Role of anti-Col (V) immunity in primary graft dysfunction

描述（由申请人提供）：原发性移植物功能障碍（Primary Graft Dysfunction， PGD）是指肺移植术后严重的急性肺损伤。PGD对肺移植后的预后有重要影响，显著增加发病率、死亡率和成本。因此，减少PGD的发生率将显著改善肺移植后的临床和经济结果。尽管PGD对肺移植具有明确的重要性，但关于PGD风险增加机制的基本问题仍未得到解答。V型胶原蛋白[col(V)]是一种天然的肺胶原蛋白，可能在肺部炎症的情况下暴露并引起自身免疫。我们小组最近的工作表明，对col(V)的体液免疫和细胞免疫都参与了PGD的发病机制。此外，我们之前的研究表明，在移植手术之前，受体对col(V)的自身免疫就存在，因此可以用来预测PGD。然而，移植前肺部疾病相关的抗col(V)免疫尚未被定义，并且这种免疫反应作为PGD预测因子的效用尚不清楚。此外，参与抗col(V)诱导的PGD的T细胞亚群尚不清楚，抗col(V)抗体介导的损伤机制尚未报道。利用一项大型前瞻性多中心临床研究，以及我们的大鼠肺移植模型再现了临床情况，我们假设对冷(V)的自身免疫影响受体肺移植后PGD的风险，并可用于预测PGD。这一转化应用结合了两位主要研究人员的优势，他们是第一个定义临床PGD和抗冷(V)免疫在PGD发病机制中的优势。该应用程序将利用作为肺移植结果组的一部分收集的数据，这是一个正在进行的PGD发病机制的10个中心队列研究，由克里斯蒂博士担任PI。实验室的目标是扩展威尔克斯博士在印第安纳大学的先前发现。我们的目标是通过人类和实验室模型中的抗col(V)自身免疫来深入了解PGD的机制，测试抗col(V)抗体在预测临床PGD中的效用，并为肺移植中col(V)耐受性策略的临床试验奠定基础。为了实现这些目标，将采用实验室和临床方法来提供关于col(V)自身免疫在PGD发病机制中的作用的全面、综合的知识体系。临床和生物学目标将完全整合，以应用从实验室到人群的机械洞察力，并测试临床观察的机械基础。该应用程序的输出将为潜在的临床试验提供所需的数据。

DESCRIPTION (provided by applicant): Primary Graft Dysfunction (PGD) is severe acute lung injury after lung transplantation. PGD has a major impact on outcomes following lung transplantation, markedly increasing morbidity, mortality, and cost. Thus, reduction in the incidence of PGD would dramatically improve clinical and economic outcomes following lung transplantation. Despite the clear importance of PGD to lung transplantation, fundamental questions about mechanisms that increase PGD risk remain unanswered. Type V collagen [col(V)] is a native lung collagen that may become exposed and cause autoimmunity in the setting of lung inflammation. Recent work by our group suggests that both humoral and cellular immunity to col(V) are involved in PGD pathogenesis. Furthermore, our prior studies suggest that autoimmunity to col(V) is present in recipients prior to the transplant procedure and may thus be used to predict PGD. However, the pre-transplant lung diseases associated anti-col(V) immunity have not been defined, and the utility of this immune response as a predictor of PGD is unknown. Furthermore, the T cell subset involved in anti-col(V)-induced PGD is unknown, and mechanisms of anti-col(V) antibody mediated injury have not been reported. Utilizing a large prospective multicenter clinical study, and our rat lung transplant model that reproduces the clinical condition, we hypothesize that autoimmunity to col(V) influences the risk of PGD following lung transplantation in recipients, and can be utilized to predict PGD. This translational application combines the strengths of the two principal investigators whom were the first to define clinical PGD, and anti- col(V) immunity in the pathogenesis PGD. The application will leverage data collected as part of the Lung Transplant Outcomes Group, which is an ongoing 10 center cohort study of PGD pathogenesis, with Dr. Christie as PI. Laboratory aims will be expand prior discoveries by Dr. Wilkes at IU. The goals of our Aims are to provide insight into the mechanisms of PGD by anti-col(V) autoimmunity in human and laboratory models, to test the utility of anti-col(V) antibodies in prediction of clinical PGD, and to set the stage for clinical trials of tolerance strategies to col(V) in lung transplantation. To achieve these aims, both laboratory and clinical methods will be employed to provide a comprehensive, integrated body of knowledge on the role of col(V) autoimmunity in PGD pathogenesis. Clinical and biological aims will be fully integrated to apply mechanistic insight from laboratory to human populations, and to test the mechanistic underpinnings of clinical observations. The output of this application will provide needed data for potential clinical trials. PUBLIC HEALTH RELEVANCE: Primary graft dysfunction (PGD) is a severe acute lung injury syndrome occurring in the days after lung transplantation, markedly increasing morbidity, mortality, and cost. Type V collagen [col(V)] is a native lung collagen that may become exposed and cause autoimmunity in the setting of lung inflammation, and recent work by our group suggests that auto-immunity to col(V) is involved in PGD pathogenesis. The goals of our highly translational Aims are to provide insight into the mechanisms of PGD by anti-col(V) autoimmunity in human and laboratory models, to test the utility of anti-col(V) antibodies in prediction of clinical PGD, and to conduct pre-clinical studies that set the stage for clinical trials of tolerance strategies to col(V) in lung transplantation.