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

描述(申请人提供)：原发移植物功能障碍(PGD)是肺移植后的严重急性肺损伤。PGD对肺移植后的预后有重大影响，显著增加了发病率、死亡率和成本。因此，降低PGD的发生率将极大地改善肺移植后的临床和经济结果。尽管PGD在肺移植中具有明显的重要性，但关于增加PGD风险的机制的基本问题仍未得到解答。V型胶原[COL(V)]是一种天然的肺胶原蛋白，在肺部炎症的背景下可能暴露并引起自身免疫。我们课题组最近的工作表明，对COL(V)的体液免疫和细胞免疫都参与了PGD的发病。此外，我们先前的研究表明，受体在移植手术前存在对COL(V)的自身免疫，因此可以用来预测PGD。然而，移植前肺部疾病与抗胶(V)免疫相关还没有定义，这种免疫反应作为PGD的预测因子的作用也是未知的。此外，T细胞亚群参与抗胶原(V)诱导的PGD的机制尚不清楚，抗胶(V)抗体介导的损伤机制尚未见报道。利用一项大型前瞻性多中心临床研究，以及我们复制的大鼠肺移植临床情况的模型，我们假设对COL(V)的自身免疫影响受者肺移植后PGD的风险，并可用于预测PGD。这一翻译应用结合了最先定义临床PGD的两位主要研究人员的优势，以及在PGD发病机制中的抗胶原(V)免疫。该应用程序将利用作为肺移植结果小组的一部分收集的数据，该小组是一项正在进行的关于PGD发病机制的10中心队列研究，克里斯蒂博士担任PI。实验室的目标将是扩展威尔克斯博士在伊利诺伊州的先前发现。我们的目标是在人体和实验室模型中通过抗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中的作用，并为肺移植中COL(V)耐受策略的临床试验奠定基础。为了达到这些目标，实验室和临床方法将被用来提供关于COL(V)自身免疫在PGD发病机制中的作用的全面、完整的知识体系。临床和生物学目标将完全结合起来，将实验室的机械洞察力应用到人类群体中，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。 公共卫生相关性：原发性移植物功能障碍(PGD)是一种严重的急性肺损伤综合征，发生在肺移植后数天，显著增加发病率、死亡率和成本。V型胶原[COL(V)]是一种天然的肺胶原蛋白，在肺部炎症的背景下可能暴露并引起自身免疫，本课题组最近的工作表明，对COL(V)的自身免疫参与了PGD的发病。我们高度翻译的目标是在人类和实验室模型中通过抗COL(V)自身免疫来洞察PGD的机制，测试抗COL(V)抗体在预测临床PGD中的作用，并进行临床前研究，为肺移植中COL(V)耐受策略的临床试验奠定基础。

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.