Abstract Introduction Respiratory viral infections, particularly those caused by rhinoviruses (RV), during early childhood are associated with an increased risk of developing asthma later in life. Moreover, viral infections contribute to exacerbations in both asthma and chronic obstructive pulmonary disease (COPD). Dupilumab, an antibody targeting the IL-4α receptor, is an approved therapy for asthma that inhibits IL-4 and IL-13 signaling. The Th2 cytokines IL-4, IL-13, and IL-33 play key roles in immunological pathways involved in disease development and exacerbations. The aim of this study was to investigate whether dupilumab can reduce virus-induced asthma exacerbations in a human ex vivo setting. Methods Human precision-cut lung slices (PCLS) were used as a complex ex vivo model to study virus-induced exacerbations in an asthma-like phenotype. This phenotype was induced by incubation with IL-4, IL-13, IL-33, or combinations of these cytokines. Airway hyperresponsiveness was evaluated by methacholine (Mch)-induced bronchoconstriction. The therapeutic effect of dupilumab was assessed in comparison to medium controls. Exacerbation was modeled by infection with RV16 and analyzed using the same parameters. Results In medium controls, Mch-induced bronchoconstriction showed an EC50 value of 25.1 µM. Treatment with IL-4, IL-13, and IL-33 induced airway hyperresponsiveness, reducing the EC50 to 7.9 µM. Hyperresponsiveness tended to be strongest when PCLS were treated with all three cytokines and subsequently infected with RV16. Dupilumab attenuated the cytokine-induced hyperresponsiveness, shifting the EC50 to higher Mch concentrations (15 µM). In the virus-infected setting, a similar trend towards reduced hyperresponsiveness was observed following dupilumab treatment. Conclusion Stimulation with Th2 cytokines induced an asthma-like phenotype in human PCLS, characterized by enhanced methacholine sensitivity. RV16 infection further seemed to intensify this response, mimicking viral exacerbation. Dupilumab reduced both cytokine- and virus-induced hyperresponsiveness, confirming its inhibitory role in IL-4/IL-13-mediated pathways. These findings demonstrate the suitability of our human ex vivo setting to test immunotherapies and hints at the potential of dupilumab to attenuate viral asthma exacerbations. This abstract is funded by: German Center for Lung Research (DZL)
Röpken et al. (Fri,) studied this question.