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The following is a summary of “Dual inhibition of airway inflammation and fibrosis by common β cytokine receptor blockade,” published in the March 2024 issue of Allergy & Immunology by Wang, et al.
Patients with severe asthma often exhibit eosinophilic type 2 (T2), neutrophilic, or mixed inflammation, which contributes to airway remodeling and exacerbations, presenting a significant treatment challenge. The common β (βc) receptor is involved in signaling for three cytokines—GM-CSF, IL-5, and IL-3—which collectively drive T2 and neutrophilic inflammation. For a study, researchers sought to elucidate the pathogenesis of βc receptor-mediated inflammation and remodeling in severe asthma and to explore the potential of βc antagonism as a therapeutic approach for mixed granulocytic airway disease.
They analyzed βc gene expression in bronchial biopsy specimens from patients with mild-to-moderate and severe asthma. They established asthma-like pathology and airway remodeling in human βc transgenic mice using house dust mite extract and Aspergillus fumigatus extract (ASP) models. Lung tissue gene expression was assessed via RNA sequencing. They also utilized the monoclonal antibody CSL311, targeting the shared cytokine binding site of βc, to block βc signaling.
In patients with severe asthma, βc gene expression was elevated. Treatment with CSL311 effectively reduced lung neutrophils, eosinophils, and interstitial macrophages, improving airway pathology and lung function in an acute steroid-resistant house dust mite extract model. Chronic intranasal exposure to ASP induced airway inflammation, fibrosis, and impaired lung function, all of which were mitigated by CSL311 treatment. Additionally, CSL311 normalized the ASP-induced fibrosis-associated extracellular matrix gene expression network and markedly reduced signatures of cellular inflammation in the lung.
βc cytokines play a role in driving steroid-resistant mixed myeloid cell airway inflammation and fibrosis. The anti-βc antibody CSL311 demonstrated efficacy in inhibiting mixed T2/neutrophilic inflammation and severe asthma-like pathology while also reversing fibrosis gene signatures induced by exposure to common environmental allergens
Reference: jacionline.org/article/S0091-6749(23)01394-5/fulltext