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

抗 Col (V) 免疫在原发性移植物功能障碍中的作用

• 批准号: 8073018
• 负责人: Jason D Christie
• 金额: $ 55.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-14 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073018
• 关键词: Accounting; Acute; Acute Lung Injury; Antibodies; Apoptotic; Autoantibodies; Autoimmunity; Autologous; B-Lymphocytes; Binding; Biological; Biological Markers; Blood Vessels; CD46 Antigen; CD8B1 gene; Cellular Immunity; Characteristics; Chronic; Clinic; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Collagen; Collagen Type V; Complement; Complement 3a; Complement 5a; Complement Activation; Complement Inactivators; Consensus; Critical Illness; Data; Development; Diagnostic; Diffuse; Doctor of Medicine; Epithelial; Epithelial Cells; Frequencies; Functional disorder; Funding; Future; Goals; Grant; Heart-Lung Transplantation; Human; Humoral Immunities; Immune Tolerance; Immune response; Immunity; Immunization; Immunology; In Vitro; Inbred WKY Rats; Incidence; Injury; Interleukin-17; International; Intervention; Intervention Trial; Isogenic transplantation; Knowledge; Laboratories; Laboratory Study; Link; Lung; Lung Inflammation; Lung Transplantation; Lung diseases; Measures; Mediating; Methods; Modeling; Morbidity - disease rate; Motivation; Multicenter Studies; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Organ Preservation; Outcome; Output; Pathogenesis; Pathology; Patients; Perioperative Care; Physiology; Plasma; Population; Predictive Value; Prevention; Principal Investigator; Procedures; Process; Production; Property; Pulmonary Edema; Rattus; Recovery; Registries; Regulation; Reperfusion Injury; Reporting; Research; Risk; Risk Factors; Role; Sampling; Science; Small Interfering RNA; Societies; Splenocyte; Staging; Survivors; Syndrome; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Testing; Therapeutic; Transplantation; Woman; Work; advanced disease; airway epithelium; base; cell injury; cell type; cost; cytotoxic; cytotoxicity; economic outcome; expectation; feeding; genetic regulatory protein; high risk; improved; in vivo; insight; mortality; novel; oral tolerance; preclinical study; prevent; prognostic; prospective; public health relevance; symposium; tool

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.

描述（由申请人提供）：初级移植功能障碍（PGD）是肺移植后严重的急性肺损伤。 PGD​​对肺移植后的结局有重大影响，显着提高了发病率，死亡率和成本。因此，PGD发病率的降低将大大改善肺移植后的临床和经济结局。 尽管PGD对肺移植的重要性显而易见，但有关增加PGD风险的机制的基本问题仍未得到解决。 V型胶原蛋白[Col（V）]是一种本地肺胶原蛋白，在肺部炎症的情况下可能会暴露并引起自身免疫性。我们小组的最新工作表明，对Col（V）的体液和细胞免疫都参与PGD发病机理。此外，我们先前的研究表明，在移植程序之前，受体中存在自身免疫性（V），因此可以用于预测PGD。但是，尚未定义移植前肺疾病相关的抗Col（V）免疫，并且该免疫反应作为PGD的预测指标的实用性尚不清楚。此外，尚不清楚参与抗Col（V）诱导的PGD的T细胞子集，抗Col（V）抗体介导的损伤的机制尚未报道。 利用一项大型的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状况，我们假设自身免疫性会影响受体中肺部肺移植后PGD的风险，并且可以利用可预测PGD。这种翻译应用结合了第一个定义临床PGD的两个主要研究者的优势，并在发病机理中抗Col（V）免疫力。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，这是一项正在进行的10个中心队列PGD发病机理的中心研究，而Christie博士为PI。实验室的目标将扩大Wilkes博士在IU的先前发现。 我们目标的目标是洞悉人和实验室模型中抗COL（V）自身免疫性的PGD机制，以测试抗Col（V）抗体在预测临床PGD中的实用性，并为在Lung Transplantation中（V）col（V）耐受性试验的临床试验阶段为临床试验设定阶段。为了实现这些目标，将采用实验室和临床方法来提供有关Col（V）自身免疫性在PGD发病机理中作用的全面，综合的知识。临床和生物学目标将被充分整合以应用实验室的机械洞察力，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。 公共卫生相关性：原发性移植功能障碍（PGD）是一种严重的急性肺损伤综合征，发生在肺移植后的几天中，显着提高了发病率，死亡率和成本。 V型胶原蛋白[Col（v）]是一种本地肺胶原蛋白，在肺部炎症的情况下可能会暴露并引起自身免疫性，而我们的小组最近的工作表明，与Col（V）的自身免疫性与PGD发病机理有关。我们高度翻译目的的目标是洞悉人和实验室模型中抗Col（V）自身免疫性的PGD机制，以测试抗Col（V）抗体在临床PGD预测中的实用性，并在临床前进行临床研究，从而为Col（V v）的临床临床试验进行临床试验。