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

“肝移植中供体特异性调节性 T 细胞治疗”

• 批准号: 8264452
• 负责人: JEFFREY A BLUESTONE
• 金额: $ 24.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264452
• 关键词: Acute; Adrenal Cortex Hormones; Adverse effects; Alloantigen; Anti-Inflammatory Agents; Anti-inflammatory; Antithymoglobulin; Autologous; B-Lymphocytes; Biological Markers; Bystander Suppression; Cell Therapy; Cells; Clinical; Clinical Protocols; Clinical Trials; Clinical trial protocol document; Collaborations; Communication; Conduct Clinical Trials; Data Analyses; Data Collection; Development; Disease; Dose; Ensure; Failure; Frequencies; Future; Goals; Graft Tolerance; Grant; Histology; Immune; Immune Tolerance; Immune response; Immune system; Immunologic Monitoring; Immunologics; Immunology; Immunophenotyping; Immunosuppression; Immunosuppressive Agents; Incidence; Infusion procedures; Institutional Review Boards; Investigational Drugs; Learning; Life; Link; Liver; Liver Failure; Maintenance; Mediating; Mission; Mononuclear; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Organ; Organ Transplantation; Oryctolagus cuniculus; Outcome; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phenotype; Pre-Clinical Model; Prevention; Process; Regimen; Regulation; Regulatory T-Lymphocyte; Research; Research Personnel; Safety; Secure; Sirolimus; Solid; T cell therapy; T-Lymphocyte; Tacrolimus; Testing; Therapeutic; Tissues; Toxic effect; Translating; Transplant Recipients; Transplantation; Tumor Debulking; allograft rejection; base; design; isoimmunity; liver biopsy; liver transplantation; mortality; mouse model; mycophenolate mofetil; open label; peripheral blood; prevent; response; safety testing; sample collection

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". PUBLIC HEALTH RELEVANCE: Regulatory T cells (Tregs) have recently been shown to be critical for the development of natural and acquired immunologic tolerance in a variety of settings, suggesting that Treg administration may be useful for the therapeutic induction of immunologic tolerance. Organ transplant recipients continue to suffer from immunologic rejection as well as serious side effects from non-specific immunosuppressive medication. Our long-term objective is to develop Treg cell therapy to induce transplant tolerance so that immunosuppression can be minimized or withdrawn. Therefore, we propose to develop the first clinical trial in solid organ transplantation to test the safety of an immunosuppression regimen that favors the development of Tregs, in conjunction with an infusion of donor-specific Tregs in the liver transplant setting.

描述（由申请人提供）：本项目的长期目标是开发一种基于调节性T细胞（Treg）的方法，用于诱导肝移植受者的供体特异性免疫耐受。肝移植可以挽救肝衰竭的生命。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。虽然不断完善的免疫抑制方案，大大降低了移植后急性排斥反应的发生率，长期的结果停滞不前，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，以便可以最小化或完全撤销免疫抑制。在过去的十年中，我们已经了解到，器官移植的耐受性与THBG的发展和持续存在有关。在多个临床前模型中，已证明TdR的治疗性施用在控制同种异体移植物排斥和诱导供体特异性耐受方面的功效。同种异体抗原特异性Treg通过提供靶向治疗而不是不加选择地调节，比非特异性Treg更有效且可能更安全。在移植环境中基于Treg的方案的关键点是，由于供体反应性T细胞的频率异常高，需要宿主同种异体反应性库的“减积”和辅助免疫抑制来为Treg创造更有利的环境以控制同种异体免疫并确保长期移植物耐受。我们的目标是将这些基础和临床研究结果转化为实用和有效的临床方案。我们计划在Treg支持性免疫抑制方案的背景下测试供体特异性Tlag的使用，作为诱导肝移植耐受的方法。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给予单次递增剂量的供体特异性调节性T细胞的安全性。我们将对研究患者进行机制分析，以评估Treg治疗对受体对供体的免疫反应性的影响。R34赠款将允许研究人员最终确定临床试验方案的所有方面，Treg制造和伴随的机制研究， 沿着的是确保试验新药和机构审查委员会对试验的批准。据我们所知，这一提议代表了THBE在实体器官移植中诱导移植物耐受的首次应用。它与NIAID的目标非常一致，即“评估包括致耐受性，抗炎和免疫调节策略在内的治疗和预防免疫介导疾病的方法”。 公共卫生关系：调节性T细胞（Treg）最近已被证明对于在各种环境中天然和获得性免疫耐受的发展至关重要，这表明Treg施用可用于免疫耐受的治疗性诱导。器官移植受者继续遭受免疫排斥以及非特异性免疫抑制药物的严重副作用。我们的长期目标是开发Treg细胞疗法以诱导移植耐受，从而使免疫抑制最小化或撤销。因此，我们建议在实体器官移植中开展第一项临床试验，以测试在肝移植环境中输注供体特异性THBG的同时，有利于THBG发展的免疫抑制方案的安全性。