Prevention of Lung Transplant Injury with Adenosine 2A Receptor Agonis

点击翻译按钮获取中文摘要

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.