Transplant Tolerance in Non-Human Primates

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。 我们已经开发了基于CD28和CD40/CD154 T细胞共刺激阻断的新的非清髓方案，以允许在恒河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。然而，我们的初步数据表明，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的诱导和由此产生的对固体器官移植的耐受是可以实现的，并保持了保护性免疫。该项目的目标是在我们的初步发现的基础上，开发和优化策略，以诱导非人类灵长类动物移植肾的稳定大嵌合和移植耐受。具体地说，在这项建议中，我们将确定1)在基于共刺激阻断的免疫抑制的背景下，增加MHC配型对实体器官移植嵌合体耐受性和耐受性的影响，2)基于共刺激阻断的免疫调节策略在诱导持久嵌合和耐受方面的必要组件，以及3)耗尽受者自然杀伤细胞，或提供带有调节性或常规T细胞的过继免疫治疗对嵌合体、肾移植存活、抗供者免疫反应和移植后保护性免疫的影响。我们建议的统一目的是开发临床适用的方案，以诱导对实体器官移植的耐受，同时保持移植受者的免疫能力。

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 immunosuppression 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. We have developed 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. However, our preliminary 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. The goal of this project is to build on our preliminary findings and develop and optimize strategies to induce stable macrochimerism and transplantation tolerance to renal allografts in non-human primates. Specifically, in this proposal we will determine 1) the effect of increasing MHC matching on chimerism durability and tolerance to solid organ transplants in the context of costimulation blockade-based immunosuppression, 2) the necessary components to our costimulation blockade based immunomodulation strategy in inducing durable chimerism and tolerance, and 3) the effect that depletion of recipient natural killer cells, or delivery of adoptive immunotherapy with either regulatory or conventional T cells will have on chimerism, survival of renal allografts, the anti-donor immune response and on post-transplant protective immunity. The unifying purpose of our proposal is to develop clinically applicable protocols for the induction of tolerance to solid organ allografts while preserving immune competence in the transplant recipient.