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

基本信息

批准号：
10673082
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
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/10673082
关键词：
Adopted Allograft Tolerance Amanitins Antibodies Antibody Therapy Antibody-drug conjugates Apoptosis B-Lymphocytes BCL2 gene Bone Marrow Transplantation CD28 gene CD8-Positive T-Lymphocytes CD8B1 gene Cadaver Cells Chimerism Chronic Clinical Data Engraftment FDA approved Failure Funding Goals Graft Survival Heart Heart Transplantation Human IL17 gene Immune Tolerance Immunosuppression Inflammatory Interferon Type II Interleukin-6 Kidney Kidney Transplantation Laboratories 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 Proliferating Protocols documentation Radiation Regimen Regulatory T-Lymphocyte Risk T memory cell T-Lymphocyte Testing Time Toxic effect Transplantation Whole-Body Irradiation allograft rejection clinical application clinical trial readiness clinically relevant conditioning cost design effector T cell experience heart allograft improved innovation isoimmunity kidney allograft novel novel strategies preservation programs success

项目摘要

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.

项目概要/摘要该计划的统一目标是设计新的创新策略，以实现临床相关 2个月延迟耐受诱导方案中的心脏同种异体移植耐受，该方案诱导短暂或该计划应用程序的 PI 最近开发了新颖的协议。首次在食蟹猴中实现了 MHC 完全不匹配心脏的长期、稳定耐受这一显着的结果是通过结合短暂的混合嵌合现象在心脏受体中获得的。最近的试点研究已经证明了供体肾联合移植的可行性。用抑制 CD8 的方法取代以前对供肾联合移植的要求效应/记忆 T 细胞和增强宿主调节 T 细胞项目 3 将建立在临床适用的基础上。 Madsen 团队开发的心脏耐受诱导平台（2 个月的 D-Protocol；在项目 1) 中的概述和详细信息以及 Pierson/Azimzadeh 实验室在双重技术方面的丰富经验我们将测试 NHP 心脏同种异体移植模型中的共刺激途径阻断是否增强。途径阻断（αCD2 与 αCD154 和/或 αCD28）可以替代肾协同的需要移植，同时评估 αCD2（目标 1）或 JAK 1/3（目标 2）或 Bcl-2（目标 3）的抑制作为替代方案以及消除或抑制耐受性效应记忆 T 细胞的潜在补充方法 (TEM) 细胞并降低毒性（消除对 αCD8 的需要并减少或消除宿主全身辐射 (TBI)) 在 2 个月的 D 方案中，以初步结果为指导，我们还将部署 TReg 支持治疗（从项目 1) 和使用 αCD117-鹅膏菌素抗体药物偶联物的无辐射调理（来自项目 2）使用基于 αCD2 的增强共刺激阻断，旨在减少或消除对辐射的需求核心 A 将阐明与成功相关的细胞和分子机制。或未能始终如一地在三个协调但不同的项目 3 目标中诱导宽容，并使项目 1 中不同但密切一致的目标的结果之间的机械信息比较 2. 我们预计项目 3 中的一个或多个目标将产生创新、有效和安全的耐受性协议将在资助期结束前准备好在心脏受者身上进行临床试验，并加强我们对临床相关背景下耐受诱导的理解。