ALLOANTIBODIES TO MHC INDUCES AUTOIMMUNITY AND OBLITERATIVE AIRWAY DISEASE (OAD)

MHC 同种抗体可诱发自身免疫和闭塞性气道疾病 (OAD)

• 批准号: 7907752
• 负责人: THALACHALLOUR MOHANAKUMAR
• 金额: $ 38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-06 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7907752
• 关键词: Allografting; Animals; Antibodies; Apoptosis; Autoantigens; Autoimmune Process; Autoimmunity; B-Lymphocytes; Binding; Biological Assay; Bronchiolitis Obliterans; CD4 Positive T Lymphocytes; Cells; Cellular Infiltration; Chronic; Clinical; Collagen; Development; Disease; Disease model; Endothelial Cells; Epithelial; Epithelial Cells; Epitopes; Flow Cytometry; Goals; Helper-Inducer T-Lymphocyte; Human; Human Development; IL17 gene; Immune response; Immunity; Immunosuppressive Agents; Inbred BALB C Mice; Injury; Institutes; Isoantibodies; Kinetics; Laboratories; Lead; Lesion; Ligation; Liquid substance; Lung; Lung Transplantation; Lymphoid Cell; MHC Class I Genes; Mediating; Messenger RNA; Methods; Modeling; Molecular; Mus; Natural Killer Cells; Natural regeneration; Operative Surgical Procedures; Pathogenesis; Pathology; Perioperative; Phenotype; Play; Process; Production; Regimen; Regulatory T-Lymphocyte; Reporting; Respiratory Tract Infections; Reverse Transcriptase Polymerase Chain Reaction; Role; Seminal; Sendai virus; Signal Transduction; Specificity; Staging; Syndrome; T-Lymphocyte; Techniques; Testing; Time; To autoantigen; Transgenic Organisms; Transplantation; Tubulin; Vascular Diseases; Viral; Virus Diseases; autoreactive T cell; base; cell injury; chemokine; cytokine; enzyme linked immunospot assay; immune activation; immunopathology; improved; in vivo; lung allograft; lymph nodes; novel; novel therapeutics; pre-clinical; prevent; public health relevance; reconstitution; respiratory; small airways disease

DESCRIPTION (provided by applicant): Lung transplantation (LTx) is a treatment option for end-stage pulmonary parenchymal and vascular diseases. However, long-term survival of the lung allograft is limited by the development of bronchiolitis obliterans syndrome (BOS), a condition unresponsive to therapy and often fatal. Using a newly developed anti-MHC induced model of obliterative airway disease (OAD) and LTx model, we have obtained evidence for a seminal role for alloMHC antibodies (Abs) in inducing autoimmunity, leading to the pathogenesis of OAD. Further, using a sendai viral infection, we have demonstrated an important role for post- transplant viral infection in epithelial destruction and fibroproliferation which parallels BOS following respiratory infections in LTx recipients. The goals of this project are to: 1) define the immunopathology of OAD induced by Abs to MHC class I. Towards this, we will determine: a) kinetics of auto-Ab production to collagen V and K-11 tubulin, b) define the role of T regulatory cells in the production of auto-Abs, c) analyze BAL fluid for their cytokine content, d) determine the phenotype of infiltrating cells and their cytokine, d) define the specificity of infiltrating T cells to autoantigens collagen V and K-11 tubulin, and e) determine the autoantigenic epitopes for helper T cell stimulation and Ab production. 2) Determine the mechanism of OAD development following the administration of anti-MHC class I. Towards this, we will determine; a) role of autoreactive T cellls or Abs to K-11 tubulin alone to cause OAD in native lung and in the transplanted lung, b) the role of Abs to MHC to augment OAD development together with self reactive T cells and Abs, c) mechanism by which Abs to MHC induce autoimmunity including the role of IL17 in this process, and d) the signaling cascades following ligation of autoantigen K-11 tubulin with its specific Ab in airway epithelial cells. 3) Define the role of viral infection in augmenting the development of OAD induced by anti-MHC class I. Towards this we will; a) determine the kinetics and strength of auto-Ab production and cellular infiltration, and b) determine the mechanism by which T regulatory cells are deleted following viral infection. The overall goal of this proposal is to employ unique preclinical murine models of OAD and viral infections to define the cellular and molecular mechanisms leading to autoimmunity in the pathogenesis of BOS following clinical LTx. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to employ unique preclinical murine models of obliterative airway disease and viral infections to define the cellular and molecular mechanisms leading to the pathogenesis of bronchiolitis obliterans syndrome following clinical lung transplant.

描述（由申请人提供）：肺移植（LTx）是终末期肺实质和血管疾病的一种治疗选择。然而，同种异体肺移植物的长期存活受到闭塞性细支气管炎综合征（BOS）的限制，这种疾病对治疗无反应并且通常是致命的。使用新开发的抗 MHC 诱导的闭塞性气道疾病 (OAD) 模型和 LTx 模型，我们获得了同种 MHC 抗体 (Abs) 在诱导自身免疫、导致 OAD 发病机制中发挥重要作用的证据。此外，利用仙台病毒感染，我们证明了移植后病毒感染在上皮破坏和纤维增殖中的重要作用，这与 LTx 受者呼吸道感染后的 BOS 相似。该项目的目标是：1) 定义 I 类 MHC 抗体诱导的 OAD 的免疫病理学。为此，我们将确定：a) 产生胶原蛋白 V 和 K-11 微管蛋白的自身抗体的动力学，b) 定义T 调节细胞在自身抗体产生中的作用，c) 分析 BAL 液中的细胞因子含量，d) 确定浸润细胞及其细胞因子的表型，d) 定义将 T 细胞浸润至自身抗原胶原蛋白 V 和 K-11 微管蛋白，以及 e) 确定辅助 T 细胞刺激和抗体产生的自身抗原表位。 2)确定施用抗MHC I类后OAD发展的机制。为此，我们将确定； a) 单独的自身反应性 T 细胞或 K-11 微管蛋白抗体在自体肺和移植肺中引起 OAD 的作用，b) MHC 抗体与自身反应性 T 细胞和抗体一起增强 OAD 发育的作用，c) MHC 抗体诱导自身免疫的机制，包括 IL17 在此过程中的作用，以及 d) 自身抗原 K-11 微管蛋白与其在气道上皮中的特异性抗体连接后的信号级联细胞。 3) 明确病毒感染在增强抗 MHC I 类诱导的 OAD 发展中的作用。为此，我们将； a) 确定自身抗体产生和细胞浸润的动力学和强度，b) 确定病毒感染后 T 调节细胞被删除的机制。该提案的总体目标是采用独特的 OAD 和病毒感染的临床前小鼠模型来定义临床 LTx 后 BOS 发病机制中导致自身免疫的细胞和分子机制。 公共健康相关性：该提案的总体目标是采用独特的闭塞性气道疾病和病毒感染的临床前小鼠模型来定义导致临床肺移植后闭塞性细支气管炎综合征发病机制的细胞和分子机制。