Core A: Elucidating the Mechanisms Underlying Mixed-Chimerism Based Tolerance

核心摘要/摘要 通过短暂的混合造血，在猴和患者中已经实现了肾移植耐受 嵌合体然而，到目前为止，我们目前的混合嵌合体方案一直未能诱导 对其他免疫原性更强的移植物的耐受性，包括心脏。加强我们的混合嵌合体策略， 实现心脏移植耐受是我们整个项目的主要目标。我们会完成的 目的：通过检验使用新的嵌合体技术增强目前的混合嵌合体方案的总体假设， 获得持久的、高水平的供体嵌合体的策略将导致有效和安全的耐受方案 可以迅速转移到心脏移植的人类受体身上。核心A的具体目标是测试 由项目1-3中描述的体内治疗产生的机制假设。改善我们 机械理解的宽容诱导程序的工作和那些不将告知 未来协议的设计。我们将通过以下方式来测试这些机制假设：1）通过以下方式来破译机制： 其中供体造血混合嵌合体、白细胞恢复和记忆T细胞的同种免疫影响 耐受诱导，2）确定成功的耐受方案是否与细胞外囊泡相关 产生和供体抗原交叉敷料，和3）评估T细胞缺失和调节在 拒绝与宽容了解驱动免疫反应向排斥反应的机制， 项目1-3中描述的混合嵌合体方案治疗的猴子的耐受性将大大有助于 改进这些协议，并设计未来可在项目中测试的公差策略 1-3以期快速转化为人类心脏移植受体。

CORE SUMMARY / ABSTRACT Tolerance of kidney allografts has been achieved in monkeys and patients via transient mixed hematopoietic chimerism. However, until now, our current mixed chimerism protocols have consistently failed to induce tolerance of other more immunogenic transplants, including hearts. Enhancing our mixed chimerism strategy to achieve tolerance of heart allografts is the main objective of our overall Program. We will accomplish this objective by testing the overall hypothesis that enhancing current mixed chimerism protocols using novel strategies that achieve durable, high level donor chimerism will lead to an effective and safe tolerance protocol that can be rapidly translated to human recipients of heart allografts. The specific goal of Core A is to test mechanistic hypotheses generated by the in vivo treatments described in Projects 1-3. Improving our mechanistic understanding of tolerance inducing procedures that work and those that do not will inform the design of future protocols. We will test these mechanistic hypotheses by 1) deciphering the mechanisms by which donor hematopoietic mixed chimerism, leukocyte recovery, and alloimmunity by memory T cells affect tolerance induction, 2) determining if successful tolerance protocols are associated with extracellular vesicle generation and donor antigen cross-dressing, and 3) evaluating the role of T cell deletion and regulation in rejection vs. tolerance. Understanding the mechanisms driving the immune response towards rejection or tolerance in monkeys treated with the mixed chimerism protocols described in Projects 1-3 will contribute greatly to the refinement of those protocols and to the design of future tolerance strategies that can be tested in Projects 1-3 in anticipation of rapid translation to human heart transplant recipients.