Project 2: Next-Generation Mixed Chimerism Induction for Heart Allograft Tolerance

项目 2：用于心脏同种异体移植耐受的下一代混合嵌合诱导

• 批准号: 10270361
• 负责人: Leslie S Kean
• 金额: $ 66.32万
• 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/10270361
• 关键词: Address; Allograft Tolerance; Allografting; Antibodies; Antibody-drug conjugates; Bone Marrow Stem Cell; Cells; Chest; Chimerism; Chronic; Clinic; Clinical; Data; Defect; Development; Engraftment; Goals; Half-Life; Heart Diseases; Heart Transplantation; Hematopoietic; Hematopoietic Stem Cell subsets; Homeostasis; Human; Immune Tolerance; Immunity; Immunosuppression; Kidney; Life; Lung; Lymphoproliferative Disorders; Marrow; Methods; Morbidity - disease rate; Mus; Mutation; Organ; PTPRC gene; Patient risk; Patients; Proto-Oncogene Protein c-kit; Protocols documentation; Regimen; Regulatory T-Lymphocyte; Risk; Rosaniline Dyes; Safety; Sirolimus; Stem cell transplant; TNFSF4 gene; Testing; Therapeutic; Toxic effect; Translating; Translations; Transplant Recipients; Transplantation Tolerance; allograft rejection; base; cancer risk; clinical translation; clinically translatable; conditioning; design; genotoxicity; graft vs host disease; heart allograft; heart-lung allograft; high risk; immunomodulatory strategy; immunoregulation; improved; innovation; irradiation; lung allograft; mTOR inhibition; mortality; next generation; nonhuman primate; novel; novel strategies; post-transplant; preservation; prevent; stem cells; success

PROJECT SUMMARY / ABSTRACT Heart transplantation represents the best therapeutic option for patients with end-stage cardiac disease. However, while one-year success rates are reasonable, heart transplant recipients encounter high rates of morbidity and mortality, both from allograft rejection and from immunosuppression-associated toxicities. Given these issues, the ultimate goal is immune tolerance induction, which promises life-long graft acceptance without chronic immunosuppression. While tolerance to kidneys has been achieved in non-human primates (NHPs) and in humans with transient mixed chimerism, the same protocols have failed to induce tolerance to heart (and lung) allografts. Importantly, although lung allografts will not be studied in this Project, our recent findings in lung recipients provide proof of principle that durable mixed chimerism can be achieved in NHP thoracic allograft recipients which results in long term tolerance. This represents a major advance. However, this first success employed agents that are not currently clinically available, and conferred ongoing risks of graft-versus-host disease (GVHD) and of post-transplant lymphoproliferative disorder. These data, along with murine studies, suggest that durable mixed chimerism represents a robust platform for thoracic organ tolerance induction, but that improved strategies are needed, with a focus on preventing GVHD, preserving protective immunity, and rapid clinical translation. In this Project, we will address three major hurdles in translating durable chimerism- based strategies for heart transplant tolerance to the clinic: (A) Controlling graft versus host disease (GVHD) during chimerism-induction; (B) Developing novel methods of recipient conditioning that are non-genotoxic; and (C) Inducing chimerism using the safest and most efficiently engrafting subset of hematopoietic stem cells. We will do so by completing the following Specific Aims: Specific Aim 1: To induce durable mixed chimerism, optimize Treg homeostasis and preserve protective immunity with OX40L blockade and mTOR inhibition. Specific Aim 2: To develop toxicity-free induction by using antibody-drug conjugate (ADC)-based non-genotoxic conditioning to induce durable mixed-chimerism and transplant tolerance. Specific Aim 3: To induce durable chimerism with a highly purified subset of stem cells capable of rapid multilineage engraftment. If successful, this project will optimize durable chimerism induction strategies for heart allograft tolerance, amenable to immediate clinical translation.

项目摘要 /摘要 心脏移植是终末期心脏病患者的最佳治疗选择。 但是，尽管一年的成功率是合理的，但心脏移植的接收者遇到高率 来自同种异体移植排斥和免疫抑制相关的毒性，发病率和死亡率。给出 这些问题，最终的目标是免疫耐受性诱导，它承诺没有终身的移植物接受 慢性免疫抑制。虽然在非人类灵长类动物（NHP）和 在具有短暂混合嵌合主义的人类中，相同的方案未能诱导对心脏（和肺）的宽容 同种异体移植。重要的是，尽管在这个项目中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，可以在NHP胸腔同种异体移植物中实现耐用的混合嵌合体 获得长期公差的接收者。这代表了一个重大进步。但是，第一个成功 当前尚未临床上可用的雇用代理商，并赋予了持续的移植物抗宿主风险 疾病（GVHD）和移植后淋巴增生性疾病。这些数据，以及鼠研究 表明耐用的混合嵌合体代表了胸部器官耐受性诱导的强大平台，但 需要改进的策略，重点是防止GVHD，保留保护性免疫和 快速临床翻译。在这个项目中，我们将解决翻译持久性嵌合主义的三个主要障碍 - 基于心脏移植对诊所的耐受性的策略：（a）控制移植与宿主疾病（GVHD） 在嵌合诱导期间； （b）开发非生物毒性的新型受体调节方法；和 （c）使用最安全，最有效的造血干细胞子集诱导嵌合体。我们 将完成以下特定目标：特定目的1：诱导耐用的混合嵌合，优化 Treg稳态并通过OX40L阻断和MTOR抑制保护保护性免疫。具体目标 2：通过使用抗体 - 药物结合物（ADC）的非生物毒性调节来发展无毒性诱导 诱导耐用的混合介质和移植耐受性。特定目的3：用 高度纯化的干细胞子集，能够快速多动植入。如果成功，这个项目将 优化对心脏同种异体耐受性的耐用嵌合感诱导策略，可以立即进行临床 翻译。