Prevention of Lung Transplant Injury with Adenosine 2A Receptor Agonist

 描述(申请人提供)：我们的实验室一直致力于开发治疗方法，以提高肺移植的成功率。腺苷2A受体(A2AR)激动剂对移植后肺缺血再灌注损伤(IRI)具有保护作用。最近，我们使用了A2AR激动剂和FDA最近批准的体外肺灌流(EVLP)平台来提高供体肺的恢复率。这项建议是根据我们的实验室发现设计的第一项人类临床试验，评估FDA批准的A2AR激动剂瑞格腺苷在肺移植中的应用。临床表现为原发性移植物功能障碍(PGD)的IRI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肺，因为原发移植物功能障碍的风险很大，因此在多器官捐赠者中，肺是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(闭塞性毛细支气管炎)的重要危险因素，是移植后1年以上死亡的主要原因。目前，临床上还没有治疗药物。 预防PGD，治疗仅限于支持性策略。我们已经证明，IRI的早期起始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一系列事件，导致中性粒细胞(末端效应细胞)进入同种异体移植物。在我们的临床前模型中，用A2AR激动剂治疗可以有效地抑制这些免疫细胞的激活，并显著减轻肺IRI。为了增加可移植供肺的数量，开发了EVLP，使边缘供肺能够进行测试、修复和成功移植。我们已经证明，在EVLP期间对边缘供者肺进行A2AR激动剂治疗可以促进康复，从而导致成功的移植。这项提案将把我们长期的研究转移到床边，使用两个特定的目标来研究瑞格腺苷在人类肺移植中的安全性。在这项建议中将使用瑞格腺苷，因为它已被FDA批准用于人体心脏成像，并已接受了一项随机临床安全性试验，用于治疗镰状细胞患者。此外，目前，瑞格腺苷正被用于评估镰状细胞患者的疗效的后续第二阶段多中心试验。我们预计，肺移植受者接受瑞格腺苷治疗将是安全的，并将减少PGD的发生率。我们还预计，在EVLP期间用瑞格腺苷治疗边缘供体肺将允许更多的此类肺成功移植。显然，扩大供体肺池和预防PGD，将从根本上推动肺移植领域的发展。这项试验具有很高的创新性，因为它从两种不同的方式给药：1)移植时的受体输液，2)在EVLP中的供体肺输注。

 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.