Abstract
Lung transplantation is the treatment option for a variety of end stage pulmonary diseases. Post transplant development of antibodies (Abs) against donor HLA and non-HLA antigens have been associated with acute and chronic rejection of transplanted organs. Development of bronchiolitis obliterans syndrome (BOS) following lung transplantation has been correlated with de novo production of anti-donor-HLA Abs. However, only a portion of the patients with BOS demonstrate detectable anti-donor-HLA Abs. Airway epithelium is considered as a major target for lung allograft rejection. In this study we demonstrate that many BOS+ patients (12 of 36) develop Abs reactive to epithelial cell antigen that is distinct from HLA. Further, de novo production of anti-epithelial cell antibody precedes clinical onset of BOS. N-terminal sequencing and BLASTX analysis as well as blocking with K-alpha1 tubulin specific antibody identified the epithelial antigen as K-α1 tubulin. Binding of the de novo produced anti-K-α1 tubulin antibodies to the airway epithelial cells resulted in the increased expression of transcription factors (TCF5 and c-Myc), leading to increased expression of fibrogenic growth factors, activation of cell cycle signaling and fibro-proliferation, the central events in immunopathogenesis of BOS following human lung transplantation.