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。 然而，尽管一年的成功率是合理的，心脏移植接受者却遇到了很高的 来自同种异体移植排斥反应和免疫抑制相关毒性的发病率和死亡率。vt.给出 这些问题的最终目标是诱导免疫耐受，这承诺终身接受移植物而不需要 慢性免疫抑制。虽然对肾脏的耐受性已经在非人类灵长类动物(NHP)和 在患有短暂混合嵌合体的人类中，同样的方案未能诱导对心脏(和肺)的耐受。 异体移植。重要的是，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 接受者提供了在NHP同种异体胸腔移植中可以实现持久混合嵌合体的原则证据 这会带来长期的耐受性。这是一个重大进步。然而，这第一次成功 使用了目前尚不能在临床上获得的药物，并带来了移植物抗宿主的持续风险 疾病(GVHD)和移植后淋巴组织增生性疾病。这些数据，以及对老鼠的研究， 提示持久的混合嵌合体代表了胸部器官耐受诱导的强大平台，但是 需要改进战略，重点是预防GVHD，保护保护性免疫，以及 快速临床翻译。在这个项目中，我们将解决翻译持久嵌合体的三个主要障碍- 基于临床的心脏移植耐受策略：(A)控制移植物抗宿主病(GVHD) 在嵌合体诱导期间；(B)开发非遗传毒性的受体条件作用的新方法；以及 (C)使用最安全和最有效的造血干细胞移植亚群诱导嵌合体。我们 将通过完成以下具体目标来做到这一点：具体目标1：诱导持久的混合嵌合体，优化 通过OX40L阻断和mTOR抑制，保持Treg动态平衡和保护性免疫。特定目标 2.以抗体-药物结合物(ADC)为基础的非遗传毒性条件下的无毒诱导 诱导持久的混合嵌合体和移植耐受。具体目标3：诱导持久的嵌合体 一种高度纯化的干细胞亚群，能够快速多系植入。如果成功，这个项目将 优化心脏移植耐受的持久嵌合体诱导策略，符合即时临床要求 翻译。