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的目标是开发一种安全有效的治疗方法，以促进器官移植 在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相互作用的 用于移植耐受的过继免疫细胞疗法的方法，调节性树突细胞（DCreg）和 调节性T细胞（Treg）和它们的组合构成该U19应用。已完成的工作 该奖项表明，使用逐渐减少钙调磷酸酶抑制的最小免疫抑制（IS）药物方案， （他克莫司）联合共刺激阻断剂（CTLA 4 Ig），MHC不匹配的同种异体肾移植物 单独使用任一种细胞疗法都可以延长存活。因此，给予供体来源的DCreg a 移植前一周，或移植后7周开始延迟给予Treg， 恒河猴中的中位肾移植存活时间，尽管未诱导移植耐受。如在 在最初的资助奖中，我们假设，使用相同的免疫抑制药物方案， 结合过继转移的DCreg的组合免疫调节功能， 移植和移植后Treg将促进无IS药物的供体特异性耐受。在这种类型-4 扩展，我们将完成机制研究（由于机构限制而延迟 为应对COVID-19大流行，旨在提高对每个细胞体内命运的理解 产品以及每种细胞疗法如何影响抗供体免疫反应性，重点是它们对 免疫效应子和调节细胞功能。此外，延期将允许我们执行延迟的 联合细胞疗法移植实验在我们资助的奖项中提出，我们将（在项目1中） 测试组合DCreg + Treg方法和（在项目2中）抗炎剂的潜力 抗IL-6受体抗体以增强组合细胞治疗方案的治疗效果。无论是 项目，将对外周血和淋巴结单核细胞进行机制研究， 移植物活组织检查以阐明潜在机制。拟议中的研究将利用这一成功 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 （arTreg）离体。两个扩展项目的目标是： 项目1 目的1：完成关于移植前或移植后输注影响的机制研究 供体来源的DCreg对恒河猴肾移植物存活的影响 目的2：进行联合移植前DCreg输注和延迟移植后arTreg输注 输注对恒河猴移植肾存活影响及其机制研究 计划2 目的1：完成IL-6 R阻断对移植肾影响的机制研究 体外扩增的arTreg的存活率和治疗功效 目的2：确定IL-6 R阻断对肾移植物存活的影响， 联合细胞疗法和潜在机制 除了高度互动的机制研究外，两个项目还将评估新的生物标志物 （eomesodermin）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）和移植项目的支持。 病理学和组织成像核心（核心B），并将使用NIAID NHP试剂中的试剂 Resource.