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疗法以改善肺移植成功。 我们已经显示了腺苷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，我们使用了A2AR激动剂与最近的FDA相结合 批准的前肺灌注（EVLP）平台可提高供体肺的可恢复性率。这 提案是基于我们评估FDA的实验室发现设计的第一个人类临床试验 已批准的A2AR激动剂Regadenoson，用于肺移植。临床上呈现主要移植物的IRI 功能障碍（PGD）仍然是肺移植早期死亡率和发病率的最常见原因 收件人。外科医生避免使用边缘供体肺的使用，因为原发性移植功能障碍的风险是 很棒，因此，肺是多器官捐赠者中任何固体器官的最少使用的。此外 PGD​​是慢性同种异体移植排斥（支气管炎闭塞性）的重要危险因素，这是 接收者的死亡率超过1年的移植。目前尚无治疗剂的临床可用 预防PGD，治疗仅限于支持策略。 我们已经表明，IRI的早期发起人是激活的巨噬细胞和不变的NKT细胞 （天然杀手T细胞）在供体肺中，通过释放细胞因子来行动造成一系列事件 这导致将中性粒细胞（末端效应细胞）带入同种异体移植物。在我们的临床前模型中 用A2AR激动剂有效抑制这些免疫细胞的激活，并显着减弱肺IRI。在 为了增加可移植供体肺的数量，已经开发出EVLP并启用边际 供体肺进行测试，修复并成功移植。我们已经证明了a2ar激动剂 EVLP期间边缘供体肺的治疗可增强康复，从而成功移植。 该建议将使用两个特定的目标将我们的长期研究转化为床边 研究雷加诺森在人肺移植中的安全性。该提案将使用Regadenoson 因为它已被FDA批准用于人类用于心脏成像，并且已经进行了随机临床 镰状细胞患者输注的安全试验治疗急性胸部综合征。此外，目前Regadenoson 正在使用后2阶段的多中心试验中使用，评估了镰状细胞患者的功效。我们 预计肺移植接受者的雷加纳森森治疗将是安全的，并且会降低发生率 PGD​​。我们还预计，在EVLP期间，用Regadenoson治疗边缘供体肺将允许 这些肺有更多的成功移植。显然，供体肺池的扩展和 如本提案所述，预防PGD将从根本上推进肺移植场。这 试验具有很高的创新性，因为它从两种不同的方式接近雷加森的传递：1） 移植时的受体输注和2）EVLP上的供体肺输注。