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

• 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
• 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

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，使用包括共刺激阻断的短期最小免疫抑制（IS）药物方案 (CoSB CTLA 4 Ig/贝拉西普）+递减雷帕霉素，我们已经表明，成熟抗性，供体来源的 移植前1周输注DCreg可安全延长恒河猴肾移植物存活时间， 伴随着供体反应性记忆T细胞（T细胞）反应的选择性衰减， 可能有助于克服NHP和人类移植耐受诱导的关键障碍。 我们现在将确定是否有一种新的，修改的，无CNI的IS方案，（i）更允许延长 移植物存活和（ii）我们假设将增强DCreg的免疫调节功能，可以实现 供体特异性耐受性。最近有证据表明，淋巴细胞耗竭后，CoSB（贝拉西普） 和雷帕霉素维持（我们用于证明DCreg在猴子中的疗效的2种药物方案）可以 在移植患者中控制CoSB耐药排斥反应，减少CoSB（贝拉西普）耐药TcR。 然而，没有达到操作公差。值得注意的是，供体DCreg输注（一周 移植前）与围手术期淋巴细胞耗竭，促进永久，供体特异性同种异体移植物存活， 啮齿动物这表明DCreg输注后的淋巴细胞耗竭不会干扰其治疗效果。 效果此外，淋巴细胞清除后输注DCreg也可促进无限期移植 生存因此，我们假设，抗成熟恒河猴DCreg，给予ATG- 淋巴细胞耗竭，CoSB和雷帕霉素治疗的肾移植受体，将诱导免疫学变化， 选择性减弱供体反应性TdR，有助于供体特异性耐受。我们进一步假设 宿主同种异体反应性T细胞应答的新生物标志物分析（特别是它们的Eomes表达） 将与IS的安全撤出相关并可预测IS的安全撤出。我们的具体目标是： 目的1：探讨供者DCreg输注对移植肾的影响 给予联合淋巴细胞清除（ATG）、贝拉西普和雷帕霉素（ABR）的NHP中的存活率。 目的2：探讨供者DCreg输注对移植肾的影响 联合给予ATG、非消耗性α CD 40 mAb和雷帕霉素（AAR）的NHP的存活率。 目的3：比较移植后供者与受者来源的DCreg输注对 联合给予ATG、CoSB和雷帕霉素（ABR或AAR）的NHP肾移植物存活率。 每个目标将伴随着全面的，合理设计的机制研究，将阐明 过继转移的DCreg的贩运、命运和免疫调节功能以及潜在的 机制等