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: 9329522
• 负责人: Angus W Thomson
• 金额: $ 146.02万
• 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/9329522
• 关键词: Acute; Address; Adoptive Transfer; Allografting; Antigens; Antithymoglobulin; Biopsy; Biostatistics Core; CD28 gene; Cardiovascular system; Cell Therapy; Cell physiology; Cells; Chronic; Clinical Data; Cyclosporine; Data; Dendritic Cells; Dose; Ensure; Eragrostis; Goals; Graft Survival; Hematopoietic Stem Cell Transplantation; Human; Immune; Immune Tolerance; Immunity; Immunosuppressive Agents; In Situ; Incidence; Infusion procedures; Interleukin-2; Kidney; Kidney Transplantation; Lead; Macaca mulatta; Maintenance; Modeling; National Institute of Allergy and Infectious Disease; Neoadjuvant Therapy; Organ Transplantation; Outcome; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Reagent; Recovery; Regimen; Regulatory T-Lymphocyte; Renal function; Research; Resistance; Resources; Role; Safety; Sirolimus; Specificity; T memory cell; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Tissue imaging; Transplant Recipients; Transplantation; Vaccines; Withdrawal; attenuation; base; clinically relevant; design; graft function; immunoreaction; immunoregulation; improved; kidney allograft; nonhuman primate; novel; novel marker; permissiveness; 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.

我们的远程目标是开发一种无CNI的治疗方法来安全促进器官移植 宽容。两种承诺的完整性但交互式方法，用于调节免疫细胞疗法 移植公差，-DCREG和TREG，包括此U19应用程序。他们将分享一本小说是毒品方案， 合理设计的，以增强移植受体中这些细胞的调节功能。在项目1中，我们 初步数据表明，移植前供体衍生的DCREG输注促进肾脏同种异体移植 短期内的恒河猕猴中的生存最小是共刺激封锁的方案（COSB）和 锥形雷帕霉素。此效果与供体反应性记忆T细胞（TMEM）的选择性衰减有关 回答。最近的临床数据表明，淋巴细胞论和COSB和雷帕霉素维持 防止抗COSB急性排斥反应并有选择地抑制供体反应性TMEM的恢复 没有实现操作耐受性。因此，我们假设一种方案包括ATG，COSB和 雷帕霉素（i）更允许扩展移植物存活，并且（ii）结合了 适当转移的DCREG的免疫调节功能将促进无毒品特定于供体特定的 宽容。在项目2中，我们将解决Treg Therapy的缺点（Treg时机，特异性，不稳定或 转换为Teff）最近在我们小组最近的NHP研究中强调了。我们将通过建立我们的 在扩大高度抑制的，供体的异化性恒河猴（Artreg）的成功方面的成功，并基于 我们最近发现IL-2 +TGFβ1/FC可以选择性地促进恒河猴，同时抑制Th17反应。 我们假设将ATG，COSB和雷帕霉素治疗的移植延迟了Artreg给药 接受者以及低剂量IL-2和TGFβ1/FC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。我们的总体目标是： 项目1：确定DCREG输注的能力促进肾脏肾移植 NHP的耐受性给定的ATG（淋巴结序列）和COSB（Belatacept或αCD40MAB）加上耐受性 雷帕霉素维护。 项目2：确定同种反应性Treg促进肾移植的能力 NHP的耐受性给定ATG，COSB（BELATACEPT）加上雷帕霉素维护 低剂量IL-2±HUTGFβ1FC。 这两个项目都将通过高度交互的机械研究和评估新型生物标志物来完成 （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。 它们将得到行政和生物统计学核心（核心A）和移植病理的支持 和组织成像核心（核心B），并利用NIAID NHP试剂资源中的试剂。