New Approaches to Inducing Cardiac Allograft Tolerance

项目总结/摘要 获得耐受性，定义为在没有持续免疫抑制的情况下， 移植的最终目的。在非人灵长类动物中已经实现了肾移植的耐受性 （NHPs）和使用非清髓性预处理和供体骨髓的组合在人类中进行 DMBT移植导致短暂的供体嵌合体。然而，到目前为止，短暂的混合嵌合体 在NHP中实现肾移植长期耐受的方案一直未能诱导 心脏移植受者的耐受性。众所周知，一些器官，如肾脏和肝脏， 而其他的，如心脏和肺，是“耐受性”。尽管有免疫屏障 我们的实验室最近开发了新的协议，首次实现了 在食蟹猴受体中长期稳定耐受心脏移植。这个显著的结果是 通过包括供体肾共移植在仅表现出短暂混合嵌合体的心脏受体中获得， 这增强了宿主调节性T细胞在混合嵌合状态调节后的作用。而 肾和心脏联合移植产生了显着的效果，这种策略并不广泛 由于使用实验性药物和仅牺牲肾脏以 诱导心脏耐受性。虽然本项目不研究同种异体肺移植，但我们最近在肺移植中的发现， 接受者提供的原则证明，持久的混合嵌合体可以在NHP中实现，并且这种状态 导致耐药胸部器官的长期耐受性;这些是第一批对肺耐药的NHP 同种异体移植因此，这个整体计划的统一目标是设计创新的混合嵌合体 单独心脏接受者的策略，要么放大调节性T细胞的贡献， 巨噬细胞在瞬时混合嵌合体方案（项目1）或实现持久的混合嵌合体 （项目2），同时使用临床相关药物进行宿主调节（项目3）。项目1将侧重于 增强调节性T细胞和巨噬细胞在诱导瞬时混合免疫应答的方案中的作用 嵌合体项目2将专注于使用下一代调节实现持久的混合嵌合体 方案，创新的免疫抑制平台。项目3将研究新的、临床适用的药物 其增强共刺激阻断并降低毒性。核心A将研究 项目1-3中描述的治疗影响宿主免疫应答。该计划将在这样的组织 核心A中的早期机械发现/进展将为项目1-3的目标提供信息和改进。的 本申请中描述的补充模型和方法是本计划的独特优势 项目我们预计，这些高度互动的项目将共同产生一个或多个安全和有效的 在资助结束前，将为心脏移植受者的临床试验做好准备的耐受性方案 期

PROJECT SUMMARY / ABSTRACT Achieving tolerance, defined as long-term allograft survival in the absence of ongoing immunosuppression, is the ultimate goal in transplantation. Tolerance of kidney allografts has been achieved in non-human primates (NHPs) and in humans using a combination of non-myeloablative conditioning and donor bone marrow transplantation (DMBT) that results in transient donor chimerism. However, until now, transient mixed-chimerism protocols that achieve long-term tolerance of kidney allografts in NHPs have consistently failed to induce tolerance in recipients of heart allografts. It is well known that some organs, such as kidney and liver, are “tolerance-prone” while others, such as heart and lung, are “tolerance-resistant.” Despite the immune barriers posed by the heart, our laboratory has recently developed novel protocols that have, for the first time, achieved long-term, stable tolerance of heart transplants in cynomolgus monkey recipients. This remarkable result was attained in heart recipients exhibiting only transient mixed chimerism by including donor kidney cotransplantation, which enhanced the contributions of host regulatory T cells following mixed chimerism conditioning. While the combination of kidney and heart transplantation produced remarkable results, this strategy does not have wide clinical feasibility due to the use of experimental agents and the ethical barrier of sacrificing a kidney simply to induce heart tolerance. Although lung allografts will not be studied in this Program, our recent findings in lung recipients provide proof of principle that durable mixed chimerism can be achieved in NHPs and that this state results in long term tolerance of resistant thoracic organs; these were the first NHPs to become tolerant of lung allografts. Thus, the unifying goal of this overall Program is to design innovative mixed chimerism strategies for heart alone recipients that either amplify the contributions of regulatory T cells and macrophages in transient mixed chimerism protocols (Project 1) or achieve durable mixed chimerism (Project 2) while using clinically-relevant agents for host conditioning (Project 3). Project 1 will focus on enhancing the contribution of regulatory T cells and macrophages in protocols which induce transient mixed chimerism. Project 2 will focus on achieving durable mixed chimerism using next-generation conditioning regimens, innovative immunosuppression platforms. Project 3 will investigate novel, clinically-applicable, agents which enhance costimulation blockade and diminish toxicity. Core A will investigate the mechanisms by which treatments described in Projects 1-3 influence the host immune response. The Program will be organized in such a way that early mechanistic discoveries/advances in Core A will inform and refine the aims of Projects 1-3. The complementary models and approaches described in this application are unique strengths of this program project. We anticipate that together, these highly interactive projects will generate one or more safe and effective tolerance protocols that will be ready for clinical trial(s) in heart allograft recipients by the end of the funding period.