Transplant Tolerance in Non-Human Primates

非人类灵长类动物的移植耐受性

• 批准号: 7916877
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 23.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916877
• 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。 项目1：跨越不同程度的MHC差异的共刺激阻断、嵌合体和耐受性(Larsen，Christian P.) 项目1说明(由申请人提供)：免疫耐受，即接受同种异体移植物而不受免疫抑制，同时保持受者的保护性免疫的现象，是解决急性和慢性排斥以及由此产生的对毒性免疫抑制疗法的长期依赖问题的一种解决办法。在啮齿动物模型中移植耐受研究的巨大成功表明，类似的包括骨髓移植和造血细胞嵌合体在内的耐受诱导技术可以在临床前和临床情况下实现，从而使实体器官移植发生革命性的变化。非人灵长类动物模型具有许多重要属性，使它们能够作为关键的临床前模型，以便在 在小鼠身上获得的基本见解以及这些见解在病人护理中的应用。其中最多的 主要的耐受诱导策略是CD28/CD40 T细胞共刺激阻断和混合嵌合体诱导。通过利用我们从活体猕猴捐献者身上动员的外周血干细胞诱导嵌合体的能力，我们建议对具有不同程度MHC差异的移植对实施共刺激阻断和基于嵌合体的耐受诱导策略的影响进行系统分析。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术期保护性免疫的保存。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。具体地说，本项目的目标将涉及1)基于CD28/CD40共刺激-阻断的嵌合体/耐受诱导方案在显示供者和受者之间不同程度MHC匹配的移植上的有效性，2)嵌合体和耐受诱导的免疫调节策略的必要组成部分，以及3)抑制自然杀伤细胞介导的同种异体反应的有效性，以减少对受体调节和/或供者外周血干细胞促进跨越MHC障碍的耐受的需要。我们相信，在这种移植环境中诱导稳定的供者嵌合体和免疫耐受的能力将对结果产生很大影响。 这是移植的一项重要技术，有望使许多移植受者摆脱复杂的终生免疫抑制方案及其伴随的毒性。