Adoptive Cellular Therapies to Enhance Tolerance and Protective Immunity

移植代表了许多以终末期为特征的疾病治疗的标准护理 器官衰竭。移植后，患者必须严格坚持终身、多药联合治疗。 极大地增加心血管疾病、感染和恶性肿瘤的风险的养生法。 免疫耐受，同种异体移植物在没有免疫抑制的情况下被接受的现象 保护接受者的保护性免疫，是解决急性和慢性疾病问题的一种方法 排斥反应和由此导致的对毒性免疫抑制疗法的长期依赖。的发展。 耐受性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 扩大器官、组织和细胞移植在癌症等疾病中的应用 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 疾病。在啮齿动物模型中，成功的实体器官移植耐受是通过 将造血嵌合诱导与T细胞共刺激阻断相结合的策略。然而，鉴于 啮齿动物和人类免疫系统之间的显著差异，这些策略需要 在临床应用之前，在翻译模型中进行严格的测试。非人恒河猴 灵长类模型有许多重要的属性，使它们能够作为关键的临床前模型 以便将在小鼠身上获得的基本洞察力与它们在患者护理中的应用联系起来。在这个项目中，我们将 利用我们从活着的动员的外周血干细胞诱导嵌合体的能力 对恒河猴捐献者进行系统分析的影响，共刺激阻断和 基于嵌合体的耐受诱导策略对具有不同程度MHC的移植对具有 贫富差距。这些研究将集中在过继免疫疗法添加到我们的 标准嵌合诱导方案在提高嵌合体稳定性和免疫功能中的作用 移植。我们建议的统一目的是开发临床适用的诱导方案。 在保持移植受者免疫能力的同时，对实体器官移植的耐受性。 具体地说，在这项提案中，我们将确定1)使用调节性T细胞进行过继免疫治疗 提高混合嵌合体的稳定性和诱导移植耐受；以及2)是否 供者淋巴细胞输注过继免疫治疗可提高移植后免疫功能 跨越MHC屏障的混合造血嵌合体的诱导。

Transplantation represents the standard-of-care for the treatment of many diseases characterized by endstage organ failure. After transplantation, patients must rigidly adhere to lifelong, multi-agent treatment regimens that dramatically increase the risks of cardiovascular disease, infections and malignancies. 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 development of tolerogenic strategies 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. In rodent models, successful solid-organ transplantation tolerance has been created through strategies coupling hematopoietic chimerism-induction with T cell costimulation blockade. However, given the significant differences between the rodent and human immune systems, these strategies require rigorous testing in a translational model prior to their clinical application. Rhesus macaque 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 to their application to patient care. In this project, we will take advantage of our ability to induce chimerism using mobilized peripheral blood stem cells from living Rhesus macaque donors to perform a systematic analysis of the impact that a costimulation blockade and chimerism-based tolerance induction strategy has on transplant pairs having varying degrees of MHC disparity. These studies will focus on the efficacy of the addition of adoptive immunotherapies to our standard chimerism-induction regimen in increasing chimerism stability and immune competence after transplant. 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, in this proposal, we will determine 1) whether adoptive immunotherapy using regulatory T cells improves the stability of mixed chimerism and the induction of transplantation tolerance; and 2) whether adoptive immunotherapy using donor lymphocyte infusions improves immune competence after the induction of mixed hematopoietic chimerism across MHC barriers.