Synergistic effect of antibodies to human leukocyte antigens and defensins in pathogenesis of bronchiolitis obliterans syndrome after human lung transplantation

BACKGROUND This study aims to determine the role of antibodies to donor-mismatched human leukocyte antigen (HLA) developed during the post-transplant period in inducing defensins and their synergistic role in the pathogenesis of chronic rejection bronchiolitis obliterans syndrome (BOS) after human lung transplantation (LTx) METHODS Bronchoalveolar lavage (BAL) and serum from 21 BOS+ LTx patients were assayed for beta-defensins human neutrophil peptides (HNP) 1-3 (enzyme-linked immunosorbent assay [ELISA]) and anti HLA antibodies (Luminex Luminex Corp Austin TX) Human airway epithelial cells (AEC) were treated with anti-HLA antibodies HNP-1/2, or both, and the levels of beta-defensin were measured by ELISA Using a mouse model of obliterative airway disease Induced by anti-major histocompatibility (MHC) class-I antibodies, we quantitatively and qualitatively determined neutrophil infiltration by myeloperoxidase (MPO) staining and activity by MPO assay, and defensin levels in the BAL RESULTS In human LTx patients, higher defensin levels correlated with presence of circulating anti-HLA antibodies (p < 0 05) AEC treated with anti-HLA antibodies or HNP-1/2 produced beta defensin with synergistic effects in combination (612 +/- 06 vs 520 +/- 23 pg/ml anti-HLA antibody, or 590 +/- 10 pg/ml for HNP treatment p < 0 05) Neutrophil numbers (6-fold) and activity (5 5-fold) were higher in the lungs of mice treated with anti MHC antibodies vs control A 2-fold increase in alpha-defensin and beta defensin levels was also present in BAL on Day 5 after anti MHC administrations CONCLUSIONS Anti-HLA antibodies developed during the post-transplant period and alpha-defensins stimulated beta defensin production by epithelial cells, leading to increased cellular infiltration and inflammation Chronic stimulation of epithelium by antibodies to MHC and resulting increased levels of defensins induce growth factor production and epithelial proliferation contributing to the development of chronic rejection after LTx J Heart Lung Transplant 2010 29 1330-6 (C) 2010 International Society for Heart and Lung Transplantation All rights reserved