TRANSPLANT TOLERANCE IN NON-HUMAN PRIMATES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 移植已成为许多终末期器官衰竭的首选治疗方法。虽然短期结果有所改善，但长期结果仍然不足。为了维持他们的同种异体移植，患者必须严格遵守终身治疗方案，使用昂贵的免疫抑制剂，大大增加心血管疾病、感染和恶性肿瘤的风险。在不需要铬免疫抑制的情况下促进同种异体组织接受的策略的发展，不仅可以降低这些威胁生命的并发症的风险，而且可以极大地扩大器官、组织和细胞移植在疾病中的应用，如血红蛋白疾病和遗传免疫缺陷、I型糖尿病，以及可能的其他自身免疫性疾病。 在过去的一年里，我们在开发新的非清髓性方案方面取得了重大进展，使用CD28和CD40/CD154T细胞共刺激-基于阻断的疗法来允许在猕猴中诱导高水平的造血嵌合体。然而，在MHC完全不一致的情况下，这种嵌合体是短暂的，不会赋予实体器官移植免疫耐受性，并导致移植受者显著的免疫缺陷。因此，我们对Yerkes群体进行了系谱和MHC分析，这使得我们在过去的一年里，在已知家族关系和MHC相似的恒河猴捐赠者和接受者之间进行了第一次骨髓移植。我们的数据表明，在移植供者和受者之间MHC配型增加的情况下，基于共刺激阻断的持久嵌合体诱导和由此产生的对固体器官移植的耐受性是可以实现的，并保持保护性免疫。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Transplantation has emerged as the preferred method of treatment for many forms of end-stage organ failure. While short-term results have improved, long-term outcomes remain inadequate. To maintain their allografts, patients must rigidly adhere to life-long treatment regimens using costly immunosuppressive agents that dramatically increase the risks of cardiovascular disease, infections and malignancies. The development of strategies to promote the acceptance of allogeneic tissues without the need for chromic immunosupression could not only reduce the risk of these life-threatening complications, but also greatly expand the application of organ, tissue and cellular transplantation for diseases such as the hemoglobinopathies and genetic immunodeficiencies, Type I diabetes, and possibly other autoimmune diseases. In the past year, we have made significant progress towards the development of novel non-myeloablative protocols using CD28 and CD40/CD154 T cell costimulation-blockade-based therapeutics to permit the induction of high levels of hematopoietic chimerism in Rhesus macaques. However, in the setting of full MHC disparity, this chimerism was transient, did not confer immune tolerance to solid organ transplants, and resulted in significant immunodeficiency in transplant recipients. We therefore undertook a pedigree and MHC analysis of the Yerkes colony which has allowed us, in the past year, to perform the first bone marrow transplants between rhesus macaque donors and recipients with known familial relationships and MHC similarity. Our data suggests that in the setting of increased MHC matching between transplant donors and recipients, costimulation blockade-based induction of durable chimerism and resultant tolerance to solid organ transplants is achievable, with preservation of protective immunity.