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

项目摘要/摘要 该计划的统一目标是设计新的和创新的战略，以实现临床相关 同种异体心脏移植耐受在2个月延迟耐受诱导方案中的应用 持久的混合嵌合体。该程序应用的PI最近开发了新的协议 首次实现了对食蟹猴完全MHC不匹配心脏的长期、稳定的耐受性 猴子。在心脏受者中，通过结合短暂的混合嵌合体获得了这一显著的结果 供肾联合移植方案。最近的试点研究证明了 用既抑制CD8又抑制CD8的方法取代以前对供体肾脏联合移植的要求 效应/记忆T细胞和增强宿主调节性T细胞。项目3将建立在临床适用的 心脏耐受诱导平台由Madsen团队开发(为期2个月的D-协议；在 项目1中的概述和详细信息)以及Pierson/Azimzadeh实验室在DUAL 共刺激通路阻断NHP同种异体心脏移植模型。我们将测试增强的共刺激效应 途径阻断(αCD2与αCD154和/或αCD28)可以取代对肾脏联合的需求 评估αCD2(目标1)或抑制JAK1/3(目标2)或抑制Bcl2(目标3)的同时进行移植 以及耗尽或抑制耐受效应记忆T细胞的潜在互补方法 (TM)细胞，降低毒性(消除对αCD8的需要，减少或消除宿主全身照射 (TBI))在2个月的D-议定书中。根据初步结果，我们还将部署Treg支持性治疗(来自 项目1)和使用αCD117-Amanitin抗体药物结合物的无辐射调理(来自项目2) 使用基于αCD2的增强型共刺激阻断，旨在减少或消除对辐射和 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 或未能始终如一地在三个协调但不同的项目3目标中诱导容忍，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 2.我们预计项目3中的一个或多个目标将产生创新、有效和安全的容忍度 将在资助期结束前准备好在心脏接受者身上进行临床试验的方案，并增强 我们在临床相关背景下对耐受诱导的理解。

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.