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: 10457400
• 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/10457400
• 关键词: Allograft Tolerance; Bone Marrow Transplantation; Chimerism; Chronic; Clinical Trials; Complement; Data; Development; FRAP1 gene; Funding; Goals; Graft Survival; Heart; Heart-Lung Transplantation; Hematopoietic; High Density Lipoproteins; Histocompatibility Antigens Class I; Human; Immune; Immune Tolerance; Immunity; Immunologic Memory; Immunosuppression; Inflammation; Interleukin-2; Kidney; Laboratories; Lead; Macaca fascicularis; 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; base; conditioning; heart allograft; immune activation; inhibitor; kidney allograft; liver allograft; mTOR Inhibitor; mTOR protein; macrophage; 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.

项目概要/摘要 诱导免疫耐受是器官移植领域的最终目标。达到一种状态 如果没有慢性免疫抑制及其相关的耐受性，耐受性将导致移植物无限期存活。 发病率/死亡率，并有望预防/减少慢性排斥反应。同种异体肾移植的耐受性 通过联合使用非清髓性药物，在非人类灵长类动物 (NHP) 和人类中实现了这一目标 调理和供体骨髓移植导致短暂的混合造血嵌合。 然而，相同的混合嵌合方案未能在 NHP 心脏同种异体移植受者中诱导耐受。 这反映了肾（和肝）耐受诱导存在器官特异性差异的事实 同种异体移植物“容易产生耐受性”，而心脏（和肺）移植物则“具有耐受性”。尽管免疫 为了克服同种异体心脏移植带来的障碍，我们的实验室最近开发了一种新颖的方案，首次 时间，在食蟹猴中实现了对完全 MHC 不匹配的同种异体心脏移植物的长期、稳定耐受。 通过将瞬时混合嵌合方案与 供体肾联合移植增强了宿主调节性 T 细胞 (Treg) 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 接受短暂混合嵌合疗法的受体中的巨噬细胞将诱导长期和 单独移植同种异体心脏的耐受性稳定。我们将通过 1）早期增强来检验这个假设 使用离体扩展的供体特异性 MHC 反应性 CAR Tregs 代替供体的宿主调节机制 肾脏，2）通过靶向增强常规宿主Tregs和输注的CAR Tregs的功能和稳定性 DEPTOR 和 IL-2 途径，以及 3) 使用下一代 mTORi 特异性纳米疗法来缓解早期症状 先天性炎症并促进调节性巨噬细胞。这些研究将由项目 2 补充， 这将检验一个推论假设，即开发能够诱导 持久的混合嵌合现象将在心脏接受者中诱导强大的耐受性，而项目 3 将研究 混合嵌合后促进Treg细胞同时限制记忆T细胞的新型共刺激阻断策略 调理。通过阐明和区分有效和有效的细胞和分子机制 对于无效的方案，核心 A 将告知并完善每个项目中提出的治疗策略。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项目 嵌合耐受方案将于年底前准备好在同种异体心脏移植受者中进行临床试验 资助期限。