Project 1: Augmenting Regulatory Mechanisms in Protocols of Transient Mixed Chimerism

项目 1：增强瞬时混合嵌合方案中的监管机制

• 批准号: 10673076
• 负责人: Joren C Madsen
• 金额: $ 75.02万
• 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/10673076
• 关键词: Allograft Tolerance; Allografting; Bone Marrow Transplantation; Cell physiology; Chimerism; Chronic; Combination immunotherapy; Complement; Data; Development; FRAP1 gene; Funding; Goals; Graft Survival; Heart; Hematopoietic; High Density Lipoproteins; Histocompatibility Antigens Class I; Human; Immune; Immune Tolerance; Immunity; Immunologic Memory; Immunosuppression; Inflammation; Interleukin-2; Kidney; Laboratories; Liver; Lung; Macaca fascicularis; Macrophage; Molecular; Morbidity - disease rate; Myeloid Cells; Nanoimmunotherapy; Organ; Organ Transplantation; Pathway interactions; Phase I Clinical Trials; Phase II Clinical Trials; Protocols documentation; Regimen; Regulatory T-Lymphocyte; Resistance; Sirolimus; T memory cell; Testing; Time; Training; Transplantation; clinical trial readiness; conditioning; heart allograft; immune activation; inhibitor; kidney allograft; mTOR Inhibitor; mTOR protein; mortality; mutant; nanobiologic; nanotherapy; next generation; nonhuman primate; novel; novel strategies; platelet protein P47; prevent; treatment strategy; ubiquitin-protein ligase

PROJECT SUMMARY / ABSTRACT Induction of immune tolerance is the ultimate goal in the field of organ transplantation. Achieving a state of tolerance would lead to indefinite graft survival without chronic immunosuppression and its associated morbidity/mortality and is expected to prevent/reduce of chronic rejection. Tolerance of kidney allografts has been achieved in non-human primates (NHPs) and in humans by using a combination of nonmyeloablative conditioning and donor bone marrow transplantation that results in transient mixed hematopoietic chimerism. However, identical mixed chimerism protocols have failed to induce tolerance in NHP heart allograft recipients. This reflects the fact that there are organ-specific differences in tolerance induction with kidney (and liver) allografts being “tolerance-prone” and heart (and lung) grafts being “tolerance-resistant.” Despite the immune barriers posed by heart allografts, our laboratory has recently developed a novel protocol that has, for the first time, achieved long-term, stable tolerance of fully MHC mismatched heart allografts in cynomolgus monkeys. This remarkable result was attained in heart recipients by combining a transient mixed chimerism protocol with donor kidney cotransplantation which enhanced the contributions of host regulatory T cells (Tregs). Based on our preliminary data, we hypothesize that promoting the contributions of regulatory T cells and/or macrophages in recipients undergoing a transient mixed chimerism regimen will induce long-term and stable tolerance of heart allografts transplanted alone. We will test this hypothesis by 1) augmenting early host regulatory mechanisms using ex vivo expanded donor-specific MHC-reactive CAR Tregs in lieu of donor kidneys, 2) enhancing the function and stability of conventional host Tregs and infused CAR Tregs by targeting the DEPTOR and IL-2 pathways, and 3) using next-generation mTORi-specific nanotherapy to mitigate early innate inflammation and promote regulatory macrophages. These studies will be complemented by Project 2, which will test the corollary hypothesis that the development of conditioning regimens capable of inducing durable mixed chimerism will induce robust tolerance in heart recipients, and Project 3, that will investigate a novel costimulation blockade strategy to promote Tregs while constraining memory T cells after mixed chimerism conditioning. By elucidating and differentiating cellular and molecular mechanisms underlying effective versus ineffective protocols, Core A will inform and refine the treatment strategies proposed in each Project. We anticipate that together, these highly interactive projects will generate one or more safe and effective mixed chimerism tolerance protocols that will be ready for clinical trial in heart allograft recipients by the end of the funding period.

项目总结/摘要 诱导免疫耐受是器官移植领域的最终目标。达到一种 耐受性将导致无限期的移植物存活，而无慢性免疫抑制及其相关的 发病率/死亡率，并预期预防/减少慢性排斥反应。同种异体肾移植的耐受性 在非人灵长类动物（NHP）和人类中，通过使用非清髓性 预处理和供体骨髓移植，导致短暂的混合造血嵌合体。 然而，相同的混合嵌合体方案未能诱导NHP心脏移植受者的耐受。 这反映了肾脏（和肝脏）的耐受性诱导存在器官特异性差异的事实 同种异体移植物是“易耐受的”，心脏（和肺）移植物是“耐受的”。尽管免疫 由于心脏移植物造成的障碍，我们的实验室最近开发了一种新的方案， 时间，在食蟹猴中实现了对完全MHC不匹配的心脏同种异体移植物的长期稳定耐受。 这一显著的结果是通过将短暂的混合嵌合体方案与 供体肾共移植，增强了宿主调节性T细胞（T细胞）的贡献。基于 根据我们的初步数据，我们假设促进调节性T细胞和/或 接受暂时性混合嵌合方案的受体中的巨噬细胞将诱导长期和 稳定耐受单独移植的同种异体心脏。我们将通过以下方式来检验这一假设：1）增加早期 使用离体扩增的供体特异性MHC反应性CAR T细胞代替供体的宿主调节机制 2）通过靶向增强常规宿主T细胞和输注的CAR T细胞的功能和稳定性， DEPTOR和IL-2通路，以及3）使用下一代mTORi特异性纳米疗法来减轻早期 先天性炎症和促进调节巨噬细胞。这些研究将得到项目2的补充， 这将检验一个推论假设，即条件反射疗法的发展能够诱导 持久的混合嵌合体将在心脏受体中诱导强大的耐受性，而项目3将研究 一种新的共刺激阻断策略，在混合嵌合体后促进T细胞活化，同时限制记忆T细胞 条件反射通过阐明和区分细胞和分子机制， 核心A将为每个项目中提出的治疗策略提供信息并加以改进。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混合 嵌合体耐受方案，将准备在心脏移植受体的临床试验结束时， 融资期。