New Approaches to Inducing Cardiac Allograft Tolerance

项目摘要/摘要 实现耐受性，定义为在没有持续免疫抑制的情况下同种异体移植的长期存活，是 移植的最终目标。在非人类灵长类动物中实现了同种异体肾移植的耐受 (NHP)和在人类中使用非清髓性调节和供体骨髓的组合 导致一过性供者嵌合体的移植(DMBT)。然而，到目前为止，短暂的混合嵌合体 在NHP中实现同种异体肾移植长期耐受的方案一直未能诱导 同种异体心脏移植患者的耐受性。众所周知，有些器官，如肾脏和肝脏， “易耐受”，而其他器官，如心脏和肺，则“耐受”。尽管有免疫屏障 在心脏的作用下，我们的实验室最近开发出了新的方案，首次实现了 食蟹猴心脏移植受者长期、稳定的耐受性。这一显著的结果是 在仅表现出短暂混合嵌合体的心脏受者中，包括供体肾联合移植， 这增强了宿主调节性T细胞在混合嵌合条件下的贡献。而当 肾心联合移植效果显著，这一策略并没有广泛应用 由于实验药物的使用和牺牲肾脏只是为了 诱导心脏耐受。虽然同种异体肺移植不会在这个项目中进行研究，但我们最近在肺部的发现 接受者提供原则证据，证明在卫生保健计划中可以实现持久的混合嵌合体，并且这种状态 导致耐药胸部器官的长期耐受性；这些是第一批对肺产生耐受性的NHP 异体移植。因此，这个总体计划的统一目标是设计创新的混合嵌合体 单独心脏受者的策略，要么放大调节性T细胞的贡献，要么 瞬时混合嵌合体方案中的巨噬细胞(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条件调节(项目3)。项目1将重点放在 增强调节性T细胞和巨噬细胞在诱导短暂性混合反应中的作用 嵌合体。项目2将专注于使用下一代条件调节实现持久的混合嵌合体 治疗方案，创新的免疫抑制平台。项目3将研究新的、临床适用的药物 增强协同刺激、阻断和降低毒性。核心A将调查通过哪些机制 项目1-3中描述的治疗方法影响宿主的免疫反应。该计划将以这样的方式组织 核心A的早期机械性发现/进展将为项目1-3的目标提供信息并加以完善。这个 本申请中描述的互补模型和方法是该计划的独特优势 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 在基金结束前准备好在心脏移植受者中进行临床试验的耐受性方案(S) 句号。

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.