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: 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
• 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

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 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 构成了 U19 应用程序。他们将分享一种新颖的 IS 药物治疗方案， 合理设计以增强移植受者中这些细胞的调节功能。在项目1中，我们的 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 锥形雷帕霉素。这种效应与供体反应性记忆 T 细胞 (Tmem) 的选择性衰减有关 回应。最近的临床数据表明，淋巴细胞清除后辅以 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 未达到操作容忍度。因此，我们假设包含 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 宽容。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 我们小组最近的一项 NHP 研究中强调了 Teff 的转换。我们将通过建立我们的 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。 我们假设延迟对 ATG、CoSB 和雷帕霉素治疗的移植物施用 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。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 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高度互动的机制研究并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。