"Donor-Specific Regulatory T Cell Therapy in Liver Transplantation"

描述(由申请人提供)：该项目的长期目标是开发一种基于调节性T细胞(Treg)的方法来诱导肝移植受者的供者特异性免疫耐受。肝移植可以成为治疗肝功能衰竭的救命药物。然而，移植肝脏的维持需要持续的免疫抑制，以防止宿主免疫系统的排斥反应。虽然不断改进的免疫抑制方案大大降低了移植后急性排斥反应的发生率，但长期结果却停滞不前，部分原因是与免疫抑制相关的发病率和死亡率。因此，研究的一个主要焦点是促进对移植肝脏的耐受性，以便最大限度地减少或完全取消免疫抑制。在过去的十年里，我们了解到器官移植的耐受性与Tregs的发展和持久性有关。在多种临床前模型中，治疗性给药Tregs在控制同种异体移植排斥反应和诱导供者特异性耐受方面已被证明有效。同种异体抗原特异性Treg通过提供靶向治疗而不是不分青红皂白的调节，比非特异性Treg更有效，潜在更安全。在移植环境中，基于Treg方案的一个关键点是，由于供者反应性T细胞的频率非常高，需要“去除”宿主同种异体反应谱系和辅助免疫抑制，以便为Tregs控制同种异体免疫和确保长期移植耐受创造更有利的环境。我们的目标是将这些基本和临床发现转化为实际和有效的临床方案。我们计划在Treg支持性免疫抑制方案的背景下测试供者特异性Treg的UE，作为诱导肝移植耐受的一种方法。作为第一步，我们建议进行一项开放标签、单中心、I期剂量递增试验，以确定在肝移植患者中应用单次递增剂量的供体特异性Tregs的安全性。我们将对研究患者进行机械分析，以评估Treg疗法对受者对供者的免疫反应性的影响。R34拨款将允许研究人员敲定临床试验方案、Treg制造和伴随的机械研究的所有方面， 同时确保研究新药和机构审查委员会对试验的批准。据我们所知，这一建议代表了Tregs在实体器官移植中的第一次应用，以诱导移植耐受。它与NIAID的目标非常一致，即“评估包括耐受性、抗炎和免疫调节策略在内的治疗和预防免疫介导性疾病的方法”。

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop a regulatory T cell (Treg)-based approach for the induction of donor-specific immunologic tolerance in liver transplant recipients. Liver transplantation can be life-saving therapy for live failure. However, the maintenance of the transplanted liver requires continuous immunosuppression to prevent rejection by the host immune system. Although ongoing refinement of immunosuppression regimens has substantially reduced the incidence of acute rejection after transplantation, long-term outcomes have stagnated partly due to morbidity and mortality associated with immunosuppression. Therefore, a main focus of research has been to promote tolerance to transplanted livers so that immunosuppression can be minimized or completely withdrawn. In the past decade, we have learned that tolerance in organ transplantation is linked to the development and persistence of Tregs. In multiple preclinical models, therapeutic administration of Tregs has proven efficacy in controlling allograft rejection and inducing donor-specific tolerance. Alloantigen-specific Treg are more effective and potentially safer than non-specific Treg by offering targeted therapy instead of indiscriminate regulation. A key point in Treg-based regimens in the transplant setting is that, because of the exceptionally high frequency of donor-reactive T cells, "debulking" of the host alloreactive repertoire and adjunct immunosuppression are needed to create a more favorable setting for Tregs to control alloimmunity and to ensure long-term graft tolerance. We aim to translate these basic and clinical findings into a practical and effective clinical protocol. We plan to test the ue of donor- specific Tregs in the context of a Treg-supportive immunosuppression regimen as an approach to induce liver transplant tolerance. As a first step, we propose to conduct an open-label, single center, phase I, dose escalation trial to determine the safety of administering a single escalating dose of donor-specific Tregs in liver transplant patients. We will perform mechanistic analyses of the study patients to assess the impact of the Treg therapy on recipient's immune reactivity to the donor. The R34 grant will allow the investigators to finalize all facets of the clinical trial protocol, Treg manufacturing, and concomitant mechanistic studies, along with securing Investigational New Drug and Institutional Review Board approvals for the trial. To our knowledge, this proposal represents the first application of Tregs in solid organ transplantation to induce graft tolerance. It is strongly aligned with NIAID's goal to "evaluate approaches that include tolerogenic, anti-inflammatory, and immunomodulatory strategies to treat and prevent immune-mediated diseases".