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: 8076746
• 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/8076746
• 关键词: Allografting; Animals; Antibodies; Apoptosis; Autoantigens; Autoimmune Process; Autoimmunity; B-Lymphocytes; Binding; Biological Assay; Bronchiolitis Obliterans; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Transplantation; Cells; Cellular Infiltration; Chronic; Clinical; Collagen; Development; Disease; Disease model; Endothelial Cells; Epithelial; Epithelial Cells; Epitopes; Flow Cytometry; Goals; Health; 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; 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（申请人提供）：肺移植（LTx）是终末期肺实质和血管疾病的治疗选择。然而，肺移植的长期生存受到闭塞性细支气管炎综合征（BOS）的发展的限制，这是一种对治疗无反应且通常致命的疾病。通过新建立的抗mhc诱导的闭塞性气道疾病（OAD）模型和LTx模型，我们已经获得了alloMHC抗体（Abs）在诱导自身免疫，导致OAD发病中的重要作用的证据。此外，通过仙台病毒感染，我们证明了移植后病毒感染在LTx受者呼吸道感染后上皮破坏和纤维增殖中的重要作用。本项目的目标是：1)明确抗体诱导OAD对MHC i类的免疫病理。为此，我们将确定：a)自身抗体对V型胶原和K-11微管蛋白产生的动力学，b)确定T调节细胞在自身抗体产生中的作用，c)分析BAL液中细胞因子的含量，d)确定浸润细胞及其细胞因子的表型，d)确定浸润T细胞对自身抗原V型胶原和K-11微管蛋白的特异性，e)确定辅助T细胞刺激和Ab产生的自身抗原表位。2)确定抗mhc i类药物后OAD发展的机制，为此我们将确定；a)自身反应性T细胞或抗体单独对抗K-11微管蛋白在原生肺和移植肺中引起OAD的作用，b)抗体对抗MHC与自身反应性T细胞和抗体一起增强OAD发展的作用，c)抗体对抗MHC诱导自身免疫的机制，包括IL17在这一过程中的作用，以及d)自身抗原K-11微管蛋白与其特异性抗体在气道上皮细胞中连接后的信号级联反应。3)明确病毒感染在增强抗mhc i类诱导的OAD发展中的作用。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。本提案的总体目标是采用独特的临床前小鼠OAD和病毒感染模型来确定临床LTx后BOS发病过程中导致自身免疫的细胞和分子机制。