BackgroundSevere asthmatics can present with eosinophilic type 2 (T2), neutrophilic or mixed inflammation that drives airway remodeling and exacerbations and represents a major treatment challenge. The common beta (βc) receptor signals for three cytokines GM-CSF, IL-5 and IL-3, that collectively mediate T2 and neutrophilic inflammation. ObjectivesTo determine the pathogenesis of βc receptor mediated inflammation and remodeling in severe asthma, and to investigate βc antagonism as a therapeutic strategy for mixed granulocytic airway disease. Methodsβc gene expression was analysed in bronchial biopsies from mild/moderate and severe asthmatics. House dust mite extract (HDM) and Aspergillus fumigatus extract (ASP) models were used to establish asthma-like pathology and airway remodeling in human βc transgenic mice. Lung tissue gene expression was analysed by RNA-sequencing. The monoclonal antibody CSL311 targeting the shared cytokine binding site of βc was used to block βc signaling. Resultsβc gene expression was increased in severe asthmatics. CSL311 potently reduced lung neutrophils, eosinophils and interstitial macrophages, and improved airway pathology and lung function in the acute steroid resistant HDM model. Chronic intranasal ASP exposure induced airway inflammation and fibrosis and impaired lung function that was inhibited by CSL311. CSL311 normalised the ASP-induced fibrosis-associated extracellular matrix gene expression network and strongly reduced signatures of cellular inflammation in the lung. Conclusionsβc cytokines drive steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-βc antibody CSL311 effectively inhibits mixed T2/neutrophilic inflammation and severe asthma-like pathology and reverses fibrosis gene signatures induced by exposure to commonly encountered environmental allergens.

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