Foxp3+ Treg Cells & Primary Graft Dysfunction in Clinical Lung Tx Recipients

描述(申请人提供)：在现代，器官移植已被证明是解决严重或终末期肾脏、心脏和肝脏疾病的一种越来越重要的方法，但不幸的是，肺移植的结果在患者和移植物存活率方面已经相当落后。造成这一较差结果的主要因素之一是在肺移植的最初几天内发展为原发移植物功能障碍(PGD)。宾夕法尼亚大学的杰森·克里斯蒂博士在过去十年里一直在研究PGD背后的病理生理学，并正在进行由NIH资助的临床研究，在成人肺移植前后采集血液样本。免疫学中一个重要的新概念是FOXP3+T调节(Treg)细胞是免疫反应正常调节的关键，而Treg功能降低可能在临床上导致多种形式的自身免疫和炎症。我们推测，先前存在的Treg数目或功能缺陷，或肺移植导致的Treg数目或功能缺陷，可能与PGD的发生有关。我们建议通过使用我们开发的最先进的Treg功能测试来验证这一假设，方法是评估在NIH资助的克里斯蒂博士基础研究中接受研究的患者，该研究将持续到2014年。这项辅助研究的目的1)将在术前评估Treg数量和/或功能的各个方面，并试图询问Treg功能的任何变化是否与PGD的发生率或严重程度相关。这项辅助研究的目的2)将评估PGD在TX后非常早期的发展是否与Treg数量和/或功能减少有关。我们的研究将提供关于肺TX这一临床上高度重要的问题的第一个信息。我们的发现，使用从3个活跃的肺移植中心(哥伦比亚，印第安纳，宾夕法尼亚)获得的样本，可能导致新的诊断或治疗干预措施，涉及Treg细胞治疗，或使用药物来增强Treg功能，以克服或显著降低肺移植后PGD的发生率和严重程度。

DESCRIPTION (provided by applicant): In the modern era, organ transplantation has proven increasingly important as a solution to severe or end- stage diseases of the kidney, heart and liver, but unfortunately the results of lung transplantation have lagged considerably in terms of patient and graft survival rates. One of the main contributors to this poorer outcome is the development of primary graft dysfunction (PGD) within the first few days of lung transplantation. Dr. Jason Christie at UPenn has been studying the pathophysiology underlying PGD for the past decade, and has NIH- funded clinical studies underway in which blood samples are being collected pre- and post-lung transplantation in adults. An important new concept in immunology is that FOXP3+ T-regulatory (Treg) cells are key to normal regulation of immune responses, and that decreased Treg function likely contributes, clinically, to many forms of autoimmunity and inflammation. We hypothesize that pre-existing defects in Treg numbers or function, or defects in Treg numbers or function as a result of lung transplantation, may contribute to the development of PGD. We propose to test this hypothesis by assessing patients undergoing study in the underlying NIH-funded study of Dr. Christie that will last until 2014, using state-of-the art tests of Treg function that we have developed. Aim 1) of this ancillary study will assess aspects of Treg numbers and/or function pre-operatively and seek to ask whether any changes in Treg function are associated with increased rates or severity of PGD. Aim 2) of this ancillary study will asses whether the development of PGD in the very early post-Tx period is associated with decreased Treg numbers and/or function. Our studies will provide the first information on this clinically highly significant problem in lung Tx. Our findings, using samples obtained from 3 active lung transplant centers (Columbia, Indiana, Penn), may lead to new diagnostic or therapeutic interventions involving Treg cells therapies, or use of agents to enhance Treg function, in the very early post-operative period so as to overcome, or markedly decrease, the incidence and severity of PGD post-lung transplantation.