Ex-vivo three-dimensional model of T2-asthma: effects of the monoclonal antibody against interleukin-4 receptor α

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Introduction: Severe asthma treatment is hindered by the lack of reliable cellular or animal models that allow in vitro pharmacological testing and evaluation of tissue responses. Aims: To develop a novel ex vivo three-dimensional (3D) co-culture model of type 2 (T2) asthma to mimic pathological airway mucosa and assess the therapeutic effects of dupilumab, a human monoclonal antibody targeting the interleukin-4 receptor α (IL-4Rα). Methods: An ex vivo 3D co-culture model of T2-asthma was developed using human airway mucosa cultured at the air-liquid interface. The model was enriched with mature dendritic cells and activated T helper 2 lymphocytes. The pathological phenotype was characterized by measuring transepithelial electrical resistance and quantifying inflammatory mediators via enzyme immunoassays. The effects of dupilumab were evaluated through molecular analyses of cytokines and chemokines using multiplex immunoassays, along with immunohistochemical assessments. Results: The inclusion of immune cells resulted in a significant increase in IL-4 (p<0.0001) and IL-13 (p<0.005), confirming the establishment of a Th2 inflammatory state. Dupilumab led to a marked reduction in these cytokines (p<0.0001). In addition, significant increases in the level of IL-1α and alpha-SMA, as markers of fibrosis, were detected in the model treated with IL-4 and 13 (p<0.0001); in contrast, a reduction of their expression was observed with dupilumab (p<0.0001). Conclusions: The ex vivo 3D model successfully replicates key features of T2 asthma pathophysiology and demonstrates dupilumab’s efficacy in acting on features of inflammation and tissue remodeling.

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