Prevention of Lung Transplant Injury with Adenosine 2A Receptor Agonis

腺苷 2A 受体激动剂预防肺移植损伤

• 批准号: 10225225
• 负责人: Christine L Lau
• 金额: $ 43.67万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-12 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225225
• 关键词: Acute; Address; Adenosine; Adult; Agonist; Allografting; Alveolar; Anti-Inflammatory Agents; Attenuated; Biological Markers; Blood; Bronchiolitis; Bronchiolitis Obliterans; Cardiovascular system; Cells; Chronic; Clinical; Clinical Trials Design; Cytotoxic T-Lymphocytes; Data; Diffuse; Donor person; Dose; Dose-Limiting; Effector Cell; Event; FDA approved; Feasibility Studies; Flow Cytometry; Functional disorder; Future; Goals; Human; Hypoxemia; Immune; Incidence; Inflammation; Inflammatory; Infusion procedures; Injury; Knowledge; Laboratories; Liquid substance; Lung; Lung Transplantation; Measures; Mediating; Methods; Morbidity - disease rate; Multi-Institutional Clinical Trial; Multicenter Trials; Myocardial perfusion; Neutrophil Infiltration; Organ; Patients; Perfusion; Pharmaceutical Preparations; Phase; Pilot Projects; Placebos; Population; Pre-Clinical Model; Prevention; Preventive therapy; Primary Prevention; Process; Randomized; Receptor Activation; Rehabilitation therapy; Reperfusion Injury; Request for Proposals; Research; Respiratory physiology; Risk; Risk Factors; Safety; Sickle Cell; Sickle Cell Anemia; Solid; Surgeon; Techniques; Testing; Therapeutic Agents; Time; Toxic effect; Translating; Transplant Recipients; Transplantation; acute chest syndrome; allograft rejection; base; chemokine; cytokine; design; effective therapy; follow-up; heart imaging; immune activation; improved; inflammatory marker; innovation; lung ischemia; macrophage; mortality; neutrophil; novel; novel strategies; novel therapeutics; perfusion imaging; pilot trial; post-transplant; pre-clinical; prevent; primary endpoint; protective effect; pulmonary rehabilitation; receptor; response; safety and feasibility; safety study; success; therapy development; tissue injury

Our laboratory has focused on developing therapies to improve the success of lung transplantation. We have shown the protective effects of adenosine 2A receptor (A2AR) agonists on post-transplant lung ischemia-reperfusion injury (IRI). More recently we have used A2AR agonists combined with a recently FDA approved ex-vivo lung perfusion (EVLP) platform to improve the recoverability rates of donor lungs. This proposal is the first human clinical trial designed based on our laboratory discoveries evaluating the FDA approved A2AR agonist, regadenoson, in lung transplantation. IRI which clinically presents as primary graft dysfunction (PGD) continues to be the most common cause of early mortality and morbidity in lung transplant recipients. Use of marginal donor lungs is avoided by surgeons because the risk of primary graft dysfunction is great, and for this reason the lungs are the least used of any solid organ in multi-organ donors. Furthermore PGD is a significant risk factor for chronic allograft rejection (bronchiolitis obliterans), the primary cause of mortality in recipients beyond 1-year of transplant. Currently no therapeutic agents are clinically available to prevent PGD, and treatments are limited to supportive strategies. We have shown that the early initiators of IRI are activated macrophages and invariant NKT cells (Natural killer T-cells) in the donor lung setting into action a cascade of events through release of cytokines that results in bringing neutrophils (the end effector cells) into the allograft. In our preclinical models, treatment with A2AR agonists potently inhibits activation of these immune cells and significantly attenuates lung IRI. In order to increase the number of transplantable donor lungs, EVLP has been developed and enables marginal donor lungs to be tested, rehabilitated and successfully transplanted. We have shown that A2AR agonist treatment of marginal donor lungs during EVLP enhances rehabilitation leading to successful transplantation. This proposal will translate our long-standing research to the bedside using two specific aims designed to study the safety of regadenoson in human lung transplantation. Regadenoson will be used in this proposal because it is FDA-approved for use in humans for cardiac imaging and has undergone a randomized clinical safety trial for infusion in sickle cell patients to treat acute chest syndrome. Furthermore currently regadenoson is being used in the follow-up Phase 2 multi-centered trial evaluating efficacy in sickle cell patients. We anticipate that regadenoson treatment of lung transplant recipients will be safe and will decrease the incidence of PGD. We also anticipate that treatment of marginal donor lungs with regadenoson during EVLP will permit a greater number of these lungs to be successfully transplanted. Clearly, expansion of the donor lung pool and prevention of PGD, as described in this proposal, would radically advance the field of lung transplantation. This trial is highly innovative because it approaches the delivery of regadenoson from two different ways: 1) recipient infusion at the time of transplantation, and 2) donor lung infusion while on EVLP.

我们的实验室致力于开发提高肺移植成功率的疗法。 我们已经证明了腺苷 2A 受体 (A2AR) 激动剂对移植后肺的保护作用 缺血再灌注损伤（IRI）。最近，我们使用 A2AR 激动剂与最近 FDA 批准的药物相结合 批准的离体肺灌注（EVLP）平台可提高供体肺的恢复率。这 该提案是第一个根据我们实验室发现设计的人体临床试验，评估 FDA 批准 A2AR 激动剂 regadenoson 用于肺移植。 IRI 临床上表现为原发移植物 功能障碍（PGD）仍然是肺移植早期死亡和发病的最常见原因 收件人。外科医生避免使用边缘供体肺，因为原发性移植物功能障碍的风险是 太好了，因此，在多器官捐献者中，肺是所有实体器官中使用最少的。此外 PGD​​ 是慢性同种异体移植排斥（闭塞性细支气管炎）的一个重要危险因素，而慢性同种异体移植排斥是导致慢性同种异体移植排斥的主要原因。 移植后 1 年以上受者的死亡率。目前临床上尚无可用的治疗药物 预防 PGD，治疗仅限于支持性策略。 我们已经证明 IRI 的早期启动者是活化的巨噬细胞和不变的 NKT 细胞 供体肺中的（自然杀伤 T 细胞）通过释放细胞因子启动一系列事件 这导致将中性粒细胞（末端效应细胞）带入同种异体移植物中。在我们的临床前模型中，治疗 与 A2AR 激动剂一起有效抑制这些免疫细胞的激活并显着减弱肺部 IRI。在 为了增加可移植供体肺的数量，EVLP 已被开发出来，并能够实现边际移植 供体肺将接受测试、康复并成功移植。我们已经证明 A2AR 激动剂 EVLP 期间边缘供体肺的治疗可增强康复能力，从而实现移植的成功。 该提案将利用设计的两个具体目标将我们长期的研究转化为临床 研究热加腺苷在人肺移植中的安全性。本提案将使用 Regadenoson 因为它已获得 FDA 批准用于人体心脏成像，并且已经过随机临床试验 镰状细胞病患者输注治疗急性胸部综合征的安全性试验。此外，目前热加腺松 正在用于评估镰状细胞患者疗效的后续 2 期多中心试验。我们 预计肺移植受者的热加腺苷治疗将是安全的并且会降低发病率 胚胎植入前诊断 (PGD)。我们还预计，在 EVLP 期间用 regadenoson 治疗边缘供体肺将允许 更多数量的肺能够成功移植。显然，供体肺池的扩大和 正如该提案中所描述的，PGD 的预防将从根本上推进肺移植领域的发展。这 该试验具有高度创新性，因为它通过两种不同的方式来递送热加腺苷：1) 移植时接受者输注，以及 2) EVLP 期间供体肺输注。