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

NHP 肾移植中的调节性树突状细胞治疗、耐受性促进及潜在机制

• 批准号: 10596904
• 负责人: Angus W Thomson
• 金额: $ 82.54万
• 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/10596904
• 关键词: Acute; Address; Adoptive Transfer; Allografting; Biopsy; Biostatistics Core; CD28 gene; Cardiovascular system; Cell Therapy; Cell physiology; Cells; Cellular immunotherapy; Chronic; Clinical Data; Cyclosporine; Data; Dendritic Cell Therapy; Dendritic Cells; Dose; Ensure; Eragrostis; Goals; Graft Survival; Hematopoietic Stem Cell Transplantation; Human; Immune; Immune Tolerance; Immunity; In Situ; Incidence; Infusion procedures; Interleukin-2; Kidney Transplantation; Lead; Macaca mulatta; Maintenance; Modeling; Monoclonal Antibodies; National Institute of Allergy and Infectious Disease; Neoadjuvant Therapy; Organ Transplantation; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Reagent; Recovery; Regimen; Regulatory T-Lymphocyte; Renal function; Research; Resistance; Resources; Rhesus; Role; Safety; Sirolimus; Specificity; T memory cell; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Tissue imaging; Transplant Recipients; Transplantation; Transplantation Tolerance; Treg therapy; Vaccines; Withdrawal; antigen-specific T cells; attenuation; clinically relevant; graft function; immunoreaction; immunoregulation; improved; kidney allograft; nonhuman primate; novel; novel marker; pathology imaging; prevent; programs; rational design; response; success

Our long-range objective is to develop a CNI-free therapeutic approach to safely promote organ transplant tolerance. Two promising complementary but interactive approaches to regulatory immune cell therapy for transplant tolerance,- DCreg and Treg, comprise this U19 application. They will share a novel IS drug regimen, rationally-designed to enhance the regulatory function of these cells in graft recipients. In Project 1, our preliminary data show that donor-derived DCreg infusion before transplantation promotes renal allograft survival in rhesus macaques receiving a short-term, minimal IS regimen of costimulation blockade (CoSB) and tapered rapamycin. This effect is associated with selective attenuation of donor-reactive memory T cell (Tmem) responses. Recent clinical data show that lymphodepletion followed by CoSB and rapamycin maintenance prevents CoSB-resistant acute rejection and selectively inhibits recovery of donor-reactive Tmem, although operational tolerance was not achieved. We therefore hypothesize that a regimen comprising ATG, CoSB and rapamycin that (i) is more permissive to extended graft survival and that (ii) incorporates the immunomodulatory function of adoptively-transferred DCreg, will promote IS-drug free, donor-specific tolerance. In Project 2, we will address shortcomings of Treg therapy (Treg timing, specificity, instability or conversion to Teff) recently underscored in a recent NHP study by our group. We will do so by building on our success in expanding highly-suppressive, donor-alloreactive rhesus Treg (arTreg) ex vivo, and on the basis of our recent finding that IL-2 + TGFβ1/Fc can selectively promote rhesus Treg, while inhibiting Th17 responses. We hypothesize that delayed arTreg administration to ATG, CoSB and rapamycin-treated transplant recipients, together with low-dose IL-2 and TGFβ1/Fc, will enhance their stability/persistence, promote their suppressive function, overcome Tmem activity and promote transplant tolerance. Our Overall Aims are: Project 1: To determine the capacity of DCreg infusion to promote operational renal transplant tolerance in NHP given combined ATG (lymphodepletion) and CoSB (belatacept or αCD40 mAb) plus rapamycin maintenance. Project 2: To determine the capacity of alloreactive Treg to promote operational renal transplant tolerance in NHP given combined ATG, CoSB (belatacept) plus rapamycin maintenance, together with low-dose IL-2 ± huTGFβ1Fc. Both projects will be accompanied by highly-interactive, mechanistic studies and assess novel biomarker (eomesodermin) expression by alloreactive Tmem as a potential predictor of transplant outcome/tolerance. They will be supported by an Administrative and Biostatistics Core (Core A) and a Transplant Pathology and Tissue Imaging Core (Core B), and utilize agents from the NIAID NHP Reagent Resource.

我们的长期目标是开发一种无CNI的治疗方法，以安全地促进器官移植 宽容两种有前途的互补但相互作用的调节性免疫细胞治疗方法， 移植耐受性、- DCreg和Treg包括该U19应用。他们将分享一种新的IS药物方案， 合理设计以增强这些细胞在移植受体中的调节功能。在项目1中，我们 初步数据显示，移植前输注供体来源的DCreg可促进肾移植 接受短期、最小IS共刺激阻断（CoSB）方案的恒河猴的存活率， 递减雷帕霉素这种效应与供体反应性记忆T细胞（TCRs）的选择性衰减有关 应答最近的临床数据显示，淋巴细胞耗竭后维持CoSB和雷帕霉素 预防CoSB耐药的急性排斥反应，并选择性抑制供体反应性THBG的恢复， 没有达到操作公差。因此，我们假设包括ATG、CoSB和 雷帕霉素，其（i）更允许延长移植物存活，并且（ii）结合了 过继转移DCreg的免疫调节功能，将促进IS-无药物，供体特异性 宽容在项目2中，我们将解决Treg治疗的缺点（Treg时机，特异性，不稳定性或不稳定性）。 转化为Teff）最近在我们小组最近的NHP研究中强调。为此，我们将在 成功体外扩增高度抑制性、供体同种异体反应性恒河猴Treg（arTreg），并基于 我们最近发现IL-2 + TGFβ1/Fc可以选择性地促进恒河猴Treg，同时抑制Th 17应答。 我们假设延迟给予ATG、CoSB和雷帕霉素处理的移植物的arTreg， 受体与低剂量IL-2和TGFβ1/Fc一起，将增强其稳定性/持久性，促进其 抑制功能，克服Tclase活性和促进移植耐受。我们的总体目标是： 项目1：确定DCreg输注促进肾移植手术的能力 NHP联合ATG（淋巴细胞清除）和CoSB（贝拉西普或α CD 40 mAb）+ 雷帕霉素维持 项目2：确定同种异体反应性Treg促进肾移植手术的能力 联合给予ATG、CoSB（贝拉西普）加雷帕霉素维持的NHP耐受性， 低剂量IL-2 ± huTGFβ1Fc。 这两个项目都将伴随着高度互动的机制研究，并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。 他们将得到行政和生物统计核心（核心A）和移植病理学的支持。 和组织成像核心（核心B），并利用来自NIAID NHP试剂资源的试剂。