A Novel MHC Class I Transgenic Mouse Model With Lung Specific Expression Demonstrates That Antibodies to MHC Class I Induces Epithelial Injury, Autoimmunity and Obliterative Airway Disease (OAD).

Abstract

Aim: Antibodies (Abs) to mismatched Donor HLA and lung associated self-antigens (SAgs) have been shown to play an important role in immunopathogenesis of chronic rejection (Bronchiolitis Obliterans Syndrome, BOS) following lung transplantation. Antibody mediated epithelial injury has been implicated in development of BOS. Clara cells in the lung epithelium secrete anti-inflammatory Clara Cell Secretory Protein (CCSP) to protect the bronchiolar epithelium. This study is aimed at developing a novel MHC class I transgenic mouse model to elucidate the role of clara cells in inducing epithelial injury following administration of antibodies to MHC Class I. Methods: We developed a transgenic mouse model where lung specific expression of MHC class I is obtained by cloning H2KD gene under CCSP promoter. Anti-MHC or isotype control were administered intravenously. The lungs were harvested on day 15 and 30 for histopathological analysis. Morphometric analysis of cellular infiltration, epithelial abnormalities and fibrosis was determined by H&E and Trichome staining. The alloimmune responses to MHC and the induction of autoimmune responses to lung SAgs (Kα1 Tubulin and Col V) were determined by ELISA. Using ELISpot the frequency of SAg specific IFN-γ, IL-10 and IL-17 secreting T cells were enumerated. Results: The transgenic mouse model demonstrated lung specific expression of H2KD. Intravenous administration of anti-MHC developed cellular infiltration around vessels and bronchiole by day 15 and further increased on day 30, followed by epithelial injury, fibrosis, and occlusion of the distal airways similar to BOS following lung transplantation. This was accompanied by decreased expression of CCSP in the lungs. Mice receiving the anti-H2KD showed increased development of Abs to SAgs. Administration of anti-H2KD also showed increased frequency of IFN-γ, IL-4 and IL-17 secreting T cells against SAgs in the lungs. Conclusion: Using a novel transgenic mouse model with lung specific expression of MHC we demonstrate that anti-MHC induces damage to Clara cells and decrease in CCSP expression resulting in the development of autoimmunity and OAD. This model of OAD will enable us to define the role of Clara cells in antibody mediated cellular injury leading to chronic rejection.