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

• 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
• 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

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.

项目总结/摘要 诱导特异性免疫耐受是器官移植的最终目的。基于 我们的实验室通过对非人类灵长类动物长达数十年的研究开发了一种调理方案 (NHP)目前，在HLA不匹配的人肾移植受者中， 是通过混合嵌合体方法实现的。然而，这种方法的广泛临床应用 诱导耐受性的方法受到骨髓抑制疗法毒性的阻碍（例如，TBI或 环磷酰胺）。因此，有必要制定一项 允许异基因造血干细胞（HSC）植入的可靠无毒预处理方案 没有非选择性骨髓抑制治疗虽然实现移植已经极其困难 Cippa等人最近报道了一种新的方法， 使用B细胞淋巴瘤-2（Bcl-2）抑制剂的HSC植入，无骨髓抑制治疗。在这项研究中， 通过有效但选择性Bcl-2抑制剂ABT-737诱导持续的混合嵌合体， 联合应用共刺激受体阻断剂和环孢霉素，成功诱导了皮肤移植耐受， 实现了完全的MHC差异。拟议的R21探索性项目的主要目标是 翻译这一新的啮齿动物骨髓移植研究与ABT-263（navitoclax），口服类似物 的ABT-737，非人灵长类动物肾移植模型，从而开发出一种更临床可行的 使用混合嵌合体方法诱导肾移植耐受的方案。由于我们之前的研究 表明诱导嵌合体后NHP和人类受体实现肾移植耐受， 调节性T细胞（TcB）依赖性，了解Bcl-2抑制对同种异体反应性T细胞的影响， 我们就能确定移植的结果。因此，本研究的另一个重要目的是 评估ABT-263对各种T细胞亚群的影响，以阐明免疫耐受后的机制。 诱导混合嵌合体。