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物，患者必须严格遵守终身治疗方案，使用昂贵的免疫抑制剂，这大大增加了心血管疾病、感染和恶性肿瘤的风险。在不需要慢性免疫抑制的情况下促进异体组织接受的策略的发展不仅可以降低这些危及生命的并发症的风险，而且还可以极大地扩大器官、组织和细胞移植在血红蛋白病和遗传免疫缺陷、I型糖尿病以及可能的其他自身免疫性疾病等疾病中的应用。

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.