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

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，肺移植物的长期存活受到闭塞性细支气管炎综合征（BOS）的发展的限制，BOS是一种对治疗无反应且通常致命的疾病。利用新近建立的抗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）在诱导自身免疫中的重要作用的证据，从而导致OAD的发病。此外，使用仙台病毒感染，我们已经证明了移植后病毒感染在上皮破坏和纤维增生中的重要作用，这与LTx受体中呼吸道感染后的BOS相似。本研究的目的是：1）明确抗MHC I类抗体诱导OAD的免疫病理学机制。为此，我们将确定：a）针对胶原V和K-11微管蛋白的自身抗体产生的动力学，B）确定T调节细胞在自身抗体产生中的作用，c）分析BAL液的细胞因子含量，d）确定浸润细胞及其细胞因子的表型，d）确定浸润T细胞对自身抗原胶原V和K-11微管蛋白的特异性，和e）确定用于辅助T细胞刺激和Ab产生的自身抗原表位。2)确定抗MHC I类抗体给药后OAD发生的机制。为此，我们将决定; a）自身反应性T细胞或针对K-11微管蛋白的Ab单独在天然肺和移植肺中引起OAD的作用，B）针对MHC的Ab与自身反应性T细胞和Ab一起增强OAD发展的作用，c）针对MHC的Ab诱导自身免疫的机制，包括IL 17在该过程中的作用，和d）在气道上皮细胞中自身抗原K-11微管蛋白与其特异性Ab连接后的信号级联。3)明确病毒感染在增强抗MHC I类抗体诱导的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，和B）确定病毒感染后T调节细胞缺失的机制。本提案的总体目标是采用OAD和病毒感染的独特临床前小鼠模型，以确定导致临床LTx后BOS发病机制中自身免疫的细胞和分子机制。 公共卫生相关性：本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，以确定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。

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.