Transplant Tolerance in Non-Human Primates

非人类灵长类动物的移植耐受性

• 批准号: 7632237
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 288.36万
• 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/7632237
• 关键词: Transplant; Tolerance; Non; Human; Primates

DESCRIPTION (provided by applicant): 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. PROJECT 1: Costimulation blockade, chimerism and tolerance across varying degrees of MHC disparity (Larsen, Christian P.) PROJECT 1 DESCRIPTION (provided by applicant): Immune tolerance, the phenomenon by which the allograft is accepted without immunosuppression while preserving the recipient's protective immunity, represents a solution to the problems of acute and chronic rejection and the resulting long-term reliance on toxic immunosuppressive therapies. The significant success of transplantation tolerance studies in rodent models has suggested that similar tolerance-induction techniques involving bone marrow transplant and hematopoietic chimerism could be achieved in preclinical and clinical situations, thus revolutionizing solid organ transplantation. Non-human primate models have a number of important attributes that allow them to serve as critical preclinical models in order to bridge the basic insights gained in mice and the application of these insights to patient care. Among the most prominent of the tolerance induction strategies are CD28/CD40 T cell costimulation blockade and mixed chimerism induction. By taking advantage of our ability to induce chimerism using mobilized peripheral blood stem cells from living Rhesus macaque donors, we propose to perform a systematic analysis of impact of a costimulation blockade and chimerism-based tolerance induction strategy in transplant pairs having varying degrees of MHC disparity. These studies also are focused on understanding the immune consequences of transplant, specifically on evaluating the anti-donor response and the preservation of protective immunity in the peritransplant period. 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. Specifically, the aims in this project will address 1) the effectiveness of a CD28/CD40 costimulation-blockade-based chimerism/tolerance induction protocol on transplants displaying varying degrees of MHC matching between the donor and recipient, 2) the necessary components of the immunomodulatory strategy for chimerism and tolerance induction, and 3) the efficacy of inhibiting Natural Killer cell-mediated alloreactivity in order to decrease the need for recipient conditioning and/or donor peripheral blood stem cells to promote tolerance across MHC barriers. We believe the ability to induce stable donor chimerism and immune tolerance in this transplant setting would have a large impact on the outcome of transplantation, and holds the promise of relieving many transplant recipients from the requirement for complicated life-long immunosuppressive regimens and their attendant toxicities.

描述（由申请人提供）：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。 项目1：不同程度MHC差异的共刺激阻断、嵌合和耐受 （Larsen，Christian P.） 项目1描述（由申请人提供）：免疫耐受是指在不使用免疫抑制的情况下接受同种异体移植物，同时保留受者的保护性免疫的现象，代表了急性和慢性排斥反应问题以及由此导致的对毒性免疫抑制治疗的长期依赖的解决方案。在啮齿动物模型中移植耐受性研究的显著成功表明，涉及骨髓移植和造血嵌合体的类似耐受诱导技术可以在临床前和临床情况下实现，从而彻底改变实体器官移植。非人灵长类动物模型具有许多重要的属性，这些属性使它们能够作为关键的临床前模型，以桥接 在小鼠中获得的基本见解以及这些见解在患者护理中的应用。的最 耐受性诱导策略的突出之处在于CD 28/CD 40 T细胞共刺激阻断和混合嵌合诱导。通过利用我们的能力，诱导嵌合体动员外周血干细胞从活的恒河猴供体，我们建议进行系统的分析，共刺激阻断和嵌合体为基础的耐受性诱导策略的影响移植对具有不同程度的MHC差异。这些研究还侧重于了解移植的免疫后果，特别是评估抗供体反应和移植围手术期保护性免疫的保存。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。具体而言，本项目的目标将涉及1）基于CD 28/CD 40共刺激-阻断的嵌合/耐受诱导方案对供体和受体之间显示不同程度MHC匹配的移植物的有效性，2）嵌合和耐受诱导的免疫调节策略的必要组成部分，和3）抑制自然杀伤细胞介导的同种异体反应性以减少对受体调节和/或供体外周血干细胞的需要以促进跨越MHC屏障的耐受性的功效。我们相信在这种移植环境中诱导稳定的供体嵌合体和免疫耐受的能力将对结果产生很大的影响 这是一种新的移植方法，有望减轻许多移植受者对复杂的终身免疫抑制方案及其伴随的毒性的需求。