Transplant Tolerance in Non-Human Primates

非人类灵长类动物的移植耐受性

• 批准号: 7918039
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 191.78万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918039
• 关键词: Transplant; Tolerance; Non; Human; Primates

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.

移植已成为许多形式的终末期器官衰竭的首选治疗方法。虽然短期结果有所改善，但长期结果仍然不够。为了维持他们的同种异体移植物，患者必须严格遵守使用昂贵的免疫抑制剂的终身治疗方案，这大大增加了心血管疾病，感染和恶性肿瘤的风险。发展促进接受同种异体组织而不需要铬免疫抑制的策略不仅可以降低这些危及生命的并发症的风险，而且还可以大大扩展器官、组织和细胞移植在血红蛋白病和遗传性免疫缺陷、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。 我们已经开发了新的非清髓性方案，使用CD 28和CD 40/CD 154 T细胞共刺激阻断为基础的治疗，以允许在恒河猴中诱导高水平的造血嵌合体。然而，在完全MHC不一致的情况下，这种嵌合状态是短暂的，不赋予实体器官移植的免疫耐受性，并导致移植受者的显著免疫缺陷。然而，我们的初步数据表明，在移植供体和受体之间的MHC匹配增加的情况下，基于共刺激阻断的持久嵌合体的诱导和由此产生的对实体器官移植的耐受是可以实现的，并保留保护性免疫。本项目的目标是建立在我们的初步研究结果，并制定和优化策略，以诱导稳定的巨嵌合体和移植耐受的非人灵长类动物的肾移植。具体地，在该提议中，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匹配对嵌合体持久性和对实体器官移植的耐受性的影响，2）我们的基于共刺激阻断的免疫调节策略在诱导持久的嵌合体和耐受性中的必要组分，以及3）受体自然杀伤细胞的消耗，或用调节性或常规T细胞进行过继免疫治疗的递送将对嵌合状态、肾同种异体移植物的存活、抗供体免疫应答和移植后保护性免疫产生影响。我们的建议的统一目的是开发临床上适用的协议，诱导耐受实体器官移植，同时保持移植受体的免疫能力。