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。两种有希望的互补但交互的调节性免疫细胞治疗方法 移植耐受性-DCreg和Treg组成了这一U19应用。他们将分享一本关于药物治疗的小说， 合理设计以增强移植受者这些细胞的调节功能。在项目1中，我们的 初步数据显示，移植前输注供者来源的DCreg促进同种异体肾移植 接受短期、最低限度的协同刺激阻断(COSB)方案的恒河猴存活 递减雷帕霉素。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。最近的临床数据显示，淋巴枯竭之后是COSB和雷帕霉素的维持 防止COSB耐药的急性排斥反应，并选择性地抑制供体反应性TMEM的恢复，尽管 没有实现操作容忍度。因此，我们假设由ATG、COSB和 雷帕霉素(I)更容易延长移植物的存活时间，并且(II)结合了 过继转移的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研究中强调了这一点。我们将通过在我们的基础上 成功地在体外扩增高度抑制、供体同种异体反应的恒河猴Treg(ArTreg)，并基于 我们最近发现，IL-2+转化生长因子β1/Fc可以选择性地促进恒河猴Treg，同时抑制Th17反应。 我们推测，在ATG、COSB和雷帕霉素治疗的移植中，延迟给予artreg 受体与小剂量IL-2和转化生长因子β1/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，促进移植耐受。我们的总体目标是： 项目1：确定DCreg输注促进手术肾移植的能力 非霍奇金淋巴瘤患者联合给予ATG和COSB(贝拉泰塞或αCD40mAb)后的耐受性 雷帕霉素维持剂。 项目2：确定同种异体反应性Treg促进手术肾移植的能力 NHP的耐受性给予ATG、COSB(Belatacept)加雷帕霉素维持，以及 小剂量IL-2±huTGFβ1Fc。 这两个项目都将伴随着高度互动的机械性研究和评估新的生物标记物 (Eomesodermin)的表达可作为移植结果/耐受的潜在预测指标。 他们将由一个行政和生物统计核心(核心A)和一个移植病理学提供支助。 和组织成像核心(核心B)，并利用来自NIAID NHP试剂资源的试剂。