Prevention of Lung Transplant Injury with Adenosine 2A Receptor Agonist

 描述（由申请人提供）：我们的实验室专注于开发治疗方法，以提高肺移植的成功率。我们已经证明了腺苷2A受体（A2AR）激动剂对移植后肺缺血再灌注损伤（IRI）的保护作用。最近，我们已经使用A2AR激动剂与最近FDA批准的离体肺灌注（EVLP）平台组合来提高供体肺的可恢复率。该提案是基于我们的实验室发现设计的第一个人体临床试验，评估FDA批准的A2AR激动剂regadenoson在肺移植中的作用。IRI在临床上表现为原发性移植物功能障碍（PGD），仍然是肺移植受者早期死亡和发病的最常见原因。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很大，因此肺是多器官供体中使用最少的实体器官。此外，PGD是慢性同种异体移植排斥反应（闭塞性细支气管炎）的重要风险因素，这是移植后1年以上接受者死亡的主要原因。目前，临床上没有治疗剂可用于 预防PGD，治疗仅限于支持性策略。我们已经表明，IRI的早期启动者是活化的巨噬细胞和不变的NKT细胞（自然杀伤T细胞）。 供体肺通过释放细胞因子启动级联反应，导致中性粒细胞（终末效应细胞）进入同种异体移植物。在我们的临床前模型中，用A2AR激动剂治疗有效地抑制了这些免疫细胞的活化并显著减弱了肺IRI。为了增加可移植供体肺的数量，已经开发了EVLP，并使边缘供体肺能够被测试、康复和成功移植。我们已经表明，在EVLP期间边缘供体肺的A2AR激动剂治疗增强了康复，导致成功的移植。这项提案将把我们长期的研究转化为床旁研究，使用两个特定的目的来研究regadenoson在人类肺移植中的安全性。Regadenoson将用于本提案，因为它是FDA批准用于人类心脏成像，并已接受了一项随机临床安全性试验，用于镰状细胞患者的输注，以治疗急性胸部综合征。此外，目前Regadenoson正在用于后续的2期多中心试验，评估镰状细胞患者的疗效。我们预计，regadenoson治疗肺移植受者将是安全的，并将降低PGD的发病率。我们还预计，在EVLP期间用regadenoson治疗边缘供体肺将允许更多的这些肺成功移植。显然，如本提案所述，扩大供体肺库和预防PGD将从根本上推动肺移植领域的发展。这项试验是高度创新的，因为它从两种不同的方式来处理regadenoson的递送：1）移植时的受体输注，以及2）EVLP时的供体肺输注。

 DESCRIPTION (provided by applicant): 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 i 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, treatmnt 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.