Anti-IL-5 treatment (mepolizumab) reduces eosinophil-associated TGF-β: Relationship to deposition of extracellular matrix proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics

Abstract

Rationale Eosinophil-derived TGF-β has been implicated in remodeling events associated with allergic inflammation. We hypothesized that specific reduction of bronchial mucosal eosinophils with anti-IL-5 treatment would reduce markers of airway remodeling in asthma. Methods Bronchoscopy was performed before, and after, three infusions of a humanized, monoclonal antibody directed against IL-5 (mepolizumab) in 24 atopic asthmatics in a randomized, double blind, placebo-controlled study. Expression of TGF-β1 mRNA by airway eosinophils was assessed by in situ hybridization and TGF-β1 protein was measured in BAL fluid by ELISA. The thickness and density of tenascin, lumican and procollagen III immunoreactivity in the reticular basement membrane (RBM) of bronchial biopsies were quantified from images collected using confocal microscopy and were related to eosinophil numbers. Results Anti-IL-5 treatment was associated with a significant reduction in the numbers (p=0.03), and percentage (p=0.04), of airway eosinophils expressing mRNA for TGF-β1, and the concentration of TGF-β1 in bronchoalveolar lavage fluid (p=0.04). At baseline, airway eosinophil infiltration and extracellular matrix protein deposition was increased in the RBM of asthmatics compared to nonasthmatic controls. Treatment of asthmatics with anti-IL-5 antibody, which specifically decreased airway eosinophil numbers (p<0.01), significantly reduced the expression of tenascin (p=0.004), lumican (p=0.008) and procollagen III (p=0.007) in the bronchial mucosal RBM when compared to placebo. Conclusions Eosinophil-associated TGF-β may contribute to tissue remodeling processes in asthma by regulating the deposition of extracellular matrix proteins.