Activation of human airway epithelial cells by non-HLA antibodies developed after lung transplantation: A potential etiological factor for bronchiolitis obliterans syndrome

Background. The main cause of morbidity and mortality after lung transplant ation (LT) is bronchiolitis obliterans syndrome (BOS), Anti-HLA antibodies development after LT has been shown to play an important role in BOS pathog enesis, However, the nature of non-HLA antibodies developed after LT and th eir role in BOS pathogenesis have not been determined. Methods. Sera from 16 BOS+ patients and 11 BOS-patients were collected at 1 2, 24, 36, and 48 months after LT. Anti-HLA class I and class II antibodies were absorbed with pooled human platelets and pooled human lymphoblastoid cell lines, respectively. Then, the presence of non-HLA antibodies against several cell lines from different origin was determined by flow cytometric analysis. Antibody-positive samples were tested for induction of proliferat ion and growth factor production in two selected airway epithelial cell (AE C) lines. Results, Five of 16 BOS+ patients (31.2%) and 0 of 11 BOS- patients (0%) de veloped anti-AEC antibodies after LT (P=0.05). No reactivity against endoth elial cells, lymphocytes, monocytes, or granulocytes was detected. Further analysis of two selected sera demonstrated the development of reactivity ag ainst a 60-kDa antigen expressed by 60% of AEC lines and only 12% of cell l ines from other tissues. Antibody binding to this antigen induced intracell ular Ca++ influx, tyrosine phosphorylation, proliferation, and up-regulatio n of transforming growth factor-beta and heparin-binding epidermal growth f actor mRNA transcription in AECs, Conclusions, These results indicate that anti-AEC antibodies may play a rol e in the immunopathogenesis of BOS in the absence of anti-HLA antibodies.