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

核心 A：阐明基于混合嵌合体的耐受性的潜在机制

基本信息

批准号：
10457399
负责人：
GILLES A BENICHOU
金额：
$ 27.72万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10457399
关键词：
Affect Allograft Tolerance Allografting Antigens Automobile Driving Biological Assay Biological Markers Blood Cells Chimerism Clinical Clinical Trials Diagnosis Dual-role transvestism Future Generations Genes Goals Heart Heart Transplantation Hematopoietic Human Immune response Kidney Leukocytes Maintenance Mediating Monkeys Mus Nature Pathogenicity Patients Phenotype Play Procedures Protocols documentation Recovery Regulation Regulatory T-Lymphocyte Role Serum Specificity T memory cell T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Translating Transplant Recipients Transplantation Transplantation Tolerance Work base clinically relevant design exosome extracellular vesicles heart allograft immunogenic immunoregulation improved in vivo isoimmunity kidney allograft nonhuman primate novel strategies programs translation to humans vesicular release

项目摘要

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.

核心摘要/摘要通过短暂的混合造血，猴子和患者已经实现了同种异体肾移植的耐受性嵌合现象。然而，到目前为止，我们目前的混合嵌合协议一直未能诱导对其他更具免疫原性的移植物（包括心脏）的耐受性。增强我们的混合嵌合策略实现同种异体心脏移植的耐受性是我们总体计划的主要目标。我们将完成这个通过测试总体假设来实现目标，即使用新颖的增强当前混合嵌合协议实现持久、高水平供体嵌合的策略将导致有效且安全的耐受方案可以快速转化为心脏同种异体移植的人类接受者。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制假设。改善我们的对有效和无效的耐受诱导程序的机械理解将告知未来协议的设计。我们将通过以下方式测试这些机制假设：1）破译机制供体造血混合嵌合、白细胞恢复和记忆 T 细胞的同种免疫会影响哪些因素耐受诱导，2) 确定成功的耐受方案是否与细胞外囊泡相关生成和供体抗原异装，以及 3) 评估 T 细胞删除和调节的作用拒绝与容忍。了解驱动免疫反应产生排斥或排斥反应的机制使用项目 1-3 中描述的混合嵌合方案治疗的猴子的耐受性将做出巨大贡献完善这些协议以及设计可以在项目中进行测试的未来容忍策略 1-3 预计可快速转化为人类心脏移植受者。