Adoptive Cellular Therapies to Enhance Tolerance and Protective Immunity

移植是治疗许多终末期疾病的标准治疗方法 器官衰竭移植后，患者必须严格遵守终身，多剂治疗 治疗方案会显著增加心血管疾病、感染和恶性肿瘤的风险。 免疫耐受是指移植物在无免疫抑制的情况下被接受， 保护接受者的保护性免疫力，代表了急性和慢性疾病的解决方案。 排斥反应以及由此导致的对毒性免疫抑制疗法的长期依赖。的发展 致耐受性策略不仅可以降低这些危及生命的并发症的风险， 扩大器官、组织和细胞移植的应用， 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 疾病在啮齿类动物模型中，成功的实体器官移植耐受已经通过以下方式产生： 将造血嵌合诱导与T细胞共刺激阻断偶联的策略。但鉴于 啮齿动物和人类免疫系统之间的显著差异，这些策略需要 在其临床应用之前，在平移模型中进行严格测试。非人恒河猴 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 以便将在小鼠中获得的基本见解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 利用我们的能力，使用动员的外周血干细胞诱导嵌合体， 恒河猴供体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的MHC的移植对具有不同程度的免疫耐受性。 差距这些研究将重点关注在我们的研究中加入过继免疫疗法的疗效。 标准嵌合体诱导方案在增加嵌合体稳定性和免疫能力中的作用 移植我们建议的统一目的是制定临床适用的诱导方案 对实体器官移植的耐受性，同时保留移植受体的免疫能力。 具体来说，在这项提案中，我们将确定1）是否使用调节性T细胞的过继免疫疗法 提高混合嵌合体的稳定性和移植耐受的诱导;和2）是否 使用供体淋巴细胞输注的过继免疫疗法改善了移植后的免疫能力。 诱导跨越MHC屏障的混合造血嵌合体。

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.