"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: 8728396
• 负责人: JEFFREY A BLUESTONE
• 金额: $ 5.72万
• 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/8728396
• 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".

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，用于诱导肝移植受者中供体特异性免疫耐受性。肝移植可以是挽救生命的疗法，以实现现场失败。但是，移植的肝脏维持需要连续免疫抑制，以防止宿主免疫系统排斥。尽管对免疫抑制方案的持续细化大大降低了移植后急性排斥的发生率，但长期结局部分由于与免疫抑制相关的发病率和死亡率所致。因此，研究的主要重点是促进对移植肝脏的耐受性，以便可以将免疫抑制作用最小化或完全撤离。在过去的十年中，我们了解到器官移植的宽容与Tregs的发展和持久性有关。在多个临床前模型中，TREG的治疗施用在控制同种异体移植排斥和诱导供体特异性公差方面已证明有效。通过提供靶向治疗而不是不加区分的调节，同种抗原特异性的Treg比非特异性Treg更有效，更可能更安全。在移植设置中基于TREG的方案的一个关键点是，由于供体反应性T细胞的频率异常高，主机的同种异体反应性曲目和辅助免疫抑制作用需要更有利的设置来控制AlloMunimity并确保长期的耐受性。我们旨在将这些基本和临床发现转化为实用有效的临床方案。我们计划在treg支持的免疫抑制方案的背景下测试供体特异的UE，作为诱导肝移植耐受性的一种方法。作为第一步，我们建议进行开放标签，单个中心，I期，剂量升级试验，以确定在肝移植患者中给予单个升级剂量的供体特异性Treg的安全性。我们将对研究患者进行机械分析，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，TREG制造和随之而来的机械研究的所有方面， 以及确保调查新药和机构审查委员会批准该试验。据我们所知，该建议代表了Treg在固体器官移植中的首次应用以诱导移植物耐受性。它与NIAID的目标密切相符，即“评估包括耐受性，抗炎和免疫调节策略来治疗和预防免疫介导的疾病的方法”。