Biomarker for eosinophil and T-cell recruitment induced by interleukin-13 as a therapeutic target for allergic asthma tested in human precision-cut lung slices

Background: Novel therapeutic strategies are required for patients with severe asthma. On molecular level interleukin IL-4 and (IL)-13 are considered as key cytokines of airway inflammation and hyperresponsiveness in the pathogenesis of asthma. IL-13 and IL-4 as key cytokines in asthma share the same dimeric receptor complex of IL-4Ra and IL-13Ra1. Targeting the soluble IL-13 or IL-4Ra subunit can be novel anti-inflammatory therapeutics. Precision-cut lung slices (PCLS) of human lung tissue display human microanatomy and functionality of the respiratory tract and were used as a ex vivo tissue model for evaluation of new biopharmaceuticals. Method: PCLS were prepared from human lungs. Cytokine release and airway hyperresponsiveness were measured after incubation of PCLS with 1-100 nM IL-13. Antagonists were assessed in presence of IL-13 for 24 h. Eotaxin-3 and TARC were measured by ELISA. PCLS containing airways were pre-incubated with IL-13. Bronchoconstriction was induced by addition of methacholine and visualized by videomicroscopy. Results: Eotaxin-3 and TARC as biomarkers for eosinophil and T-cell recruitment were significantly elevated by human IL-13 in dose-dependent manner. Both cytokines were significantly reduced by addition of specific inhibitors acting either on the IL-13 ligand itself or the IL-4Ra chain of the IL-13/IL-4 receptor complex. Human IL-13 induced hyperreagibility resulted in decreased EC50 values of 47 nM compared to 180 nM of control and a 15% stronger bronchoconstriction in the presence of IL-13. Conclusion: This study shows that PCLS can be used to mimic allergic asthma by IL-13 induced inflammation and airway hyperreagibility in human lungs. The effect of different inhibitors developed as asthma therapeutics could be compared on reduction of eotaxin-3 and TARC in human lung tissue