing T cells may provide an efficient way of generating large populations of Ag specific Tregs. Studies are ongoing as to the efficacy of each of these approaches in models of auto-immunity and GvHD, and from initial indications we expect these methods to show considerable efficacy in the treatment of immune mediated pathology.

Acknowledgements

The authors would like to thank Mario Perro for his constructive discussions.

References

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16. Tarbell KV, Petit L, Zuo X, Toy P, Luo X, Mqadmi A, Yang H, Suthanthiran M, Mojsov S, and Steinman RM. Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med. 2007;204:191-201.

17. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, and Bluestone JA. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004;199:1455-1465.

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Introduction

Tregs play a crucial role in maintaining immune tolerance during normal homeostasis as well as controlling and resolving active immune responses [1]. Several different groups of regulatory T cells have been identified, which play varying roles in the maintenance of physiological immune tolerance [2]. The most intensely studied of these are the FoxP3+ Tregs, which will be the focus of the remainder of this review. Until recently it was thought that FoxP3+ Tregs were generated exclusively in the thymus, hence their common description as natural Tregs. However, it has now been demonstrated that a proportion of FoxP3+ Tregs are generated in the periphery from conventional CD4+ T cells, termed adaptive Tregs [3]. FoxP3+ Tregs exert regulation via a number of different mechanisms, which at present remain poorly defined. The known mediators of these mechanisms can broadly be split into the contact-dependent mechanisms, including membrane-bound TGFβ [4], CTLA-4 [5, 6] and intra-cellular/peri-cellular adenosine compound generation [7, 8]; and the contact-independent cytokine mediated mechanisms, which include the effects of IL-10 [9] and TGFβ [10].

TCR gene transfer into Tregs

Like conventional T cells, Tregs require stimulation via TCR interaction with a cognate peptide: MHC complex in order to exert suppression [11]; therefore they would be malleable to specificity re-direction by TCR gene transfer. Tregs are capable of potently suppressing T cell responses at naïve, effector and memory stages. In addition they have also been demonstrated to act on various other immune cells, including B cells [12], DCs [5], and monocytes [13]. Many aspects of Treg-mediated suppression make them ideal candidates for Ag targeted therapy of immuno-pathology. Firstly, although Tregs require Ag specific stimulation via the TCR, they suppress in an Ag non-specific manner [11]. This phenomenon, termed linked suppression, means that a Treg of one specificity can suppress a conventional T cell of an unrelated specificity provided the cognate Ag for both is expressed on the same antigen-presenting cell (APC). Utilizing this phenomenon of linked suppression along with an intelligent Ag targeting, it would be possible to direct suppression toward the organ or tissue which is affected regardless of whether the causative epitope, or indeed any of the epitopes additionally involved by antigenic spreading, have been identified. Secondly, Treg-mediated tolerance against one peptide specificity can be transferred to other related specificities [14]. This process, referred to as infectious tolerance, is mediated by modulation of dendritic cells (DC) and de novo induction of adaptive Tregs, and would allow for the generation of long lasting multi-epitope mediated tolerance regardless of the limits of the Ag specificity and persistence of the transferred Tregs. Thirdly, Tregs are an endogenous immune control mechanism, present in all healthy individuals. It is clear that all normal inflammatory protective immune responses are elicited in the presence of Tregs, indicating that re-establishing tolerance via Treg adoptive transfer would not preclude future protective immune responses. This is supported by skin graft models, in which Treg-induced tolerance to allo-grafted skin on the flank was not affected by the rejection of a distinct skin allograft on the contra-lateral flank [15]. If these properties of Tregs could be effectively harnessed they could provide the therapeutic panacea for clinical immune pathology, namely a long lasting Ag-specific control without the complications of a general immune suppression.

2008-2-en-Wright-et-al-Figure-1_01.jpg

Figure 1. Linked suppression and infectious tolerance. Two important concepts of Treg function are linked suppression and infectious tolerance. Linked suppression allows that a Treg of specificity A can suppress a conventional T cell of specificity B provided the cognate antigen for both is expressed on the same antigen presenting cell. This suppression can occur either via the intermediary of the antigen-presenting cell or directly by soluble mediators or Treg to T cell interaction. Infectious tolerance is the process whereby the tolerogenic state of the Treg is transferred to a previously non-tolerogenic T cell. Again, this phenomenon can occur indirectly, via the generation of a tolerogenic DC or directly via interactions between the Treg and conventional T cell.

Tregs in autoimmunity

There are numerous examples of the use of Tregs to prevent murine models of autoimmunity. However, to the best of our knowledge there are only three examples of reversion of ongoing autoimmunity using Tregs. Intriguingly, two of those studies were carried out using Ag specific Tregs [16, 17]. The third was carried out in a model where the Treg niche was empty before adoptive transfer of the Tregs [18]. It is postulated that the reconstitution of this niche may have created a situation whereby Ag-specific expansion of the Tregs was favored – hence providing the level of Ag specificity required to reverse the ongoing disease. It is compelling that in the former study non-obese diabetic mice were reverted from ongoing autoimmunity using a Treg population specific for a single pancreatic Ag [17]. In this elegant study the authors demonstrated that a transgenic monoclonal Treg population was capable of reverting disease by controlling a multiple epitope T cell responses against peptides derived from an entire organ. This work is a clear indication that Ag specificity is required to revert ongoing autoimmunity, and that Tregs specific to a single disease-related Ag may be sufficient to control a complex and advanced immune response. The importance of Ag specificity in autoimmunity, therefore, is of clear importance: autoimmunity is rarely a predictable disease and typically presents after the establishment of a strong immune response and considerable damage.

Tregs in transplantation

Hematopoietic stem cell transplantation is an effective treatment for a number of hematological diseases, but is accompanied by the potential for development of graft versus host disease (GvHD). Several murine studies have demonstrated the efficacy of adoptive Treg transfer in curing GvHD. In addition to this, whilst the adoptive transfer of Tregs in murine models could prevent GvHD, they did not impact on the advantageous graft versus leukemia (GvL) response. The need for Ag-specific targeting in the prevention of GvHD is less clear than is seen in an autoimmune setting. This is probably due to two factors. Firstly, the Tregs are being adoptively transferred into irradiated and hence lymphopenic hosts, and the subsequent expansion of the Tregs to fill their niche may allow for the preferential expansion of allo-Ag specific Tregs. Secondly, and directly related to the first point, there is likely to be a larger proportion of allo-Ag specific Tregs than auto-Ag specific Tregs in the autoimmune situation. Interestingly in GvHD, Ag-specific Tregs offer only marginal improvement in protection upon adoptive transfer when compared with polyclonal Tregs [19, 20]. These promising pre-clinical studies using polyclonal Tregs have encouraged two separate groups to begin early clinical trials in adoptive Treg transfer in the treatment of human GvHD. However, the potential efficacy of polyclonal Tregs in the treatment of GvHD does not negate the need to examine the potential of Ag-targeted Tregs to treat this disease. Indeed, it should be noted that in all three of the murine studies quoted here, very high number of Tregs were transferred to induce tolerance (around 1:1 Treg:conventional T cell). It is likely that if these Tregs were Ag-specific the number could be reduced substantially. In addition, work is ongoing to identify the distinguishing factors between the development of GvHD and GvL; any advancement in our understanding of this difference will likely allow for targeted Treg therapy to prevent GvHD without impacting on GvL.

There is a clear correlation in the clinical setting between solid organ transplant tolerance and Treg levels. In contrast to autoimmune and GvHD settings, prevention of solid organ rejection by polyclonal Treg transfer in murine models has not been demonstrated. However, numerous studies have demonstrated that the transfer of Tregs from previously tolerized mice is sufficient to prevent rejection of solid organs [21]. More recently, it has been additionally demonstrated that Tregs expanded in vitro against allo-antigen are capable of mediating prevention of rejection [15, 22]. These latter studies also highlighted the importance of Tregs directed against indirect allo-Ag in preventing chronic rejection. Both strategies demonstrate the need for Ag specificity targeted against the most appropriate Ag to induce Treg-mediated tolerance.

FoxP3+ Tregs: Potential for antigen specific therapy

It is clear that Ag specificity will be an important factor in successfully translating the promising pre-clinical data into a clinical setting. There are many obstacles to generating Ag-specific Tregs, mainly related to the physiological nature of Tregs as a small population of poorly responsive (in vitro) T cells. Whilst in vitro protocols to expand Ag specific Tregs have advanced in recent years [23] they still represent at present a labor intensive, expensive, and flawed process. Identification of a functional Treg population is at present an imperfect process. Whilst the transcription FoxP3 is generally considered as the only reliable Treg marker, as an intracellular protein it is of no use in identifying functional Tregs. For this reason Tregs are generally identified by a constellation of surface markers, mainly CD4 and CD25. However, CD4+CD25+ population also includes a contaminating fraction of activated conventional T cells. Expansion of this bulk population—whether Ag-specific or polyclonal—leads to an outgrowth of this contaminating conventional T cells population [24]. The more expansion required, the more outgrowth of these cells is seen. The numerous rounds of stimulation required to achieve a sufficient numbers of Ag-specific Tregs for effective treatment in a human setting, if at all possible, would undoubtedly lead to substantial outgrowth of this contaminating population. This contamination population of conventional T cells could potentially be a risk in exacerbating disease. Numerous surface markers have been added to CD4+CD25+ in identifying Tregs (GITR, CD127, CD39, FR4, HLA-DR CD45RA) [25-29] and although many of them allow for higher purity Treg sorting, each additional parameter leads to a decrease in the proportion of Tregs obtained. This is a practical problem when dealing with a population of cells already limited by their paucity.

We are currently examining TCR gene transfer into bead-sorted CD4+CD25+ Tregs. We have been consistently able to express a TCR of known specificity in 60-90% of polyclonally activated Tregs after a single round of activation and transduction. These Tregs demonstrate in vitro Ag-dependent linked suppression of a naïve TCR transgenic CD8+ T cells up-to 30 fold greater than that seen in absence of Ag. With appropriate modifications, including exploration of alternative Treg sorting strategies and optimizing (i.e., reducing) proliferation and transduction protocols, this approach could be used to generate large populations of Ag-specific highly pure Tregs. Other advantages of this approach include the ability to select TCR from outside the normal Treg TCR repertoire. It may be possible to use higher affinity TCR generated in the conventional T cell repertoire or indeed generate high affinity TCR using the allo-restricted strategy [30]. However, it is also important to acknowledge that safety issues must be addressed before the routine use of TCR gene transfer into Tregs. Briefly, those risks primarily involve the danger of development of malignancy caused by insertional mutagenesis and the potential for the creation of unknown specificity TCR from mis-pairing of the endogenous and introduced TCR. The risk of insertional mutagenesis is greatly decreased in mature T cells compared to hematopoietic stem cells, but it remains an important consideration before proceeding with any form of stable gene insertion. The second issue is the generation of novel specificity TCR through mis-pairing of the introduced TCR alpha or beta chains with the corresponding alpha and beta chains endogenously expressed in each T cell. These novel TCR have not been thymically educated and may potentially be strongly self-reactive. It is unclear what the effect of any self-reactive TCR generated through mis-pairing might have in Tregs. It is possible that TCR mis-pairing may be less of an issue in Tregs which are proposed to have a bias in TCR selection towards self specific Ag:MHC complexes. However, it cannot be ruled out that Tregs with a TCR affinity greater than that normally selected during Treg TCR selection may mediate inappropriate suppression. There is considerable effort being employed in addressing these issues in conventional T cells and any advance in TCR gene therapy in that setting will almost certainly be applicable Tregs (see King et al. in this issue for more in-depth review of these issues).

Genetically induced Treg-like T cells

As well as the use of naturally occurring Tregs to treat immune-pathology, there have also been a number of studies using genetically modified “Treg-like” cells. It is well documented that ectopic expression of the regulatory transcription factor FoxP3 induces Treg-like function in conventional murine T cells [31]. Similar to the study described earlier in NOD mice, two studies demonstrated the transduction of FoxP3 into pancreatic islet specific transgenic CD4+ and CD8+ T cells was capable of ameliorating diabetes in NOD mice [32, 33]. FoxP3 expression in polyclonal T cells had no affect in these models. Similar findings have been demonstrated in GvHD settings [34] and solid organ transplantation [35]. Transfer of this concept into a human setting is hindered by subtle differences in the expression and function of FoxP3 in human T cells. Human conventional T cells have been shown to transiently up-regulate FoxP3 subsequent to activation, without the acquisition of any regulatory function. In addition, the ectopic expression of FoxP3 does not consistently instill the same level of regulatory function in human T cells [36]. However, a recent study has demonstrated that lenti-viral mediated expression of FoxP3 in human T cells under a constitutive (i.e., activation state independent) promoter produces consistently efficient regulatory like phenotype [37].

We are currently examining the potential of co-transfer of TCR genes along with the FoxP3 transcription factor using a single tri-cistronic vector to generate functionally suppressive T cells. Subsequent to transduction these cells show limited proliferation and little or no IFNγ and IL-2 secretion. Whilst in our hands the level of Ag-dependent suppression elicited by these T cells is less marked than TCR expressing CD4+CD25+ Tregs, it has proven a reliable method of generating large numbers of homogenous TCR expressing Treg-like T cells. It should also be noted that although the in vitro linked suppression assay is a useful indicator of suppressive ability it is not always completely predictive of the level of suppression in vivo. It will be interesting to compare these two types of regulatory T cells in vivo.

2008-2-en-Wright-et-al-Figure-2_01.jpg

Figure 2. Generating antigen specific Tregs using TCR gene transfer; two approaches. Using lenti or retro viral gene transfer it is possible to generate antigen-specific suppressive T cells. Two strategies have been utilized to achieve this: (A) Gene transfer of TCR alpha and beta chains of a TCR of known specificity into a poly-clonally activated population of sorted Tregs, and (B) Co-transfer of the genes encoding TCR alpha/beta chains and the regulatory transcription factor FoxP3 into a poly-clonally activated population of conventional CD4+ T cells.

Conclusion

There is now a substantial body of evidence in pre-clinical models for the efficacy of Tregs in the treatment of immuno-pathology. However, as yet there are only two ongoing human clinical trials, both in a GvHD setting. Many unanswered questions and obstacles stand in the way of utilizing Tregs to their maximal effect. Not least amongst these is the question of how to generate sufficiently large populations of Ag-specific regulatory T cells. Here we have highlighted the importance of Ag specificity and proposed that TCR gene transfer into polyclonally expanded Tregs as well as artificially generating FoxP3+ TCR expressing T cells may provide an efficient way of generating large populations of Ag specific Tregs. Studies are ongoing as to the efficacy of each of these approaches in models of auto-immunity and GvHD, and from initial indications we expect these methods to show considerable efficacy in the treatment of immune mediated pathology.

Acknowledgements

The authors would like to thank Mario Perro for his constructive discussions.

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Райт Г.П., Кинг Дж-Вай-Линг, Штаусс Х.Дж.

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Регуляторные Т-клетки (Трег) способны сильно подавлять
Т-клеточные реакции на стадии «наивных» клеток, эффекторной фазе и в клетках памяти. Кроме того, они также действуют на различные другие имунные клетки, включая В-клетки, дендритные клетки и моноциты. Многие аспекты Трег-опосредованной супрессии делают их идеальными кандидатами для антиген-направленного лечения иммунопатологических состояний. Наша и другие лаборатории показали, что перенос гена Т-клеточного рецептора (TCR) является эффективным способом переориентации специфичности основной популяции Т-клеток на определенный антиген. До сих пор существенные усилия вкладывались в применение переноса гена TCR в обычные CD8+ и CD4+ клетки, для того, чтобы запускать или усиливать иммунные реакции. Но до сих пор было немного исследований по потенциальному использованию генной терапииTCR на другом крае этого спектра – для контроля иммунопатологических процессов с применением Т-регуляторных клеток. Здесь мы кратко обсуждаем сведения, указывающие на то, что генерация  антиген-специфических Трег, в потенциале – через перенос гена TCR, может быть эффективным лечением различных форм иммунопатологии и кратко упоминаются трудности на пути понимания полного потенциала этого типа терапии. Проводилась адоптивная пересадка этих Т-регуляторных клеток облученным мышам, и дальнейшее размножение Трег с заполнением ниши может дать возможность для преимущественной экспансии клеток, специфичных к аллоантигенам. Имеется четкая корреляция в клинических условиях между толерантностью при трансплантации органов и уровням Трег. Здесь мы подчеркнули важность специфичности антигенов и предположили, что перенос гена TCR в размножающиеся поликлональные Т-клетки, продуцирующие FoxP3+ TCR, может обеспечить эффективный путь генерирования больших количеств антигенспецифических Трег-клеток.

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Graham P. Wright, Judy Wai-Ling King and Hans J. Stauss

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Department of Immunology, Royal Free Hospital, University College London, UK

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Our lab and others have demonstrated T cell receptor (TCR) gene transfer as an efficient way of redirecting the specificity of a bulk T cell population to that of a known antigen. Thus far there has been considerable effort put into the use of TCR gene transfer into conventional CD8+ and CD4+ T cells in order to initiate or augment immune responses. There has, as yet, been little investigation into the potential use of TCR gene therapy at the other end of the spectrum: control of immune pathology using regulatory T cells. Here we will briefly discuss the evidence indicating that the generation of Ag-specific Tregs, potentially via TCR gene transfer, may be an efficacious treatment for various forms of immune-pathology and briefly outline the challenges towards realizing the full potential of this type of therapy.

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Graham P. Wright, Judy Wai-Ling King and Hans J. Stauss

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Graham P. Wright, Judy Wai-Ling King and Hans J. Stauss

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Our lab and others have demonstrated T cell receptor (TCR) gene transfer as an efficient way of redirecting the specificity of a bulk T cell population to that of a known antigen. Thus far there has been considerable effort put into the use of TCR gene transfer into conventional CD8+ and CD4+ T cells in order to initiate or augment immune responses. There has, as yet, been little investigation into the potential use of TCR gene therapy at the other end of the spectrum: control of immune pathology using regulatory T cells. Here we will briefly discuss the evidence indicating that the generation of Ag-specific Tregs, potentially via TCR gene transfer, may be an efficacious treatment for various forms of immune-pathology and briefly outline the challenges towards realizing the full potential of this type of therapy.

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Our lab and others have demonstrated T cell receptor (TCR) gene transfer as an efficient way of redirecting the specificity of a bulk T cell population to that of a known antigen. Thus far there has been considerable effort put into the use of TCR gene transfer into conventional CD8+ and CD4+ T cells in order to initiate or augment immune responses. There has, as yet, been little investigation into the potential use of TCR gene therapy at the other end of the spectrum: control of immune pathology using regulatory T cells. Here we will briefly discuss the evidence indicating that the generation of Ag-specific Tregs, potentially via TCR gene transfer, may be an efficacious treatment for various forms of immune-pathology and briefly outline the challenges towards realizing the full potential of this type of therapy.

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Department of Immunology, Royal Free Hospital, University College London, UK

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Department of Immunology, Royal Free Hospital, University College London, UK

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Райт Г.П., Кинг Дж-Вай-Линг, Штаусс Х.Дж.

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Райт Г.П., Кинг Дж-Вай-Линг, Штаусс Х.Дж.

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Кроме того, они также действуют на различные другие имунные клетки, включая В-клетки, дендритные клетки и моноциты. Многие аспекты Трег-опосредованной супрессии делают их идеальными кандидатами для антиген-направленного лечения иммунопатологических состояний. Наша и другие лаборатории показали, что перенос гена Т-клеточного рецептора (TCR) является эффективным способом переориентации специфичности основной популяции Т-клеток на определенный антиген. До сих пор существенные усилия вкладывались в применение переноса гена TCR в обычные CD8+ и CD4+ клетки, для того, чтобы запускать или усиливать иммунные реакции. Но до сих пор было немного исследований по потенциальному использованию генной терапииTCR на другом крае этого спектра – для контроля иммунопатологических процессов с применением Т-регуляторных клеток. Здесь мы кратко обсуждаем сведения, указывающие на то, что генерация  антиген-специфических Трег, в потенциале – через перенос гена TCR, может быть эффективным лечением различных форм иммунопатологии и кратко упоминаются трудности на пути понимания полного потенциала этого типа терапии. Проводилась адоптивная пересадка этих Т-регуляторных клеток облученным мышам, и дальнейшее размножение Трег с заполнением ниши может дать возможность для преимущественной экспансии клеток, специфичных к аллоантигенам. Имеется четкая корреляция в клинических условиях между толерантностью при трансплантации органов и уровням Трег. Здесь мы подчеркнули важность специфичности антигенов и предположили, что перенос гена TCR в размножающиеся поликлональные Т-клетки, продуцирующие FoxP3+ TCR, может обеспечить эффективный путь генерирования больших количеств антигенспецифических Трег-клеток.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3408) "

Регуляторные Т-клетки (Трег) способны сильно подавлять
Т-клеточные реакции на стадии «наивных» клеток, эффекторной фазе и в клетках памяти. Кроме того, они также действуют на различные другие имунные клетки, включая В-клетки, дендритные клетки и моноциты. Многие аспекты Трег-опосредованной супрессии делают их идеальными кандидатами для антиген-направленного лечения иммунопатологических состояний. Наша и другие лаборатории показали, что перенос гена Т-клеточного рецептора (TCR) является эффективным способом переориентации специфичности основной популяции Т-клеток на определенный антиген. До сих пор существенные усилия вкладывались в применение переноса гена TCR в обычные CD8+ и CD4+ клетки, для того, чтобы запускать или усиливать иммунные реакции. Но до сих пор было немного исследований по потенциальному использованию генной терапииTCR на другом крае этого спектра – для контроля иммунопатологических процессов с применением Т-регуляторных клеток. Здесь мы кратко обсуждаем сведения, указывающие на то, что генерация  антиген-специфических Трег, в потенциале – через перенос гена TCR, может быть эффективным лечением различных форм иммунопатологии и кратко упоминаются трудности на пути понимания полного потенциала этого типа терапии. Проводилась адоптивная пересадка этих Т-регуляторных клеток облученным мышам, и дальнейшее размножение Трег с заполнением ниши может дать возможность для преимущественной экспансии клеток, специфичных к аллоантигенам. Имеется четкая корреляция в клинических условиях между толерантностью при трансплантации органов и уровням Трег. Здесь мы подчеркнули важность специфичности антигенов и предположили, что перенос гена TCR в размножающиеся поликлональные Т-клетки, продуцирующие FoxP3+ TCR, может обеспечить эффективный путь генерирования больших количеств антигенспецифических Трег-клеток.

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Регуляторные Т-клетки (Трег) способны сильно подавлять
Т-клеточные реакции на стадии «наивных» клеток, эффекторной фазе и в клетках памяти. Кроме того, они также действуют на различные другие имунные клетки, включая В-клетки, дендритные клетки и моноциты. Многие аспекты Трег-опосредованной супрессии делают их идеальными кандидатами для антиген-направленного лечения иммунопатологических состояний. Наша и другие лаборатории показали, что перенос гена Т-клеточного рецептора (TCR) является эффективным способом переориентации специфичности основной популяции Т-клеток на определенный антиген. До сих пор существенные усилия вкладывались в применение переноса гена TCR в обычные CD8+ и CD4+ клетки, для того, чтобы запускать или усиливать иммунные реакции. Но до сих пор было немного исследований по потенциальному использованию генной терапииTCR на другом крае этого спектра – для контроля иммунопатологических процессов с применением Т-регуляторных клеток. Здесь мы кратко обсуждаем сведения, указывающие на то, что генерация  антиген-специфических Трег, в потенциале – через перенос гена TCR, может быть эффективным лечением различных форм иммунопатологии и кратко упоминаются трудности на пути понимания полного потенциала этого типа терапии. Проводилась адоптивная пересадка этих Т-регуляторных клеток облученным мышам, и дальнейшее размножение Трег с заполнением ниши может дать возможность для преимущественной экспансии клеток, специфичных к аллоантигенам. Имеется четкая корреляция в клинических условиях между толерантностью при трансплантации органов и уровням Трег. Здесь мы подчеркнули важность специфичности антигенов и предположили, что перенос гена TCR в размножающиеся поликлональные Т-клетки, продуцирующие FoxP3+ TCR, может обеспечить эффективный путь генерирования больших количеств антигенспецифических Трег-клеток.

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Introduction

Adoptive T cell transfer has seen clinical success in the treatment of both malignancies and viral infections. However, one of the main limitations of this strategy has been the difficulty in producing sufficient quantities of antigen-specific T cells. In addition, donor lymphocyte infusions are commonly associated with graft-versus-host disease (GvHD), which carries with it significant morbidity and mortality. Retroviral T cell receptor (TCR) gene transfer is an attractive new strategy by which large numbers of autologous, antigen-specific T cells can be generated, since the TCR is the sole determinant of T cell specificity. The introduced TCR specificity can be targeted against viral antigens or poorly immunogenic targets such as tumor associated antigens, and recent clinical trial data has demonstrated the feasibility of this technique in melanoma patients. Furthermore, TCR gene transfer also has the potential to generate antigen-specific regulatory T cells. This review will focus on recent advances in the field of TCR gene transfer and explore the potential clinical applications of this strategy.

Adoptive T cell transfer for tumor immunotherapy

Adoptive transfer of allogeneic hematopoietic stem cells (HSC) is an established treatment for hematological malignancies. Donor T cells are responsible for mediating the graft-versus- leukemia effect, but this is associated with graft-versus-host disease in up to 50% of transplant recipients. One of the most exciting applications of TCR gene transfer is the ability to generate autologous T cells that recognize leukemia or tumor antigens (Figure 1). There are a number of tumor associated antigens (TAA) that are being evaluated as targets for the immunotherapy of malignancies. However, while they are over-expressed on tumors, they are also expressed on normal tissues, albeit at low levels. Autologous T cells which naturally recognize tumor antigens with high affinity are subject to tolerance mechanisms such as deletion or anergy. Hence, although autologous T cell responses against tumor antigens can be detected in patients with malignancies, they are generally of low avidity. Since it has been shown that the transduced T cell population demonstrates the same functional avidity as the original parent T cell from which the TCR genes are cloned, one of the advantages of TCR gene therapy is that a high avidity TCR can be selected for transfer into target T cells. There are several methods by which high avidity cytotoxic T lymphocytes (CTL) specific for TAAs can be generated. Immunization of HLA transgenic mice, the allo-restricted approach, in vitro mutagenesis of TCRs, and in vitro selection using phage display have been used to generate TCRs with increased peptide/MHC binding affinity.

Figure 1. TCR gene transfer.
(i) A T cell bearing the appropriate TCR is identified, (ii) the alpha and beta TCR chains genes are isolated and cloned into a retroviral vector, (iii) the vector is used to transfect a packaging cell line which produces viral particles containing the genes of interest: (iv). (v) Target T cells are transduced with the recombinant viral particles; (vi) when the genes integrate into the host DNA the target cells express the desired TCR.

2008-2-en-King-et-al-Figure-1.jpg


Transduced T cells have been shown to contribute to tumor clearance in murine models , and the first clinical trial of TCR gene transfer was recently reported. Retroviral gene transfer was used to transduce peripheral blood lymphocytes taken from patients with melanoma, with the genes encoding the α and β chains of a TCR with specificity for a MART 1 peptide presented by HLA-A*0201. The 17 patients in the gene transfer study were lymphodepleted prior to receiving autologous T cells transduced with the MART-1 TCR. The engineered T cells persisted in 15 patients, and the two patients with the highest levels of circulating anti-melanoma T cells showed objective regression of metastatic lesions and remained in remission 18 months after treatment. The results of this study prove that retroviral TCR gene transfer can be used to confer anti-tumor specificity upon a large number of autologous T cells, and that these T cells can engraft in patients and persist at high levels long term.

TCR gene transfer to generate anti viral T cells

A further application for TCR gene transfer is to generate virus-specific T cells for the treatment of immunosuppressed patients who have undergone HSC transplantation. After GvHD, post transplant viral infection is the next major cause of morbidity and mortality in transplant recipients. Adoptive T cell transfer has been shown to be an effective treatment for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection in transplant recipients. Donor-derived CMV specific CD8 T cells which had been expanded in vitro were then infused into HSC transplant recipients with good effect. Similarly, donor-derived EBV specific T cell lines have been used to treat EBV related post-transplant proliferative disease. However, the major limitation of this strategy is that it is not possible to generate virus-specific CTL from all HSC donors using in vitro expansion techniques. TCR gene transfer has the ability to overcome this obstacle and confer upon donor T cells TCR specificities that are not present in the endogenous donor repertoire. This technique also has the advantage of generating large numbers of virus-specific CTL far more rapidly than standard in vitro expansion approaches, which would be of clear benefit in a clinical scenario where a patient presents acutely with significant morbidity. While clinical trial data is still pending, this strategy has great potential for the treatment of viral infections in HSC recipients.

Augmenting TCR gene transfer

In recent years, several groups have explored the means by which TCR gene transfer can be optimized. Modern vector designs aim to increase exogenous TCR expression on target cells by combining α and β chains in a single vector linked by viral self cleaving 2A sequences, rather than internal ribosome entry sites. Codon optimization of TCR gene sequences has also been shown to result in increased TCR expression in human CD8+ T cells, and increased antigen-specific IFNγ release.

In parallel with these vector modifications, recent research efforts have been directed towards increasing the preferential pairing of exogenous α and β chains with each other. It has been demonstrated that exogenous TCRs are able to mispair with endogenous TCR chains (Figure 2). Any mispairing may reduce the expression density and hence the efficacy of the desired TCR, since the density of TCR expression on the cell surface has been shown to correlate with avidity. A number of strategies have recently been employed to address this issue. TCRs have been engineered to include an additional cysteine residue in the constant regions of the α and β chains, resulting in the formation of a second disulphide bond between them. T cells transduced with cysteine-modified receptors showed increased tetramer binding, secreted more cytokine, and showed increased antigen specific lysis when co-cultured with specific tumor cell lines, compared with T cells expressing wild type TCR. Hybrid TCRs have also been designed to incorporate murine constant regions and human variable regions. These hybrid TCRs show reduced mispairing with fully human TCRs when introduced into human T cells, combined with superior cell surface expression and biological activity. However, there is a possibility that a human host will mount an immune response against the murine component of such a TCR. In the same way that murine monoclonal antibodies have become increasingly humanized for clinical use, it is likely that murinization of the TCR constant region will be minimized to reduce its immunogenicity, if this strategy is to be used in a clinical setting.

2008-2-en-King-et-al-Figure-2.jpg

Figure 2: exogenous and endogenous TCR chains compete for CD3 molecules for surface expression, and can mispair to form mixed dimers of unknown specificity. TCR α and β chains must form a complex with the ζ,δ,ε and γ CD3 chains in order for the TCR to be expressed on the cell surface. Following retroviral TCR gene transfer, there is competition between the endogenous TCR (A) and the exogenous TCR (B) for CD3. Increasing the availability of CD3 chains could increase the density of expression, and hence functional avidity, of the exogenous TCR. C: mispairing of endogenous and exogenous TCR chains leads to mixed dimer formation. These TCR have the potential to be autoreactive, and also reduce the CD3 available for expression of the desired TCR (B).


Strategies such as murinization of constant domains and cysteine modification of TCR chains reduce mispairing and increase the "strength" of a TCR. Recent data has shown that "strong" TCRs are expressed at high levels following retroviral gene transfer, whereas "weak" TCRs are poorly expressed because they compete poorly against the endogenous TCR repertoire for CD3 molecules. Research is ongoing into whether there are specific amino acid sequences in the TCR constant domain that contribute towards "strength." An alternative strategy that is currently being investigated is the cotransduction of TCR along with the genes encoding the CD3 complex. Endogenous and exogenous TCR chains are in competition for a limited pool of CD3 molecules, and exogenous TCR chains are likely to be present in excess, since their production is under the control of a retroviral promoter. The expectation would be that cotransducing with both TCR and CD3 molecules would increase the availability of CD3 molecules, which would have a more profound effect on expression of the exogenous TCR whose α and β chains are present in excess. 

Safety concerns

Although there is no evidence of off-target toxicity in murine models to date, it has been demonstrated that exogenous TCR are able to mispair with endogenous TCR chains, resulting in the expression of TCRs that have not undergone thymic education. These TCR, with unpredictable specificities, have the potential to be autoreactive. The strategies described above have been employed to both reduce mispairing and to increase expression of the desired TCR. Research is ongoing into alternative means by which the risk of mispairing may be reduced. It has recently been shown that TCR α and β chains which have each been linked to a CD3ζ chain did not mispair with endogenous TCR chains in a Jurkat T cell model. Since γδ TCR chains cannot mispair with αβ TCR chains, transferring αβ TCR chains into γδ T cells should not result in any mispairing, and has previously been shown to result in the expression of exogenous αβ TCR which produce cytokine and lyse target cells in an antigen-specific manner. Transduction of viral-specific T cells is a strategy by which the potential number of mixed dimers can be reduced; since anti viral responses consist of T cells with a restricted TCR repertoire. An alternative approach would be to transduce HSC with TCR genes. In vitro generation of mature, antigen-specific T cells by TCR gene transfer into thymus or cord-derived HSC has recently been reported. Allelic exclusion of the endogenous TCR β chain meant that mixed dimer formation was reduced, but not entirely avoided due to some endogenous α chain expression. However, while the risk of transformation of mature T cells is low, the risk in HSC may be higher, making this a less appealing strategy. In a clinical trial of X linked severe combined immunodeficiency disease, 4 children treated with HSC retrovirally transduced with the common γ chain developed T lymphoproliferative disorders. This was later found to be secondary to retroviral insertion into the LMO-2 oncogene intron on chromosome 11, with subsequent upregulation. Although there is no evidence to date of transformation of mature T cells with retroviral vectors, the use of lentiviral vectors is also being investigated, since it has been shown that lentiviral vectors insert near promoters at a lower frequency.

While there is a concern that low avidity, TAA specific CTL from the autologous repertoire may not be efficacious, high avidity, self-reactive CTL may pose the opposite problem. The majority of targets for tumor immunotherapy are over-expressed self proteins, and therefore there is a risk that targeting TAA may result in autoimmune damage. In murine models and in clinical trials it has been demonstrated that the successful induction of CTL responses against melanoma TAAs (such as melan A or gp100) has been associated with the development of vitiligo. T cell therapies targeting TAAs with a more ubiquitous distribution have not been studied in the same detail as yet, although it has been shown that high avidity p53 specific CTLs (generated in p53-/- transgenic mice) can provide tumor protection without causing autoimmune damage in mice. A moderately high affinity TCR was used in the TCR gene therapy trial, and work is now ongoing by the same group to test a higher avidity TCR. It remains to be seen whether any morbidity resulting from autoimmune disease outweighs the associated anti tumor benefit. A balance needs to be struck between TAA specific CTL which are of high enough avidity to mediate tumor killing, but which do not cause significant autoimmune damage to healthy tissue. It is likely that a large discrepancy between the expression level of the target antigen on tumor tissue compared to that on normal tissue will be an important factor in this regard, as will the pattern of distribution of the TAA in normal tissue. 

Conclusion

Although TCR gene transfer holds promise, there may yet be obstacles to overcome with respect to either the safety or the efficacy of this strategy. While mispairing of endogenous and exogenous TCR chains may result in off target toxicity, high avidity CTL may cause on target toxicity by attacking normal tissues that express low levels of the target antigen. However, recent clinical trial data has demonstrated that TCR gene transfer is an effective means by which a defined population of antigen specific T cells can be generated which persist following adoptive transfer into patients. Research is ongoing to address the safety issues and to improve the expression of retrovirally introduced TCRs. Furthermore, while the adoptive transfer of antigen specific regulatory cells has been less well explored to date, this warrants further investigation as there are a number of potential clinical applications for such a strategy. Although unanswered questions remain, it is evident that TCR gene transfer holds clear promise for the treatment of malignancies and viral infections and may have potential to treat unwanted immunopathology in the future. 

References

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2. Dembic Z, Haas W, Weiss S, et al. Transfer of specificity by murine alpha and beta T-cell receptor genes. Nature. 1986;320:232-238.

3. Clay TM, Custer MC, Sachs J, Hwu P, Rosenberg SA, Nishimura MI. Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. J Immunol. 1999;163:507-513.

4. Kessels HW, de Visser KE, Kruisbeek AM, Schumacher TN. Circumventing T-cell tolerance to tumour antigens. Biologicals. 2001;29:277-283.

5. Sadovnikova E, Jopling LA, Soo KS, Stauss HJ. Generation of human tumor-reactive cytotoxic T cells against peptides presented by non-self HLA class I molecules. Eur J Immunol. 1998;28:193-200.

6. Sadovnikova E, Stauss HJ. Peptide-specific cytotoxic T lymphocytes restricted by nonself major histocompatibility complex class I molecules: reagents for tumor immunotherapy. Proc Natl Acad Sci U S A. 1996;93:13114-13118.

7. Oka Y, Elisseeva OA, Tsuboi A, et al. Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type Wilms' tumor gene (WT1 ) product. Immunogenetics. 2000;51:99-107.

8. Rubinstein MP, Kadima AN, Salem ML, et al. Transfer of TCR genes into mature T cells is accompanied by the maintenance of parental T cell avidity. J Immunol. 2003;170:1209-1217.

9. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298:850-854.

10. Gao L, Bellantuono I, Elsasser A, et al. Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood. 2000;95:2198-2203.

11. Xue SA, Gao L, Hart D, et al. Elimination of human leukemia cells in NOD/SCID mice by WT1-TCR gene-transduced human T cells. Blood. 2005;106:3062-3067.

12. Kessels HW, Wolkers MC, van DB, van d, V, Schumacher TN. Immunotherapy through TCR gene transfer. Nat Immunol. 2001;2: 957-961.

13. Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006;314:126-129.

14. Peggs KS, Verfuerth S, Pizzey A, et al. Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines. Lancet. 2003;362:1375-1377.

15. Walter EA, Greenberg PD, Gilbert MJ, et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995;333:1038-1044.

16. Heslop HE, Ng CY, Li C, et al. Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nat Med. 1996;2:551-555.

17. Haque T, Wilkie GM, Taylor C, et al. Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet. 2002;360:436-442.

18. Szymczak AL, Workman CJ, Wang Y, et al. Correction of multi-gene deficiency in vivo using a single 'self-cleaving' 2A peptide-based retroviral vector. Nat Biotechnol. 2004;22:589-594.

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20. Thomas S, Xue SA, Cesco-Gaspere M, et al. Targeting the Wilms tumor antigen 1 by TCR gene transfer: TCR variants improve tetramer binding but not the function of gene modified human T cells. J Immunol. 2007;179:5803-5810.

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26. Van der Veken, LT, Hagedoorn RS, van Loenen MM, Willemze R, Falkenburg JH, Heemskerk MH. Alphabeta T-cell receptor engineered gammadelta T cells mediate effective antileukemic reactivity. Cancer Res. 2006;66:3331-3337.

27. Heemskerk MH, Hoogeboom M, Hagedoorn R, Kester MG, Willemze R, Falkenburg JH. Reprogramming of virus-specific T cells into leukemia-reactive T cells using T cell receptor gene transfer. J Exp Med. 2004;199:885-894.

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29. Zhao Y, Parkhurst MR, Zheng Z, et al. Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via Notch signaling. Cancer Res. 2007;67:2425-2429.

30. Recchia A, Bonini C, Magnani Z, et al. Retroviral vector integration deregulates gene expression but has no consequence on the biology and function of transplanted T cells. Proc Natl Acad Sci U S A. 2006;103:1457-1462.

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36. Spiotto MT, Fu YX, Schreiber H. Tumor immunity meets autoimmunity: antigen levels and dendritic cell maturation. Curr Opin Immunol. 2003;15:725-730.

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Introduction

Adoptive T cell transfer has seen clinical success in the treatment of both malignancies and viral infections. However, one of the main limitations of this strategy has been the difficulty in producing sufficient quantities of antigen-specific T cells. In addition, donor lymphocyte infusions are commonly associated with graft-versus-host disease (GvHD), which carries with it significant morbidity and mortality. Retroviral T cell receptor (TCR) gene transfer is an attractive new strategy by which large numbers of autologous, antigen-specific T cells can be generated, since the TCR is the sole determinant of T cell specificity. The introduced TCR specificity can be targeted against viral antigens or poorly immunogenic targets such as tumor associated antigens, and recent clinical trial data has demonstrated the feasibility of this technique in melanoma patients. Furthermore, TCR gene transfer also has the potential to generate antigen-specific regulatory T cells. This review will focus on recent advances in the field of TCR gene transfer and explore the potential clinical applications of this strategy.

Adoptive T cell transfer for tumor immunotherapy

Adoptive transfer of allogeneic hematopoietic stem cells (HSC) is an established treatment for hematological malignancies. Donor T cells are responsible for mediating the graft-versus- leukemia effect, but this is associated with graft-versus-host disease in up to 50% of transplant recipients. One of the most exciting applications of TCR gene transfer is the ability to generate autologous T cells that recognize leukemia or tumor antigens (Figure 1). There are a number of tumor associated antigens (TAA) that are being evaluated as targets for the immunotherapy of malignancies. However, while they are over-expressed on tumors, they are also expressed on normal tissues, albeit at low levels. Autologous T cells which naturally recognize tumor antigens with high affinity are subject to tolerance mechanisms such as deletion or anergy. Hence, although autologous T cell responses against tumor antigens can be detected in patients with malignancies, they are generally of low avidity. Since it has been shown that the transduced T cell population demonstrates the same functional avidity as the original parent T cell from which the TCR genes are cloned, one of the advantages of TCR gene therapy is that a high avidity TCR can be selected for transfer into target T cells. There are several methods by which high avidity cytotoxic T lymphocytes (CTL) specific for TAAs can be generated. Immunization of HLA transgenic mice, the allo-restricted approach, in vitro mutagenesis of TCRs, and in vitro selection using phage display have been used to generate TCRs with increased peptide/MHC binding affinity.

Figure 1. TCR gene transfer.
(i) A T cell bearing the appropriate TCR is identified, (ii) the alpha and beta TCR chains genes are isolated and cloned into a retroviral vector, (iii) the vector is used to transfect a packaging cell line which produces viral particles containing the genes of interest: (iv). (v) Target T cells are transduced with the recombinant viral particles; (vi) when the genes integrate into the host DNA the target cells express the desired TCR.

2008-2-en-King-et-al-Figure-1.jpg


Transduced T cells have been shown to contribute to tumor clearance in murine models , and the first clinical trial of TCR gene transfer was recently reported. Retroviral gene transfer was used to transduce peripheral blood lymphocytes taken from patients with melanoma, with the genes encoding the α and β chains of a TCR with specificity for a MART 1 peptide presented by HLA-A*0201. The 17 patients in the gene transfer study were lymphodepleted prior to receiving autologous T cells transduced with the MART-1 TCR. The engineered T cells persisted in 15 patients, and the two patients with the highest levels of circulating anti-melanoma T cells showed objective regression of metastatic lesions and remained in remission 18 months after treatment. The results of this study prove that retroviral TCR gene transfer can be used to confer anti-tumor specificity upon a large number of autologous T cells, and that these T cells can engraft in patients and persist at high levels long term.

TCR gene transfer to generate anti viral T cells

A further application for TCR gene transfer is to generate virus-specific T cells for the treatment of immunosuppressed patients who have undergone HSC transplantation. After GvHD, post transplant viral infection is the next major cause of morbidity and mortality in transplant recipients. Adoptive T cell transfer has been shown to be an effective treatment for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection in transplant recipients. Donor-derived CMV specific CD8 T cells which had been expanded in vitro were then infused into HSC transplant recipients with good effect. Similarly, donor-derived EBV specific T cell lines have been used to treat EBV related post-transplant proliferative disease. However, the major limitation of this strategy is that it is not possible to generate virus-specific CTL from all HSC donors using in vitro expansion techniques. TCR gene transfer has the ability to overcome this obstacle and confer upon donor T cells TCR specificities that are not present in the endogenous donor repertoire. This technique also has the advantage of generating large numbers of virus-specific CTL far more rapidly than standard in vitro expansion approaches, which would be of clear benefit in a clinical scenario where a patient presents acutely with significant morbidity. While clinical trial data is still pending, this strategy has great potential for the treatment of viral infections in HSC recipients.

Augmenting TCR gene transfer

In recent years, several groups have explored the means by which TCR gene transfer can be optimized. Modern vector designs aim to increase exogenous TCR expression on target cells by combining α and β chains in a single vector linked by viral self cleaving 2A sequences, rather than internal ribosome entry sites. Codon optimization of TCR gene sequences has also been shown to result in increased TCR expression in human CD8+ T cells, and increased antigen-specific IFNγ release.

In parallel with these vector modifications, recent research efforts have been directed towards increasing the preferential pairing of exogenous α and β chains with each other. It has been demonstrated that exogenous TCRs are able to mispair with endogenous TCR chains (Figure 2). Any mispairing may reduce the expression density and hence the efficacy of the desired TCR, since the density of TCR expression on the cell surface has been shown to correlate with avidity. A number of strategies have recently been employed to address this issue. TCRs have been engineered to include an additional cysteine residue in the constant regions of the α and β chains, resulting in the formation of a second disulphide bond between them. T cells transduced with cysteine-modified receptors showed increased tetramer binding, secreted more cytokine, and showed increased antigen specific lysis when co-cultured with specific tumor cell lines, compared with T cells expressing wild type TCR. Hybrid TCRs have also been designed to incorporate murine constant regions and human variable regions. These hybrid TCRs show reduced mispairing with fully human TCRs when introduced into human T cells, combined with superior cell surface expression and biological activity. However, there is a possibility that a human host will mount an immune response against the murine component of such a TCR. In the same way that murine monoclonal antibodies have become increasingly humanized for clinical use, it is likely that murinization of the TCR constant region will be minimized to reduce its immunogenicity, if this strategy is to be used in a clinical setting.

2008-2-en-King-et-al-Figure-2.jpg

Figure 2: exogenous and endogenous TCR chains compete for CD3 molecules for surface expression, and can mispair to form mixed dimers of unknown specificity. TCR α and β chains must form a complex with the ζ,δ,ε and γ CD3 chains in order for the TCR to be expressed on the cell surface. Following retroviral TCR gene transfer, there is competition between the endogenous TCR (A) and the exogenous TCR (B) for CD3. Increasing the availability of CD3 chains could increase the density of expression, and hence functional avidity, of the exogenous TCR. C: mispairing of endogenous and exogenous TCR chains leads to mixed dimer formation. These TCR have the potential to be autoreactive, and also reduce the CD3 available for expression of the desired TCR (B).


Strategies such as murinization of constant domains and cysteine modification of TCR chains reduce mispairing and increase the "strength" of a TCR. Recent data has shown that "strong" TCRs are expressed at high levels following retroviral gene transfer, whereas "weak" TCRs are poorly expressed because they compete poorly against the endogenous TCR repertoire for CD3 molecules. Research is ongoing into whether there are specific amino acid sequences in the TCR constant domain that contribute towards "strength." An alternative strategy that is currently being investigated is the cotransduction of TCR along with the genes encoding the CD3 complex. Endogenous and exogenous TCR chains are in competition for a limited pool of CD3 molecules, and exogenous TCR chains are likely to be present in excess, since their production is under the control of a retroviral promoter. The expectation would be that cotransducing with both TCR and CD3 molecules would increase the availability of CD3 molecules, which would have a more profound effect on expression of the exogenous TCR whose α and β chains are present in excess. 

Safety concerns

Although there is no evidence of off-target toxicity in murine models to date, it has been demonstrated that exogenous TCR are able to mispair with endogenous TCR chains, resulting in the expression of TCRs that have not undergone thymic education. These TCR, with unpredictable specificities, have the potential to be autoreactive. The strategies described above have been employed to both reduce mispairing and to increase expression of the desired TCR. Research is ongoing into alternative means by which the risk of mispairing may be reduced. It has recently been shown that TCR α and β chains which have each been linked to a CD3ζ chain did not mispair with endogenous TCR chains in a Jurkat T cell model. Since γδ TCR chains cannot mispair with αβ TCR chains, transferring αβ TCR chains into γδ T cells should not result in any mispairing, and has previously been shown to result in the expression of exogenous αβ TCR which produce cytokine and lyse target cells in an antigen-specific manner. Transduction of viral-specific T cells is a strategy by which the potential number of mixed dimers can be reduced; since anti viral responses consist of T cells with a restricted TCR repertoire. An alternative approach would be to transduce HSC with TCR genes. In vitro generation of mature, antigen-specific T cells by TCR gene transfer into thymus or cord-derived HSC has recently been reported. Allelic exclusion of the endogenous TCR β chain meant that mixed dimer formation was reduced, but not entirely avoided due to some endogenous α chain expression. However, while the risk of transformation of mature T cells is low, the risk in HSC may be higher, making this a less appealing strategy. In a clinical trial of X linked severe combined immunodeficiency disease, 4 children treated with HSC retrovirally transduced with the common γ chain developed T lymphoproliferative disorders. This was later found to be secondary to retroviral insertion into the LMO-2 oncogene intron on chromosome 11, with subsequent upregulation. Although there is no evidence to date of transformation of mature T cells with retroviral vectors, the use of lentiviral vectors is also being investigated, since it has been shown that lentiviral vectors insert near promoters at a lower frequency.

While there is a concern that low avidity, TAA specific CTL from the autologous repertoire may not be efficacious, high avidity, self-reactive CTL may pose the opposite problem. The majority of targets for tumor immunotherapy are over-expressed self proteins, and therefore there is a risk that targeting TAA may result in autoimmune damage. In murine models and in clinical trials it has been demonstrated that the successful induction of CTL responses against melanoma TAAs (such as melan A or gp100) has been associated with the development of vitiligo. T cell therapies targeting TAAs with a more ubiquitous distribution have not been studied in the same detail as yet, although it has been shown that high avidity p53 specific CTLs (generated in p53-/- transgenic mice) can provide tumor protection without causing autoimmune damage in mice. A moderately high affinity TCR was used in the TCR gene therapy trial, and work is now ongoing by the same group to test a higher avidity TCR. It remains to be seen whether any morbidity resulting from autoimmune disease outweighs the associated anti tumor benefit. A balance needs to be struck between TAA specific CTL which are of high enough avidity to mediate tumor killing, but which do not cause significant autoimmune damage to healthy tissue. It is likely that a large discrepancy between the expression level of the target antigen on tumor tissue compared to that on normal tissue will be an important factor in this regard, as will the pattern of distribution of the TAA in normal tissue. 

Conclusion

Although TCR gene transfer holds promise, there may yet be obstacles to overcome with respect to either the safety or the efficacy of this strategy. While mispairing of endogenous and exogenous TCR chains may result in off target toxicity, high avidity CTL may cause on target toxicity by attacking normal tissues that express low levels of the target antigen. However, recent clinical trial data has demonstrated that TCR gene transfer is an effective means by which a defined population of antigen specific T cells can be generated which persist following adoptive transfer into patients. Research is ongoing to address the safety issues and to improve the expression of retrovirally introduced TCRs. Furthermore, while the adoptive transfer of antigen specific regulatory cells has been less well explored to date, this warrants further investigation as there are a number of potential clinical applications for such a strategy. Although unanswered questions remain, it is evident that TCR gene transfer holds clear promise for the treatment of malignancies and viral infections and may have potential to treat unwanted immunopathology in the future. 

References

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Кинг Дж.-Вай-Линг, Райт Г.П., Штаусс Х.Дж.

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Адоптивный перенос Т-клеток рассматривается как успешный клинический подход к терапии злокачественных заболеваний и вирусных инфекций. Однако одним из основных ограничений этой стратегии является сложность производства достаточных количеств антиген-специфических Т-клеток. Кроме того, инфузии донорских лимфоцитов часто ассоциированы с развитием болезни «трансплантат против хозяина» (РТПХ), что заставляет считаться со значительной заболеваемостью и смертностью. Перенос ретровирусного Т-клеточного рецептора (TCR) является привлекательной новой стратегией, при которой TCR является единственной детерминантой Т-клеточной специфичности. Введенные TCR нужной специфичности могут быть направлены против вирусных антигенов или слабо иммуногенных целевых молекул, как, например опухоль-ассоциированных антигенов, и недавние сведения о клинических испытаниях показали возможность этой технологии у больных меланомой. Более того, перенос гена TCR представляет собой также потенциальное средство генерации антиген-специфических регуляторных Т-клеток. В этом обзоре будет обращено особое внимание на современные достижения в области переноса гена TCR и исследования потенциальных клинических приложений этой стратегии.

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Judy Wai-Ling King, Graham P. Wright and Hans J. Stauss

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Department of Immunology, Royal Free Hospital, University College London, UK

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Adoptive T cell transfer has seen clinical success in the treatment of both malignancies and viral infections. However, one of the main limitations of this strategy has been the difficulty in producing sufficient quantities of antigen-specific T cells. In addition, donor lymphocyte infusions are commonly associated with graft-versus-host disease (GvHD), which carries with it significant morbidity and mortality. Retroviral T cell receptor (TCR) gene transfer is an attractive new strategy by which large numbers of autologous, antigen-specific T cells can be generated, since the TCR is the sole determinant of T cell specificity. The introduced TCR specificity can be targeted against viral antigens or poorly immunogenic targets such as tumor associated antigens, and recent clinical trial data has demonstrated the feasibility of this technique in melanoma patients. Furthermore, TCR gene transfer also has the potential to generate antigen-specific regulatory T cells. This review will focus on recent advances in the field of TCR gene transfer and explore the potential clinical applications of this strategy.

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Judy Wai-Ling King, Graham P. Wright and Hans J. Stauss

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Judy Wai-Ling King, Graham P. Wright and Hans J. Stauss

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Adoptive T cell transfer has seen clinical success in the treatment of both malignancies and viral infections. However, one of the main limitations of this strategy has been the difficulty in producing sufficient quantities of antigen-specific T cells. In addition, donor lymphocyte infusions are commonly associated with graft-versus-host disease (GvHD), which carries with it significant morbidity and mortality. Retroviral T cell receptor (TCR) gene transfer is an attractive new strategy by which large numbers of autologous, antigen-specific T cells can be generated, since the TCR is the sole determinant of T cell specificity. The introduced TCR specificity can be targeted against viral antigens or poorly immunogenic targets such as tumor associated antigens, and recent clinical trial data has demonstrated the feasibility of this technique in melanoma patients. Furthermore, TCR gene transfer also has the potential to generate antigen-specific regulatory T cells. This review will focus on recent advances in the field of TCR gene transfer and explore the potential clinical applications of this strategy.

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Adoptive T cell transfer has seen clinical success in the treatment of both malignancies and viral infections. However, one of the main limitations of this strategy has been the difficulty in producing sufficient quantities of antigen-specific T cells. In addition, donor lymphocyte infusions are commonly associated with graft-versus-host disease (GvHD), which carries with it significant morbidity and mortality. Retroviral T cell receptor (TCR) gene transfer is an attractive new strategy by which large numbers of autologous, antigen-specific T cells can be generated, since the TCR is the sole determinant of T cell specificity. The introduced TCR specificity can be targeted against viral antigens or poorly immunogenic targets such as tumor associated antigens, and recent clinical trial data has demonstrated the feasibility of this technique in melanoma patients. Furthermore, TCR gene transfer also has the potential to generate antigen-specific regulatory T cells. This review will focus on recent advances in the field of TCR gene transfer and explore the potential clinical applications of this strategy.

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Department of Immunology, Royal Free Hospital, University College London, UK

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Адоптивный перенос Т-клеток рассматривается как успешный клинический подход к терапии злокачественных заболеваний и вирусных инфекций. Однако одним из основных ограничений этой стратегии является сложность производства достаточных количеств антиген-специфических Т-клеток. Кроме того, инфузии донорских лимфоцитов часто ассоциированы с развитием болезни «трансплантат против хозяина» (РТПХ), что заставляет считаться со значительной заболеваемостью и смертностью. Перенос ретровирусного Т-клеточного рецептора (TCR) является привлекательной новой стратегией, при которой TCR является единственной детерминантой Т-клеточной специфичности. Введенные TCR нужной специфичности могут быть направлены против вирусных антигенов или слабо иммуногенных целевых молекул, как, например опухоль-ассоциированных антигенов, и недавние сведения о клинических испытаниях показали возможность этой технологии у больных меланомой. Более того, перенос гена TCR представляет собой также потенциальное средство генерации антиген-специфических регуляторных Т-клеток. В этом обзоре будет обращено особое внимание на современные достижения в области переноса гена TCR и исследования потенциальных клинических приложений этой стратегии.

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Адоптивный перенос Т-клеток рассматривается как успешный клинический подход к терапии злокачественных заболеваний и вирусных инфекций. Однако одним из основных ограничений этой стратегии является сложность производства достаточных количеств антиген-специфических Т-клеток. Кроме того, инфузии донорских лимфоцитов часто ассоциированы с развитием болезни «трансплантат против хозяина» (РТПХ), что заставляет считаться со значительной заболеваемостью и смертностью. Перенос ретровирусного Т-клеточного рецептора (TCR) является привлекательной новой стратегией, при которой TCR является единственной детерминантой Т-клеточной специфичности. Введенные TCR нужной специфичности могут быть направлены против вирусных антигенов или слабо иммуногенных целевых молекул, как, например опухоль-ассоциированных антигенов, и недавние сведения о клинических испытаниях показали возможность этой технологии у больных меланомой. Более того, перенос гена TCR представляет собой также потенциальное средство генерации антиген-специфических регуляторных Т-клеток. В этом обзоре будет обращено особое внимание на современные достижения в области переноса гена TCR и исследования потенциальных клинических приложений этой стратегии.

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Introduction

One of the main challenges of current leukemia research is the rarity of leukemias. The incidence of the various leukemias per 100,000 population/year range between around 1 (ALL) and 3-4 (CLL). The challenge is met by collaboration within cooperative groups and networks. Integration of leukemia research in Europe has been achieved to a high degree by cooperation at the level of national leukemia study groups, notably CML study groups, and by networking on national and European levels. The German CML Study Group (founded in 1982) was one of the cofounders of the European Investigators on CML Group (EI-CML), which was initiated by S. Tura, Bologna, in 1992. Fig. 1 shows the distribution of national CML study groups in Europe. On a German level, the German CML Study Group, together with other German leukemia study groups, started the German Competence Network “Akute und chronische Leukämien” (KNL) in 1997, which was funded by the German Ministry for Education and Research in 1999. The KNL, which combines all leukemia study groups in one country and the EI-CML, which combines all European groups cooperating on one leukemia, started the European LeukemiaNet (ELN) in 2002. This has been funded by the European Commission (EC) as a Network of Excellence (NoE) from 2004 onwards. Fig. 2 shows a flow diagram of the integration of leukemia research in Europe.

2008-2-en-Hehlmann-et-al-Fig-01.jpg

2008-2-en-Hehlmann-et-al-Fig-02.jpg


The groups forming the ELN all have convincing records in promoting leukemia research and improving survival for patients with leukemia. An example is the German CML Study Group, with its 600 participants in about 300 centers (Fig. 3). The group has conducted 5 major randomized studies over the past 25 years, which has improved survival of CML patients in Germany significantly from a median survival time of 3-4 years in 1983 to an expected median of about 25 years in 2008. Fig. 4 shows the improvement of survival in the trials of the German CML Study Group up to the present time. The current 5-year-survival of 93% in CML Study IV is better than that reported by any other study group.

2008-2-en-Hehlmann-et-al-Fig-3.jpg

2008-2-en-Hehlmann-et-al-Fig-4.jpg


The ELN, representing a collaboration of European leukemia study groups and their interdisciplinary partner groups, currently comprises 147 centers in 28 countries (Fig. 5), and involves about 1,000 physicians and scientists. The participating leukemia study groups are caring for some 10,000 leukemia patients across Europe. Cooperation is amongst 95 national leukemia study groups and 102 interdisciplinary partner groups as depicted in Figs. 6 and 7.

2008-2-en-Hehlmann-et-al-Fig-5.jpg

2008-2-en-Hehlmann-et-al-Fig-6_01.jpg

2008-2-en-Hehlmann-et-al-Fig-7.jpg


The goals of the ELN are to strengthen scientific and technological excellence in research and treatment of leukemias, promote clinical trials, prepare guidelines, and spread excellence. The success of the European approach in improving research and patient outcome is well illustrated by the paradigm chronic myeloid leukemia (CML).

Paradigm CML
1847: Term “Leukämie” coined
1960: Philadelphia chromosome discovered
1985: Fusion gene BCR-ABL detected
1990: BCR-ABL induces leukemia in mice
1998: BCR-ABL TK inhibitor imatinib in phase I
2008: Median survival (expected) 25 years

The term “leukemia” was coined  in 1847 [1]  to describe patients with what was later recognized to be CML. The name was later given to the whole group of leukemias. CML became the first neoplastic disease regularly associated with a chromosomal aberration, the Philadelphia-translocation (1960) [2]. CML also became the first neoplastic disease in which the molecular pathogenesis was elucidated. In 1985, the fusion gene BCR-ABL coding for a BCR-ABL fusion tyrosine kinase (TK) was detected [3], and in 1990 it was shown that BCR-ABL can induce leukemia in mice [4, 5]. This finding prompted experiments to inhibit BCR-ABL TK via specific inhibitors [6]. In 1998, a phase I trial with the TK inhibitor imatinib was started. The outcome was striking. Even patients with advanced disease achieved cytogenetic remissions [7]. This success was achieved by the cooperation of academic research with drug development by the pharmaceutical industry. The development of a “targeted” therapy for CML would not have been possible without close cooperation among all players in the field (trial groups, groups in cytogenetic and molecular research, pharmaceutical industry, etc.)

The molecular elucidation of CML pathogenesis relied heavily on earlier research with retroviruses and oncogenes. In this research an acute leukemia-inducing murine retrovirus, termed Abelson Virus, was found to contain a 5.6 kb long cellular RNA-sequence which, due to its oncogenic potential, was termed an “ABL oncogene”. In the human genome, ABL is located on chromosome 9, from where part of it is translocated to chromosome 22 in exchange for a larger piece of chromosome 22 called the “breakpoint cluster region” (BCR), which is in turn translocated to chromosome 9 adjacent to the remaining ABL sequences. According to the locations of the breakpoint and the size of the resulting fusion proteins, 3 sizes of proteins can be identified: a p210 BCR-ABL protein, which is regularly associated with CML; a p190 BCR-ABL protein, which is predominantly found in ALL; and a p230 BCR-ABL protein, which is found in a rare form of CML called “chronic neutrophilic leukemia” or CNL. The BCR-ABL proteins with the locations of the TKs are depicted in Fig. 8. Due to these findings, CML became the first neoplastic disease in which elucidation of pathogenesis led to a rationally designed therapy targeted at the cause of the disease. The 6-year-survival rate with imatinib in the so-called “IRIS trial”, a randomized comparison of imatinib with the former standard therapy interferon α (IFN), currently stands at 88%, with a complete cytogenetic remission rate of 82% [8]. The development of survival in CML in various trials during the years 1979-2008 is depicted in Fig. 9. Imatinib has been shown to be superior to IFN, and the survival rate with imatinib is better than with any other therapy.

2008-2-en-Hehlmann-et-al-Fig-8.jpg

2008-2-en-Hehlmann-et-al-Fig-9.jpg


The problem with current imatinib therapy is that – due to various reasons – within 6 years about 37% of patients do not respond satisfactorily or at all to imatinib, or are suspended from treatment. This is in part due to resistance mutations [9], but also to disease evolution or adverse effects. Therefore various treatment optimization trials were started to improve imatinib therapy either by combination with other agents such as IFN or araC, or by increasing the imatinib dosage. One of these studies, the German 5-arm randomized CML Study IV (GEIST), started in 2002 and has currently recruited more than 1200 patients (Fig. 10). With a survival rate of 94% in the primary imatinib arms, it is more successful than in any other current study. After 36 months, rates of major cytogenetic responses in the primary imatinib arms are close to 90%, of complete cytogenetic remissions more than 85%, and of major molecular remissions around 79%.

2008-2-en-Hehlmann-et-al-Fig-10.jpg


Once blast crisis (BC) develops, prognosis remains poor. Median survival of 605 patients with BC in the German CML Studies I, II, III and IIIA (recruitment 1983–2003) is 4 months (Fig. 11). Only 21 patients remain alive; 15 of them after transplantation.

2008-2-en-Hehlmann-et-al-Fig-11.jpg


One study of the German CML Study Group (CML-Study III) has evaluated the role of stem cell transplantation by randomized comparison with best available drug treatment [10]. After a median observation time of more than 8 years with an observation time up to 11 years, a significant survival advantage for best available drug treatment was determined (Fig. 12). It is concluded that drug treatment now should be first line therapy for CML. Stem cell transplantation remains an important second line option and may be given first line on an individual basis.

2008-2-en-Hehlmann-et-al-Fig-12.jpg


Various second line TK inhibitors are currently in various phases of evaluation. Dasatinib, which is 325 times more potent than imatinib, has been shown to have an 18-month-survival outcome of  96% in imatinib resistant or intolerant patients [11, 12]. In the chronic phase, 100 mg dasatinib once a day has been shown to be equally effective and less toxic than 2x70 mg. Dasatinib has remarkable activity in BC with a 2-year-survival of 38% in myeloid and 26% in lymphoid BC. A relevant property of dasatinib is its ability to pass the blood/brain barrier [13]. Nilotinib is about 30 times more potent than imatinib, and also has good activity in blast crisis with a 12-month-survival rate of 42% [14].

In conclusion, dasatinib and nilotinib have hematologic and cytogenetic efficacy in imatinib resistant and intolerant CML in all phases, and are active against all BCR-ABL TK-mutations except T315I. Main toxicities are cytopenias and pleural effusions (dasatinib). After dasatinib and nilotinib treatment new resistance mutations have been observed. For mutation I255V/K both drugs are not sufficiently efficacious at the standard dose, and a dose increase is recommended. In F317L, nilotinib is efficacious, in Y253H dasatinib. Agents in clinical studies include dasatinib and nilotinib in randomized evaluation for first line therapy; bosutinib, INNO406, histone deacetylase inhibitors, aurora kinase inhibitors and others, alone or in combination with other agents, in phase I and II and more in preclinical evaluation.

A major goal of the ELN is the development of guidelines for diagnosis and treatment in leukemias. CML management recommendations were published in 2006 [15], APL guidelines in 2008 [16], an update for CML is planned for 2009, and AML guidelines are in preparation. The current CML recommendations are summarized in the algorithm in Fig. 13 [17]. In case of intolerance, toxicity or pregnancy IFN is recommended, in case of imatinib failure or resistance, 2nd generation TK inhibitors or allo-SCT. In the case of suboptimal response patients should be observed closely, and an increase of imatinib dosage should be attempted. If the treatment effect is less than expected or the toxicity unusually high, compliance should be checked, interactions with other drugs or food considered and the imatinib blood levels determined. 

2008-2-en-Hehlmann-et-al-Fig-13.jpg


Challenges remaining and requiring new modes of cooperation concern geographic variations and demographics, quality controlled outcome of CML for international comparability, the availability of standardized diagnostics Europe-wide and globally, the role of TK inhibitor trough levels for response and outcome, and the provision of continued information and communication to all players in the field. In order to address these topics, a public-private partnership between the CML members of ELN and Novartis Oncology Europe has been initiated: the European Treatment and Outcome Study (EUTOS) for CML (Fig. 14).

2008-2-en-Hehlmann-et-al-Fig-14.jpg

The goals of this cooperation are expansion of the European CML registry, standardized molecular monitoring on an international basis, pharmacological monitoring and the spread of excellence. The contract was signed between the University of Heidelberg as legal representative of the ELN and Novartis in June 2007.


In summary, leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.

References

1. Virchow R. Weißes Blut (Leukämie). Archiv für path Anat. 1847;1:563.

2. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science. 1960;132:1497-1501.

3. Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985;315:550-554.

4. Daley GQ, van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247:824-830.

5. Heisterkamp N, Jenster G, ten Hoeve J, et al. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990;344:251-253.

6. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Medic. 1996;2:561-566.

7. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037.

8. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.

9. Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia. 2004;18:1321-1331.

10. Hehlmann R, Berger U, Pfirrmann M, et al. Drug treatment is superior to allografting as first line therapy in chronic myeloid leukemia. Blood. 2007;109:4686-4692.

11. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531-2541.

12. Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22:1200-1206.

13. Porkka K, Koskenvesa P, Lundan T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood. 2008;112:1005-1012.

14. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib (AMN107), a novel, highly active, selective BCR-ABL tyrosine kinase inhibitor in patients with Philadelphia-Chromosome (Ph) positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) who are resistant to imatinib mesylate therapy. N Engl J Med. 2006;2542-2551.

15. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809-1820.

16. Sanz MA, Grimwade D, Tallman MS, et al. Guidelines on the management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2008;prepublished online September 23,2008.

17. Hehlmann R, Hochhaus A, Baccarani M. Chronic myeloid leukaemia. Lancet. 2007;370:342-350.

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Introduction

One of the main challenges of current leukemia research is the rarity of leukemias. The incidence of the various leukemias per 100,000 population/year range between around 1 (ALL) and 3-4 (CLL). The challenge is met by collaboration within cooperative groups and networks. Integration of leukemia research in Europe has been achieved to a high degree by cooperation at the level of national leukemia study groups, notably CML study groups, and by networking on national and European levels. The German CML Study Group (founded in 1982) was one of the cofounders of the European Investigators on CML Group (EI-CML), which was initiated by S. Tura, Bologna, in 1992. Fig. 1 shows the distribution of national CML study groups in Europe. On a German level, the German CML Study Group, together with other German leukemia study groups, started the German Competence Network “Akute und chronische Leukämien” (KNL) in 1997, which was funded by the German Ministry for Education and Research in 1999. The KNL, which combines all leukemia study groups in one country and the EI-CML, which combines all European groups cooperating on one leukemia, started the European LeukemiaNet (ELN) in 2002. This has been funded by the European Commission (EC) as a Network of Excellence (NoE) from 2004 onwards. Fig. 2 shows a flow diagram of the integration of leukemia research in Europe.

2008-2-en-Hehlmann-et-al-Fig-01.jpg

2008-2-en-Hehlmann-et-al-Fig-02.jpg


The groups forming the ELN all have convincing records in promoting leukemia research and improving survival for patients with leukemia. An example is the German CML Study Group, with its 600 participants in about 300 centers (Fig. 3). The group has conducted 5 major randomized studies over the past 25 years, which has improved survival of CML patients in Germany significantly from a median survival time of 3-4 years in 1983 to an expected median of about 25 years in 2008. Fig. 4 shows the improvement of survival in the trials of the German CML Study Group up to the present time. The current 5-year-survival of 93% in CML Study IV is better than that reported by any other study group.

2008-2-en-Hehlmann-et-al-Fig-3.jpg

2008-2-en-Hehlmann-et-al-Fig-4.jpg


The ELN, representing a collaboration of European leukemia study groups and their interdisciplinary partner groups, currently comprises 147 centers in 28 countries (Fig. 5), and involves about 1,000 physicians and scientists. The participating leukemia study groups are caring for some 10,000 leukemia patients across Europe. Cooperation is amongst 95 national leukemia study groups and 102 interdisciplinary partner groups as depicted in Figs. 6 and 7.

2008-2-en-Hehlmann-et-al-Fig-5.jpg

2008-2-en-Hehlmann-et-al-Fig-6_01.jpg

2008-2-en-Hehlmann-et-al-Fig-7.jpg


The goals of the ELN are to strengthen scientific and technological excellence in research and treatment of leukemias, promote clinical trials, prepare guidelines, and spread excellence. The success of the European approach in improving research and patient outcome is well illustrated by the paradigm chronic myeloid leukemia (CML).

Paradigm CML
1847: Term “Leukämie” coined
1960: Philadelphia chromosome discovered
1985: Fusion gene BCR-ABL detected
1990: BCR-ABL induces leukemia in mice
1998: BCR-ABL TK inhibitor imatinib in phase I
2008: Median survival (expected) 25 years

The term “leukemia” was coined  in 1847 [1]  to describe patients with what was later recognized to be CML. The name was later given to the whole group of leukemias. CML became the first neoplastic disease regularly associated with a chromosomal aberration, the Philadelphia-translocation (1960) [2]. CML also became the first neoplastic disease in which the molecular pathogenesis was elucidated. In 1985, the fusion gene BCR-ABL coding for a BCR-ABL fusion tyrosine kinase (TK) was detected [3], and in 1990 it was shown that BCR-ABL can induce leukemia in mice [4, 5]. This finding prompted experiments to inhibit BCR-ABL TK via specific inhibitors [6]. In 1998, a phase I trial with the TK inhibitor imatinib was started. The outcome was striking. Even patients with advanced disease achieved cytogenetic remissions [7]. This success was achieved by the cooperation of academic research with drug development by the pharmaceutical industry. The development of a “targeted” therapy for CML would not have been possible without close cooperation among all players in the field (trial groups, groups in cytogenetic and molecular research, pharmaceutical industry, etc.)

The molecular elucidation of CML pathogenesis relied heavily on earlier research with retroviruses and oncogenes. In this research an acute leukemia-inducing murine retrovirus, termed Abelson Virus, was found to contain a 5.6 kb long cellular RNA-sequence which, due to its oncogenic potential, was termed an “ABL oncogene”. In the human genome, ABL is located on chromosome 9, from where part of it is translocated to chromosome 22 in exchange for a larger piece of chromosome 22 called the “breakpoint cluster region” (BCR), which is in turn translocated to chromosome 9 adjacent to the remaining ABL sequences. According to the locations of the breakpoint and the size of the resulting fusion proteins, 3 sizes of proteins can be identified: a p210 BCR-ABL protein, which is regularly associated with CML; a p190 BCR-ABL protein, which is predominantly found in ALL; and a p230 BCR-ABL protein, which is found in a rare form of CML called “chronic neutrophilic leukemia” or CNL. The BCR-ABL proteins with the locations of the TKs are depicted in Fig. 8. Due to these findings, CML became the first neoplastic disease in which elucidation of pathogenesis led to a rationally designed therapy targeted at the cause of the disease. The 6-year-survival rate with imatinib in the so-called “IRIS trial”, a randomized comparison of imatinib with the former standard therapy interferon α (IFN), currently stands at 88%, with a complete cytogenetic remission rate of 82% [8]. The development of survival in CML in various trials during the years 1979-2008 is depicted in Fig. 9. Imatinib has been shown to be superior to IFN, and the survival rate with imatinib is better than with any other therapy.

2008-2-en-Hehlmann-et-al-Fig-8.jpg

2008-2-en-Hehlmann-et-al-Fig-9.jpg


The problem with current imatinib therapy is that – due to various reasons – within 6 years about 37% of patients do not respond satisfactorily or at all to imatinib, or are suspended from treatment. This is in part due to resistance mutations [9], but also to disease evolution or adverse effects. Therefore various treatment optimization trials were started to improve imatinib therapy either by combination with other agents such as IFN or araC, or by increasing the imatinib dosage. One of these studies, the German 5-arm randomized CML Study IV (GEIST), started in 2002 and has currently recruited more than 1200 patients (Fig. 10). With a survival rate of 94% in the primary imatinib arms, it is more successful than in any other current study. After 36 months, rates of major cytogenetic responses in the primary imatinib arms are close to 90%, of complete cytogenetic remissions more than 85%, and of major molecular remissions around 79%.

2008-2-en-Hehlmann-et-al-Fig-10.jpg


Once blast crisis (BC) develops, prognosis remains poor. Median survival of 605 patients with BC in the German CML Studies I, II, III and IIIA (recruitment 1983–2003) is 4 months (Fig. 11). Only 21 patients remain alive; 15 of them after transplantation.

2008-2-en-Hehlmann-et-al-Fig-11.jpg


One study of the German CML Study Group (CML-Study III) has evaluated the role of stem cell transplantation by randomized comparison with best available drug treatment [10]. After a median observation time of more than 8 years with an observation time up to 11 years, a significant survival advantage for best available drug treatment was determined (Fig. 12). It is concluded that drug treatment now should be first line therapy for CML. Stem cell transplantation remains an important second line option and may be given first line on an individual basis.

2008-2-en-Hehlmann-et-al-Fig-12.jpg


Various second line TK inhibitors are currently in various phases of evaluation. Dasatinib, which is 325 times more potent than imatinib, has been shown to have an 18-month-survival outcome of  96% in imatinib resistant or intolerant patients [11, 12]. In the chronic phase, 100 mg dasatinib once a day has been shown to be equally effective and less toxic than 2x70 mg. Dasatinib has remarkable activity in BC with a 2-year-survival of 38% in myeloid and 26% in lymphoid BC. A relevant property of dasatinib is its ability to pass the blood/brain barrier [13]. Nilotinib is about 30 times more potent than imatinib, and also has good activity in blast crisis with a 12-month-survival rate of 42% [14].

In conclusion, dasatinib and nilotinib have hematologic and cytogenetic efficacy in imatinib resistant and intolerant CML in all phases, and are active against all BCR-ABL TK-mutations except T315I. Main toxicities are cytopenias and pleural effusions (dasatinib). After dasatinib and nilotinib treatment new resistance mutations have been observed. For mutation I255V/K both drugs are not sufficiently efficacious at the standard dose, and a dose increase is recommended. In F317L, nilotinib is efficacious, in Y253H dasatinib. Agents in clinical studies include dasatinib and nilotinib in randomized evaluation for first line therapy; bosutinib, INNO406, histone deacetylase inhibitors, aurora kinase inhibitors and others, alone or in combination with other agents, in phase I and II and more in preclinical evaluation.

A major goal of the ELN is the development of guidelines for diagnosis and treatment in leukemias. CML management recommendations were published in 2006 [15], APL guidelines in 2008 [16], an update for CML is planned for 2009, and AML guidelines are in preparation. The current CML recommendations are summarized in the algorithm in Fig. 13 [17]. In case of intolerance, toxicity or pregnancy IFN is recommended, in case of imatinib failure or resistance, 2nd generation TK inhibitors or allo-SCT. In the case of suboptimal response patients should be observed closely, and an increase of imatinib dosage should be attempted. If the treatment effect is less than expected or the toxicity unusually high, compliance should be checked, interactions with other drugs or food considered and the imatinib blood levels determined. 

2008-2-en-Hehlmann-et-al-Fig-13.jpg


Challenges remaining and requiring new modes of cooperation concern geographic variations and demographics, quality controlled outcome of CML for international comparability, the availability of standardized diagnostics Europe-wide and globally, the role of TK inhibitor trough levels for response and outcome, and the provision of continued information and communication to all players in the field. In order to address these topics, a public-private partnership between the CML members of ELN and Novartis Oncology Europe has been initiated: the European Treatment and Outcome Study (EUTOS) for CML (Fig. 14).

2008-2-en-Hehlmann-et-al-Fig-14.jpg

The goals of this cooperation are expansion of the European CML registry, standardized molecular monitoring on an international basis, pharmacological monitoring and the spread of excellence. The contract was signed between the University of Heidelberg as legal representative of the ELN and Novartis in June 2007.


In summary, leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.

References

1. Virchow R. Weißes Blut (Leukämie). Archiv für path Anat. 1847;1:563.

2. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science. 1960;132:1497-1501.

3. Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985;315:550-554.

4. Daley GQ, van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247:824-830.

5. Heisterkamp N, Jenster G, ten Hoeve J, et al. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990;344:251-253.

6. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Medic. 1996;2:561-566.

7. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031-1037.

8. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.

9. Hochhaus A, La Rosee P. Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia. 2004;18:1321-1331.

10. Hehlmann R, Berger U, Pfirrmann M, et al. Drug treatment is superior to allografting as first line therapy in chronic myeloid leukemia. Blood. 2007;109:4686-4692.

11. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531-2541.

12. Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22:1200-1206.

13. Porkka K, Koskenvesa P, Lundan T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood. 2008;112:1005-1012.

14. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib (AMN107), a novel, highly active, selective BCR-ABL tyrosine kinase inhibitor in patients with Philadelphia-Chromosome (Ph) positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) who are resistant to imatinib mesylate therapy. N Engl J Med. 2006;2542-2551.

15. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809-1820.

16. Sanz MA, Grimwade D, Tallman MS, et al. Guidelines on the management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2008;prepublished online September 23,2008.

17. Hehlmann R, Hochhaus A, Baccarani M. Chronic myeloid leukaemia. Lancet. 2007;370:342-350.

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Хельман Р., Саусселе С.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12401" ["VALUE"]=> array(2) { ["TEXT"]=> string(488) "<p>В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(476) "

В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12377" ["VALUE"]=> string(29) "10.3205/ctt-2008-en-000015.01" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(29) "10.3205/ctt-2008-en-000015.01" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12420" ["VALUE"]=> array(2) { ["TEXT"]=> string(90) "<p class="Autor">R. Hehlmann, S. Saußele<p class="Autor">" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(58) "

R. Hehlmann, S. Saußele

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Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12422" ["VALUE"]=> array(2) { ["TEXT"]=> string(736) "<p>Presented at the 2nd Raissa Gorbacheva Memorial Symposium in St. Petersburg, Russia, on 20 September 2008.</p> <p class="bodytext">Leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(702) "

Presented at the 2nd Raissa Gorbacheva Memorial Symposium in St. Petersburg, Russia, on 20 September 2008.

Leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12378" ["VALUE"]=> string(60) "Integration of leukemia research in Europe: the paradigm CML" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(60) "Integration of leukemia research in Europe: the paradigm CML" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12389" ["VALUE"]=> array(2) { ["TEXT"]=> string(8845) "<p class="bodytext"> Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии (Рис. 2). В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г. </p> <p class="bodytext"> Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5). </p> <img width="421" alt="2008-2-en-Hehlmann-et-al-Figure-2.jpg" src="/upload/medialibrary/b9e/2008_2_en_hehlmann_et_al_figure_2.jpg" height="360" title="2008-2-en-Hehlmann-et-al-Figure-2.jpg" align="left"> <div style="margin-left:460px;"> <img width="434" alt="2008-2-en-Hehlmann-et-al-Fig-5_04.jpg" src="/upload/medialibrary/357/2008_2_en_hehlmann_et_al_fig_5_04.jpg" height="346" title="2008-2-en-Hehlmann-et-al-Fig-5_04.jpg"> </div> <p class="bodytext"> <br> Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4). </p> <p> <img width="473" alt="2008-2-en-Hehlmann-et-al-Fig-13_03.jpg" src="/upload/medialibrary/d34/2008_2_en_hehlmann_et_al_fig_13_03.jpg" height="358" title="2008-2-en-Hehlmann-et-al-Fig-13_03.jpg" align="left"> </p> <div style="margin-left:490px;"> <img width="475" alt="2008-2-en-Hehlmann-et-al-Fig-4_03.jpg" src="/upload/medialibrary/7d1/2008_2_en_hehlmann_et_al_fig_4_03.jpg" height="341" title="2008-2-en-Hehlmann-et-al-Fig-4_03.jpg"><br> <p> </p> </div> <p class="bodytext"> <br> Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.<br> <br> Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.<br> <br> Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.<br> <br> Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы. <br> <br> Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14) </p> <p> <img width="447" alt="2008-2-en-Hehlmann-et-al-Fig-14_03.jpg" src="/upload/medialibrary/2ba/2008_2_en_hehlmann_et_al_fig_14_03.jpg" height="371" title="2008-2-en-Hehlmann-et-al-Fig-14_03.jpg"><br> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(8305) "

Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии (Рис. 2). В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г.

Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5).

2008-2-en-Hehlmann-et-al-Figure-2.jpg
2008-2-en-Hehlmann-et-al-Fig-5_04.jpg


Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4).

2008-2-en-Hehlmann-et-al-Fig-13_03.jpg

2008-2-en-Hehlmann-et-al-Fig-4_03.jpg


Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.

Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.

Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.

Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы.

Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14)

2008-2-en-Hehlmann-et-al-Fig-14_03.jpg

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R. Hehlmann, S. Saußele

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Presented at the 2nd Raissa Gorbacheva Memorial Symposium in St. Petersburg, Russia, on 20 September 2008.

Leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.

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Presented at the 2nd Raissa Gorbacheva Memorial Symposium in St. Petersburg, Russia, on 20 September 2008.

Leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.

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Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany

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Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany

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Хельман Р., Саусселе С.

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"Европейская сеть по изучению лейкозов" } ["LINK_ELEMENT_VALUE"]=> bool(false) } ["CONTACT"]=> array(38) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12374" ["VALUE"]=> string(2) "87" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(2) "87" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(59) "Rüdiger Hehlmann" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12401" ["VALUE"]=> array(2) { ["TEXT"]=> string(488) "<p>В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(476) "

В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(476) "

В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей.

" } ["FULL_TEXT_RU"]=> array(37) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "12389" ["VALUE"]=> array(2) { ["TEXT"]=> string(8845) "<p class="bodytext"> Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии (Рис. 2). В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г. </p> <p class="bodytext"> Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5). </p> <img width="421" alt="2008-2-en-Hehlmann-et-al-Figure-2.jpg" src="/upload/medialibrary/b9e/2008_2_en_hehlmann_et_al_figure_2.jpg" height="360" title="2008-2-en-Hehlmann-et-al-Figure-2.jpg" align="left"> <div style="margin-left:460px;"> <img width="434" alt="2008-2-en-Hehlmann-et-al-Fig-5_04.jpg" src="/upload/medialibrary/357/2008_2_en_hehlmann_et_al_fig_5_04.jpg" height="346" title="2008-2-en-Hehlmann-et-al-Fig-5_04.jpg"> </div> <p class="bodytext"> <br> Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4). </p> <p> <img width="473" alt="2008-2-en-Hehlmann-et-al-Fig-13_03.jpg" src="/upload/medialibrary/d34/2008_2_en_hehlmann_et_al_fig_13_03.jpg" height="358" title="2008-2-en-Hehlmann-et-al-Fig-13_03.jpg" align="left"> </p> <div style="margin-left:490px;"> <img width="475" alt="2008-2-en-Hehlmann-et-al-Fig-4_03.jpg" src="/upload/medialibrary/7d1/2008_2_en_hehlmann_et_al_fig_4_03.jpg" height="341" title="2008-2-en-Hehlmann-et-al-Fig-4_03.jpg"><br> <p> </p> </div> <p class="bodytext"> <br> Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.<br> <br> Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.<br> <br> Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.<br> <br> Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы. <br> <br> Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14) </p> <p> <img width="447" alt="2008-2-en-Hehlmann-et-al-Fig-14_03.jpg" src="/upload/medialibrary/2ba/2008_2_en_hehlmann_et_al_fig_14_03.jpg" height="371" title="2008-2-en-Hehlmann-et-al-Fig-14_03.jpg"><br> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(8305) "

Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии (Рис. 2). В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г.

Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5).

2008-2-en-Hehlmann-et-al-Figure-2.jpg
2008-2-en-Hehlmann-et-al-Fig-5_04.jpg


Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4).

2008-2-en-Hehlmann-et-al-Fig-13_03.jpg

2008-2-en-Hehlmann-et-al-Fig-4_03.jpg


Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.

Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.

Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.

Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы.

Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14)

2008-2-en-Hehlmann-et-al-Fig-14_03.jpg

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Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии (Рис. 2). В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г.

Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5).

2008-2-en-Hehlmann-et-al-Figure-2.jpg
2008-2-en-Hehlmann-et-al-Fig-5_04.jpg


Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4).

2008-2-en-Hehlmann-et-al-Fig-13_03.jpg

2008-2-en-Hehlmann-et-al-Fig-4_03.jpg


Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.

Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.

Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.

Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы.

Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14)

2008-2-en-Hehlmann-et-al-Fig-14_03.jpg

" } } } }
Том 1, Номер 2
01.12.2008
Том 1, Номер 2
Главный редактор
Афанасьев Б. В. (Санкт-Петербург, Россия)
Со-редакторы
Вагемакер Г. (Роттердам, Нидерланды)
Цандер А. Р. (Гамбург, Германия)
Заместитель главного редактора
Чухловин А. Б. (Санкт-Петербург, Россия)
Фезе Б. (Гамбург, Германия)
Новик А. А. (Москва, Россия)
Ответственный редактор
Клаудиа Кольтценбург (Гамбург, Германия)
Редакционная коллегия
Алейникова О. В. (Минск, Беларусь)
Алянский А. Л. (Санкт-Петербург, Россия)
Анагносту А. (Бостон, США)
Андреефф М. (Хьюстон, США)
Бaйков В. (Санкт-Петербург, Россия)
Баранов В. С. (Санкт-Петербург, Россия)
Бархатов И. М. (Санкт-Петербург, Россия)
Баум К. (Ганновер, Германия)
Бахер У. (Гамбург, Германия)
Билько Н. М. (Киев, Украина)
Борсет М. (Трондхейм, Норвегия)
Быков В. Л. (Санкт-Петербург, Россия)
Бюхнер Т. (Мюнстер, Германия)
Вестенфельдер К. (Солт-Лейк-Сити, США)
Вилесов А. Д. (Санкт-Петербург, Россия)
Вислофф Ф. (Осло, Норвегия)
Дини Дж. (Генуя, Италия)
Дризе Н. (Москва, Россия)
Галибин О. В. (Санкт-Петербург, Россия)
Ганзер А. (Ганновер, Германия)
Гранов Д. А. (Санкт-Петербург, Россия)
Звартау Э. Э. (Санкт-Петербург, Россия)
Зверев О. Г. (Санкт-Петербург, Россия)
Зубаровская Л. С.(Санкт-Петербург, Россия)
Иванов Р. А. (Москва, Россия)
Климко Н. Н. (Санкт-Петербург, Россия)
Коза В. (Пльзень, Чехия)
Кольб Х. (Мюнхен, Германия)
Коноплева М. (Хьюстон, США)
Крегер Н. (Гамбург, Германия)
Маликов А. Я. (Санкт-Петербург, Россия)
Менткевич Г. Л. (Москва, Россия)
Михайлова Н. Б. (Санкт-Петербург, Россия)
Наглер А. (Тель Хашомер, Израиль)
Неворотин А. И. (Санкт-Петербург, Россия)
Немков А. С. (Санкт-Петербург, Россия)
Нет Р. (Гамбург, Германия)
Остертаг В. (Гамбург, Германия)
Палутке М. (Детройт, США)
Румянцев А. Г. (Москва, Россия)
Савченко В. Г. (Москва, Россия)
Смирнов А. В. (Санкт-Петербург, Россия)
Тец В. В. (Санкт-Петербург, Россия)
То Б. (Аделаида, Австралия)
Тотолян А. А. (Санкт-Петербург, Россия)
Усс А. Л. (Минск, Беларусь)
Феррара Дж. (Энн Арбор, США)
Фиббе В. (Лейден, Нидерланды)
Штамм К. (Берлин, Германия)
Эвераус Х. (Тарту, Эстония)
Эгеланд Т. (Осло, Норвегия)
Эльстнер Е. (Берлин, Германия)
Эмануэль В. Л. (Санкт-Петербург, Россия)
Обзор выпуска

Продвигаясь вперед

Всего лишь несколько месяцев минуло с выхода пилотного выпуска журнала «Клеточная терапия и трансплантация» (КТТ), и наградой за это стал опыт взаимного общения с авторами, рецензентами и читателями.

В отличие от текущих статей и обзоров по ряду интересных тем, этот выпуск содержит специальный раздел «Терапия мезенхимными клетками» (7 статей из 15).

В том же разделе, в дополнение к статьям про МСК, Мариуш Ратайчак и соавт. сообщает о небольших стволовых клетках эмбрионального типа (НСКЭТ) и их потенциале при регенерации тканей.

Из смежных областей мы публикуем специальную лекцию Тима Ханта «Вхождение и выход из митоза», которую он читал на симпозиуме в Вильзеде в 2008 г. Она публикуется совместно с нашим порталом-партнером www.wilsede-science-connections.com, ресурсы которого в мультимедийной сфере мы начинаем делать доступными для более широкой аудитории.

Мы особенно хотим стимулировать молодых исследователей-медиков к тому, чтобы их первые работы прошли независимое рецензирование и были опубликованы в КТТ. Начиная с этого выпуска, страница «Содержание» будет содержать обозначение
«1-аяМП», обозначающее авторов, для которых данная статья в КТТ является первой статьей в международном журнале.

Мы хотели бы поблагодарить нижеследующих коллег за проведение независимого рецензирования данного выпуска КТТ: Ульрику Бахер, Алексея Б. Чухловина, Бориса Фезе, Николая Н. Климко, Николауса Крегера, Клаудию Ланге, Катарину Лебланк, Николая Н. Мамаева, Людмилу С. Зубаровскую.

Борис Владимирович Афанасьев, Аксель Рольф Цандер


От управляющего редактора

Поскольку КТТ является журналом открытого доступа, то как читатели, так и авторы могут получить весьма большие выгоды. В чем же выиграют авторы? Из списков наших публикаций в Сети вы можете непосредственно выйти на Вашу статью в журнале КТТ. Наш читатель может нажать мышкой на эту ссылку, и статья немедленно будет доступной, причем бесплатно. Это означает, что любой читатель в Сети имеет доступ к Вашей статье и без дополнительных усилий может цитировать Вашу статью из журнала КТТ в своей собственной работе.

Статьи журнала КТТ уже содержатся в перечнях CAS и DOAJ, с дальнейшим ростом их известности в перспективе. 

Я очень рада тому, что я веду этот журнал с точки зрения менеджерской и производственной работы, совместно с нашим издательским офисом, расположенным как в Гамбурге, так и в Санкт-Петербурге. Наша производственная команда также является зоной дискуссии для различных образов мышления и это – исключительный опыт создания научного журнала совместно, как в отношении управления, так и в плане технологии.

Я хотела бы поблагодарить нижеперечисленных коллег за помощь нам в столь удачном старте: bitfarmers.com (в том числе Михаэля Хирдеса, Джину Штайнер и Михаэля Зендке), а также Рене Хорнунга, Людмилу Лашковскую, Викторию Левенко, Яну Оникийчук, Мелиссу Притчард, Ютту Реберс, Анну Старикову и Оксану Жебель.

Если Вы, как авторы и/или читатели, желаете задать какие-либо вопросы, предложения или комментарии, то они в высшей степени приветствуются. Прошу Вас контактировать со мной напрямую, благодарю Вас.

Клаудия Кольтценбург
managingeditor@spam is badctt-journal.com

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Тим Хант

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Клетки входят в митоз (в более общем виде – в М-фазу цикла), когда активируются комплексы CDK1/циклин. Фосфорилирование при посредстве этих и других митотических протеинкиназ отвечает за реорганизацию клетки и запуск перехода в метафазу.
Наша работа проводилась в основном на ооцитах и яйцеклетках лягушек и клеточных экстрактах. Нашей целью было выяснить, сколько белков должно быть фосфорилировано, чтобы достичь этого состояния и пытались оценить число митотических «мишеней» для различных сочетаний циклина и CDK на определенный момент.
Выход из митоза, начинающийся с перехода от метафазы к анафазе, происходит тогда, когда активируется фактор, способствующий анафазе (АРС/С), который метит полиубикитиновыми цепями небольшое число целевых белков, включая циклины и секурин, что обозначает их как мишени для протеолиза в протеасомах. При этом хроматиды разделяются и движутся к противоположным полюсам клетки, где они деконденсируются и снова формируют функционально активное клеточное ядро. При цитокинезе идет разделение на две дочерние клетки. Митотические фосфопротеины возвращаются к своему интерфазному (гипо- или нефосфорилированному) состоянию.
Недавно мы случайно открыли, что фактор, ответственный за это дефосфорилирование после митоза, совершенно неактивен в экстрактах из клеток М-фазы (состояние митоза), и реактивируется при выходе клеток из митоза. Это объясняет, каким образом белки могут почти полностью переходить в гиперфосфорилированное состояние: здесь не только активируются киназы, но и отключаются фосфатазы, противодействующие этому. Представлены доказательства, которые привели нас к такому заключению. Они получены при исследованиях экстрактов яйцеклеток лягушки, выведенных из цитостатического блока путем добавления CaCl2, а также того факта, что кальцинейрин (протеинфосфатаза 2В) играет роль в уходе от сцепления с CSF. Однако реальная работа по восстановлению белков в их интерфазном гиперфосфорилированном состоянии осуществляется фактором, который мы назвали фосфатазой Х. Принадлежность и регуляция этого фактора подлежит дальнейшему обсуждению.

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Tim Hunt

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Cell Cycle Control Laboratory, Cancer Research UK, South Mimms, UK

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Cells enter mitosis (more generally, M-phase, and much of our work has been in frog oocytes and eggs and extracts thereof) when CDK1/cyclin complexes are activated. Phosphorylation by these, and other mitotic protein kinases, is responsible for reorganizing the cell and initiating progression to metaphase.
We would like to know how many proteins needs to be phosphorylated how much to bring about this state of affairs, and have been trying to enumerate the mitotic targets for various cyclin-CDK combinations for some time. I’ll talk about our approaches, difficulties and findings.
Exit from mitosis, starting at the metaphase to anaphase transition, occurs when the anaphasepromoting factor (APC/ C) is activated and tags a small number of target proteins, including cyclins and securin, with polyubiquitin chains that signal their proteolysis by the proteasome. Chromatids part and move to opposite poles of the cell where they decondense and re-form a functional nucleus.
Cytokinesis separates the two daughter cells. Mitotic phosphoproteins revert to their interphase un- or hypo-phosphorylated state.
We recently made the accidental discovery that the activity responsible for this postmitotic dephosphorylation is almost completely inactive in M-phase cell extracts, and is reactivated when cells exit mitosis. This explains how proteins can become almost completely converted to hyperphosphorylated states: not only are kinases activated, but the counteracting phosphatase(s) are concomitantly shut down. I will present the evidence that has led us to this conclusion. It stems from studies of frog egg extracts released from cytostatic factor (CSF) arrest by added CaCl2, and the discovery that calcineurin (protein phosphatase 2B) plays a role in escaping the clutches of CSF. But the real work of restoring proteins to their interphase state of hypophosphorylation is performed by an activity we call ‘Phosphatase X’, whose identity and regulation I shall discuss.

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Видеолекция


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Вхождение в митоз и выход из него (Видеолекция)

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Тим Хант

Клетки входят в митоз (в более общем виде – в М-фазу цикла), когда активируются комплексы CDK1/циклин. Фосфорилирование при посредстве этих и других митотических протеинкиназ отвечает за реорганизацию клетки и запуск перехода в метафазу.
Наша работа проводилась в основном на ооцитах и яйцеклетках лягушек и клеточных экстрактах. Нашей целью было выяснить, сколько белков должно быть фосфорилировано, чтобы достичь этого состояния и пытались оценить число митотических «мишеней» для различных сочетаний циклина и CDK на определенный момент.
Выход из митоза, начинающийся с перехода от метафазы к анафазе, происходит тогда, когда активируется фактор, способствующий анафазе (АРС/С), который метит полиубикитиновыми цепями небольшое число целевых белков, включая циклины и секурин, что обозначает их как мишени для протеолиза в протеасомах. При этом хроматиды разделяются и движутся к противоположным полюсам клетки, где они деконденсируются и снова формируют функционально активное клеточное ядро. При цитокинезе идет разделение на две дочерние клетки. Митотические фосфопротеины возвращаются к своему интерфазному (гипо- или нефосфорилированному) состоянию.
Недавно мы случайно открыли, что фактор, ответственный за это дефосфорилирование после митоза, совершенно неактивен в экстрактах из клеток М-фазы (состояние митоза), и реактивируется при выходе клеток из митоза. Это объясняет, каким образом белки могут почти полностью переходить в гиперфосфорилированное состояние: здесь не только активируются киназы, но и отключаются фосфатазы, противодействующие этому. Представлены доказательства, которые привели нас к такому заключению. Они получены при исследованиях экстрактов яйцеклеток лягушки, выведенных из цитостатического блока путем добавления CaCl2, а также того факта, что кальцинейрин (протеинфосфатаза 2В) играет роль в уходе от сцепления с CSF. Однако реальная работа по восстановлению белков в их интерфазном гиперфосфорилированном состоянии осуществляется фактором, который мы назвали фосфатазой Х. Принадлежность и регуляция этого фактора подлежит дальнейшему обсуждению.

Статьи о терапии мезенхимными клетками

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Гуч А., Доти Дж., Флорес Дж., Свенсон Л., Тегель Ф., Райсс Р. Г., Ланге К., Цандер А. Р., Ху Дж., Пул С., Жанг П., Вестенвельдер К.

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Авторы [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_RU] => Array ( [ID] => 26 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Организации [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 26 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => [VALUE] => [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 10881 [VALUE] => Array ( [TEXT] => <p class="bodytext">Наши обширные данные доклинического исследования, показывают, что острое повреждение почек (ОПП), индуцированное ишемией/реперфузией – резистентное к лечению осложнение у больных - может эффективно лечиться путем назначения аллогенных мезенхимных стволовых клеток (МСК). На этом основании в настоящее время проводится одобренная FDA I фаза клинических испытаний (<a href="http://www.clinicaltrials.gov" target="_blank">www.clinicaltrials.gov</a>; NCT00733876) больных, которые имели высокий риск развития тяжелой ОПП после хирургии на открытом сердце. В рамках испытаний безопасности метода, инфузии аллогенных МСК проводили больным после завершения хирургического вмешательства при аорто-коронарном шунтировании или хирургии клапанов сердца. В исследовании участвовали лица старше 65 лет с наличием почечных заболеваний, сахарного диабета, артериальной гипертензии, коронарной болезни сердца, тяжелой сердечной недостаточности и/или хронической обструктивной болезни легких. Введение МСК проводили по возрастающей, причем первым пяти больным проводилась инфузия клеток в определенной низкой дозе на кг массы тела через бедренный катетер, помещенный в надпочечную часть аорты. Данное сообщение содержит обобщенные сведения о клиническом течении у этих пяти больных, которых лечили по этому протоколу. Почечная функция не нарушалась после операции ни у одного из больных, и на текущий момент не выявлено побочных эффектов или тяжелых негативных явлений. Однако один из больных внезапно скончался через 26 суток после выписки по причинам, которые были расценены главным исследователем и членами Совета по мониторингу данных и безопасности, как не относящиеся к препарату и способу его применения. Следующая группа из пяти больных получит MСК в средней дозе на кг массы тела, и, если при этой дозе не возникнут проблемы с безопасностью, то еще пять больных будут пролечены при высокой дозе МСК на кг массы тела. Предварительная эффективность терапии МСК для профилактики и лечения послеоперационного ОПП в этом контингенте высокого риска (кардиохирургических больных) будет определяться по сравнению исходов у испытуемых лиц (частоты, тяжести и длительности послеоперационного ОПП, временной или постоянной зависимости от диализа, длительности госпитализации или гибели до 30 сут.), и в большой группе больных исторического контроля (база данных на <a href="http://www.STS.org" target="_blank">www.STS.org</a>).<br /> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Наши обширные данные доклинического исследования, показывают, что острое повреждение почек (ОПП), индуцированное ишемией/реперфузией – резистентное к лечению осложнение у больных - может эффективно лечиться путем назначения аллогенных мезенхимных стволовых клеток (МСК). На этом основании в настоящее время проводится одобренная FDA I фаза клинических испытаний (www.clinicaltrials.gov; NCT00733876) больных, которые имели высокий риск развития тяжелой ОПП после хирургии на открытом сердце. В рамках испытаний безопасности метода, инфузии аллогенных МСК проводили больным после завершения хирургического вмешательства при аорто-коронарном шунтировании или хирургии клапанов сердца. В исследовании участвовали лица старше 65 лет с наличием почечных заболеваний, сахарного диабета, артериальной гипертензии, коронарной болезни сердца, тяжелой сердечной недостаточности и/или хронической обструктивной болезни легких. Введение МСК проводили по возрастающей, причем первым пяти больным проводилась инфузия клеток в определенной низкой дозе на кг массы тела через бедренный катетер, помещенный в надпочечную часть аорты. Данное сообщение содержит обобщенные сведения о клиническом течении у этих пяти больных, которых лечили по этому протоколу. Почечная функция не нарушалась после операции ни у одного из больных, и на текущий момент не выявлено побочных эффектов или тяжелых негативных явлений. Однако один из больных внезапно скончался через 26 суток после выписки по причинам, которые были расценены главным исследователем и членами Совета по мониторингу данных и безопасности, как не относящиеся к препарату и способу его применения. Следующая группа из пяти больных получит MСК в средней дозе на кг массы тела, и, если при этой дозе не возникнут проблемы с безопасностью, то еще пять больных будут пролечены при высокой дозе МСК на кг массы тела. Предварительная эффективность терапии МСК для профилактики и лечения послеоперационного ОПП в этом контингенте высокого риска (кардиохирургических больных) будет определяться по сравнению исходов у испытуемых лиц (частоты, тяжести и длительности послеоперационного ОПП, временной или постоянной зависимости от диализа, длительности госпитализации или гибели до 30 сут.), и в большой группе больных исторического контроля (база данных на www.STS.org).
[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Описание/Резюме [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [DOI] => Array ( [ID] => 28 [TIMESTAMP_X] => 2016-04-06 14:11:12 [IBLOCK_ID] => 2 [NAME] => DOI [ACTIVE] => Y [SORT] => 500 [CODE] => DOI [DEFAULT_VALUE] => [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 80 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 28 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => [USER_TYPE_SETTINGS] => [HINT] => [PROPERTY_VALUE_ID] => 10843 [VALUE] => 10.3205/ctt-2008-en-000028.01 [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => 10.3205/ctt-2008-en-000028.01 [~DESCRIPTION] => [~NAME] => DOI [~DEFAULT_VALUE] => ) [AUTHOR_EN] => Array ( [ID] => 37 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Author [ACTIVE] => Y [SORT] => 500 [CODE] => AUTHOR_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 37 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 10863 [VALUE] => Array ( [TEXT] => <p class="Autor">Anna Gooch<sup>1</sup>, John Doty<sup>2</sup>, Jean Flores<sup>2</sup>, LeAnne Swenson<sup>2</sup>, Florian E Toegel<sup>1,3</sup>, George R Reiss<sup>4</sup>, Claudia Lange<sup>5</sup>, Axel R Zander<sup>5</sup>, Zhuma Hu<sup>1</sup>, Scott Poole<sup>1</sup>, Ping Zhang<sup>1</sup> and Christof Westenfelder<sup>1,6</sup> </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Anna Gooch1, John Doty2, Jean Flores2, LeAnne Swenson2, Florian E Toegel1,3, George R Reiss4, Claudia Lange5, Axel R Zander5, Zhuma Hu1, Scott Poole1, Ping Zhang1 and Christof Westenfelder1,6 

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 10864 [VALUE] => Array ( [TEXT] => <p class="bodytext"><sup>1</sup>Division of Nephrology, Department of Medicine, University of Utah Health Sciences Center and George E. Wahlen VA HCS, Salt Lake City, Utah, USA; <sup>2</sup>Division of Cardiovascular Surgery, Intermountain Medical Center, Murray, Utah, USA; <sup>3</sup>Jacobi Hospital, Albert Einstein College of Medicine affiliated Medical Center, Bronx, New York, USA; <sup>4</sup>Division of Cardiovascular Surgery, Department of Surgery, University of Utah Health Sciences Center, and Research Service, George E. Wahlen VA HCS, Salt Lake City, Utah, USA; <sup>5</sup>Bone Marrow Transplantation Center, University of Hamburg, Germany; <sup>6</sup>Department of Physiology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA <br /> <br /> <b>Correspondence: </b><br> Christof Westenfelder, MD, Section of Nephrology (111 N), George E. Wahlen VA Health Sciences Center, 500 Foothill Blvd., Salt Lake City, UT 84148, USA<br> E-mail: <a href="javascript:linkTo_UnCryptMailto('qempxs.glvmwxsj2aiwxirjiphivDlwg2yxel2ihy');" class="mail">christof.westenfelder@<span style="display:none;">spam is bad</span>hsc.utah.edu</a> </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

1Division of Nephrology, Department of Medicine, University of Utah Health Sciences Center and George E. Wahlen VA HCS, Salt Lake City, Utah, USA; 2Division of Cardiovascular Surgery, Intermountain Medical Center, Murray, Utah, USA; 3Jacobi Hospital, Albert Einstein College of Medicine affiliated Medical Center, Bronx, New York, USA; 4Division of Cardiovascular Surgery, Department of Surgery, University of Utah Health Sciences Center, and Research Service, George E. Wahlen VA HCS, Salt Lake City, Utah, USA; 5Bone Marrow Transplantation Center, University of Hamburg, Germany; 6Department of Physiology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
 
Correspondence:
Christof Westenfelder, MD, Section of Nephrology (111 N), George E. Wahlen VA Health Sciences Center, 500 Foothill Blvd., Salt Lake City, UT 84148, USA
E-mail: christof.westenfelder@spam is badhsc.utah.edu

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 10914 [VALUE] => Array ( [TEXT] => <p class="bodytext">Based on our extensive pre-clinical data that show that ischemia/reperfusion-induced Acute Kidney Injury (AKI), an essentially treatment resistant complication in patients, can be effectively treated by the administration of allogeneic Mesenchymal Stem Cells (MSC), an FDA approved, Phase I Clinical Trial (<a href="http://www.clinicaltrials.gov" target="_blank">www.clinicaltrials.gov</a>; NCT00733876) in patients who are at high risk of developing severe AKI post open heart surgery is currently being conducted. In this safety trial, patients who are undergoing on-pump coronary artery bypass surgery or cardiac valve repair, who are older than 65 years, with underlying renal disease, diabetes mellitus, hypertension, coronary artery disease, congestive heart failure and/or chronic obstructive pulmonary disease will be infused with allogeneic MSC following completion of surgery. The MSC are dosed in an escalating fashion, the initial five patients being infused via a femoral catheter that is placed into the suprarenal aorta with a defined low dose of MSC/kg body weight. This report summarizes the clinical course of the first five patients that have been treated according to this protocol. The renal function did not deteriorate post operatively in any of these patients, nor were adverse (AE) or severe adverse events (SAE) observed to date. However, one patient died suddenly 26 days after discharge from causes that both the principal investigator and the members of the Data and Safety Monitoring Board judged as being unrelated to the study drug and its route of administration. The next group of five study subjects will receive an intermediate dose of MSC/kg body weight, and if no safety concerns arise with this dose, the final five patients will be treated with a high dose of MSC/kg body weight. Preliminary efficacy of MSC therapy in the prevention and treatment of post-operative AKI in this high risk cohort of cardiac surgery patients will be assessed by comparing outcomes in study subjects (frequency, severity and duration of post-operative AKI, dialysis dependency [temporary, permanent], length of stay, and death at 30 days) to those in a large number of historical controls (data base at <a href="http://www.STS.org" target="_blank">www.STS.org</a>).<br /><br /> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Based on our extensive pre-clinical data that show that ischemia/reperfusion-induced Acute Kidney Injury (AKI), an essentially treatment resistant complication in patients, can be effectively treated by the administration of allogeneic Mesenchymal Stem Cells (MSC), an FDA approved, Phase I Clinical Trial (www.clinicaltrials.gov; NCT00733876) in patients who are at high risk of developing severe AKI post open heart surgery is currently being conducted. In this safety trial, patients who are undergoing on-pump coronary artery bypass surgery or cardiac valve repair, who are older than 65 years, with underlying renal disease, diabetes mellitus, hypertension, coronary artery disease, congestive heart failure and/or chronic obstructive pulmonary disease will be infused with allogeneic MSC following completion of surgery. The MSC are dosed in an escalating fashion, the initial five patients being infused via a femoral catheter that is placed into the suprarenal aorta with a defined low dose of MSC/kg body weight. This report summarizes the clinical course of the first five patients that have been treated according to this protocol. The renal function did not deteriorate post operatively in any of these patients, nor were adverse (AE) or severe adverse events (SAE) observed to date. However, one patient died suddenly 26 days after discharge from causes that both the principal investigator and the members of the Data and Safety Monitoring Board judged as being unrelated to the study drug and its route of administration. The next group of five study subjects will receive an intermediate dose of MSC/kg body weight, and if no safety concerns arise with this dose, the final five patients will be treated with a high dose of MSC/kg body weight. Preliminary efficacy of MSC therapy in the prevention and treatment of post-operative AKI in this high risk cohort of cardiac surgery patients will be assessed by comparing outcomes in study subjects (frequency, severity and duration of post-operative AKI, dialysis dependency [temporary, permanent], length of stay, and death at 30 days) to those in a large number of historical controls (data base at www.STS.org).

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Первичный отчет о фазе I клинических испытаний: профилактика и лечение острого послеоперационного повреждения почек аллогенными мезенхимными стволовыми клетками у кардиохирургических больных при операциях на открытом сердце

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Гуч А., Доти Дж., Флорес Дж., Свенсон Л., Тегель Ф., Райсс Р. Г., Ланге К., Цандер А. Р., Ху Дж., Пул С., Жанг П., Вестенвельдер К.

Наши обширные данные доклинического исследования, показывают, что острое повреждение почек (ОПП), индуцированное ишемией/реперфузией – резистентное к лечению осложнение у больных - может эффективно лечиться путем назначения аллогенных мезенхимных стволовых клеток (МСК). На этом основании в настоящее время проводится одобренная FDA I фаза клинических испытаний (www.clinicaltrials.gov; NCT00733876) больных, которые имели высокий риск развития тяжелой ОПП после хирургии на открытом сердце. В рамках испытаний безопасности метода, инфузии аллогенных МСК проводили больным после завершения хирургического вмешательства при аорто-коронарном шунтировании или хирургии клапанов сердца. В исследовании участвовали лица старше 65 лет с наличием почечных заболеваний, сахарного диабета, артериальной гипертензии, коронарной болезни сердца, тяжелой сердечной недостаточности и/или хронической обструктивной болезни легких. Введение МСК проводили по возрастающей, причем первым пяти больным проводилась инфузия клеток в определенной низкой дозе на кг массы тела через бедренный катетер, помещенный в надпочечную часть аорты. Данное сообщение содержит обобщенные сведения о клиническом течении у этих пяти больных, которых лечили по этому протоколу. Почечная функция не нарушалась после операции ни у одного из больных, и на текущий момент не выявлено побочных эффектов или тяжелых негативных явлений. Однако один из больных внезапно скончался через 26 суток после выписки по причинам, которые были расценены главным исследователем и членами Совета по мониторингу данных и безопасности, как не относящиеся к препарату и способу его применения. Следующая группа из пяти больных получит MСК в средней дозе на кг массы тела, и, если при этой дозе не возникнут проблемы с безопасностью, то еще пять больных будут пролечены при высокой дозе МСК на кг массы тела. Предварительная эффективность терапии МСК для профилактики и лечения послеоперационного ОПП в этом контингенте высокого риска (кардиохирургических больных) будет определяться по сравнению исходов у испытуемых лиц (частоты, тяжести и длительности послеоперационного ОПП, временной или постоянной зависимости от диализа, длительности госпитализации или гибели до 30 сут.), и в большой группе больных исторического контроля (база данных на www.STS.org).

Статьи о терапии мезенхимными клетками

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Ратайчак М.З., Кучал М., Шин Д.М., Руи Л., Друкала Ю., Марлиш В., Ратайчак Я., Зуба-Сурма Э.К.

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Накапливаются сведения о том, что ткани взрослого организма содержат популяцию весьма примитивных плюрипотентных стволовых клеток (СК). В недавних исследованиях наша группа провела идентификацию небольших по размеру стволовых клеток в костном мозге мыши и других органах взрослыго организма. Эти клетки экспрессируют маркеры, характерные для стволовых клеток, происходящих эпибласта/зародышевых клеток. Мы назвали эти клетки «очень маленькими стволовыми клетками, схожими с эмбриональным» (МСКЭ). Мы предположили, что эти клетки, которые накапливаются в период ранней гаструляции в развивающихся тканях/органах, играют важную роль в обороте тканеспецифических/коммитированных популяций СК. На основании этого, мы допускаем, что зародышевая линия клеток является не только источником, но и «основой или костяком» для фракции стволовых клеток во взрослом организме. Мы показали, что МСКЭ могут быть мобилизованы в периферическую кровь, и число этих циркулирующих клеток повышается в период стресса и повреждений тканей/органов (например, при инфаркте миокарда, инсульте). Кроме того, наши данные указывают на то, что МСКЭ защищены от неконтролируемой пролиферации и образования тератом вследствие уникального типа метилирования отдельных генов, который реализуется по механизму соматического геномного импринтинга. Наконец, мы предполагаем, что МСКЭ в патологических ситуациях могут быть вовлечены в развитие некоторых злокачественных заболеваний (например, таратом, герминальных опухолей, сарком в детском возрасте).

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Mariusz Z. Ratajczak1,2, Magda Kucia1, Dong-Myung Shin1, Liu Rui1, Justyna Drukala1, Wojtek Marlicz2, Janina Ratajczak1, Ewa K. Zuba-Surma1

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 11143 [VALUE] => Array ( [TEXT] => <p class="bodytext"><sup>1</sup>Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA; <br> <sup>2</sup>Department of Physiopathology, Pomeranian Medical University, Szczecin, Poland</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

1Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA; 
2Department of Physiopathology, Pomeranian Medical University, Szczecin, Poland

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 11144 [VALUE] => Array ( [TEXT] => <p class="bodytext">Accumulating evidence demonstrates that adult tissue contains a population of very primitive pluripotent stem cells (PSCs). Recently, our group identified a population of very small SCs in murine bone marrow (BM) and other adult organs that express several markers characteristic for epiblast/germ line-derived SCs. We named these rare cells “very small embryonic like stem cells (VSELs).” We hypothesized that these cells, which are deposited during early gastrulation in developing tissues/organs, play an important role in the turnover of tissue-specific/committed SCs. Based on this, we envision that germ line is not only the origin but also a “basis/skeleton” for the SC compartment in adult life forms. We noticed that VSELs could be mobilized into peripheral blood (PB) and the number of these cells circulating in PB increases during stress and tissue/organ injuries (e.g., heart infarct, stroke). Furthermore, our data indicates that VSELs are protected from uncontrolled proliferation and teratoma formation by a unique pattern of methylation of selected somatic imprinted genes. Finally, we envision that in pathological situations, VSELs could be involved in the development of some malignancies (e.g., teratomas, germinal tumors, pediatric sarcomas).</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Accumulating evidence demonstrates that adult tissue contains a population of very primitive pluripotent stem cells (PSCs). Recently, our group identified a population of very small SCs in murine bone marrow (BM) and other adult organs that express several markers characteristic for epiblast/germ line-derived SCs. We named these rare cells “very small embryonic like stem cells (VSELs).” We hypothesized that these cells, which are deposited during early gastrulation in developing tissues/organs, play an important role in the turnover of tissue-specific/committed SCs. Based on this, we envision that germ line is not only the origin but also a “basis/skeleton” for the SC compartment in adult life forms. We noticed that VSELs could be mobilized into peripheral blood (PB) and the number of these cells circulating in PB increases during stress and tissue/organ injuries (e.g., heart infarct, stroke). Furthermore, our data indicates that VSELs are protected from uncontrolled proliferation and teratoma formation by a unique pattern of methylation of selected somatic imprinted genes. Finally, we envision that in pathological situations, VSELs could be involved in the development of some malignancies (e.g., teratomas, germinal tumors, pediatric sarcomas).

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Уникальная популяция мобильных небольших эмбрионоподобных стволовых клеток (МСКЭ) сохраняется в тканях взрослого организма: физиологические и патологические последствия

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Ратайчак М.З., Кучал М., Шин Д.М., Руи Л., Друкала Ю., Марлиш В., Ратайчак Я., Зуба-Сурма Э.К.

Накапливаются сведения о том, что ткани взрослого организма содержат популяцию весьма примитивных плюрипотентных стволовых клеток (СК). В недавних исследованиях наша группа провела идентификацию небольших по размеру стволовых клеток в костном мозге мыши и других органах взрослыго организма. Эти клетки экспрессируют маркеры, характерные для стволовых клеток, происходящих эпибласта/зародышевых клеток. Мы назвали эти клетки «очень маленькими стволовыми клетками, схожими с эмбриональным» (МСКЭ). Мы предположили, что эти клетки, которые накапливаются в период ранней гаструляции в развивающихся тканях/органах, играют важную роль в обороте тканеспецифических/коммитированных популяций СК. На основании этого, мы допускаем, что зародышевая линия клеток является не только источником, но и «основой или костяком» для фракции стволовых клеток во взрослом организме. Мы показали, что МСКЭ могут быть мобилизованы в периферическую кровь, и число этих циркулирующих клеток повышается в период стресса и повреждений тканей/органов (например, при инфаркте миокарда, инсульте). Кроме того, наши данные указывают на то, что МСКЭ защищены от неконтролируемой пролиферации и образования тератом вследствие уникального типа метилирования отдельных генов, который реализуется по механизму соматического геномного импринтинга. Наконец, мы предполагаем, что МСКЭ в патологических ситуациях могут быть вовлечены в развитие некоторых злокачественных заболеваний (например, таратом, герминальных опухолей, сарком в детском возрасте).

Статьи о терапии мезенхимными клетками

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Бархатов И. М., Румянцев С. А., Владимирская Е. Б., Афанасьев Б. В.

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Авторы [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_RU] => Array ( [ID] => 26 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Организации [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 26 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => [VALUE] => [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 5626 [VALUE] => Array ( [TEXT] => <h2>Резюме</h2> <h2>Введение </h2> <p class="bodytext"> В условиях монослойной культуры клетки пуповинной крови способны прикрепляться к пластику и по своей морфологии напоминают культивируемые в сходных условиях мезенхимальные стволовые клетки (МСК) костного мозга. Однако присутствие в прилипающей фракции пуповинной крови МСК до сих пор не является очевидным. Данное исследование выполнено с целью определения состава и ряда функциональных свойств МСК-подобных клеток в монослойной культуре пуповинной крови (МКПК) человека. </p> <h2>Материалы и методы</h2> <p> Исследовали сорок три образца пуповинной крови, полученые в срочных родах на фоне неосложненной беременности у рожениц при атравматичном заборе. Исследования проводили после  19-31 часов хранения образца. Ядросодержащие клетки выделяли на градиенте плотности фиколла (1,077 г/мл), затем помещали в полную культуральную среду, содержащую среду DMEM LG, эмбриональную телячью сыворотку - 30%, пенициллин  (100 Ед/мл), стрептомицин (0,1 мг/мл). Анализ фенотипа монослойной культуры ПК и ее мононуклеарной фракции проводили на проточном цитофлюориметре FACScan. Были использованы следующие конъюгированные флюорохромами антитела: CD34 PE; CD34 FITC, CD45 FITC; CD45 PE; CD14 FITC; CD31 PE; CD31 FITC; CD61 FITC; CD3 FITC; CD19 PE; CD117 PE; HLA ABC FITC; HLA DR.  С целью определения гемостимулирующих свойств монослойной культуры ПК проводили клонирование гранулоцитарно-макрофагальных предшественников (КОЕ-ГМ) в культуральной системе «агаровая капля-жидкая среда». В качестве источника колониестимулирующей активности ПК использовали МКПК. Клетками-мишенями были КОЕ-ГМ мононуклеарной фракции ПК, дающие клональный рост в агаровой культуре. Для индукции дифференцировки МСК-подобных клеток ПК в адипогенном и остеогенном направлении клетки помещали в полную среду с добавлением  дексаметазона (1х10<sup>-7</sup> М); инсулина (1х10<sup>-9</sup> М) или β-глицерофосфата (7х10<sup>-3</sup> М); дексаметазона (1х10<sup>-8</sup> М); аскорбиновой кислоты (2х10<sup>-4</sup> М) соответственно. Оценка экспрессии генов (CDH11,VCAM1, ITGB1, IL6ST, TFRC, ALCAM, MPL, TPO, ENG, NT5E, IL6R, BGLAP, COL1A2, AFP, LPL, ACTA1, TNNI3, TPM1)  проводилось методом RT-PCR (амплификация продуктов обратной транскрипции). </p> <h2>Результаты</h2> <p> В большинстве случаев культура клеток, прилипших к пластику была гетерогенна: наблюдали узкие веретенообразные клетки и большие полигональные. В ряде образцов обнаруживали небольшие колонии (до 100 клеток). В 3 из 43 исследованных образцов ПК наблюдали крупные колонии, численностью более 1000 плотноупакованных, имеющих типичную для фибробластов веретенообразную форму клеток. При анализе преобладающих клеточных типов было выявлено, что большую часть прикрепленных к пластику клеток составляли гемопоэтические клетки (медиана 60,17%). Около трети от всей СD45-положительной популяции составляли СD14-положительные клетки. Остальные негемопоэтические клетки представляли собой фенотипически гетерогенную популяцию. На фоне длительного культивирования и последовательного пассирования фенотип культуры меняется – отмечается элиминация из культуры гемопоэтических клеток и увеличение доли МСК и ЭКП. При инициации культуры значительно изменяется соотношение ГСК- и ЭКП-подобных клеток среди CD34-положительной популяции в пользу ЭКП. МСК-подобные клетки МКПК способны к дифференцировке в адипоциты и остеобласты, что подтверждается специфической окраской и свидетельствует в пользу их функциональной состоятельности. В ряде культур индукция дифференцировки инициировала открепление большей части клеток. Прилипающая фракция первичной монослойной культуры оказывает стимулирующее влияние на колониеобразование КОЕ-ГМ, по характеру и силе воздействия близкое стандартному лейкоцитарному фидеру. Преимущественное влияние на их пролиферативную активность оказывают клеточные элементы с маркерами МСК (CD90<sup>+</sup>CD31<sup>-</sup>). Удлинение временных параметров получения и хранения образцов ПК приводят к снижению гемостимулирующей активности. При сравнении экспрессии ряда генов выявлено, что профиль экспрессии МСК костного мозга и клеток МКПК идентичен за исключением тромбопоэтина, экспрессия гена которого не отмечалась в МКПК. </p> <h2>Заключение</h2> <p> Пуповинная кровь содержит субпопуляции клеток негемопоэтического происхождения,  фенотипически и функционально сходных с МСК костного мозга. Однако их низкая концентрация, а также сниженная репопулирующая активность в стандартных культуральных условиях, ставят под сомнение возможное использование ПК в качестве альтернативного источника МСК. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Резюме

Введение

В условиях монослойной культуры клетки пуповинной крови способны прикрепляться к пластику и по своей морфологии напоминают культивируемые в сходных условиях мезенхимальные стволовые клетки (МСК) костного мозга. Однако присутствие в прилипающей фракции пуповинной крови МСК до сих пор не является очевидным. Данное исследование выполнено с целью определения состава и ряда функциональных свойств МСК-подобных клеток в монослойной культуре пуповинной крови (МКПК) человека.

Материалы и методы

Исследовали сорок три образца пуповинной крови, полученые в срочных родах на фоне неосложненной беременности у рожениц при атравматичном заборе. Исследования проводили после  19-31 часов хранения образца. Ядросодержащие клетки выделяли на градиенте плотности фиколла (1,077 г/мл), затем помещали в полную культуральную среду, содержащую среду DMEM LG, эмбриональную телячью сыворотку - 30%, пенициллин  (100 Ед/мл), стрептомицин (0,1 мг/мл). Анализ фенотипа монослойной культуры ПК и ее мононуклеарной фракции проводили на проточном цитофлюориметре FACScan. Были использованы следующие конъюгированные флюорохромами антитела: CD34 PE; CD34 FITC, CD45 FITC; CD45 PE; CD14 FITC; CD31 PE; CD31 FITC; CD61 FITC; CD3 FITC; CD19 PE; CD117 PE; HLA ABC FITC; HLA DR.  С целью определения гемостимулирующих свойств монослойной культуры ПК проводили клонирование гранулоцитарно-макрофагальных предшественников (КОЕ-ГМ) в культуральной системе «агаровая капля-жидкая среда». В качестве источника колониестимулирующей активности ПК использовали МКПК. Клетками-мишенями были КОЕ-ГМ мононуклеарной фракции ПК, дающие клональный рост в агаровой культуре. Для индукции дифференцировки МСК-подобных клеток ПК в адипогенном и остеогенном направлении клетки помещали в полную среду с добавлением  дексаметазона (1х10-7 М); инсулина (1х10-9 М) или β-глицерофосфата (7х10-3 М); дексаметазона (1х10-8 М); аскорбиновой кислоты (2х10-4 М) соответственно. Оценка экспрессии генов (CDH11,VCAM1, ITGB1, IL6ST, TFRC, ALCAM, MPL, TPO, ENG, NT5E, IL6R, BGLAP, COL1A2, AFP, LPL, ACTA1, TNNI3, TPM1)  проводилось методом RT-PCR (амплификация продуктов обратной транскрипции).

Результаты

В большинстве случаев культура клеток, прилипших к пластику была гетерогенна: наблюдали узкие веретенообразные клетки и большие полигональные. В ряде образцов обнаруживали небольшие колонии (до 100 клеток). В 3 из 43 исследованных образцов ПК наблюдали крупные колонии, численностью более 1000 плотноупакованных, имеющих типичную для фибробластов веретенообразную форму клеток. При анализе преобладающих клеточных типов было выявлено, что большую часть прикрепленных к пластику клеток составляли гемопоэтические клетки (медиана 60,17%). Около трети от всей СD45-положительной популяции составляли СD14-положительные клетки. Остальные негемопоэтические клетки представляли собой фенотипически гетерогенную популяцию. На фоне длительного культивирования и последовательного пассирования фенотип культуры меняется – отмечается элиминация из культуры гемопоэтических клеток и увеличение доли МСК и ЭКП. При инициации культуры значительно изменяется соотношение ГСК- и ЭКП-подобных клеток среди CD34-положительной популяции в пользу ЭКП. МСК-подобные клетки МКПК способны к дифференцировке в адипоциты и остеобласты, что подтверждается специфической окраской и свидетельствует в пользу их функциональной состоятельности. В ряде культур индукция дифференцировки инициировала открепление большей части клеток. Прилипающая фракция первичной монослойной культуры оказывает стимулирующее влияние на колониеобразование КОЕ-ГМ, по характеру и силе воздействия близкое стандартному лейкоцитарному фидеру. Преимущественное влияние на их пролиферативную активность оказывают клеточные элементы с маркерами МСК (CD90+CD31-). Удлинение временных параметров получения и хранения образцов ПК приводят к снижению гемостимулирующей активности. При сравнении экспрессии ряда генов выявлено, что профиль экспрессии МСК костного мозга и клеток МКПК идентичен за исключением тромбопоэтина, экспрессия гена которого не отмечалась в МКПК.

Заключение

Пуповинная кровь содержит субпопуляции клеток негемопоэтического происхождения,  фенотипически и функционально сходных с МСК костного мозга. Однако их низкая концентрация, а также сниженная репопулирующая активность в стандартных культуральных условиях, ставят под сомнение возможное использование ПК в качестве альтернативного источника МСК.

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Barkhatov I. M.1, Roumiantsev S. A.2, Vladimirskaya E. B.2, Afanasyev B. V.1

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1Saint-Petersburg Pavlov State Medical University, Russia;
2Russian Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

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Summary

Objectives

It’s known that during cultivation, adherent cells of umbilical cord blood (UCB) form a monolayer reminiscent, in its composition, of the stromal monolayer of bone marrow (BM) culture. However, the presence of mesenchymal stem cells (MSCs) in UCB still remains uncertain. This study was performed to investigate the composition and some functional characteristics of MSC-like cell populations revealed in the cord blood monolayer culture.

Materials and methods

Forty-three human UCB samples were under study. All the samples were obtained during full-term deliveries. To produce monolayer cultures, mononuclear cell fractions from UCB were cultivated in a culture medium containing DMEM with 20% FCS, supplied with 1% Pen/Strep. Phenotypic patterns of UCB culture were assessed with a panel of monoclonal antibodies specific for CD34; CD117; CD45; CD14; CD3; CD19; CD31; CD90; HLA DR; and HLA ABC. To determine the functional characteristics of MSCs derived from UCB culture, their differentiation ability and stimulation of hematopoietic colony formation activity were evaluated.

Results

In most cases, the cultures of plastic-adherent cells proved to be heterogeneous. Both spindle-shaped and polygonal cells were observed. In some samples, clonal growth could be detected. However, the number of fibroblastoid cells did not increase 100 cells per colony. Large colonies were registered in three UCB samples of the 43 under study. As evidenced by immune phenotyping, the monolayer UCB cultures were rather polymorphic and dissimilar in each sample. Most of the cells present in the cultures were macrophages (CD45+). However, we also found different amounts of presumably mesenchymal cells, including cells with an endothelial phenotype (CD34+CD31+).

Specific staining showed that the cells from a UCB monolayer culture have the capacity to differentiate into adipocytes and osteoblasts. In some cultures, however, induction of differentiation lead to the detachment of a major cell fraction. Hemostimulatory ability of UCB monolayer cultures depended on the phenotype composition of the monolayer culture. CD45+ and CD14+ cells, evidently, are stimulatory for granulocyte-macrophage colony formation. Moreover, levels of non-hematopoietic subpopulations (CD90+CD31-) in UCB cultures showed a direct correlation with the numbers of CFU-GM colonies produced.

Conclusion

UCB contains a subpopulation of non-hematopoietic cells possessing phenotypic and some functional characteristics of bone marrow derived mesenchymal stem cells. However, the low content and variable numbers of such cells provide some doubts on the viability of UCB as an alternative source for MSC.

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Состав и функциональные особенности монослойной культуры пуповинной крови человека

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Бархатов И. М., Румянцев С. А., Владимирская Е. Б., Афанасьев Б. В.

Резюме

Введение

В условиях монослойной культуры клетки пуповинной крови способны прикрепляться к пластику и по своей морфологии напоминают культивируемые в сходных условиях мезенхимальные стволовые клетки (МСК) костного мозга. Однако присутствие в прилипающей фракции пуповинной крови МСК до сих пор не является очевидным. Данное исследование выполнено с целью определения состава и ряда функциональных свойств МСК-подобных клеток в монослойной культуре пуповинной крови (МКПК) человека.

Материалы и методы

Исследовали сорок три образца пуповинной крови, полученые в срочных родах на фоне неосложненной беременности у рожениц при атравматичном заборе. Исследования проводили после  19-31 часов хранения образца. Ядросодержащие клетки выделяли на градиенте плотности фиколла (1,077 г/мл), затем помещали в полную культуральную среду, содержащую среду DMEM LG, эмбриональную телячью сыворотку - 30%, пенициллин  (100 Ед/мл), стрептомицин (0,1 мг/мл). Анализ фенотипа монослойной культуры ПК и ее мононуклеарной фракции проводили на проточном цитофлюориметре FACScan. Были использованы следующие конъюгированные флюорохромами антитела: CD34 PE; CD34 FITC, CD45 FITC; CD45 PE; CD14 FITC; CD31 PE; CD31 FITC; CD61 FITC; CD3 FITC; CD19 PE; CD117 PE; HLA ABC FITC; HLA DR.  С целью определения гемостимулирующих свойств монослойной культуры ПК проводили клонирование гранулоцитарно-макрофагальных предшественников (КОЕ-ГМ) в культуральной системе «агаровая капля-жидкая среда». В качестве источника колониестимулирующей активности ПК использовали МКПК. Клетками-мишенями были КОЕ-ГМ мононуклеарной фракции ПК, дающие клональный рост в агаровой культуре. Для индукции дифференцировки МСК-подобных клеток ПК в адипогенном и остеогенном направлении клетки помещали в полную среду с добавлением  дексаметазона (1х10-7 М); инсулина (1х10-9 М) или β-глицерофосфата (7х10-3 М); дексаметазона (1х10-8 М); аскорбиновой кислоты (2х10-4 М) соответственно. Оценка экспрессии генов (CDH11,VCAM1, ITGB1, IL6ST, TFRC, ALCAM, MPL, TPO, ENG, NT5E, IL6R, BGLAP, COL1A2, AFP, LPL, ACTA1, TNNI3, TPM1)  проводилось методом RT-PCR (амплификация продуктов обратной транскрипции).

Результаты

В большинстве случаев культура клеток, прилипших к пластику была гетерогенна: наблюдали узкие веретенообразные клетки и большие полигональные. В ряде образцов обнаруживали небольшие колонии (до 100 клеток). В 3 из 43 исследованных образцов ПК наблюдали крупные колонии, численностью более 1000 плотноупакованных, имеющих типичную для фибробластов веретенообразную форму клеток. При анализе преобладающих клеточных типов было выявлено, что большую часть прикрепленных к пластику клеток составляли гемопоэтические клетки (медиана 60,17%). Около трети от всей СD45-положительной популяции составляли СD14-положительные клетки. Остальные негемопоэтические клетки представляли собой фенотипически гетерогенную популяцию. На фоне длительного культивирования и последовательного пассирования фенотип культуры меняется – отмечается элиминация из культуры гемопоэтических клеток и увеличение доли МСК и ЭКП. При инициации культуры значительно изменяется соотношение ГСК- и ЭКП-подобных клеток среди CD34-положительной популяции в пользу ЭКП. МСК-подобные клетки МКПК способны к дифференцировке в адипоциты и остеобласты, что подтверждается специфической окраской и свидетельствует в пользу их функциональной состоятельности. В ряде культур индукция дифференцировки инициировала открепление большей части клеток. Прилипающая фракция первичной монослойной культуры оказывает стимулирующее влияние на колониеобразование КОЕ-ГМ, по характеру и силе воздействия близкое стандартному лейкоцитарному фидеру. Преимущественное влияние на их пролиферативную активность оказывают клеточные элементы с маркерами МСК (CD90+CD31-). Удлинение временных параметров получения и хранения образцов ПК приводят к снижению гемостимулирующей активности. При сравнении экспрессии ряда генов выявлено, что профиль экспрессии МСК костного мозга и клеток МКПК идентичен за исключением тромбопоэтина, экспрессия гена которого не отмечалась в МКПК.

Заключение

Пуповинная кровь содержит субпопуляции клеток негемопоэтического происхождения,  фенотипически и функционально сходных с МСК костного мозга. Однако их низкая концентрация, а также сниженная репопулирующая активность в стандартных культуральных условиях, ставят под сомнение возможное использование ПК в качестве альтернативного источника МСК.

Статьи о терапии мезенхимными клетками

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Станкевич Ю. А., Головачева А. А., Бабенко Е. В., Алянский А. Л., Паина О. В., Зубаровская Л. С., Семенова E. В., Полынцев Д. Г., Кругляков П. В., Афанасьев Б. В.

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Эти клетки улучшают приживление ГСК после аллогенной ТГСК и способствуют репарации тканей мезенхимного происхождения, а также способны модулировать иммунный ответ <em>in vitro</em> и <em>in vivo</em>. В результате, ко-трансплантация аллогенных МСК с аллогенными ГСК гипотетически обладает такими положительными эффектами, как улучшение приживления трансплантата и восстановление баланса внутри иммунной системы. Это обстоятельство может быть использовано как для профилактики РТПХ, так и для лечения острой стероид-резистентной РТПХ или хронической РТПХ. В данном исследовании показано, что на терапию МСК  отвечают более половины пациентов со стероид-резистентной острой РТПХ. </p> <h2>Пациенты и методы</h2> <p class="bodytext"> В исследование включены пациенты от 6 до 53 лет с ОЛЛ (n=9), ОМЛ (n=7), НХЛ (n=3), МДС (n=2) и ХМЛ (n=3), которым в период с октября 2005 по май 2008 была выполнена аллогенная ТГСК от родственного (n=5) или неродственного доноров (n=19). Для приживления ГСК и профилактики острой РТПХ 8 пациентам проведена ко-трансплантация МСК и ГСК. Шестнадцать пациентов получили изолированное введение МСК для лечения стероид-резистентной РТПХ. Десяти пациентам осуществлено одно введение МСК, пять пациентов два введения и один пациент получил три введения МСК. Процесс выделения и культивирования МСК осуществляли в компании «Транс Технологии» (лицензия № 99-01-002224 от 14.07.2005). </p> <h2>Результаты</h2> <p class="bodytext"> В случае выполнения ко-трансплантации приживление лейкоцитов зарегистрировано на 21 день (от 16 до 38), тромбоцитов на 24 день (от 14 до 45). Острую РТПХ 0-I степеней наблюдали в 85,8% ко-трансплантаций, что не требовало дополнительной терапии, острая РТПХ II-IV развилась у 14,2 % пациентов. У всех пациентов хронической РТПХ не было. Инфекционные осложнения зарегистрированы у 2 пациентов (25%). Общая безрецидивная 2,5-летняя выживаемость составила 71%.<br> Результаты применения МСК для терапии РТПХ представлены в таблице 1. </p> <div class="csc-textpic csc-textpic-intext-left-nowrap"> <div class="csc-textpic-imagewrap"> <dl class="csc-textpic-image csc-textpic-firstcol csc-textpic-lastcol" style="width:600px;"> <img width="420" alt="974b56410a.jpg" src="/upload/medialibrary/98f/98f24ae7195f0030c84d9bbad4190557.jpg" height="163" title="974b56410a.jpg"> </dl> </div> </div> <span style="font-size: 17px; font-family: Cuprum, sans-serif; font-weight: bold; line-height: 24px;">Таблица 1. Результаты применения МСК для терапии РТПХ. </span> <h2>Выводы</h2> <p class="bodytext"> 1. Инфузии МСК были безопасны, не сопровождались немедленными реакциями во время введения или отсроченными МСК-ассоциированными токсичностями.<br> 2. Инфузия МСК перед аллоТГСК не влияли на приживление трансплантата ГСК. <br> 3. Инфузия МСК при ко-трансплантации в режиме кондиционирования может предотвратить развитие тяжелых форм острой или хронической РТПХ.<br> 4. Инфузия МСК для лечения резистентной острой РТПХ может быть эффективным у ряда пациентов. <br> 5. Использование МСК перед аллоТГСК не увеличивало частоту рецидивов основного заболевания.<br> 6. Использование МСК более эффективно у пациентов, получивших миелоаблативный режим кондиционирования и профилактику острой РТПХ с применением АЛГ.<br> 7. Необходимо проведение дальнейших рандомизированных клинических исследований для оценки терапевтического эффекта МСК у пациентов после аллоТГСК и определения факторов, оказывающих влияние на эффективность МСК терапии. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Резюме

Введение

Костный мозг человека содержит гемопоэтические стволовые клетки (ГСК) и негемопоэтические стволовые клетки, называемые мезенхимными стволовыми клетками (МСК). Эти клетки улучшают приживление ГСК после аллогенной ТГСК и способствуют репарации тканей мезенхимного происхождения, а также способны модулировать иммунный ответ in vitro и in vivo. В результате, ко-трансплантация аллогенных МСК с аллогенными ГСК гипотетически обладает такими положительными эффектами, как улучшение приживления трансплантата и восстановление баланса внутри иммунной системы. Это обстоятельство может быть использовано как для профилактики РТПХ, так и для лечения острой стероид-резистентной РТПХ или хронической РТПХ. В данном исследовании показано, что на терапию МСК  отвечают более половины пациентов со стероид-резистентной острой РТПХ.

Пациенты и методы

В исследование включены пациенты от 6 до 53 лет с ОЛЛ (n=9), ОМЛ (n=7), НХЛ (n=3), МДС (n=2) и ХМЛ (n=3), которым в период с октября 2005 по май 2008 была выполнена аллогенная ТГСК от родственного (n=5) или неродственного доноров (n=19). Для приживления ГСК и профилактики острой РТПХ 8 пациентам проведена ко-трансплантация МСК и ГСК. Шестнадцать пациентов получили изолированное введение МСК для лечения стероид-резистентной РТПХ. Десяти пациентам осуществлено одно введение МСК, пять пациентов два введения и один пациент получил три введения МСК. Процесс выделения и культивирования МСК осуществляли в компании «Транс Технологии» (лицензия № 99-01-002224 от 14.07.2005).

Результаты

В случае выполнения ко-трансплантации приживление лейкоцитов зарегистрировано на 21 день (от 16 до 38), тромбоцитов на 24 день (от 14 до 45). Острую РТПХ 0-I степеней наблюдали в 85,8% ко-трансплантаций, что не требовало дополнительной терапии, острая РТПХ II-IV развилась у 14,2 % пациентов. У всех пациентов хронической РТПХ не было. Инфекционные осложнения зарегистрированы у 2 пациентов (25%). Общая безрецидивная 2,5-летняя выживаемость составила 71%.
Результаты применения МСК для терапии РТПХ представлены в таблице 1.

974b56410a.jpg
Таблица 1. Результаты применения МСК для терапии РТПХ. 

Выводы

1. Инфузии МСК были безопасны, не сопровождались немедленными реакциями во время введения или отсроченными МСК-ассоциированными токсичностями.
2. Инфузия МСК перед аллоТГСК не влияли на приживление трансплантата ГСК.
3. Инфузия МСК при ко-трансплантации в режиме кондиционирования может предотвратить развитие тяжелых форм острой или хронической РТПХ.
4. Инфузия МСК для лечения резистентной острой РТПХ может быть эффективным у ряда пациентов.
5. Использование МСК перед аллоТГСК не увеличивало частоту рецидивов основного заболевания.
6. Использование МСК более эффективно у пациентов, получивших миелоаблативный режим кондиционирования и профилактику острой РТПХ с применением АЛГ.
7. Необходимо проведение дальнейших рандомизированных клинических исследований для оценки терапевтического эффекта МСК у пациентов после аллоТГСК и определения факторов, оказывающих влияние на эффективность МСК терапии.

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Stankevich Y.1, Golovacheva A.1, Babenko E.1, Alyansky A.1, Paina O.1, Zubarovskaya L.1, Semenova E.1, Polintsev D.2,
Kruglyakov P.2, Afanasyev B.1

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1Pavlov State Medical University, St. Petersburg, Russia;
2"TransTechnology" LtD, St. Petersburg, Russia

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Summary

Within bone marrow stroma, there exist subsets of nonhematopoietic cells referred to as mesenchymal stem cells (MSCs), or mesenchymal stromal cells [1]. These cells may not only improve HSC engraftment and regeneration of damaged tissues after allogeneic transplantation [7], but also modulate immune responses in vitro and in vivo [8]. Hence, co-transplantation of allogeneic HSC together with allogeneic MSC hypothetically could provide some beneficial effects, such as enhanced engraftment, acceleration of immune reconstitution [4], GVHD suppression, and it may be used for GVHD prophylaxis, like as for treatment of severe acute or chronic GVHD. This study shows that more than a half of the patients with steroid-refractory acute GVHD responded to treatment with MSCs. However, further randomized clinical trials are necessary for estimation of therapeutic effect of MSCs in allo-HSCT patients and definition of important and significant factors influenced upon MSCs infusion.

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Предварительные данные клинического использования мезенхимных стволовых клеток для профилактики и лечения РТПХ у пациентов после аллогенной ТГСК

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Станкевич Ю. А., Головачева А. А., Бабенко Е. В., Алянский А. Л., Паина О. В., Зубаровская Л. С., Семенова E. В., Полынцев Д. Г., Кругляков П. В., Афанасьев Б. В.

Резюме

Введение

Костный мозг человека содержит гемопоэтические стволовые клетки (ГСК) и негемопоэтические стволовые клетки, называемые мезенхимными стволовыми клетками (МСК). Эти клетки улучшают приживление ГСК после аллогенной ТГСК и способствуют репарации тканей мезенхимного происхождения, а также способны модулировать иммунный ответ in vitro и in vivo. В результате, ко-трансплантация аллогенных МСК с аллогенными ГСК гипотетически обладает такими положительными эффектами, как улучшение приживления трансплантата и восстановление баланса внутри иммунной системы. Это обстоятельство может быть использовано как для профилактики РТПХ, так и для лечения острой стероид-резистентной РТПХ или хронической РТПХ. В данном исследовании показано, что на терапию МСК  отвечают более половины пациентов со стероид-резистентной острой РТПХ.

Пациенты и методы

В исследование включены пациенты от 6 до 53 лет с ОЛЛ (n=9), ОМЛ (n=7), НХЛ (n=3), МДС (n=2) и ХМЛ (n=3), которым в период с октября 2005 по май 2008 была выполнена аллогенная ТГСК от родственного (n=5) или неродственного доноров (n=19). Для приживления ГСК и профилактики острой РТПХ 8 пациентам проведена ко-трансплантация МСК и ГСК. Шестнадцать пациентов получили изолированное введение МСК для лечения стероид-резистентной РТПХ. Десяти пациентам осуществлено одно введение МСК, пять пациентов два введения и один пациент получил три введения МСК. Процесс выделения и культивирования МСК осуществляли в компании «Транс Технологии» (лицензия № 99-01-002224 от 14.07.2005).

Результаты

В случае выполнения ко-трансплантации приживление лейкоцитов зарегистрировано на 21 день (от 16 до 38), тромбоцитов на 24 день (от 14 до 45). Острую РТПХ 0-I степеней наблюдали в 85,8% ко-трансплантаций, что не требовало дополнительной терапии, острая РТПХ II-IV развилась у 14,2 % пациентов. У всех пациентов хронической РТПХ не было. Инфекционные осложнения зарегистрированы у 2 пациентов (25%). Общая безрецидивная 2,5-летняя выживаемость составила 71%.
Результаты применения МСК для терапии РТПХ представлены в таблице 1.

974b56410a.jpg
Таблица 1. Результаты применения МСК для терапии РТПХ. 

Выводы

1. Инфузии МСК были безопасны, не сопровождались немедленными реакциями во время введения или отсроченными МСК-ассоциированными токсичностями.
2. Инфузия МСК перед аллоТГСК не влияли на приживление трансплантата ГСК.
3. Инфузия МСК при ко-трансплантации в режиме кондиционирования может предотвратить развитие тяжелых форм острой или хронической РТПХ.
4. Инфузия МСК для лечения резистентной острой РТПХ может быть эффективным у ряда пациентов.
5. Использование МСК перед аллоТГСК не увеличивало частоту рецидивов основного заболевания.
6. Использование МСК более эффективно у пациентов, получивших миелоаблативный режим кондиционирования и профилактику острой РТПХ с применением АЛГ.
7. Необходимо проведение дальнейших рандомизированных клинических исследований для оценки терапевтического эффекта МСК у пациентов после аллоТГСК и определения факторов, оказывающих влияние на эффективность МСК терапии.

Статьи о терапии мезенхимными клетками

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	Ю. Л. Шевченко, А. А. Новик, А. Н. Кузнецов, Б. В. Афанасьев, И. А. Лисуков, O. А. Рукавицын, А. А. Мясников, <br> В. Я. Мельниченко, Д. А. Федоренко, T. И. Ионова, Р. А. Иванов, Г. Городокин
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Ю. Л. Шевченко, А. А. Новик, А. Н. Кузнецов, Б. В. Афанасьев, И. А. Лисуков, O. А. Рукавицын, А. А. Мясников,
В. Я. Мельниченко, Д. А. Федоренко, T. И. Ионова, Р. А. Иванов, Г. Городокин

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Введение

Рассеянный склероз (РС) – хроническое прогрессирующее заболевание центральной нервной системы, которое клинически проявляется мультисистемной неврологической симптоматикой, а патоморфологически характеризуется образованием множественных очагов демиелинизации в белом веществе головного и спинного мозга. Основным механизмом, приводящим к повреждению миелина, является опосредованная Т-лимфоцитами реакция гиперчувствительности замедленного типа, а непосредственными клетками-эффекторами иммунопатологического процесса – макрофаги.

Существующие методы лечения не позволяют достичь устойчивого терапевтического эффекта при рассеянном склерозе. Выдвигалась гипотеза, основанная на доклинических данных, о высокой эффективности аллогенной транплантации стволовых кроветворных клеток (ТСКК). Однако высокая посттрансплантационная летальность не позволила приступить к клиническим исследованиям данного вида терапии РС. По мнению большинства экспертов одним из наиболее перспективных методов лечения РС на сегодняшний день является высокодозная химиотерапия (ВДТ) с аутологичной трансплантацией стволовых кроветворных клеток (АуТСКК). Начиная с 1995 года, безопасность ВДТ+AyТКСК при РС была изучена в ряде клинических исследований. Тем не менее, объем информации о клинической эффективности данного метода и, особенно, о его влиянии на качество жизни больных РС, остается недостаточным. Кроме того, большинство пациентов, включенных в вышеупомянутые исследования, имели вторично-прогрессирующую форму РС и значительную степень инвалидизации со значением шкалы EDSS 4.5-8.5 баллов. К сожалению, даже полное прекращение активности иммунопатологического процесса у таких больных не может привести к значительному улучшению качества жизни. Поэтому вопрос об оптимальных сроках проведения трансплантации по-прежнему остается открытым.

В статье приведены результаты проспективного многоцентрового исследования безопасности и эффективности ВДТ+АуТКСК при РС, которое было начато в 1999 году и в настоящее время объединяет 5 крупных российских медицинских центров. Изучали влияние ВДТ+АуТКСК на клиническое течение и показатели качества жизни больных с разными формами и стадиями РС.

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Yury L. Shevchenko1, Andrei A. Novik1, Alexey N. Kuznetsov1, Boris V. Afanasiev2, Igor A. Lisukov3, Oleg A. Rykavicin4, Аlexandr A. Myasnikov5, Vladimir Y. Melnichenko1, Denis A. Fedorenko1, Tatyana I. Ionova6, Roman A. Ivanov1, and Gary Gorodokin7 on behalf of the Russian Cooperative Group for Cellular Therapy

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1Pirogov National Medical Surgical Center, Moscow, Russia;
2Pavlov State Medical University, St. Petersburg, Russia;
3Institute of Clinical Immunology, Siberian Branch of Russian Academy of Science, Novosibirsk, Russia;
4Burdenko Central Military Hospital, Moscow, Russia;
5Republic Hospital, Petrozavodsk, Russia;
6Multinational Center of Quality of Life Research, St. Petersburg, Russia;
7New Jersey Center for Quality of Life and Health Outcome Research, NJ, USA

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Although there is no effective cure for this disease, high-dose chemotherapy (HDCT), together with autologous hematopoietic stem cell transplantation (auto-HSCT) offers promising results in the treatment of multiple sclerosis (MS) patients.

Methods

In this paper we present results of a prospective clinical study of safety and efficacy of HDCT+auto-HSCT in MS patients. One hundred and nine patients with various types of MS were included in this study. The patients underwent early, conventional, or salvage/late transplantation.

Results

The transplantation procedure was well tolerated by MS patients, with no transplant-related deaths at all. The efficacy analysis was performed in 79 patients. Forty-two achieved an objective improvement of neurological symptoms (defined as a ≥0.5 point decrease in EDSS score as compared to the baseline and confirmed over 6 months), and 37 patients had disease stabilization (steady EDSS level as compared to the baseline and confirmed over 6 months). Quality of life (QoL) was assessed in 44 patients. Thirty-nine patients exhibited a QoL response 1 year after transplantation.

Conclusions

This study provides ample evidence in support of HDCT+auto-HSCT efficacy in MS patients. The results obtained show that transplantation appears to be effective in patients with various types of MS.

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Значение индекса EDSS до трансплантации колебалось от 1.5 до 8.0 баллов (в среднем было равно 5.0 баллам). Длительность наблюдения составила в среднем 19 месяцев (от 6 до 108 месяцев). Активность заболевания определяли с помощью неврологического осмотра и данных магнитно-резонансной томографии.<br> Больным были выполнены следующие виды ВДТ+АуТКСК:<br> <b> - Ранняя трансплантация</b> проводилась в дебюте заболевания при наличии неблагоприятных прогностических факторов в отношении химиорезистентности или возможности тяжелой инвалидизации больного.<br> <b> - Этапная трансплантация</b> проводилась при выходе заболевания из-под контроля традиционных методов лечения и формировании вторичной химиорезистентности.<br> <b> - Трансплантация спасения</b> проводилась в далеко зашедшей стадии заболевания при высокой активности иммунопатологического процесса и быстром прогрессировании инвалидизации больного.<br> Тридцати двум больным была выполнена ранняя трансплантация (EDSS 1.5-3.0); 70 больным - этапная трансплантация (EDSS 3.5-6.5) и 7 больным - трансплантация спасения (EDSS 7.0-8.0).</p> <p> Оценку клинического ответа и ответа, связанного с качеством жизни, проводили до трансплантации, при выписке из стационара, через 3, 6, 9 и 12 месяцев после трансплантации, затем – каждые 6 месяцев в течение первых 4 лет и ежегодно впоследствии. Изучение неврологического статуса включало определение выраженности неврологического дефицита по шкале EDSS и магнитно-резонансную томографию. Качество жизни больных 16 www.ctt-journal.com 2008;1(2) оценивали с использованием опросников FACT-BMT (функциональная оценка состояния больных после трансплантации костного мозга) и FAMS (функциональная оценка больных с рассеянным склерозом). Клиническим улучшением считали уменьшение выраженности неврологической симптоматики, по меньшей мере, на 0.5 балла по шкале EDSS по сравнению с исходным уровнем, при условии, что это улучшение было подтверждено через 6 месяцев на следующем визите. Любое увеличение выраженности неврологической симптоматики по шкале EDSS считали прогрессированием заболевания. Рецидив констатировали при появлении новых симптомов или нарастании выраженности прежних симптомов, по меньшей мере, в течение 24 часов в отсутствие лихорадки у пациента, который был стабилен в течение 4 предшествующих недель. Ответ, связанный с качеством жизни, характеризовался как минимальный, умеренный, хороший или максимальный. Для определения ответа, связанного с качеством жизни, рассчитывали различия в значении интегрального показателя качества жизни до проведения трансплантации и в различные периоды времени после нее.</p> <h2>Результаты</h2> <p>У всех 79 больных со сроком наблюдения ≥9 месяцев отмечено клиническое улучшение или стабилизация в течении заболевания. Во время проведения трансплантации не было зарегистрировано ни одного смертельного исхода и тяжелых неконтролируемых побочных эффектов. Через 6 месяцев после трансплантации распределение пациентов согласно клиническому ответу было следующим: улучшение – 42 (53%) больных, стабилизация – 37 (47%) больных. Среди больных с улучшением у 20 было вторично-прогрессирующее течение, у 7 – первично-прогрессирующее, у 4 – прогрессирующе-рецидивирующее и у 11 – рецидивирующе-ремиттирующее течение. В этой группе 25 больных проведена этапная трансплантация, 15 – ранняя и 2 – трансплантация спасения. Из 37 больных, у которых зарегистрирована стабилизация заболевания, у 19 было вторично-прогрессирующее течение, у 8 – первично-прогрессирующее, у 2 – прогрессирующе-рецидивирующее и у 8 – рецидивирующе-ремиттирующее течение. В этой группе 23 больным проведена этапная трансплантация, 9 – ранняя и 5 – трансплантация спасения.</p> <p> В более длительные сроки наблюдения у 40 больных (50.6%) сохранялось улучшение, у 34 (43.1%) – стабилизация. У одного больного после 6 месяцев и двух больных после 18 месяцев стабилизации произошло повышение индекса инвалидизации. У двух пациентов прогрессирование заболевания наступило после 12 и 30 месяцев клинического улучшения. По данным МРТ у всех больных без прогрессирования заболевания после трансплантации отсутствовали активные или новые очаги поражения. В целом, 6-летняя выживаемость без прогрессии после ВДТ+АуТКСК составила 72%. Больные, у которых не было зарегистрировано признаков прогрессирования заболевания, не получали иммуномодулирующую или иммуносупрессивную терапию после трансплантации. Мониторинг качества жизни проводился у 44 пациентов, включенных в исследование. У 40 из них наблюдали улучшение показателей качества жизни через 6 месяцев после трансплантации. Улучшение параметров качества жизни установлено с помощью опросников – FACT-BMT и FAMS. Через 1 год после ВДТ+АуТКСК зарегистрировано следующее распределение пациентов в соответствии со степенью ответа, связанного с качеством жизни: у 3 больных наблюдали максимальный ответ (более чем 75% улучшение интегрального показателя качества жизни в сравнении с исходным уровнем); у 12 больных – хороший ответ (улучшение на 50-75%); у 11 больных – умеренный ответ (на 25-50%); у 13 – минимальный ответ (улучшение менее чем на 25%) и у 5 больных ответ, связанный с качеством жизни, отсутствовал. Следует отметить, что у пациентов с более длительным сроком наблюдения было отмечено дальнейшее улучшение показателей качества жизни. В статье представлена классификация типов трансплантации при рассеянном склерозе, основанная на концепции ВДТ+ТКСК при аутоиммунных заболеваниях.</p> <h2>Заключение</h2> <p>Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией кроветворных стволовых клеток является эффективным методом лечения больных рассеянным склерозом: у большинства больных после ВДТ+АуТКСК зарегистрировано клиническое улучшение или стабилизация заболевания; ВДТ+АуТКСК сопровождается существенным улучшением качества жизни больных. Результаты свидетельствуют о целесообразности изучения результатов ранней трансплантации, этапной трансплантации и трансплантации спасения. Необходимы дальнейшие исследования для определения оптимальных сроков проведения трансплан-тации и уточнения режимов кондиционирования. </p> [TYPE] => TEXT ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Материалы и методы

В исследование было включено 109 больных РС (49 мужчин, 60 женщин; средний возраст – 33 года; диапазон – 17-54): 51 с вторично-прогрессирующим течением, 19 с первично-прогрессирующим, 8 с прогрессирующе-рецидивирующим и 31 с рецидивирующе-ремиттирующим течением. Значение индекса EDSS до трансплантации колебалось от 1.5 до 8.0 баллов (в среднем было равно 5.0 баллам). Длительность наблюдения составила в среднем 19 месяцев (от 6 до 108 месяцев). Активность заболевания определяли с помощью неврологического осмотра и данных магнитно-резонансной томографии.
Больным были выполнены следующие виды ВДТ+АуТКСК:
- Ранняя трансплантация проводилась в дебюте заболевания при наличии неблагоприятных прогностических факторов в отношении химиорезистентности или возможности тяжелой инвалидизации больного.
- Этапная трансплантация проводилась при выходе заболевания из-под контроля традиционных методов лечения и формировании вторичной химиорезистентности.
- Трансплантация спасения проводилась в далеко зашедшей стадии заболевания при высокой активности иммунопатологического процесса и быстром прогрессировании инвалидизации больного.
Тридцати двум больным была выполнена ранняя трансплантация (EDSS 1.5-3.0); 70 больным - этапная трансплантация (EDSS 3.5-6.5) и 7 больным - трансплантация спасения (EDSS 7.0-8.0).

Оценку клинического ответа и ответа, связанного с качеством жизни, проводили до трансплантации, при выписке из стационара, через 3, 6, 9 и 12 месяцев после трансплантации, затем – каждые 6 месяцев в течение первых 4 лет и ежегодно впоследствии. Изучение неврологического статуса включало определение выраженности неврологического дефицита по шкале EDSS и магнитно-резонансную томографию. Качество жизни больных 16 www.ctt-journal.com 2008;1(2) оценивали с использованием опросников FACT-BMT (функциональная оценка состояния больных после трансплантации костного мозга) и FAMS (функциональная оценка больных с рассеянным склерозом). Клиническим улучшением считали уменьшение выраженности неврологической симптоматики, по меньшей мере, на 0.5 балла по шкале EDSS по сравнению с исходным уровнем, при условии, что это улучшение было подтверждено через 6 месяцев на следующем визите. Любое увеличение выраженности неврологической симптоматики по шкале EDSS считали прогрессированием заболевания. Рецидив констатировали при появлении новых симптомов или нарастании выраженности прежних симптомов, по меньшей мере, в течение 24 часов в отсутствие лихорадки у пациента, который был стабилен в течение 4 предшествующих недель. Ответ, связанный с качеством жизни, характеризовался как минимальный, умеренный, хороший или максимальный. Для определения ответа, связанного с качеством жизни, рассчитывали различия в значении интегрального показателя качества жизни до проведения трансплантации и в различные периоды времени после нее.

Результаты

У всех 79 больных со сроком наблюдения ≥9 месяцев отмечено клиническое улучшение или стабилизация в течении заболевания. Во время проведения трансплантации не было зарегистрировано ни одного смертельного исхода и тяжелых неконтролируемых побочных эффектов. Через 6 месяцев после трансплантации распределение пациентов согласно клиническому ответу было следующим: улучшение – 42 (53%) больных, стабилизация – 37 (47%) больных. Среди больных с улучшением у 20 было вторично-прогрессирующее течение, у 7 – первично-прогрессирующее, у 4 – прогрессирующе-рецидивирующее и у 11 – рецидивирующе-ремиттирующее течение. В этой группе 25 больных проведена этапная трансплантация, 15 – ранняя и 2 – трансплантация спасения. Из 37 больных, у которых зарегистрирована стабилизация заболевания, у 19 было вторично-прогрессирующее течение, у 8 – первично-прогрессирующее, у 2 – прогрессирующе-рецидивирующее и у 8 – рецидивирующе-ремиттирующее течение. В этой группе 23 больным проведена этапная трансплантация, 9 – ранняя и 5 – трансплантация спасения.

В более длительные сроки наблюдения у 40 больных (50.6%) сохранялось улучшение, у 34 (43.1%) – стабилизация. У одного больного после 6 месяцев и двух больных после 18 месяцев стабилизации произошло повышение индекса инвалидизации. У двух пациентов прогрессирование заболевания наступило после 12 и 30 месяцев клинического улучшения. По данным МРТ у всех больных без прогрессирования заболевания после трансплантации отсутствовали активные или новые очаги поражения. В целом, 6-летняя выживаемость без прогрессии после ВДТ+АуТКСК составила 72%. Больные, у которых не было зарегистрировано признаков прогрессирования заболевания, не получали иммуномодулирующую или иммуносупрессивную терапию после трансплантации. Мониторинг качества жизни проводился у 44 пациентов, включенных в исследование. У 40 из них наблюдали улучшение показателей качества жизни через 6 месяцев после трансплантации. Улучшение параметров качества жизни установлено с помощью опросников – FACT-BMT и FAMS. Через 1 год после ВДТ+АуТКСК зарегистрировано следующее распределение пациентов в соответствии со степенью ответа, связанного с качеством жизни: у 3 больных наблюдали максимальный ответ (более чем 75% улучшение интегрального показателя качества жизни в сравнении с исходным уровнем); у 12 больных – хороший ответ (улучшение на 50-75%); у 11 больных – умеренный ответ (на 25-50%); у 13 – минимальный ответ (улучшение менее чем на 25%) и у 5 больных ответ, связанный с качеством жизни, отсутствовал. Следует отметить, что у пациентов с более длительным сроком наблюдения было отмечено дальнейшее улучшение показателей качества жизни. В статье представлена классификация типов трансплантации при рассеянном склерозе, основанная на концепции ВДТ+ТКСК при аутоиммунных заболеваниях.

Заключение

Высокодозная иммуносупрессивная терапия с аутологичной трансплантацией кроветворных стволовых клеток является эффективным методом лечения больных рассеянным склерозом: у большинства больных после ВДТ+АуТКСК зарегистрировано клиническое улучшение или стабилизация заболевания; ВДТ+АуТКСК сопровождается существенным улучшением качества жизни больных. Результаты свидетельствуют о целесообразности изучения результатов ранней трансплантации, этапной трансплантации и трансплантации спасения. Необходимы дальнейшие исследования для определения оптимальных сроков проведения трансплан-тации и уточнения режимов кондиционирования.

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Трансплантация кроветворных стволовых клеток при рассеянном склерозе

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Ю. Л. Шевченко, А. А. Новик, А. Н. Кузнецов, Б. В. Афанасьев, И. А. Лисуков, O. А. Рукавицын, А. А. Мясников,
В. Я. Мельниченко, Д. А. Федоренко, T. И. Ионова, Р. А. Иванов, Г. Городокин

Введение

Рассеянный склероз (РС) – хроническое прогрессирующее заболевание центральной нервной системы, которое клинически проявляется мультисистемной неврологической симптоматикой, а патоморфологически характеризуется образованием множественных очагов демиелинизации в белом веществе головного и спинного мозга. Основным механизмом, приводящим к повреждению миелина, является опосредованная Т-лимфоцитами реакция гиперчувствительности замедленного типа, а непосредственными клетками-эффекторами иммунопатологического процесса – макрофаги.

Существующие методы лечения не позволяют достичь устойчивого терапевтического эффекта при рассеянном склерозе. Выдвигалась гипотеза, основанная на доклинических данных, о высокой эффективности аллогенной транплантации стволовых кроветворных клеток (ТСКК). Однако высокая посттрансплантационная летальность не позволила приступить к клиническим исследованиям данного вида терапии РС. По мнению большинства экспертов одним из наиболее перспективных методов лечения РС на сегодняшний день является высокодозная химиотерапия (ВДТ) с аутологичной трансплантацией стволовых кроветворных клеток (АуТСКК). Начиная с 1995 года, безопасность ВДТ+AyТКСК при РС была изучена в ряде клинических исследований. Тем не менее, объем информации о клинической эффективности данного метода и, особенно, о его влиянии на качество жизни больных РС, остается недостаточным. Кроме того, большинство пациентов, включенных в вышеупомянутые исследования, имели вторично-прогрессирующую форму РС и значительную степень инвалидизации со значением шкалы EDSS 4.5-8.5 баллов. К сожалению, даже полное прекращение активности иммунопатологического процесса у таких больных не может привести к значительному улучшению качества жизни. Поэтому вопрос об оптимальных сроках проведения трансплантации по-прежнему остается открытым.

В статье приведены результаты проспективного многоцентрового исследования безопасности и эффективности ВДТ+АуТКСК при РС, которое было начато в 1999 году и в настоящее время объединяет 5 крупных российских медицинских центров. Изучали влияние ВДТ+АуТКСК на клиническое течение и показатели качества жизни больных с разными формами и стадиями РС.

Обзорные статьи о терапии мезенхимными клетками

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Шипунова (Нифонтова) И. Н., Свинарева Д. А., Чертков И. Л., Дризе Н. И.

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В работе изучали иерархию стромальных предшественников. Известно, что при переносе костномозгового цилиндра под капсулу почки сингенных мышей очаг эктопического кроветворения образуется за счет мезенхимных стволовых клеток (МСК) донора.
У облученных реципиентов образуется очаг в 2-3 раза большего размера за счет «индуцибельных» предшественников, более дифференцированных по сравнению с МСК. Наряду с упомянутыми тестами in vivo, широко применяется метод оценки концентрации клоногенных стромальных предшественников в культуре (колониеобразующих единиц фибробластных, КОЕф). Однако, взаимное расположение описанных клеток-предшественников в иерархии стромальных стволовых клеток неясно. В работе было проанализировано изменение количества указанных предшественников в очагах, образующихся у облученных реципиентов. Показано, что КОЕф являются самыми близкими из известных на сегодняшний день потомками МСК, а «индуцибельные» предшественники – мультипотентные стромальные предшественники находятся ниже в иерархии и являются клетками, непосредственно увеличивающими размер кроветворной территории в облученных реципиентах.

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Irina Shipounova (Nifontova), Daria Svinareva, Josef Chertkov, Nina Drize

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The hierarchy of stromal precursors is the focus of this research. It has been previously shown that transplantation of the bone marrow plug under the renal capsule of the syngeneic animal leads to the formation of the foci of ectopic hematopoiesis, where a stromal microenvironment is formed by the donor's mesenchymal stem cells (MSC). In the irradiated recipients such foci are 2-3 times larger than in non-irradiated foci due to "inducible" precursors that are more differentiated than MSC. Along with the in vivo tests, the method of in vitro estimation of concentration of clonogenic stromal precursors (CFU-F) is widely used. However, the hierarchical arrangement of the described precursors is still unclear. This study describes the alterations in the number of mentioned precursors in the ectopic hematopoietic foci formed in the irradiated recipients. CFU-F was shown to be the closest MSC progeny thus far, while "inducible" precursor cells – stromal multipotent precursors – are at a lower position in the hierarchy and possibly enlarge the hematopoietic territory in the irradiated recipients directly.

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Иерархия мезенхимных стволовых клеток

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Шипунова (Нифонтова) И. Н., Свинарева Д. А., Чертков И. Л., Дризе Н. И.

В работе изучали иерархию стромальных предшественников. Известно, что при переносе костномозгового цилиндра под капсулу почки сингенных мышей очаг эктопического кроветворения образуется за счет мезенхимных стволовых клеток (МСК) донора.
У облученных реципиентов образуется очаг в 2-3 раза большего размера за счет «индуцибельных» предшественников, более дифференцированных по сравнению с МСК. Наряду с упомянутыми тестами in vivo, широко применяется метод оценки концентрации клоногенных стромальных предшественников в культуре (колониеобразующих единиц фибробластных, КОЕф). Однако, взаимное расположение описанных клеток-предшественников в иерархии стромальных стволовых клеток неясно. В работе было проанализировано изменение количества указанных предшественников в очагах, образующихся у облученных реципиентов. Показано, что КОЕф являются самыми близкими из известных на сегодняшний день потомками МСК, а «индуцибельные» предшественники – мультипотентные стромальные предшественники находятся ниже в иерархии и являются клетками, непосредственно увеличивающими размер кроветворной территории в облученных реципиентах.

Обзорные статьи о терапии мезенхимными клетками

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Ланге К., Чакироглу Ф., Шписс А., Каппалло-Оберманн Х., Цандер А. Р.

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Авторы [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_RU] => Array ( [ID] => 26 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Организации [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 26 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => [VALUE] => [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 11583 [VALUE] => Array ( [TEXT] => <p class="bodytext">Мезенхимные стромальные клетки (МСК) из костного мозга человека являются перспективными кандидатами для новых способов лечения в трансплантационной и регенеративной медицине. Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Мезенхимные стромальные клетки (МСК) из костного мозга человека являются перспективными кандидатами для новых способов лечения в трансплантационной и регенеративной медицине. Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.

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Claudia Lange, Figen Cakiroglu, Andrej Spiess, Heike Cappallo-Obermann, Axel R. Zander

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 11594 [VALUE] => Array ( [TEXT] => <p class="bodytext">Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany<br /><br /> <b>Correspondence:</b><br> Claudia Lange, Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany, <br>E-mail: <a href="javascript:linkTo_UnCryptMailto('qempxs.gpperkiDyoi2yrm1leqfyvk2hi');">cllange@<span style="display:none;">spam is bad</span>uke.uni-hamburg.de</a> </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany

Correspondence:
Claudia Lange, Clinic for Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany,
E-mail: cllange@spam is baduke.uni-hamburg.de

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 11595 [VALUE] => Array ( [TEXT] => <p class="bodytext">Human bone marrow mesenchymal stromal cells (hMSC) are promising candidates for new treatment options in transplant and regenerative medicine. However, most expansion protocols still use fetal calf serum (FCS) as growth factor supplement, which is a potential source of undesirable xenogeneic pathogens. We established an easy and reproducible expansion protocol for hMSC based on the addition of platelet lysate (PL) obtained from human thrombocyte concentrates. Both CFU-F and cumulative cell numbers were significantly increased compared to the conventional FCS-based medium. The generated cells meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. Human MSC expanded with PL revealed favorable immunological properties in vitro. Gene expression profiles showed upregulation of cell cycle and DNA replication genes and downregulation of developmental, differentiation, adipogenic and MHC II genes. Thus, PL provides a safe component for accelerated and safe hMSC expansion.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Human bone marrow mesenchymal stromal cells (hMSC) are promising candidates for new treatment options in transplant and regenerative medicine. However, most expansion protocols still use fetal calf serum (FCS) as growth factor supplement, which is a potential source of undesirable xenogeneic pathogens. We established an easy and reproducible expansion protocol for hMSC based on the addition of platelet lysate (PL) obtained from human thrombocyte concentrates. Both CFU-F and cumulative cell numbers were significantly increased compared to the conventional FCS-based medium. The generated cells meet all criteria for MSCs, e.g. plastic adherence, spindle-shaped morphology, surface marker expression, lack of hematopoietic markers, and differentiation capability into 3 mesenchymal lineages. Human MSC expanded with PL revealed favorable immunological properties in vitro. Gene expression profiles showed upregulation of cell cycle and DNA replication genes and downregulation of developmental, differentiation, adipogenic and MHC II genes. Thus, PL provides a safe component for accelerated and safe hMSC expansion.

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Лизат тромбоцитов для ускоренного размножения мезенхимных стромальных клеток человека

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Ланге К., Чакироглу Ф., Шписс А., Каппалло-Оберманн Х., Цандер А. Р.

Мезенхимные стромальные клетки (МСК) из костного мозга человека являются перспективными кандидатами для новых способов лечения в трансплантационной и регенеративной медицине. Однако большинство протоколов культивирования включают фетальную телячью сыворотку (ФТС) в качестве источника факторов роста, которая является потенциальным источником чужеродных патогенов. Недавно было показано, что лизаты тромбоцитов (ЛТ) являются безопасной заменой животной сыворотки для размножения МСК, но образующиеся МСК слабо охарактеризованы. ЛТ содержит основные факторы роста, активно секретируемые тромбоцитами: PDGF-αα, -ββ, -αβ, TGF-β1 и -β2, VEGF и EGF. Мы создали легко воспроизводимый протокол для культуры МСК с добавлением ЛТ из концентратов тромбоцитов человека. Как КОЕ-Ф, так и общее число клеток существенно возрастали, по сравнению со стандартной средой, содержащей ФТС. Образующиеся клетки соответствуют всем критериям для МСК, таким, как: прилипание к пластику, веретенообразная форма, экспрессия поверхностных маркеров, отсутствие гемопоэтических маркеров и способность к дифференцировке в три ростка мезенхимных клеток. МСК человека, размноженные с ЛТ, проявляли благоприятные иммунологические свойства в культуре. Мы проверяли иммуномодулирующие свойства МСК, размноженных с ЛТ, в смешанной лимфоцитарной реакции, проводимой с мононуклеарамии крови человека, использованными как эффекторы или облученные стимуляторы в соотношении 1:1:1. При добавлении МСК к смешанной культуре отмечалось эффективное подавление Т-клеточная пролиферации (Р=0,000004), при среднем  уровне подавления 84,8±9,7%. Этот результат подтверждается дифференциальной экспрессией генов, показывающей снижение MHC II в МСК. Кроме того, профили генной экспрессии показали активацию генов клеточного цикла и репликации ДНК, наряду с подавлением генов, связанных с развитием, дифференцировкой, адипогенезом. Таким образом, ЛТ является безопасным компонентом сред для ускоренного и безопасного размножения МСК.

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Штуте Н., Забелина Т., Фезе Б., Хассенпфлюг В., Панзе Й., Вольшке К., Айюк Ф., Шидер Х., Ренгес Х., Кратохвилл А.,
фон Хинюбер Р., Эрттманн Р., Цандер А.Р., Крегер Н.

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Состояние вопроса

Грибковые инфекции, вызванные Aspergillus or Candida, поражают, главным образом, легкие и являются основной причиной смертности при трансплантации стволовых клеток (ТСК). Больные с анамнезом или риском развития инвазивных грибковых инфекций (ИГИ), при аллогенной трансплантации стволовых клеток имеют высокий риск реактивации или прогрессии этих инфекций. В проспективном исследовании мы оценивали эффективность и безопасность каспофунгина в качестве вторичной профилактики или лечения персистирующего заболеванимя. Каспофунгин - это эхинокандин, нарушающий сборку клеточной стенки грибка посредством ингибирования β(1,3)-D-глюкансинтазы.

Методы

Двадцать восемь больных были включены в это исследование, все они были с острым лейкозом. В период ТСК, 16 больных не имели симптомов инфекции, тогда как в 12 случаях (с помощью компьютерной томографии) были отмечены признаки цветущих грибковых инфекций. До начала исследования проводился бронхоальвеолярный лаваж и УЗИ абдоминальной области. Контрольные определения галактоманнана Aspergillus и антител к Candida проводили еженедельно. Каспофунгин (по 50 мг вдень вводили внутривенно от начала кондиционирования до стабильного приживления трансплантата.

Результаты

Ни у одного из больных не проявлялось побочных эффектов, ведущих к прерыванию лечения каспофунгином. У 14 из 16 больных (88%) без признаков активной инфекции в начале трансплантации не наблюдалось грибковой инфекции после профилактики каспофунгином. В 10 из 12 случаев (83%) с радиологическими признаками активной грибковой инфекции, наблюдаемыми до трансплантации, были получены полные (n=4) или частичные (n=6) ответы после лечения каспофунгином.

Выводы

Применение каспофунгина безопасно и эффективно у больных высокого риска с ИГИ в анамнезе.

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N. Stute, T. Zabelina, N. Fehse, W. Hassenpflug, J. Panse, C. Wolschke, F. Ayuk, H. Schieder, H. Renges, A. Kratochwille, R. von Hinüber, R. Erttmann, A.R. Zander, N. Kröger

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 12047 [VALUE] => Array ( [TEXT] => <p class="bodytext">Dept of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany </p> <br> <p class="bodytext"><b>Correspondence:</b><br> Prof.  Dr. med. Nicolaus Kröger, Bone Marrow Transplant Center, University Hospital Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany, Tel.: +49-40-42803 5864, Fax: +49-40-42803 3795, E-mail: <a href="javascript:linkTo_UnCryptMailto('qempxs.rovsikivDyoi2yrm1leqfyvk2hi');" class="mail">nkroeger@<span style="display:none;">spam is bad</span>uke.uni-hamburg.de</a> </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Dept of Stem Cell Transplantation, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany


Correspondence:
Prof.  Dr. med. Nicolaus Kröger, Bone Marrow Transplant Center, University Hospital Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany, Tel.: +49-40-42803 5864, Fax: +49-40-42803 3795, E-mail: nkroeger@spam is baduke.uni-hamburg.de

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Background

Patients with a history of or ongoing invasive fungal infection (IFI) who undergo allogeneic stem cell transplantation (SCT) have a high risk of reactivation or progression. In a prospective study we evaluated the efficacy and safety of caspofungin as secondary prophylaxis or as therapy for persistent disease.

Methods

Twenty-eight adult patients were included in this study, all of whom had acute leukemia. At the time of SCT 16 patients had no signs of infection, while in 12 cases radiographic signs (CT scan) of florid fungal infections were noted. Caspofungin 50 mg intravenously was given daily from start of conditioning until stable engraftment. 

Results

No patient experienced side effects leading to the discontinuation of caspofungin. In 14 out of 16 patients (88%) without active signs of infection at start of transplantation, no fungal disease was observed after prophylaxis with caspofungin. In 10 out of 12 cases (83%) with radiographic signs of florid fungal infection pre-transplantation, complete (n=4) or partial (n=6) responses after caspofungin treatment were achieved. 

Conclusions

The use of caspofungin is safe and effective in high-risk patients with a history of IFI when undergoing allogeneic SCT.

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Каспофунгин в качестве вторичной профилактики или терапии у больных при аллогенной трансплантации стволовых клеток с предыдущей историей или риском системных или инвазивных инфекций

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Штуте Н., Забелина Т., Фезе Б., Хассенпфлюг В., Панзе Й., Вольшке К., Айюк Ф., Шидер Х., Ренгес Х., Кратохвилл А.,
фон Хинюбер Р., Эрттманн Р., Цандер А.Р., Крегер Н.

Состояние вопроса

Грибковые инфекции, вызванные Aspergillus or Candida, поражают, главным образом, легкие и являются основной причиной смертности при трансплантации стволовых клеток (ТСК). Больные с анамнезом или риском развития инвазивных грибковых инфекций (ИГИ), при аллогенной трансплантации стволовых клеток имеют высокий риск реактивации или прогрессии этих инфекций. В проспективном исследовании мы оценивали эффективность и безопасность каспофунгина в качестве вторичной профилактики или лечения персистирующего заболеванимя. Каспофунгин - это эхинокандин, нарушающий сборку клеточной стенки грибка посредством ингибирования β(1,3)-D-глюкансинтазы.

Методы

Двадцать восемь больных были включены в это исследование, все они были с острым лейкозом. В период ТСК, 16 больных не имели симптомов инфекции, тогда как в 12 случаях (с помощью компьютерной томографии) были отмечены признаки цветущих грибковых инфекций. До начала исследования проводился бронхоальвеолярный лаваж и УЗИ абдоминальной области. Контрольные определения галактоманнана Aspergillus и антител к Candida проводили еженедельно. Каспофунгин (по 50 мг вдень вводили внутривенно от начала кондиционирования до стабильного приживления трансплантата.

Результаты

Ни у одного из больных не проявлялось побочных эффектов, ведущих к прерыванию лечения каспофунгином. У 14 из 16 больных (88%) без признаков активной инфекции в начале трансплантации не наблюдалось грибковой инфекции после профилактики каспофунгином. В 10 из 12 случаев (83%) с радиологическими признаками активной грибковой инфекции, наблюдаемыми до трансплантации, были получены полные (n=4) или частичные (n=6) ответы после лечения каспофунгином.

Выводы

Применение каспофунгина безопасно и эффективно у больных высокого риска с ИГИ в анамнезе.

Статьи

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Дуросинми М. А., Фалуйи Дж. О., Ойекунле А. А. и соавт.

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Цель работы

Оценить клинический ответ и токсичность иматиниба мезилата (Гливека) у нигерийских больных хроническим миелолейкозом (ХМЛ).

Методы и клинический материал

С августа 2003 г. по август 2007 г. под наблюдением находились 98 больных с диагнозом ХМЛ (средний возраст 36 лет – от 11 до 65 лет), позитивных по Ph/bcr-abl, давших согласие на терапию, в том числе 56 мужчин и 42 женщины. Независимо от фазы заболевания, лечение Иматинибом проводилось в дозах 300-600 мг в день в госпитале OAU (Нигерия). Ответ на лечение оценивался по клиническим, гематологическим, цитогенетическим и/или молекулярным параметрам. Число клеток в крови проверяли каждые 2 недели в течение первых трех месяцев терапии. Кариотипирование повторяли каждые 6 месяцев. Регистрировали общую выживаемость и частоту полной гематологической ремиссии (ПГР) или большой цитогенетической ремиссии (БЦР, 1-34% Ph+ клеток).

Результаты

После 1 и 3 месяцев лечения полная гематологическая ремиссия была достигнута, соответственно, у 64% и 83% больных. При среднем сроке наблюдения 25 месяцев, частота ПГР и БЦР составляла 59% и 35%, соответственно. Спленомегалия и/или гепатомегалия менее 7 см от края ребер были прогностическими признаками в отношении ПГР (соответственно, p = 0.0006 и 0.034). После 12 месяцев наблюдения, общая выживаемость и выживаемость без прогрессии (ВБП) составляла, соответственно, 96% и 91%. Число бластных форм на периферии ниже 5% на момент диагноза и достижение ПГР через 6 мес. были ассоциированы со значительно лучшим выживанием (уровни p были, соответственно, 0.037 and 0.043).

Выводы

В сравнении с обычной химиотерапией и применением альфа-интерферона, как было ранее показано в Нигерии, иматиниб может индуцировать раннюю цитогенетическую ремиссию у Ph/bcr-abl- позитивных больных ХМЛ, при минимальных (побочных) заболеваниях.

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Prof. Muheez A. Durosinmi1, Prof. Julius O. Faluyi2, Dr. Anthony A. Oyekunle1, Dr. Lateef Salawu1, Dr. Ismail A. Adediran1, Dr. Norah O. Akinola1, Oluwakemi O. Bamgbade3, Dr. Charles C. Okanny4, Dr. Sulaiman Akanmu4, Dr. Oche P. Ogbe5, Dr. Tambi T. Wakama5, Dr. Chijoke A. Nwauche6, Dr. Matthew E. Enosolease7, Dr. Daye N.K. Halim7, Dr. Godwin N. Bazuaye7, Dr. Chide E. Okocha8, Dr. J. A. Olaniyi9, Dr. Titi S. Akingbola9, Dr. Victor O. Mabayoje10, Dr. Ajani A. Raji10, Dr. Aisha Mamman11, Dr. Aisha Kuliya-Gwarzo12, Dr. Obike G. Ibegbulam13, Dr. Sunday Ocheni13, Dr. Yohanna Tanko14, Dr. Oladimeji P. Arewa1, Dr. Rahman A.A. Bolarinwa1, Dr. Davidson O. Kassim1, Dr. Mohammed A. Ndakotsu1, Dr. Omotilewa A. Amusu15, Prof. O. O. Akinyanju16

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1Department of Haematology, Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, Nigeria; 2Department of Botany, Obafemi Awolowo University, Ile-Ife, Nigeria; 3Department of Pharmacy, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria; 4Department of Haematology, University of Lagos, Nigeria; 5Department of Haematology, National Hospital, Abuja, Nigeria; 6Department of Haematology, University of Port-Harcourt, Port-Harcourt, Nigeria; 7Department of Haematology, University of Benin, Nigeria; 8Department of Haematology, Nnamdi Azikiwe University, Nnewi, Nigeria; 9Department of Haematology, University College Hospital, Ibadan, Nigeria; 10Department of Haematology, Ladoke Akintola University of Technology, Osogbo, Nigeria; 11Department of Haematology, Ahmadu Bello University, Zaria, Nigeria, 12Department of Haematology, Bayero University,  Kano, Nigeria; 13Department of Haematology, University of Nigeria, Enugu, Nigeria; 14Department of Haematology, Gwagwalada Specialist Hospital, Abuja, Nigeria; 15Department of Haematology, Army Reference Hospital, Lagos, Nigeria; 16Asaju Medical Clinic, Victoria Island, Lagos, Nigeria

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Objectives

To assess response and toxicity to Imatinib mesylate (Glivec) in Nigerian Patients with chronic myeloid leukemia.

Methods

From August 2003 to August 2007, 98 consecutive, consenting patients, 56 (57%) males and 42 (43%) females, median age 36 years (range, 11-65 years) diagnosed with  CML, irrespective of disease phase received Imatinib at a dose of 300-600mg/day at the OAU Teaching Hospitals, Nigeria. Response to therapy was assessed by clinical, haematological and cytogenetic parameters. Blood counts were checked every two weeks in the first three months of therapy. Chromosome analysis was repeated sixth monthly. Overall survival (OS) and frequency of complete or major cytogenetic remission (CCR/MCR) were evaluated.  

Results

Complete haematologic remission was achieved in 64% and 83% of patients at one and three months, respectively. With a median follow-up of 25 months, the rates of CCR and MCR were 59% and 35% respectively. At 12 months of follow-up, OS and progression- free survival (PFS) were 96% and 91%, respectively. Achievement of CR at six months was associated with significantly better survival (p = 0.043).

Conclusions

Compared to treatment outcome with conventional chemotherapy and alpha interferon, as previously used in Nigeria, the results obtained with this regimen has established Imatinib as the first-line treatment strategy in patients with CML, as it is in other populations, with minimal morbidity.

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Применение Иматиниба мезилата (Гливека) у нигерийцев с хроническим миелолейкозом

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Дуросинми М. А., Фалуйи Дж. О., Ойекунле А. А. и соавт.

Цель работы

Оценить клинический ответ и токсичность иматиниба мезилата (Гливека) у нигерийских больных хроническим миелолейкозом (ХМЛ).

Методы и клинический материал

С августа 2003 г. по август 2007 г. под наблюдением находились 98 больных с диагнозом ХМЛ (средний возраст 36 лет – от 11 до 65 лет), позитивных по Ph/bcr-abl, давших согласие на терапию, в том числе 56 мужчин и 42 женщины. Независимо от фазы заболевания, лечение Иматинибом проводилось в дозах 300-600 мг в день в госпитале OAU (Нигерия). Ответ на лечение оценивался по клиническим, гематологическим, цитогенетическим и/или молекулярным параметрам. Число клеток в крови проверяли каждые 2 недели в течение первых трех месяцев терапии. Кариотипирование повторяли каждые 6 месяцев. Регистрировали общую выживаемость и частоту полной гематологической ремиссии (ПГР) или большой цитогенетической ремиссии (БЦР, 1-34% Ph+ клеток).

Результаты

После 1 и 3 месяцев лечения полная гематологическая ремиссия была достигнута, соответственно, у 64% и 83% больных. При среднем сроке наблюдения 25 месяцев, частота ПГР и БЦР составляла 59% и 35%, соответственно. Спленомегалия и/или гепатомегалия менее 7 см от края ребер были прогностическими признаками в отношении ПГР (соответственно, p = 0.0006 и 0.034). После 12 месяцев наблюдения, общая выживаемость и выживаемость без прогрессии (ВБП) составляла, соответственно, 96% и 91%. Число бластных форм на периферии ниже 5% на момент диагноза и достижение ПГР через 6 мес. были ассоциированы со значительно лучшим выживанием (уровни p были, соответственно, 0.037 and 0.043).

Выводы

В сравнении с обычной химиотерапией и применением альфа-интерферона, как было ранее показано в Нигерии, иматиниб может индуцировать раннюю цитогенетическую ремиссию у Ph/bcr-abl- позитивных больных ХМЛ, при минимальных (побочных) заболеваниях.

Статьи

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Шипунова (Нифонтова) И. Н., Сац Н. В., Свинарева Д. А., Петрова Т. В., Дризе Н. И., Савченко В. Г.

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Введение

Предыдущие исследования показали, что кроветворение у мышей, которым пересаживали гемопоэтические стволовые клетки (ГСК), маркированными ретровирусным материалом, восстанавливается за счет множества короткоживущих клонов. Такая клональная кинетика предполагает истощение гемопоэтических клонов с последующим рекрутированием новых клонов путем их пролиферации (клональная сукцессия).

Материалы и методы

В данном исследовании, клональный гемопоэз изучали в модельных опытах на мышах, причем восстановление гемопоэза исследовали, вводя вирус-инфицированные клетки костного мозга (КМ), экспрессирующие ген АДА человека, или ГСК от донора другого пола. Экспериментальные животные подвергались облучению в летальной дозе и трансплантации маркированных ГСК от мышей-доноров. Определение селезеночных колоний (КОЕ-с) у мышей-реципиентов (самок) проводили по Тиллу и Мак-Каллоху. Происхождение КОЕ-с у мышей после трансплантации отслеживали по гену smc, сцепленному с полом, или по маркеру hADA, трансдуцированному в донорские клетки. Введение Г-КСФ после трансплантации проводили ежемесячно в течение полугода. 

Результаты

Повторное введение Г-КСФ не влияло на число лейкоцитов и долю гранулоцитов в периферической крови после трансплантации. Концентрация КОЕ-с в костном мозге трансплантированных мышей не изменялась после введения Г-КСФ. Полный донорский химеризм развивался редко, обычно наблюдалось частичное возвращение к кроветворению реципиента. Доля донорских КОЕ-с от месяца к месяцу колебалась между 35 и 88%. У трансплантированных мышей, не получавших Г-КСФ, доля донорских КОЕ-с была значительно выше, чем в группе, леченной Г-КСФ (71.2±6.9% против 56.5±5.3%, р<0.05). Доля донорских КОЕ-с, маркированных hADA, в группе, получавшей Г-КСФ, была более низкой и более стабильной, чем у «нелеченых» животных (20.6±7.1% versus 45.7±6.3%). Анализ отдельных клонов у «леченых» и «нелеченых» животных не выявил достоверных различий по их среднему содержанию. Однако величина клонов существенно снижалась при введении Г-КСФ, так как клоны были представлены меньшим числом колоний. Долгоживущие клоны (выявляемые после 3 мес.) не наблюдались после длительного введения Г-КСФ.

Заключение

Повторные инъекции Г-КСФ в фармакологических дозах вызывают дисбаланс в кроветворной системе. Долгосрочные последствия мобилизации ГСК посредством Г-КСФ следует внимательно отслеживать у потенциальных доноров.

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Irina Shipounova (Nifontova), Natalia Sats, Daria Svinareva, Tatiana Petrova, Nina Drize, Valeriy Savchenko

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National Hematology Research Center, Russian Academy of Medical Science, Moscow, Russia

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Влияние длительного введения Г-КСФ на клональный состав кроветворной ткани у химер

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Шипунова (Нифонтова) И. Н., Сац Н. В., Свинарева Д. А., Петрова Т. В., Дризе Н. И., Савченко В. Г.

Введение

Предыдущие исследования показали, что кроветворение у мышей, которым пересаживали гемопоэтические стволовые клетки (ГСК), маркированными ретровирусным материалом, восстанавливается за счет множества короткоживущих клонов. Такая клональная кинетика предполагает истощение гемопоэтических клонов с последующим рекрутированием новых клонов путем их пролиферации (клональная сукцессия).

Материалы и методы

В данном исследовании, клональный гемопоэз изучали в модельных опытах на мышах, причем восстановление гемопоэза исследовали, вводя вирус-инфицированные клетки костного мозга (КМ), экспрессирующие ген АДА человека, или ГСК от донора другого пола. Экспериментальные животные подвергались облучению в летальной дозе и трансплантации маркированных ГСК от мышей-доноров. Определение селезеночных колоний (КОЕ-с) у мышей-реципиентов (самок) проводили по Тиллу и Мак-Каллоху. Происхождение КОЕ-с у мышей после трансплантации отслеживали по гену smc, сцепленному с полом, или по маркеру hADA, трансдуцированному в донорские клетки. Введение Г-КСФ после трансплантации проводили ежемесячно в течение полугода. 

Результаты

Повторное введение Г-КСФ не влияло на число лейкоцитов и долю гранулоцитов в периферической крови после трансплантации. Концентрация КОЕ-с в костном мозге трансплантированных мышей не изменялась после введения Г-КСФ. Полный донорский химеризм развивался редко, обычно наблюдалось частичное возвращение к кроветворению реципиента. Доля донорских КОЕ-с от месяца к месяцу колебалась между 35 и 88%. У трансплантированных мышей, не получавших Г-КСФ, доля донорских КОЕ-с была значительно выше, чем в группе, леченной Г-КСФ (71.2±6.9% против 56.5±5.3%, р<0.05). Доля донорских КОЕ-с, маркированных hADA, в группе, получавшей Г-КСФ, была более низкой и более стабильной, чем у «нелеченых» животных (20.6±7.1% versus 45.7±6.3%). Анализ отдельных клонов у «леченых» и «нелеченых» животных не выявил достоверных различий по их среднему содержанию. Однако величина клонов существенно снижалась при введении Г-КСФ, так как клоны были представлены меньшим числом колоний. Долгоживущие клоны (выявляемые после 3 мес.) не наблюдались после длительного введения Г-КСФ.

Заключение

Повторные инъекции Г-КСФ в фармакологических дозах вызывают дисбаланс в кроветворной системе. Долгосрочные последствия мобилизации ГСК посредством Г-КСФ следует внимательно отслеживать у потенциальных доноров.

Статьи

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Сабурова И. Ю., Оникийчук Я. С., Зотова И. И., Сологуб Г. Н., Зарайский М. И.

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Irina Y. Saburova, Yana S. Onikiychuk, Irina I. Zotova, Galina N. Sologub, Mikhail I. Zarayskiy

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Saint-Petersburg Pavlov State Medical University, Russia

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Myeloproliferative disorders (MPD) are a heterogeneous group of hematopoietic diseases accompanied by multiple hyperplasia of bone marrow cells. They are rather difficult for diagnostics and often only revealed by excluding other conditions. One of the most valuable diagnostic criteria for MPD is the V617F mutation of the JAK2 gene. The main subject of this study was to develop a routine detection technique for the JAK2V617F mutation that will be useful for primary diagnostics. To do so, we developed two pairs of primers specific for mutated and wild-type JAK2. To ensure high sensitivity and specificity in JAK2V617F detection we first adjusted the novel PCR technique on the UKE1 cell line previously shown to be homozygous for the JAK2V617F mutation. Next we isolated genomic DNA from 58 MPD patients with different diagnoses using standard techniques. The overall mutation rate in this group was found to be 29.3%. The frequency of the JAK2V617F mutation in newly diagnosed patients with non-verified MPD was 25.7%. We conclude that the detection technique for the JAK2V617F mutation developed in our laboratory represents a useful tool as a diagnostic screening method in patients with myeloproliferative disorders.

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Определение мутации V617F в гене JAK2 у пациентов с неверифицированными хроническими миелопролиферативными заболеваниями

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Сабурова И. Ю., Оникийчук Я. С., Зотова И. И., Сологуб Г. Н., Зарайский М. И.

Миелопролиферативные заболевания (МПЗ) представляют собой гетерогенную группу нарушений гемопоэза, сопровождающихся множественной гиперплазией клеток костного мозга. Их диагностика сложна и часто основывается на критериях исключения. Одним из наиболее диагностически значимых критериев для МПЗ является наличие мутации V617F в гене JAK2. Основная цель данной статьи – описание скринингового метода детекции V617F в гене JAK2, пригодного для первичной диагностики. Геномная ДНК от 58 пациентов с неверифицированным миелопролиферативным заболеванием выделялась по стандартной технологии. Детекция наличия мутации V617F в гене JAK2 проводилась с использованием двух пар праймеров, специфичных для мутантного и дикого типов генов JAK2. Использовалась клеточная линия UKE1 (Б. Фезе, Германия). Установлено, что представляемая методика выявляет наличие мутации V617F в гене JAK2 с диагностически значимой чувствительностью и специфичностью. Частота мутации в общей группе составила 29,3%. Процент встречаемости мутации V617F в гене JAK2 в группе первичных пациентов с неверифицированным диагнозом МПЗ составил 25,7%. Таким образом, разработанный нами метод определения мутации V617F в гене JAK2 может быть использован в качестве скрининговой диагностики у пациентов с неверифицированными хроническими миелопролиферативными заболеваниями.

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Райт Г.П., Кинг Дж-Вай-Линг, Штаусс Х.Дж.

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Регуляторные Т-клетки (Трег) способны сильно подавлять
Т-клеточные реакции на стадии «наивных» клеток, эффекторной фазе и в клетках памяти. Кроме того, они также действуют на различные другие имунные клетки, включая В-клетки, дендритные клетки и моноциты. Многие аспекты Трег-опосредованной супрессии делают их идеальными кандидатами для антиген-направленного лечения иммунопатологических состояний. Наша и другие лаборатории показали, что перенос гена Т-клеточного рецептора (TCR) является эффективным способом переориентации специфичности основной популяции Т-клеток на определенный антиген. До сих пор существенные усилия вкладывались в применение переноса гена TCR в обычные CD8+ и CD4+ клетки, для того, чтобы запускать или усиливать иммунные реакции. Но до сих пор было немного исследований по потенциальному использованию генной терапииTCR на другом крае этого спектра – для контроля иммунопатологических процессов с применением Т-регуляторных клеток. Здесь мы кратко обсуждаем сведения, указывающие на то, что генерация  антиген-специфических Трег, в потенциале – через перенос гена TCR, может быть эффективным лечением различных форм иммунопатологии и кратко упоминаются трудности на пути понимания полного потенциала этого типа терапии. Проводилась адоптивная пересадка этих Т-регуляторных клеток облученным мышам, и дальнейшее размножение Трег с заполнением ниши может дать возможность для преимущественной экспансии клеток, специфичных к аллоантигенам. Имеется четкая корреляция в клинических условиях между толерантностью при трансплантации органов и уровням Трег. Здесь мы подчеркнули важность специфичности антигенов и предположили, что перенос гена TCR в размножающиеся поликлональные Т-клетки, продуцирующие FoxP3+ TCR, может обеспечить эффективный путь генерирования больших количеств антигенспецифических Трег-клеток.

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Graham P. Wright, Judy Wai-Ling King and Hans J. Stauss

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Department of Immunology, Royal Free Hospital, University College London, UK

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 12347 [VALUE] => Array ( [TEXT] => <p class="bodytext">Our lab and others have demonstrated T cell receptor (TCR) gene transfer as an efficient way of redirecting the specificity of a bulk T cell population to that of a known antigen. Thus far there has been considerable effort put into the use of TCR gene transfer into conventional CD8+ and CD4+ T cells in order to initiate or augment immune responses. There has, as yet, been little investigation into the potential use of TCR gene therapy at the other end of the spectrum: control of immune pathology using regulatory T cells. Here we will briefly discuss the evidence indicating that the generation of Ag-specific Tregs, potentially via TCR gene transfer, may be an efficacious treatment for various forms of immune-pathology and briefly outline the challenges towards realizing the full potential of this type of therapy.</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Our lab and others have demonstrated T cell receptor (TCR) gene transfer as an efficient way of redirecting the specificity of a bulk T cell population to that of a known antigen. Thus far there has been considerable effort put into the use of TCR gene transfer into conventional CD8+ and CD4+ T cells in order to initiate or augment immune responses. There has, as yet, been little investigation into the potential use of TCR gene therapy at the other end of the spectrum: control of immune pathology using regulatory T cells. Here we will briefly discuss the evidence indicating that the generation of Ag-specific Tregs, potentially via TCR gene transfer, may be an efficacious treatment for various forms of immune-pathology and briefly outline the challenges towards realizing the full potential of this type of therapy.

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Генерация регуляторных Т-клеток посредством переноса Т-клеточных рецепторов

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Райт Г.П., Кинг Дж-Вай-Линг, Штаусс Х.Дж.

Регуляторные Т-клетки (Трег) способны сильно подавлять
Т-клеточные реакции на стадии «наивных» клеток, эффекторной фазе и в клетках памяти. Кроме того, они также действуют на различные другие имунные клетки, включая В-клетки, дендритные клетки и моноциты. Многие аспекты Трег-опосредованной супрессии делают их идеальными кандидатами для антиген-направленного лечения иммунопатологических состояний. Наша и другие лаборатории показали, что перенос гена Т-клеточного рецептора (TCR) является эффективным способом переориентации специфичности основной популяции Т-клеток на определенный антиген. До сих пор существенные усилия вкладывались в применение переноса гена TCR в обычные CD8+ и CD4+ клетки, для того, чтобы запускать или усиливать иммунные реакции. Но до сих пор было немного исследований по потенциальному использованию генной терапииTCR на другом крае этого спектра – для контроля иммунопатологических процессов с применением Т-регуляторных клеток. Здесь мы кратко обсуждаем сведения, указывающие на то, что генерация  антиген-специфических Трег, в потенциале – через перенос гена TCR, может быть эффективным лечением различных форм иммунопатологии и кратко упоминаются трудности на пути понимания полного потенциала этого типа терапии. Проводилась адоптивная пересадка этих Т-регуляторных клеток облученным мышам, и дальнейшее размножение Трег с заполнением ниши может дать возможность для преимущественной экспансии клеток, специфичных к аллоантигенам. Имеется четкая корреляция в клинических условиях между толерантностью при трансплантации органов и уровням Трег. Здесь мы подчеркнули важность специфичности антигенов и предположили, что перенос гена TCR в размножающиеся поликлональные Т-клетки, продуцирующие FoxP3+ TCR, может обеспечить эффективный путь генерирования больших количеств антигенспецифических Трег-клеток.

Обзорные статьи

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Кинг Дж.-Вай-Линг, Райт Г.П., Штаусс Х.Дж.

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Адоптивный перенос Т-клеток рассматривается как успешный клинический подход к терапии злокачественных заболеваний и вирусных инфекций. Однако одним из основных ограничений этой стратегии является сложность производства достаточных количеств антиген-специфических Т-клеток. Кроме того, инфузии донорских лимфоцитов часто ассоциированы с развитием болезни «трансплантат против хозяина» (РТПХ), что заставляет считаться со значительной заболеваемостью и смертностью. Перенос ретровирусного Т-клеточного рецептора (TCR) является привлекательной новой стратегией, при которой TCR является единственной детерминантой Т-клеточной специфичности. Введенные TCR нужной специфичности могут быть направлены против вирусных антигенов или слабо иммуногенных целевых молекул, как, например опухоль-ассоциированных антигенов, и недавние сведения о клинических испытаниях показали возможность этой технологии у больных меланомой. Более того, перенос гена TCR представляет собой также потенциальное средство генерации антиген-специфических регуляторных Т-клеток. В этом обзоре будет обращено особое внимание на современные достижения в области переноса гена TCR и исследования потенциальных клинических приложений этой стратегии.

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Judy Wai-Ling King, Graham P. Wright and Hans J. Stauss

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Department of Immunology, Royal Free Hospital, University College London, UK

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Adoptive T cell transfer has seen clinical success in the treatment of both malignancies and viral infections. However, one of the main limitations of this strategy has been the difficulty in producing sufficient quantities of antigen-specific T cells. In addition, donor lymphocyte infusions are commonly associated with graft-versus-host disease (GvHD), which carries with it significant morbidity and mortality. Retroviral T cell receptor (TCR) gene transfer is an attractive new strategy by which large numbers of autologous, antigen-specific T cells can be generated, since the TCR is the sole determinant of T cell specificity. The introduced TCR specificity can be targeted against viral antigens or poorly immunogenic targets such as tumor associated antigens, and recent clinical trial data has demonstrated the feasibility of this technique in melanoma patients. Furthermore, TCR gene transfer also has the potential to generate antigen-specific regulatory T cells. This review will focus on recent advances in the field of TCR gene transfer and explore the potential clinical applications of this strategy.

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Успехи в переносе Т-клеточных рецепторов для иммунотерапии

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Кинг Дж.-Вай-Линг, Райт Г.П., Штаусс Х.Дж.

Адоптивный перенос Т-клеток рассматривается как успешный клинический подход к терапии злокачественных заболеваний и вирусных инфекций. Однако одним из основных ограничений этой стратегии является сложность производства достаточных количеств антиген-специфических Т-клеток. Кроме того, инфузии донорских лимфоцитов часто ассоциированы с развитием болезни «трансплантат против хозяина» (РТПХ), что заставляет считаться со значительной заболеваемостью и смертностью. Перенос ретровирусного Т-клеточного рецептора (TCR) является привлекательной новой стратегией, при которой TCR является единственной детерминантой Т-клеточной специфичности. Введенные TCR нужной специфичности могут быть направлены против вирусных антигенов или слабо иммуногенных целевых молекул, как, например опухоль-ассоциированных антигенов, и недавние сведения о клинических испытаниях показали возможность этой технологии у больных меланомой. Более того, перенос гена TCR представляет собой также потенциальное средство генерации антиген-специфических регуляторных Т-клеток. В этом обзоре будет обращено особое внимание на современные достижения в области переноса гена TCR и исследования потенциальных клинических приложений этой стратегии.

Обзорные статьи

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Хельман Р., Саусселе С.

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В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей.

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Описание/Резюме [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [DOI] => Array ( [ID] => 28 [TIMESTAMP_X] => 2016-04-06 14:11:12 [IBLOCK_ID] => 2 [NAME] => DOI [ACTIVE] => Y [SORT] => 500 [CODE] => DOI [DEFAULT_VALUE] => [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 80 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 28 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => [USER_TYPE_SETTINGS] => [HINT] => [PROPERTY_VALUE_ID] => 12377 [VALUE] => 10.3205/ctt-2008-en-000015.01 [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => 10.3205/ctt-2008-en-000015.01 [~DESCRIPTION] => [~NAME] => DOI [~DEFAULT_VALUE] => ) [AUTHOR_EN] => Array ( [ID] => 37 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Author [ACTIVE] => Y [SORT] => 500 [CODE] => AUTHOR_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 37 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 12420 [VALUE] => Array ( [TEXT] => <p class="Autor">R. Hehlmann, S. Saußele<p class="Autor"> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

R. Hehlmann, S. Saußele

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 12421 [VALUE] => Array ( [TEXT] => <p>Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany</p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Wiesbadener Str. 7-11, 68305 Mannheim, Germany

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 12422 [VALUE] => Array ( [TEXT] => <p>Presented at the 2nd Raissa Gorbacheva Memorial Symposium in St. Petersburg, Russia, on 20 September 2008.</p> <p class="bodytext">Leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Presented at the 2nd Raissa Gorbacheva Memorial Symposium in St. Petersburg, Russia, on 20 September 2008.

Leukemias are rare diseases, the investigation into which requires multicenter activities, study groups and networking. The ELN integrates leukemia research and trial groups across Europe. Progress with CML continues to promote European integration (EUTOS for CML). Median survival with CML is now expected at 25 years. The main treatment options for CML are TK inhibition and allo-SCT. Treatment optimization trials are ongoing worldwide. Looking at the speed of current progress, the prospects for a cure of CML, and possibly other forms of leukemia, are good.

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Description / Summary [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [NAME_EN] => Array ( [ID] => 40 [TIMESTAMP_X] => 2015-09-03 10:49:47 [IBLOCK_ID] => 2 [NAME] => Name [ACTIVE] => Y [SORT] => 500 [CODE] => NAME_EN [DEFAULT_VALUE] => [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 80 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 40 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => Y [VERSION] => 1 [USER_TYPE] => [USER_TYPE_SETTINGS] => [HINT] => [PROPERTY_VALUE_ID] => 12378 [VALUE] => Integration of leukemia research in Europe: the paradigm CML [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Integration of leukemia research in Europe: the paradigm CML [~DESCRIPTION] => [~NAME] => Name [~DEFAULT_VALUE] => ) [FULL_TEXT_RU] => Array ( [ID] => 42 [TIMESTAMP_X] => 2015-09-07 20:29:18 [IBLOCK_ID] => 2 [NAME] => Полный текст [ACTIVE] => Y [SORT] => 500 [CODE] => FULL_TEXT_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 42 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 12389 [VALUE] => Array ( [TEXT] => <p class="bodytext"> Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии (Рис. 2). В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г. </p> <p class="bodytext"> Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5). </p> <img width="421" alt="2008-2-en-Hehlmann-et-al-Figure-2.jpg" src="/upload/medialibrary/b9e/2008_2_en_hehlmann_et_al_figure_2.jpg" height="360" title="2008-2-en-Hehlmann-et-al-Figure-2.jpg" align="left"> <div style="margin-left:460px;"> <img width="434" alt="2008-2-en-Hehlmann-et-al-Fig-5_04.jpg" src="/upload/medialibrary/357/2008_2_en_hehlmann_et_al_fig_5_04.jpg" height="346" title="2008-2-en-Hehlmann-et-al-Fig-5_04.jpg"> </div> <p class="bodytext"> <br> Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4). </p> <p> <img width="473" alt="2008-2-en-Hehlmann-et-al-Fig-13_03.jpg" src="/upload/medialibrary/d34/2008_2_en_hehlmann_et_al_fig_13_03.jpg" height="358" title="2008-2-en-Hehlmann-et-al-Fig-13_03.jpg" align="left"> </p> <div style="margin-left:490px;"> <img width="475" alt="2008-2-en-Hehlmann-et-al-Fig-4_03.jpg" src="/upload/medialibrary/7d1/2008_2_en_hehlmann_et_al_fig_4_03.jpg" height="341" title="2008-2-en-Hehlmann-et-al-Fig-4_03.jpg"><br> <p> </p> </div> <p class="bodytext"> <br> Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.<br> <br> Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.<br> <br> Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.<br> <br> Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы. <br> <br> Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14) </p> <p> <img width="447" alt="2008-2-en-Hehlmann-et-al-Fig-14_03.jpg" src="/upload/medialibrary/2ba/2008_2_en_hehlmann_et_al_fig_14_03.jpg" height="371" title="2008-2-en-Hehlmann-et-al-Fig-14_03.jpg"><br> </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Так, Германская группа по изучению ХМЛ, основанная в 1982 г., была в числе основателей Европейской группы по ХМЛ, впоследствии (с 2002 г.) образовалась европейская LeukemiaNet (ELN) под эгидой Европейской комиссии (Рис. 2). В Германии в исследованиях по ХМЛ объединены 600 участников из 300 центров. Германская группа провела за 25 лет 5 крупных рандомизированных исследований, причем средняя выживаемость возросла с 3-4 лет в 1983 г. до 25 лет в 2008 г.

Европейская сеть по изучению лейкозов сейчас объединяет 147 центров в 28 странах, включая около 1000 врачей и ученых, под наблюдением находятся около 10000 больных ХМЛ (Рис. 5).

2008-2-en-Hehlmann-et-al-Figure-2.jpg
2008-2-en-Hehlmann-et-al-Fig-5_04.jpg


Особый акцент делается на изучении ХМЛ, которое было наиболее эффективным в рамках ELN. Из истории исследования ХМЛ следует, что он был первой формой лейкоза с известной специфической мутацией (bcr/abl), и с 1998 г. были начаты клинические испытания иматиниба – ингибитора тирозин киназы, давшие прекрасные результаты (Рис. 13). Это был первый опыт «нацеленной» терапии лейкоза с учетом дефектного гена bcr/abl. В исследовании IRIS было показано клиническое преимущество от лечения иматинибом по сравнению с альфа-интерфероном (Рис. 4).

2008-2-en-Hehlmann-et-al-Fig-13_03.jpg

2008-2-en-Hehlmann-et-al-Fig-4_03.jpg


Новые проблемы связаны с постепенным развитием резистентности к иматинибу у части больных (не менее 37% случаев), в силу развития мутаций гена-мишени или эволюции заболевания, а иногда – из-за побочных эффектов терапии. Поэтому дальнейшие работы связаны с комбинированным лечением (совместно с интерфероном или Ара-С) или повышением дозы иматиниба, примером которых является программа GEIST (с 2002 г.), причем полная цитогенетическая ремиссия достигается более чем в 85% случаев.

Основным вопросом является тактика лечения ХМЛ в фазе бластного криза, где продолжительность жизни пока невелика. Предприняты исследования по лечению этих больных путем трансплантации стволовых клеток, по сравнению с наилучшим доступным терапевтическим методом. При длительном наблюдении (8-11 лет) было показано значительное преимущество от применения второго (терапевтического) способа по критериям выживаемости. Поэтому лекарственное лечение было рекомендовано в качестве терапии первой линии при ХМЛ. Трансплантация стволовых клеток остается важной тактикой второй линии и может назначаться в качестве средства первой линии на индивидуальной основе.

Кроме того, на испытаниях в настоящее время находятся препараты-ингибиторы тирозин-киназы второго поколения, как, например, дазатиниб, весьма эффективный у больных, ХМЛ, резистентных к иметинибу, будучи при этом менее токсичным препаратом, эффективным для использования в бластном кризе ХМЛ, способным к проникновению через гемато-энцефалический барьер. Другой препарат, нилотиниб, более чем в 30 раз мощнее иматиниба и также является эффективным при бластном кризе заболевания.

Итак, дазатиниб и нилотиниб эффективны по гематологическим и цитогенетическим критериям в иматиниб-резистентных случаях ХМЛ во всех фазах заболевания и активны при всех мутациях BCR-ABL TK, кроме T315I. Основные токсические реакции состоят в цитопении и плевральной эффузии (дазатиниб). Однако после терапии этими препаратами возникают новые мутации (I255V/K, F317L, Y253H), которые заставляют переходить на лечение другим препаратом. В настоящее время ряд других препаратов проходит клинические испытания, в том числе бозутиниб, ингибиторы гистон-деацетилазы и Аурора-киназы.

Кроме того, сеть ELN разрабатывает правила и руководства по диагностике и лечению. Проблемы состоят в географических различиях демографических особенностей контроля качества диагностики исходов заболевания, сравнения между государствами, оптимизации контактов между участниками программ. В связи с этим началось частно-общественное партнерство между ELN и фирмой Новартис Онколоджи в рамках программы EUTOS по лечению ХМЛ, с целью стандартизации мониторинга результатов, совершенствования молекулярной диагностики (Рис. 14)

2008-2-en-Hehlmann-et-al-Fig-14_03.jpg

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Интеграция исследований в области лейкозов в Европе: парадигма хронического миелолейкоза

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Хельман Р., Саусселе С.

В обзорной статье рассматриваются проблемы в исследовании хронического миелолейкоза (ХМЛ). В частности, ввиду низкой частоты лейкозов в населении, необходима интеграция исследований в Европе путем создания кооперативных групп и исследовательских сетей.

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