The Lung Transplant Clinical Trials Network (LT-CTN)

描述(申请人提供)：肺移植受者，其中97%是成年人，是实体器官移植患者中增长最快的部分。由于晚期肺部疾病发病率的增加以及肺捐赠者利用率的提高，预计这种增长将继续下去。不幸的是，患者的预后并没有得到相应的改善。肺移植后患者长期存活的中位数只有5.5年，这个数字落后于所有其他常见的移植器官。这些糟糕的结果反映了非传染性和传染性并发症的沉重负担。其中最重要的是巨细胞病毒(CMV)，这是肺移植后最常见的机会性感染。尽管目前采取了预防措施，但仍有40%的血清高危肺移植受者会受到影响。预防巨细胞病毒感染至关重要，因为它的发展与较高的移植物长期衰竭和死亡率相关。这种移植失败，被称为慢性肺移植功能障碍(CLAD)，是长期存活率低的主要原因，在五年内发生在50%的肺移植受者身上。尽管它很重要，但我们对导致CLAD的临床风险和免疫学机制的了解是基本的，并且是基于小型的单中心研究。因此，迫切需要科学严谨、设计良好的多中心肺移植研究，直接解决这些主要的移植物限制并发症。为了满足这一需求，我们建议通过CTOT建立肺移植临床试验网络(LT-CTN)，以进行肺移植中CMV和CLAD的关键临床和机制研究。我们的团队代表北美五个领先的学术肺移植中心(杜克大学、克利夫兰诊所、约翰霍普金斯大学、加州大学洛杉矶分校和多伦多大学)的关键临床和研究小组。通过解决肺移植后并发症和移植物失败的主要原因，我们建议的研究有可能直接影响CMV预防的临床实践，并促进对CLAD的机制的理解。此外，由于CMV感染和慢性同种异体移植物功能障碍是与其他实体器官移植相关的并发症，我们的机制研究可能揭示宿主反应在其他实体器官移植人群中的重要性。因此，我们拥有领导力、临床研究专业知识和基础研究深度，可以成功完成拟议的研究，为CTOT计划的整体影响做出贡献，并帮助改善患者的预后。

DESCRIPTION (provided by applicant): Lung transplant recipients, 97% of whom are adults, are the fastest growing segment of solid organ transplant patients. This growth is expected to continue due to increasing incidence of advanced lung disease as well as increasing lung donor utilization rates. Unfortunately, there have not been parallel improvements in patient outcomes. Median long-term patient survival after lung transplant is only 5.5 years, a figure that lags all other commonly transplanted organs. These poor outcomes reflect the high burden of both non-infectious and infectious complications. Foremost among these is cytomegalovirus (CMV), the most common opportunistic infection after lung transplantation. It affects > 40% of all serologically at-risk lung transplant recipients despite current prophylaxis. Prevention of CMV infection is of paramount importance since its development is associated with higher rates of long-term graft failure and death. This graft failure, known as chronic lung allograft dysfunction (CLAD), is the primary reason for poor long-term survival and occurs in >50% of lung transplant recipients within five years. Despite its importance, our understanding of the clinical risks and immunological mechanisms that lead to CLAD is rudimentary and based upon small, single center studies. Thus, there is a critical unmet need for scientifically rigorous, well-designed multicenter lung transplant research studies that directly address these major graft-limiting complications. To meet this need, we propose creation of the Lung Transplant Clinical Trials Network (LT-CTN) through CTOT to conduct key clinical and mechanistic studies of CMV and CLAD in lung transplant. Our team represents key clinical and research groups of five of the leading academic lung transplant centers in North America (Duke, Cleveland Clinic, Johns Hopkins, University of California - Los Angeles, and University of Toronto). By addressing the major causes of morbidity and graft failure after lung transplantation, our proposed studies have the potential to directly impact clinical practice for CMV prevention and advance mechanistic understanding of CLAD. Furthermore, because CMV infection and chronic allograft dysfunction are complications relevant to transplantation of other solid organs, our mechanistic studies are likely to reveal host responses important in other solid organ transplant populations. Thus, we have the leadership, clinical research expertise and basic research depth to successfully accomplish the proposed studies, contribute to the overall impact of the CTOT program, and help improve patient outcomes.