Combined blockade of IL‐25, IL‐33 and TSLP mediates amplified inhibition of airway inflammation and remodelling in a murine model of asthma

ABSTRACT Background and objective Isolated blockade of IL‐25, IL‐33 and thymic stromal lymphopoietin (TSLP) has been shown to reduce airways inflammation and hyperresponsiveness in murine asthma model. The hypothesis that combined blockade of all three cytokines can accomplish this more effectively has never been addressed. Methods We studied a murine asthma model employing sensitization and challenge with ovalbumin (OVA) or saline control. To discern the effects of IL‐33 blockade, we compared outcomes in strain identical, wild‐type and IL‐33 receptor ( St2 −/− ) gene‐deleted mice. We then examined, in the St2 −/− animals, the effects of additional, single or combined blockade of IL‐25 and TSLP with blocking antibodies. Outcomes included airways reactivity, inflammatory cellular infiltration, epithelial cell metaplasia, deposition of fibrosis‐related proteins, local Th2‐type cytokine expression and total and specific serum IgE concentrations measured by ELISA and quantitative immunohistochemistry. Results St2 −/− gene deletion significantly reduced airways reactivity, inflammatory cellular infiltration, lung tissue expression of Th2 cytokines and fibrosis related proteins and serum total IgE in response to OVA sensitization and challenge. Additional administration of anti‐IL‐25 and anti‐TSLP blocking antibodies to the St2 −/− mice further significantly reduced inflammation, Th2 cytokine expression, airways fibrosis and IgE production, while anti‐TSLP alone reduced eosinophil infiltration and local IL‐4 expression. The airways inflammatory cellular infiltrate and lung tissue expression of Th2 cytokine, but not fibrosis‐related proteins were also reduced in the presence of isotype identical, control antibodies. Conclusion Combined blockade of these three cytokines may better ameliorate airways pathological changes in this murine asthma model, with implications for human asthma.