Antibodies to MHC Class I induces autoimmunity: Role in the pathogenesis of chronic rejection¶

摘要

Alloimmunity to mismatched donor HLA-antigens and autoimmunity to self-antigens have been hypothesized to play an important role in immunopathogenesis of chronic rejection of transplanted organs. However, it is not known what role, if any, alloimmune response plays in inducing autoimmunity. To test whether antibody developed post-transplantation to mismatched donor-MHC induces autoimmunity and chronic rejection, we developed a murine model wherein anti-MHC class I antibodies or control (C1.18.4/anti-keratin) were administered intra-bronchially into native lungs. Animals receiving anti-MHC class I, but not control antibodies, developed marked cellular infiltration around vessels and bronchiole of lung by day 15 followed by epithelial hyperplasia, fibrosis and occlusion of the distal airways similar to chronic rejection following human lung transplantation. Lungs of mice receiving anti-MHC class I showed increased expression of chemokines, their receptors and growth factors and induced IL-17 as well as de novo antibodies to self-antigens, K-α1 tubulin and collagenV. IL-17 neutralization by anti-IL-17 resulted in reduction of autoantibody and lesions induced by anti-MHC class I antibodies. Thus, our results indicate that antibodies to donor-MHC can induce autoimmunity, mediated by IL-17, which plays a pivotal role in chronic rejection post-lung transplantation. Therefore, approaches to prevent autoimmunity should be considered for the treatment of chronic rejection post-lung transplantation.