Using Polyclonal Tregs to Develop a Compressed BMT Regiment for Deceased Donor Islets and Kidneys

使用多克隆 Tregs 为已故供体胰岛和肾脏开发压缩 BMT 方案

• 批准号: 9752456
• 负责人: Adam David Griesemer
• 金额: $ 76.36万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9752456
• 关键词: Address; Affect; Allogenic; American; Animals; Autoimmune Process; Autoimmunity; Bone Marrow; Bone Marrow Transplantation; Centers for Disease Control and Prevention (U.S.); Chimerism; Clinical; Clonal Deletion; Clone Cells; Collaborations; Data; Development; Diabetes Mellitus; Disease; End stage renal failure; Engraftment; Ethics; Goals; High-Throughput Nucleotide Sequencing; Hour; Human; Immune; Immune response; Immune system; Immunology procedure; Immunosuppression; Immunosuppressive Agents; In Vitro; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Kidney; Kidney Failure; Kidney Transplantation; Laboratories; Life; Living Donors; Macaca; Macaca fascicularis; Measures; Modeling; Organ Transplantation; Pancreas; Patients; Pharmaceutical Preparations; Protocols documentation; Recurrence; Regimen; Regulation; Regulatory T-Lymphocyte; Reporting; Role; Survival Rate; System; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Toxic effect; Translating; Transplantation; base; conditioning; design; diabetic; effector T cell; islet; isoimmunity; nonhuman primate; novel; patient population; patient tolerability; post-transplant; preconditioning; response; sequencing platform; statistics; tool

Project Summary: Project 1 aims to use polyclonal recipient Tregs in a compressed conditioning protocol to achieve mixed chimerism and tolerance to deceased-donor kidneys and/or islets. Islet transplantation for the cure of Type 1 diabetes (T1D) is currently limited by low 5-year survival rates. Poor islet survival is likely the result of islet loss due to alloimmune responses, recurrent autoimmunity, and toxicity from immunosuppressive drugs. Thus, this therapy can only ethically be offered to patients with life-threatening complications of T1D. Inducing tolerance to islets through the development of mixed chimerism has the potential to eliminate both alloimmune and autoimmune islet loss, as well as the need for immunosuppressive medications. There are several barriers to inducing mixed chimerism and tolerance to kidneys and/or islets using deceased donors that we aim to overcome. Our current tolerance induction regimen, developed in cynomolgus monkeys and translated to humans, involves a 6-day conditioning of the immune system prior to organ transplant and is therefore only applicable to living donation. Previous attempts to compress immune conditioning to 24 hours, to allow the use of deceased donors, failed to induce chimerism or tolerance. Additionally, durable chimerism may be required for reversal of autoimmunity in T1D patients and might then be necessary for optimal islet survival post- transplant. Since the kidney has been shown to contribute to tolerance in the case of transient chimerism, it is even more important to achieve durable chimerism in recipients of islet transplants without co-transplantation of a donor kidney if tolerance is to develop. We now have data showing that expanded polyclonal recipient Tregs can achieve markedly prolonged chimerism and more robust tolerance than has previously been possible in the cynomolgus model. We hypothesize that the addition of polyclonal recipient Tregs, that can be prepared in advance, to a compressed conditioning regimen, will permit the development of mixed chimerism and tolerance to kidneys and/or islets. Our approach targets patients with end-stage renal disease alone (Aim 1), patients with T1D and renal failure (Aim 2A), and finally T1D without renal failure (Aim 2B). Therefore, additional measures will be added in Aim 2 if durable chimerism is not achieved in Aim 1. Finally, accurate characterization of the mechanism(s) of tolerance following transient or durable chimerism in nonhuman primates is lacking, in large part due to the absence of precise tools to characterize deletional and regulatory mechanisms. In Aim 3, we will use standard immunologic assays combined with the high-throughput TCR CDR3 tracking system developed in Core B (based on the human TCR platform developed in this laboratory and modified for cynomolgus monkeys) to accurately quantify deletion/expansion of donor-reactive effector T cells and donor-specific Tregs. Islets will be provided by Core A and collaboration with Project 2 and the cores will be coordinated through Core C.

项目概要： 项目 1 旨在在压缩调理方案中使用多克隆受体 Tregs 来实现混合 对已故供体肾脏和/或胰岛的嵌合和耐受。胰岛移植治疗 1 型糖尿病 糖尿病 (T1D) 目前受到 5 年生存率较低的限制。胰岛存活率低可能是胰岛损失的结果 由于同种免疫反应、复发性自身免疫和免疫抑制药物的毒性。因此，这个 治疗只能在合乎道德的情况下提供给患有危及生命的 T1D 并发症的患者。诱导耐受 通过混合嵌合体的发展对胰岛有可能消除同种免疫和 自身免疫性胰岛丢失，以及需要免疫抑制药物。有几个障碍 使用已故捐赠者诱导混合嵌合和对肾脏和/或胰岛的耐受性，我们的目标是 克服。我们目前的耐受诱导方案是在食蟹猴中开发的，并转化为 人类，在器官移植前需要对免疫系统进行为期 6 天的调节，因此仅 适用于活体捐赠。此前曾尝试将免疫调理时间压缩至24小时，以允许使用 已故捐赠者的实验，未能诱导嵌合或耐受。此外，可能需要持久的嵌合状态 对于 T1D 患者自身免疫的逆转，可能对于术后最佳胰岛存活是必要的 移植。由于肾脏已被证明在短暂嵌合的情况下有助于耐受，因此 更重要的是在不进行联合移植的情况下在胰岛移植受者中实现持久嵌合 如果要发展耐受性，则需要使用供体肾脏。我们现在有数据显示，扩展的多克隆受体 Tregs 可以实现比以前显着延长的嵌合状态和更强大的耐受性 在食蟹猴模型中是可能的。我们假设添加多克隆受体Tregs，可以 提前准备压缩调理方案，将允许混合嵌合的发展 以及对肾脏和/或胰岛的耐受性。我们的方法针对仅患有终末期肾病的患者（目标 1)、患有 T1D 和肾衰竭的患者（目标 2A），最后是无肾衰竭的 T1D 患者（目标 2B）。所以， 如果目标 1 中未实现持久嵌合，则目标 2 中将添加额外的措施。最后，准确 非人类短暂或持久嵌合后耐受机制的表征 灵长类动物的缺失，很大程度上是由于缺乏精确的工具来表征删除和调控 机制。在目标 3 中，我们将使用标准免疫检测结合高通量 TCR Core B开发的CDR3追踪系统（基于本实验室开发的人类TCR平台） 并针对食蟹猴进行了修改）以准确量化供体反应性效应子 T 的缺失/扩展 细胞和供体特异性 Tregs。胰岛将由核心 A 提供，并与项目 2 和核心合作 将通过 Core C 进行协调。