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: 10270362
• 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/10270362
• 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.

项目总结/摘要 该计划的统一目标是设计新的和创新的战略，实现临床相关的 在2个月延迟的耐受诱导方案中， 持久的混合嵌合体该程序应用程序的PI最近开发了新的协议， 首次在食蟹猴中实现了对完全MHC错配心脏的长期稳定耐受 猴子这一显著的结果是通过在心脏受体中结合短暂的混合嵌合体而获得的。 供体肾共移植方案。最近的试点研究表明， 用既抑制CD 8+细胞， 效应/记忆T细胞和增强型宿主调节性T细胞。项目3将建立在临床适用的 Madsen团队开发的心脏耐受诱导平台（2个月D方案;在 项目1）中的概述和详细信息以及Pierson/Azimzadeh实验室在双 NHP心脏同种异体移植模型中的共刺激通路阻断。我们将测试增强的共刺激是否 通路阻断（α CD 2与α CD 154和/或α CD 28）可以取代肾共刺激的需要。 移植同时评估α CD 2（Aim 1）或抑制JAK 1/3（Aim 2）或Bcl-2（Aim 3）作为替代 和潜在的补充方法来消耗或抑制耐受性效应记忆T细胞 (TEM)细胞和降低毒性（消除对α CD 8的需要，减少或消除宿主全身照射 （TBI））在2个月D方案中。在初步结果的指导下，我们还将部署Treg支持性治疗（从 项目1）和使用α CD 117-鹅膏蕈毒肽抗体药物偶联物（来自项目2）进行的无辐射预处理 与基于α CD 2的增强型共刺激阻断，旨在减少或消除对放射的需求， 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 或未能在三个协调但不同的项目3目标中始终如一地诱导容忍，并使 项目1中不同但紧密一致的目标的结果之间的机械信息比较 和2.我们预期项目3中的一个或多个目标将产生创新、有效和安全的耐受性 在资助期结束前，将为心脏接受者的临床试验做好准备， 我们对临床相关背景下耐受诱导的理解。