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

基本信息

批准号：
10217985
负责人：
Angus W Thomson
金额：
$ 62.03万
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/10217985
关键词：
Address Adoptive Transfer Allografting Cell Therapy Cells Cellular immunotherapy Cholecalciferol Clinical Data Dendritic Cell Therapy Dendritic Cells Development Goals Graft Survival Graft Tolerance Human Immune Immunologics Immunosuppressive Agents Infusion procedures Interleukin-10 Kidney Transplantation Lead Legal patent Lymphocyte Depletion Macaca mulatta Maintenance Modeling Modification Monkeys Monoclonal Antibodies Natural Immunity Organ Transplantation Outcome Perioperative Pharmaceutical Preparations Rattus Regimen Regulation Regulatory T-Lymphocyte Resistance Rhesus Risk Rodent Sirolimus T memory cell T-Lymphocyte Testing Therapeutic Effect Transfusion Transplant Recipients Transplantation Transplantation Tolerance Treatment Efficacy Viral Withdrawal adaptive immunity attenuation clinically relevant design immunoregulation improved kidney allograft nonhuman primate novel novel marker post-transplant reconstitution response trafficking transcription factor

项目摘要

Uniquely, using a short-term minimal immunosuppressive (IS) drug regimen comprising costimulation blockade (CoSB; CTLA4Ig/belatacept) + tapered rapamycin, we have shown that maturation-resistant, donor-derived DCreg, infused 1w before transplant, can safely prolong renal allograft survival in rhesus macaques, accompanied by selective attenuation of donor-reactive memory T cell (Tmem) responses, a mechanism that may help overcome a critical barrier to transplant tolerance induction in NHP and humans. We will now ascertain whether a novel, modified, CNI-free IS regimen that is (i) more permissive to extended graft survival and (ii) that we hypothesize will enhance the immunomodulatory function of DCreg, can achieve donor-specific tolerance. There is recent evidence that lymphocyte depletion followed by CoSB (belatacept) and rapamycin maintenance (the 2-drug regimen we used to demonstrate DCreg efficacy in monkeys) can control CoSB-resistant rejection in transplant patients, with reduction in CoSB (belatacept)-resistant Tmem. However, operational tolerance was not achieved. Notably, combination of donor DCreg infusion (a week before transplant) with perioperative lymphodepletion, promotes permanent, donor-specific allograft survival in rodents. This indicates that lymphodepletion after DCreg infusion does not interfere with their therapeutic effect. Moreover, DCreg infusion post-transplant following lymphodepletion, can also promote indefinite graft survival. We therefore hypothesize that maturation-resistant rhesus DCreg, administered to ATG- lymphodepleted, CoSB and rapamycin-treated renal graft recipients, will induce immunological changes and selective attenuation of donor-reactive Tmem conducive to donor-specific tolerance. We further hypothesize that novel biomarker analyses of host alloreactive Tmem responses (in particular, their expression of Eomes) will correlate with and be predictive of safe withdrawal of IS. Our Specific Aims are: Aim 1: To determine the influence of donor-derived DCreg infusion before transplant on renal allograft survival in NHP given combined lymphodepletion (ATG), belatacept and rapamycin (ABR). Aim 2: To determine the influence of donor-derived DCreg infusion before transplant on renal allograft survival in NHP given combined ATG, non-depleting αCD40 mAb and rapamycin (AAR). Aim 3: To compare the influence of donor-versus recipient-derived DCreg infusion post-transplant on renal allograft survival in NHP given combined ATG, CoSB and rapamycin (ABR or AAR). Each Aim will be accompanied by comprehensive, rationally-designed mechanistic studies that will elucidate the trafficking, fate and immune regulatory function of the adoptively-transferred DCreg and underlying mechanisms.

独特的是，使用包含共刺激阻断的短期最小免疫抑制 (IS) 药物治疗方案（CoSB；CTLA4Ig/belatacept）+ 锥形雷帕霉素，我们已经证明，成熟抗性、供体来源 DCreg在移植前输注1周，可以安全地延长恒河猴同种异体肾移植物的存活率，伴随着供体反应性记忆 T 细胞 (Tmem) 反应的选择性减弱，这种机制可能有助于克服 NHP 和人类移植耐受诱导的关键障碍。我们现在将确定一种新颖的、改良的、无 CNI 的 IS 方案是否 (i) 更容易延长移植物存活和（ii）我们首创的将增强 DCreg 的免疫调节功能，可以实现最近有证据表明，在 CoSB（贝拉西普）之后进行淋巴细胞清除。和雷帕霉素维持治疗（我们用来证明 DCreg 在猴子中的功效的 2 种药物疗法）可以控制移植患者的 CoSB 耐药排斥反应，降低 CoSB（贝拉西普）耐药 Tmem。然而，值得注意的是，联合供体 DCreg 输注（一周）并未实现操作耐受性。移植前）和围术期淋巴细胞清除，可促进永久的、供者特异性同种异体移植物的存活这表明 DCreg 输注后的淋巴细胞清除不会干扰其治疗。此外，淋巴细胞清除后移植后输注 DCreg 也可以促进无限期移植。因此，我们将成熟抗性恒河猴 DCreg 给予 ATG-。淋巴细胞清除、CoSB 和雷帕霉素治疗的肾移植受者，将引起免疫学变化和供体反应性 Tmem 的选择性减弱有利于供体特异性耐受。宿主同种异体反应 Tmem 反应（特别是 Eomes 表达）的新型生物标志物分析将与 IS 的安全撤退相关并对其进行预测。我们的具体目标是：目标 1：确定移植前供体来源的 DCreg 输注对同种异体肾移植物的影响接受联合淋巴细胞清除（ATG）、贝拉西普和雷帕霉素（ABR）治疗的 NHP 患者的生存率。目标 2：确定移植前供体来源的 DCreg 输注对同种异体肾移植物的影响联合使用 ATG、非耗竭 αCD40 mAb 和雷帕霉素 (AAR) 后 NHP 的存活率。目标 3：比较移植后供体与受体来源的 DCreg 输注对联合使用 ATG、CoSB 和雷帕霉素（ABR 或 AAR）的 NHP 肾同种异体移植物存活率。每个目标都将伴随着全面、合理设计的机制研究，以阐明过继转移的 DCreg 及其底层的贩运、命运和免疫调节功能机制。