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

项目摘要/摘要 诱导特异性免疫耐受是器官移植的最终目标。基于 我们实验室通过对非人灵长类动物进行了数十年的研究，开发出了条件调节方案 (NHP)，人类白细胞抗原不相合的人肾移植受者成功的同种异体肾移植耐受 是通过混合嵌合体方法实现的。然而，这一技术在临床上的广泛应用 诱导耐受的方法因骨髓抑制疗法的毒性而受阻(例如，TBI或 环磷酰胺)包括在当前的调理方案中。因此，最好是开发一种 允许异基因造血干细胞(HSC)植入的可靠无毒预适应方案 如果没有非选择性的骨髓抑制治疗。尽管很难实现嫁接 没有骨髓抑制条件的同种异体HSC，Cippa等人。最近报道了一种新的方法来 在没有骨髓抑制治疗的情况下，使用B细胞淋巴瘤-2(Bcl2)抑制剂进行HSC植入。在那项研究中， 通过有效但选择性的Bcl2抑制剂ABT-737诱导持续的混合嵌合体，在 联合使用共刺激阻滞剂和环孢素，成功地诱导了同种异体皮肤移植耐受。 在完全的MHC差异中实现。拟议的探索性R21项目的主要目标是 用口服类似物ABT-263(Navitoclax)翻译这项新的啮齿动物骨髓移植研究 将ABT-737移植到非人类灵长类动物肾脏移植模型，从而开发出一种更具临床可行性的 使用混合嵌合体方法诱导肾移植耐受的方案。因为我们之前的研究 提示NHP和人类受者在诱导嵌合体后达到的肾移植耐受是 调节性T细胞(Tregs)依赖，了解Bcl-2抑制对同种异体反应性T细胞和 Tregs将使我们能够确定移植结果。因此，这项研究的另一个重要目标 目的是评价ABT-263对不同T细胞亚群的影响，以阐明耐受的机制 混合嵌合体的诱导。

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.