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

• 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
• 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

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.

我们在U19中的目标是开发一种安全有效的治疗方法来促进器官移植 在临床上与非人类灵长类动物模型中的公差。两个有希望的互补但互动 用于移植耐受性，调节树突细胞（DCREG）和 调节性T细胞（Treg）及其组合，包括此U19应用。工作已经完成 该奖项表明，使用最小的免疫抑制（IS）药物治疗方案 （他克莫司）与共同刺激阻滞（CTLA4IG）结合，MHC不匹配的肾移植移植物 单独使用任何一种细胞疗法可以延长生存。因此，给予供体衍生的DCREG A 移植前的一周或延迟的Treg施用了移植后7周，延长了 尽管没有诱导移植耐受性，但恒河猕猴中的肾移植物中位数。如 我们的原始奖项是，我们假设使用相同的免疫抑制药物方案， 在前纳入采用转移DCREG的合并免疫调节功能 移植后移植后移植将促进无药物特异性的耐受性。在此类型4中 扩展，我们将完成机械研究（由于施加的机构限制而延迟 响应于19个大流行病），旨在提高对每个细胞的体内命运的理解 产物以及每种细胞疗法如何影响抗唐纳免疫反应性，重点是它们对 免疫效应子和调节细胞功能。此外，扩展程序将使我们执行延迟 在我们的资助奖励中提出的结合细胞疗法移植实验，我们将在其中（项目1） 测试组合的DCREG + Treg方法和（在项目2中）抗炎药的潜力 抗IL-6受体抗体增强联合细胞治疗方案的治疗作用。在这两个中 项目，机械研究将在外周血和淋巴结单核细胞和 移植活检以阐明基本机制。拟议的研究将利用成功 我们在U19奖上取得了进步 （Artreg）Ex Vivo。两个项目的扩展目标是： 项目1 目的1：完成有关移植前或移植后输注影响的机械研究 王朝肾脏同种异体移植生存的供体衍生的DCREG AIM 2：用延迟移植后Artreg进行联合移植前DCREG输注 输注肾肾同种异体移植生存和随附的机械研究 项目2 目标1：完成有关IL-6R阻断对肾脏移植物的影响的完整机械研究 离体扩展的Artreg的生存和治疗功效 目标2：确定IL-6R阻滞对肾脏同种异体移植生存的影响 结合细胞疗法和基本机制 除了高度交互的机械研究外，两个项目还将评估新型生物标志物 （Eomesodermin）通过同种反应性TMEM表达作为移植结果/耐受性的潜在预测指标。 这些项目将得到行政和生物统计学核心（核心A）和移植的支持 病理和组织成像核心（核心B），并将利用NIAID NHP试剂的剂 资源。