New Approaches to Inducing Cardiac Allograft Tolerance

诱导心脏同种异体移植耐受的新方法

• 批准号: 10673071
• 负责人: Joren C Madsen
• 金额: $ 242.88万
• 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/10673071
• 关键词: Allograft Tolerance; Allografting; Antibody-drug conjugates; BCL2 gene; Bone Marrow Transplantation; Chest; Chimerism; Chronic; Clinical; Engraftment; Ethics; Exhibits; FRAP1 gene; Funding; Goals; Heart; Heart Transplantation; Hematopoietic; High Density Lipoproteins; Homeostasis; Human; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Innate Immune Response; Interleukin-2; Kidney; Kidney Transplantation; Laboratories; Life; Liver; Lung; Lung Transplantation; Macaca fascicularis; Macrophage; Modeling; Organ; Organ Survival; Organ Transplantation; Pathway interactions; Patients; Protocols documentation; Radiation; Regimen; Regulatory T-Lymphocyte; Resistance; Seminal; Signal Transduction; T memory cell; TNFSF4 gene; Time; Toxic effect; Training; Transplant Recipients; Transplantation; Vascularization; Work; clinical application; clinical trial readiness; clinically relevant; conditioning; cytokine; design; effector T cell; heart allograft; improved; innovation; insight; islet; kidney allograft; liver allograft; lung allograft; nanotherapy; next generation; nonhuman primate; novel; novel strategies; programs; stem cells; trial readiness

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.

项目概要/摘要 实现耐受性（定义为在没有持续免疫抑制的情况下长期同种异体移植物存活）是 在非人类灵长类动物中已经实现了同种异体肾移植的最终目标。 (NHP) 以及在人类中结合使用非清髓性调理和供体骨髓 移植（DMBT）会导致短暂的供体嵌合，但到目前为止，还是短暂的混合嵌合。 在 NHP 中实现同种异体肾移植长期耐受的方案始终未能诱导 心脏同种异体移植受者的耐受性 众所周知，某些器官，例如肾脏和肝脏，具有耐受性。 尽管存在免疫障碍，但其他疾病（例如心脏和肺）却“具有耐受性”。 由心脏提出，我们的实验室最近开发了新颖的方案，首次实现了 食蟹猴受者对心脏移植具有长期、稳定的耐受性。 通过包括供体肾脏联合移植，在仅表现出短暂混合嵌合状态的心脏接受者中获得， 这增强了混合嵌合调节后宿主调节性 T 细胞的贡献。 肾移植与心脏移植相结合取得了显着效果，但这一策略并未得到广泛应用 由于使用实验药物以及仅仅为了牺牲肾脏而存在的伦理障碍，临床可行性 虽然本计划不会研究肺同种异体移植物，但我们最近在肺中的发现。 接受者提供了原理证明，证明 NHP 可以实现持久的混合嵌合状态，并且这种状态 导致具有抵抗力的胸部器官的长期耐受性；这些是第一个对肺具有耐受性的 NHP。 因此，整个计划的统一目标是设计创新的混合嵌合体。 针对仅心脏受者的策略，要么放大调节性 T 细胞的贡献，要么 瞬时混合嵌合方案（项目 1）中的巨噬细胞或实现持久混合嵌合 （项目 2）同时使用临床相关药物进行宿主调节（项目 3）。 增强调节性 T 细胞和巨噬细胞在诱导瞬时混合的方案中的贡献 项目 2 将重点关注使用下一代调节实现持久的混合嵌合状态。 方案、创新的免疫抑制平台 项目 3 将研究新型的、临床适用的药物。 增强共刺激阻断并减少毒性的核心 A 将研究其机制。 项目 1-3 中描述的治疗会影响宿主免疫反应。 核心 A 的早期机械发现/进展将告知并完善项目 1-3 的目标。 本申请中描述的补充模型和方法是该计划的独特优势 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有效的项目。 耐受方案将在资助结束时准备好在同种异体心脏移植受者中进行临床试验 时期。