Inhibition of BCL-2 for induction of mixed chimerism without myelosuppressive conditioning

抑制 BCL-2 诱导混合嵌合状态，无需骨髓抑制条件

基本信息

批准号：
9168994
负责人：
TATSUO KAWAI
金额：
$ 25.12万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9168994
关键词：
Accounting Achievement Adverse effects Algorithms Allogeneic Bone Marrow Transplantation Allogenic Allograft Tolerance Apoptosis Apoptotic BCL-2 Protein BCL2 gene Bone Marrow Transplantation Cells Cessation of life Chimerism Chronic Clinical Clinical Trials Communicable Diseases Cyclophosphamide Cyclosporine Development Diabetes Mellitus Dose Drug usage Dyslipidemias Engraftment Family member Goals HLA Antigens Hematopoietic Hematopoietic stem cells Homeostasis Human Immune Tolerance Immunosuppression Immunosuppressive Agents In Vitro Individual Induction of Apoptosis Kidney Transplantation Laboratories Lymphocyte Malignant Neoplasms Malignant lymphoid neoplasm Modeling Morbidity - disease rate Mus Myelosuppressive Therapy Observational Study Organ Transplantation Outcome Peripheral Pharmaceutical Preparations Protein Family Protocols documentation Regimen Regulatory T-Lymphocyte Reporting Research Research Proposals Rodent Role Series Signal Pathway Stimulus Stress T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Toxic effect Translating Transplant Recipients Transplantation Whole-Body Irradiation analog base cardiovascular disorder risk cell type clinical application conditioning graft function improved in vivo inhibitor/antagonist interest kidney allograft nephrotoxicity neurotoxicity nonhuman primate novel novel strategies pre-clinical prevent response skin allograft

项目摘要

PROJECT SUMMARY / ABSTRACT Induction of specific immunologic tolerance is the ultimate goal of organ transplantation. Based on the conditioning regimen developed in our laboratory through decades-long research in nonhuman primates (NHP), successful renal allograft tolerance in HLA mismatched human kidney transplant recipients has now been achieved via the mixed chimerism approach. Nevertheless, widespread clinical application of this approach to tolerance induction has been hampered by the toxicity of myelosuppressive therapies (e.g., TBI or cyclophosphamide) included in the current conditioning regimen. It would therefore be desirable to develop a reliable nontoxic conditioning regimen that permits allogeneic hematopoietic stem cell (HSC) engraftment without nonselective myelosuppressive therapy. Although it has been extremely difficult to achieve engraftment of allogeneic HSC without myelosuppressive conditioning, Cippa et al. recently reported a novel approach to HSC engraftment using a B cell lymphoma-2 (Bcl-2) inhibitor, without myelosuppressive therapy. In that study, through induction of persistent mixed chimerism by a potent but selective Bcl-2 inhibitor, ABT-737, in combination with costimulatory blockade and cyclosporine, successful induction of skin allograft tolerance was achieved across a full MHC disparity. The major objective of the proposed exploratory R21 project is to translate this novel rodent bone marrow transplant study with ABT-263 (navitoclax), an orally available analog of ABT-737, to a non-human primate kidney transplant model and thereby develop a more clinically feasible protocol for inducing renal allograft tolerance using the mixed chimerism approach. Since our previous studies suggest that renal allograft tolerance achieved in NHP and human recipients after induction of chimerism is regulatory T cell (Tregs) dependent, understanding the effects of Bcl-2 inhibition on allo-reactive T cells and Tregs will enable us to determine the transplant outcome. Therefore, another important objective of this study is to evaluate the effect of ABT-263 on various T cell subsets to elucidate the mechanisms of tolerance after induction of mixed chimerism.

项目摘要 /摘要诱导特定的免疫耐受性是器官移植的最终目标。基于经过数十年的非人类灵长类动物的研究，我们的实验室制定了调节方案（NHP），HLA不匹配的人类肾脏移植受者中成功的肾脏同种异体耐受性已通过混合的嵌合法实现。然而，这是广泛的临床应用骨抑制疗法的毒性阻碍了耐受性诱导的方法（例如，TBI或TBI或环磷酰胺）包括在当前的调节方案中。因此，希望开发一个可靠的无毒条件方案，允许同种异体造血干细胞（HSC）植入没有非选择性骨髓抑制疗法。尽管很难实现植入 Cippa等人的同种异体HSC没有骨髓抑制条件。最近报道了一种新颖的方法使用B细胞淋巴瘤-2（BCL-2）抑制剂的HSC植入，无需骨髓抑制疗法。在这项研究中，通过有效但选择性的Bcl-2抑制剂ABT-737诱导持续的混合嵌合体。结合con刺激性阻滞和环孢菌素，成功诱导皮肤同种异体耐受性是跨越了完整的MHC差异。拟议的探索性R21项目的主要目标是用ABT-263（Navitoclax）翻译这种新颖的啮齿动物骨髓移植研究，这是一种口服类似物 ABT-737，非人类灵长类动物肾移植模型，从而发展更可行的使用混合嵌合方法诱导肾脏同种异体耐受性的方案。自从我们以前的研究以来表明在诱导嵌合发生后NHP和人类受体中实现的肾脏同种异体耐受性是调节性T细胞（Tregs）依赖于，了解Bcl-2抑制对异抗反应性T细胞和 Tregs将使我们能够确定移植结果。因此，本研究的另一个重要目标是评估ABT-263对各种T细胞子集的影响，以阐明后的耐受性机制诱导混合嵌合体。