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

基本信息

批准号：
10673079
负责人：
Leslie S Kean
金额：
$ 64.62万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/10673079
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 Heart Diseases Heart Transplantation Hematopoietic Hematopoietic Stem Cell subsets Homeostasis Human Immune Tolerance Immunity Immunosuppression Kidney Lung Lung Transplantation 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 cancer risk clinical translation conditioning design genotoxicity graft vs host disease heart 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 cell engraftment stem cells success

项目摘要

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.

项目概要/摘要心脏移植是终末期心脏病患者的最佳治疗选择。然而，虽然一年的成功率是合理的，但心脏移植受者的失败率很高发病率和死亡率，包括同种异体移植排斥和免疫抑制相关毒性。给定这些问题的最终目标是诱导免疫耐受，从而保证终生移植接受而无需慢性免疫抑制。虽然非人类灵长类动物 (NHP) 已经实现了对肾脏的耐受性，在具有短暂混合嵌合状态的人类中，相同的方案未能诱导对心脏（和肺）的耐受性同种异体移植物。重要的是，虽然本项目不会研究同种异体肺移植物，但我们最近在肺移植方面的发现接受者提供了原理证明，证明 NHP 胸部同种异体移植物可以实现持久的混合嵌合状态导致长期耐受的接受者。这是一个重大进步。然而，这第一次的成功使用目前临床上无法使用的药物，并带来持续的移植物抗宿主风险疾病（GVHD）和移植后淋巴增殖性疾病。这些数据与小鼠研究一起，表明持久的混合嵌合代表了胸部器官耐受性诱导的强大平台，但是需要改进策略，重点是预防 GVHD、保持保护性免疫力，以及快速临床转化。在这个项目中，我们将解决翻译持久嵌合现象的三个主要障碍 - 临床心脏移植耐受性的基础策略：（A）控制移植物抗宿主病（GVHD）在嵌合诱导期间； (B) 开发非遗传毒性的受体调节新方法；和 (C) 使用最安全且最有效的造血干细胞移植子集诱导嵌合。我们将通过完成以下具体目标来实现这一目标：具体目标 1：为了诱导持久的混合嵌合现象，优化通过 OX40L 阻断和 mTOR 抑制维持 Treg 稳态并保持保护性免疫。具体目标 2：通过使用基于抗体药物偶联物（ADC）的非基因毒性调节来开发无毒诱导诱导持久的混合嵌合和移植耐受。具体目标 3：诱导持久嵌合高度纯化的干细胞子集，能够快速进行多谱系移植。如果成功的话，这个项目将优化心脏同种异体移植耐受的持久嵌合诱导策略，适合立即临床翻译。