Methods: Mice were sensitized daily for 10 days with HDM, rested for 2 weeks, followed by challenge with HDM three times weekly for 8 weeks. Both anti-mouse IL-4Ralpha antibody (Ab) and fully human anti-human IL-4Ralpha Ab (dupilumab) were tested in wild type mice and mice humanized for IL-4 and IL-4Ralpha, respectively. Mice were treated with 50 mg/kg of either Ab twice weekly, starting at week 7 of the experiment. A separate group received mouse IL-13Ralpha2-Fc protein using the same dose and regimen. At the end of the experiment, cells obtained by left lung lobe tissue digest were analyzed by flow cytometry. Lung collagen indicative of an airway remodeling was quantified using a Sircol Dye assay, and cardiac lung lobe was used for microarray analysis of gene signature. Levels of HDM-specific IgG1 and total IgE in serum were analyzed by ELISA.
Results: HDM sensitization and challenge resulted in increased levels of IgE and HDM-specific IgG1. IgE increase was blocked by IL-4Ralpha Ab but not by IL-13Ralpha2-Fc treatment; HDM-specific IgG1 levels were not affected by either treatment. Collagen content in lung of mice treated with IL-4Ralpha mAb was similar to that observed in mock sensitized and challenged mice. Dupilumab treatment also prevented the influx of eosinophils and inflammatory dendritic cells into lung. HDM-induced changes in gene expression were largely normalized upon dupilumab treatment, as compared to mock treated and sensitized mice.
Conclusions: Our results demonstrate that blockade of IL-4 signaling via Type I and Type II receptors by IL-4Ralpha antibody suppresses inflammatory and fibrotic changes in lungs of HDM-challenged mice as well as gene signature changes driven by HDM.