Project 3: Enhanced Costimulation Blockade to Achieve Clinically Relevant Heart Allograft Tolerance

项目 3：增强共刺激阻断以实现临床相关的同种异体移植心脏耐受性

• 批准号: 10457402
• 负责人: Richard N Pierson
• 金额: $ 66.53万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/10457402
• 关键词: Adopted; Allograft Tolerance; Amanitins; Antibodies; Antibody Therapy; Antibody-drug conjugates; B-Lymphocytes; BCL2 gene; Bone Marrow Transplantation; CD28 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cadaver; Chimerism; Chronic; Clinical; Clinical Trials; Data; Engraftment; FDA approved; Failure; Funding; Goals; Graft Survival; Heart; Heart Transplantation; Human; Immune Tolerance; Immunosuppression; Inflammatory; Interferon Type II; Interleukin-17; Interleukin-6; Kidney; Kidney Transplantation; Laboratories; Lead; Lymphocyte; Macaca fascicularis; Modeling; Molecular; Monoclonal Antibodies; Monoclonal Antibody Therapy; Morbidity - disease rate; Myelosuppression; Organ Donor; Organ Transplantation; Pathogenicity; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pilot Projects; Protocols documentation; Radiation; Regimen; Regulatory T-Lymphocyte; Risk; T memory cell; T-Lymphocyte; Testing; Time; Toxic effect; Transplantation; Whole-Body Irradiation; allograft rejection; base; clinical application; clinically relevant; conditioning; cost; design; experience; heart allograft; improved; innovation; isoimmunity; kidney allograft; novel; novel strategies; preservation; programs; success; terminally differentiated effector memory (TEM) T cells

PROJECT SUMMARY / ABSTRACT The unifying goal of this Program is to design new and innovative strategies that achieve clinically-relevant heart allograft tolerance in 2-month-delayed tolerance induction protocols which induce either transient or durable mixed chimerism. The PI of this Program application has recently developed novel protocols that have, for the first time, achieved long-term, stable tolerance of fully MHC mismatched hearts in cynomolgus monkeys. This remarkable result was attained in heart recipients by combining a transient mixed chimerism protocol with donor kidney co-transplantation. Recent pilot studies have demonstrated the feasibility of replacing the previous requirement for donor kidney co-transplantation with approaches that both inhibit CD8 effector/memory T cells and enhance host regulatory T cells. Project 3 will build on the clinically-applicable heart tolerance induction platform developed by the Madsen team (2-month D-Protocol; presented in the Overview and in detail in Project 1) and the Pierson/Azimzadeh lab's extensive experience with dual costimulation pathway blockade in NHP heart allograft models. We will test whether enhanced costimulation pathway blockade (αCD2 with αCD154 and/or αCD28) can replace the requirement for renal co- transplantation while evaluating αCD2 (Aim 1) or inhibition of JAK 1/3 (Aim 2) or Bcl-2 (Aim 3) as alternative and potentially complementary approaches to deplete or inhibit tolerance-resistent effector memory T cells (TEM) cells and reduce toxicity (eliminate the need for αCD8 and reduce or eliminate host total body irradiation (TBI)) in the 2-month D-Protocol. Guided by initial results, we will also deploy TReg-supportive treatments (from Project 1) and radiation-free conditioning using αCD117-Amanitin antibody drug conjugate (from Project 2) with αCD2-based enhanced costimulation blockade, aiming to reduce or eliminate the need for radiation and thereby reduce toxicity. Core A will elucidate the cellular and molecular mechanisms associated with success or failure to consistently induce tolerance in the three coordinated but distinct Project 3 Aims, and enable mechanistically informative comparisons between results from distinct but closely aligned Aims in Projects 1 and 2. We anticipate that one or more Aims in Project 3 will generate innovative, effective, and safe tolerance protocols that will be ready for clinical trials in heart recipients by the end of the funding period, and enhance our understanding of tolerance induction in a clinically relevant context.

项目摘要 /摘要 该计划的统一目标是设计新的创新策略，以实现与临床相关的 在2个月延迟的耐受性诱导方案中，心脏同质自由抗体的耐受性，该方案诱导瞬态或 耐用的混合嵌合。该程序应用程序的PI最近开发了新的协议 首次实现了cynomolgus中完全MHC不匹配的心脏的长期稳定耐受性 猴子。通过结合瞬态混合嵌合体，将这种显着的结果附加在心脏的接受者中 供体肾脏共转移的方案。最近的试点研究表明 用均抑制CD8的方法取代先前对供体肾脏共转移的要求 效应子/记忆T细胞并增强宿主调节性T细胞。项目3将建立在临床上的基础上 由Madsen团队开发的心脏耐受感应平台（2个月的D-Protocol； 项目1）和Pierson/Azimzadeh实验室的概述和详细介绍 NHP心脏同种异体模型中的共刺激途径阻滞。我们将测试增强的共刺激 途径阻滞（具有αCD154和/或αCD28的αCD2）可以取代肾脏共同的要求 在评估αCD2（AIM 1）或抑制JAK 1/3（AIM 2）或BCL-2（AIM 3）的同时移植 并有可能完成耗尽或抑制耐耐受效应的记忆T细胞的方法 （TEM）细胞并降低毒性（消除对αCD8的需求并减少或消除宿主的全身照射 （TBI））在2个月的d-protocol中。在初始结果的指导下，我们还将部署treg支持治疗（来自 项目1）使用αCD117-氨氨酸抗体药物共轭物和无辐射调节（来自项目2） 基于αCD2的增强了共刺激阻滞，旨在减少或消除对辐射的需求和 从而降低毒性。核心A将阐明与成功相关的细胞和分子机制 或未能始终在三个协调但独特的项目3的目标中诱导宽容，并启用 在项目1中不同但密切相结合的目标的结果之间的机械信息丰富的比较1 和2。我们预计项目3中的一个或多个目标将产生创新，有效和安全的宽容 在资金期结束之前，将准备在心脏接受者进行临床试验的方案，并增强 我们对临床相关环境中耐受性诱导的理解。