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

核心摘要/摘要 通过瞬时混合造血在猴子和患者身上实现了同种异体肾移植的耐受性 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 对包括心脏在内的其他更具免疫原性的移植的耐受性。增强我们的混合嵌合体策略以 实现同种异体心脏移植的耐受性是我们整个计划的主要目标。我们会做到这一点的 目的通过验证现有的混合嵌合体协议使用新技术增强嵌合体协议的总体假设 实现持久、高水平供体嵌合的战略将导致有效和安全的耐受方案 这可以迅速转移到接受同种异体心脏移植的人身上。核心A的具体目标是测试 项目1-3中描述的体内治疗产生的机械假说。改善我们的 对有效和无效的耐受诱导程序的机械性理解将告知 未来协议的设计。我们将通过1)破译这些机制来检验这些机械假说 供者的混合造血嵌合体、白细胞恢复和记忆T细胞的同种异体免疫影响 耐受诱导，2)确定成功的耐受方案是否与细胞外小泡有关 产生和供体抗原交叉修饰，以及3)评估T细胞缺失和调节在 拒绝VS宽容。了解驱动免疫反应以应对排斥反应的机制 用项目1-3中描述的混合嵌合体方案治疗猴子的耐受性将有很大贡献 改进这些协议，设计可在项目中测试的未来容错策略 1-3，以期快速移植给人类心脏移植受者。

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.