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：
10217982
负责人：
Angus W Thomson
金额：
$ 146.85万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10217982
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 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 design graft function immunoreaction immunoregulation improved kidney allograft nonhuman primate novel novel marker pathology imaging prevent programs response success

项目摘要

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 的治疗方法来安全地促进器官移植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，组成此 U19 应用程序，他们将分享一种新颖的 IS 药物方案，合理设计以增强移植受者中这些细胞的调节功能。初步数据表明，移植前供体来源的 DCreg 输注可促进同种异体肾移植接受短期、最低限度共刺激阻断 (CoSB) IS 方案的恒河猴的存活率和这种效应与供体反应性记忆 T 细胞 (Tmem) 的选择性减弱有关。最近的临床数据表明，先进行淋巴细胞清除，然后进行 CoSB 和雷帕霉素维持治疗。防止 CoSB 耐药性急性排斥反应并选择性抑制供体反应性 Tmem 的恢复，尽管因此，我们主张采用包含 ATG、CoSB 和雷帕霉素 (i) 更容易延长移植物存活时间，并且 (ii) 包含过继转移的 DCreg 的免疫调节功能，将促进无 IS 药物、供体特异性在项目2中，我们将解决Treg疗法的缺点（Treg时机、特异性、不稳定性或我们小组最近在一项 NHP 研究中强调，我们将在我们的基础上实现这一目标。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) 我们最近发现IL-2 + TGFβ1/Fc可以选择性地促进恒河猴Treg反应，同时抑制Th17反应。我们追求延迟对 ATG、CoSB 和雷帕霉素处理的移植物施用 arTreg 接受者与低剂量 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 Tmem 活性并促进移植耐受性。项目1：确定DCreg输注促进肾移植手术的能力联合使用 ATG（淋巴细胞清除）和 CoSB（belatacept 或 αCD40 mAb）加上 NHP 的耐受性雷帕霉素维持。项目2：确定同种反应性Treg促进肾移植手术的能力 NHP 联合 ATG、CoSB（belatacept）加雷帕霉素维持治疗以及低剂量 IL-2 ± huTGFβ1Fc。这两个项目都将伴随着高度互动的机制研究和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。他们将得到行政和生物统计学核心（核心 A）以及移植病理学的支持和组织成像核心（核心 B），并利用 NIAID NHP 试剂资源中的试剂。