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Regulatory immune cell therapy, promotion of tolerance and underlying mechanisms in NHP renal transplantation

NHP肾移植中的调节性免疫细胞治疗、耐受性促进及潜在机制

基本信息

批准号：
10518430
负责人：
Angus W Thomson
金额：
$ 104.13万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-17 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10518430
关键词：
Address Adoptive Transfer Affect Allografting Anti-Inflammatory Agents Award Biopsy Biostatistics Core COVID-19 pandemic Calcineurin Cell Therapy Cell physiology Cells Cellular immunotherapy Clinical Dendritic Cells Dose Fc Receptor Funding Graft Survival Immune Immune Tolerance Immunosuppressive Agents Inflammation Infusion procedures Interleukin 6 Receptor Interleukin-2 Kidney Transplantation Lead Macaca mulatta Maintenance Modeling Modification Mononuclear National Institute of Allergy and Infectious Disease Organ Transplantation Outcome Peer Review Play Protocols documentation Reagent Regimen Regulatory T-Lymphocyte Research Resources Rhesus Role Sirolimus Site Visit Tacrolimus Testing Therapeutic Effect Time Tissue imaging Transplantation Transplantation Tolerance Treatment Efficacy Vaccines Work clinically relevant conditioning design experimental study immunoregulation improved in vivo kidney allograft lymph nodes nonhuman primate novel novel marker pandemic disease pathology imaging peripheral blood post-transplant programs response success synergism therapeutically effective transplantation therapy

项目摘要

Our objective in this U19 is to develop a safe and effective therapeutic approach to promote organ transplant tolerance in a clinically-relevant, nonhuman primate model. Two promising complementary but interactive approaches to adoptive immune cell therapy for transplant tolerance,- regulatory dendritic cells (DCreg) and regulatory T cells (Treg) and their combination, comprise this U19 application. Work already completed during the award shows that, using a minimal immunosuppressive (IS) drug regimen of tapering calcineurin inhibition (tacrolimus) combined with co-stimulation blockade (CTLA4Ig), MHC-mismatched renal allograft graft survival can be prolonged using either cell therapy alone. Thus, administration of donor-derived DCreg a week before transplant, or delayed administration of Treg commencing 7 weeks post-transplant, prolongs median kidney graft survival time in rhesus macaques, although transplant tolerance is not induced. As in the original funded award, we hypothesize that, using the same immunosuppressive drug regimen, incorporation of the combined immunomodulatory functions of adoptively-transferred DCreg before transplant and Treg post-transplant will promote IS drug-free, donor-specific tolerance. In this type-4 Extension, we will complete mechanistic studies (delayed as the result of institutional restrictions imposed in response to the COVID-19 pandemic) designed to improve understanding of the in vivo fate of each cell product and how each cell therapy affects anti-donor immune reactivity, with emphasis on their impact on immune effector and regulatory cell functions. In addition, the Extension will allow us perform the delayed combined cell therapy transplant experiments proposed in our funded award, in which we will (in Project 1) test the combined DCreg + Treg approach and (in Project 2) the potential of the anti-inflammatory agent anti-IL-6 receptor antibody to potentiate the therapeutic effect of the combined cell therapy regimen. In both projects, mechanistic studies will be performed on peripheral blood and lymph node mononuclear cells and graft biopsies to elucidate underlying mechanisms. The proposed studies will take advantage of the success we have achieved during the U19 award in expanding highly-suppressive, donor-alloreactive rhesus Treg (arTreg) ex vivo. The Aims of the two Projects for the Extension are: Project 1 Aim 1: To complete mechanistic studies concerning the influence of pre-or post-transplant infusion of donor-derived DCreg on rhesus renal allograft survival Aim 2: To perform combined pre-transplant DCreg infusion with delayed post-transplant arTreg infusion on rhesus renal allograft survival and accompanying mechanistic studies Project 2 Aim 1: To complete mechanistic studies concerning the impact of IL-6R blockade on kidney graft survival and the therapeutic efficacy of ex vivo-expanded arTreg Aim 2: To determine the impact of IL-6R blockade on kidney allograft survival in conjunction with combined cell therapy and underlying mechanisms In addition to highly-interactive, mechanistic studies, both Projects will assess novel biomarker (eomesodermin) expression by alloreactive Tmem as a potential predictor of transplant outcome/tolerance. The Projects will be supported by the Administrative and Biostatistics Core (Core A) and the Transplant Pathology and Tissue Imaging Core (Core B) and will utilize agents from the NIAID NHP Reagent Resource.

我们这次U19的目标是开发一种安全有效的治疗方法来促进器官移植临床相关的非人灵长类动物模型中的耐受性。两个有前途的互补但互动的用于移植耐受的过继性免疫细胞疗法的方法，-调节性树突状细胞（DCreg）和调节性 T 细胞 (Treg) 及其组合构成了该 U19 应用。期间工作已完成该奖项表明，使用最小免疫抑制 (IS) 药物方案逐渐减少钙调神经磷酸酶抑制（他克莫司）联合共刺激阻断（CTLA4Ig），MHC 不匹配的同种异体肾移植物单独使用任一细胞疗法都可以延长生存期。因此，给予供体来源的 DCreg a 移植前一周或移植后 7 周开始延迟 Treg 给药，会延长尽管未诱导移植耐受，但恒河猴的肾移植存活时间中位数。如在最初资助的奖项，我们假设，使用相同的免疫抑制药物治疗方案，之前整合过继转移的 DCreg 的联合免疫调节功能移植和移植后 Treg 将促进 IS 无药物、供体特异性耐受。在这个4型中延期，我们将完成机理研究（由于制度限制而推迟）为应对新冠肺炎 (COVID-19) 大流行），旨在增进对每个细胞体内命运的了解产品以及每种细胞疗法如何影响抗供体免疫反应，重点是它们对免疫效应器和调节细胞功能。此外，延期将允许我们执行延迟的我们资助的奖项中提出了联合细胞疗法移植实验，其中我们将（在项目 1 中）测试 DCreg + Treg 组合方法和（在项目 2 中）抗炎剂的潜力抗IL-6受体抗体可增强联合细胞治疗方案的治疗效果。在两者中项目，将对外周血和淋巴结单核细胞进行机制研究，移植物活检以阐明潜在机制。拟议的研究将利用成功的机会我们在 U19 奖期间在扩大高度抑制性、供体同种异体反应性恒河猴 Treg 方面取得了成就 (arTreg) 离体。这两个延期项目的目标是：项目1 目标 1：完成有关移植前或移植后输注影响的机制研究供体来源的 DCreg 对恒河猴同种异体移植肾存活率的影响目标 2：进行移植前 DCreg 输注与移植后延迟 arTreg 联合输注输液对恒河猴同种异体移植肾存活率及相关机制研究项目2 目标 1：完成有关 IL-6R 阻断对肾移植影响的机制研究离体扩增的 arTreg 的存活率和治疗效果目标 2：确定 IL-6R 阻断对肾同种异体移植物存活的影响联合细胞疗法及其潜在机制除了高度互动的机制研究之外，这两个项目还将评估新型生物标志物 (eomesodermin) 通过同种异体反应 Tmem 表达作为移植结果/耐受性的潜在预测因子。这些项目将得到行政和生物统计核心（核心 A）和移植中心的支持病理学和组织成像核心（核心 B）并将利用 NIAID NHP 试剂中的试剂资源。