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

项目总结/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，心脏移植受者遇到高利率， 发病率和死亡率，均来自同种异体移植排斥反应和免疫抑制相关毒性。给定 这些问题，最终目标是免疫耐受诱导，它承诺终身移植物接受， 慢性免疫抑制虽然在非人灵长类动物（NHP）中已经实现了对肾脏的耐受性， 在具有短暂混合嵌合体的人类中，相同的方案未能诱导对心脏（和肺） 同种异体移植重要的是，虽然本项目不研究同种异体肺移植，但我们最近在肺移植中的发现， 接受者提供了NHP胸椎同种异体移植物可以实现持久混合嵌合体的原则证据 导致长期耐受性。这是一个重大进步。然而，这第一次成功 使用目前临床上不可用的药物，并赋予移植物抗宿主的持续风险 疾病（GVHD）和移植后淋巴增生性病症。这些数据，沿着小鼠研究， 表明持久的混合嵌合体是胸部器官耐受诱导的一个强大平台，但 需要改进策略，重点是预防GVHD，保持保护性免疫， 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性策略：（A）控制移植物抗宿主病（GVHD） （B）开发非遗传毒性的受体调节的新方法;和 (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 具体目标1：为了诱导持久的混合嵌合体，优化 Treg稳态和通过0X 40 L阻断和mTOR抑制保持保护性免疫。具体目标 2：通过使用基于抗体-药物偶联物（ADC）的非遗传毒性预处理开发无毒诱导 以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， 一种能够快速多谱系移植的高度纯化的干细胞亚群。如果成功，该项目将 优化心脏移植耐受的持久嵌合体诱导策略，适合立即临床应用 翻译.

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.