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: 7889928
• 负责人: Jason D Christie
• 金额: $ 57.53万
• 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/7889928
• 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; Hypoxemia; 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）：原发性移植物功能障碍（PGD）是肺移植后严重的急性肺损伤。 PGD​​ 对肺移植后的结果有重大影响，显着增加发病率、死亡率和费用。因此，减少 PGD 的发生率将显着改善肺移植后的临床和经济结果。 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答。 V 型胶原蛋白 [col(V)] 是一种天然的肺胶原蛋白，在肺部炎症的情况下可能会暴露并引起自身免疫。我们小组最近的工作表明，针对 col(V) 的体液免疫和细胞免疫都参与了 PGD 发病机制。此外，我们之前的研究表明，在移植手术之前，受者体内就存在对 col(V) 的自身免疫，因此可用于预测 PGD。然而，与抗 col(V) 免疫相关的移植前肺部疾病尚未确定，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重现临床状况的大鼠肺移植模型，我们假设对 col(V) 的自身免疫会影响受者肺移植后进行 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 和发病机制中的抗 col(V) 免疫的人。该应用程序将利用肺移植结果小组收集的数据，该小组是一项正在进行的 10 个中心的 PGD 发病机制队列研究，克里斯蒂博士担任 PI。实验室的目标是扩展印第安纳大学威尔克斯博士先前的发现。 我们的目标是在人类和实验室模型中深入了解抗 col(V) 自身免疫的 PGD 机制，测试抗 col(V) 抗体在预测临床 PGD 中的效用，并设定肺移植中 col(V) 耐受策略的临床试验阶段。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，将实验室的机制洞察应用于人类，并测试临床观察的机制基础。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，发生在肺移植后几天，显着增加发病率、死亡率和费用。 V 型胶原蛋白 [col(V)] 是一种天然的肺胶原蛋白，在肺部炎症的情况下可能会暴露并引起自身免疫，我们小组最近的工作表明对 col(V) 的自身免疫与 PGD 发病机制有关。我们高度转化的目标是在人类和实验室模型中深入了解抗 col(V) 自身免疫的 PGD 机制，测试抗 col(V) 抗体在预测临床 PGD 中的效用，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。