Dog allergen-induced asthma in mice: a relevant model of T2low severe asthma with airway remodelling.

Objective and design: Airway remodelling (AR) is a disabling phenomenon in patients with severe asthma, yet suitable models are lacking. We previously developed a dog allergen-induced murine asthma model characterized by T2^low Th17-driven neutrophilic airway inflammation and AR. To assess its relevance to human AR associated with T2^low severe asthma, a condition characterised by poor response to inhaled steroids, we tested the steroid sensitivity of the key features of this model.

Material: Asthma was induced in C57BL/6 J mice by intranasal sensitization, followed by a three-week challenge with dog allergen.

Treatment: Daily intraperitoneal 1 mg kg^-1 dexamethasone was administrated during the last week of challenge.

Methods: We measured airway resistances in response to methacholine, cellular inflammation in bronchoalveolar lavage, lung cytokines, and quantified AR features, in response to dexamethasone.

Results: Dexamethasone-treated mice showed persistent airway hyperresponsiveness, neutrophilic inflammation, and Il17a overexpression, whereas Il22 expression was abrogated. Pathological AR features, including mucus hyperproduction, subepithelial fibrosis and smooth muscle hypertrophy were not eliminated by dexamethasone.

Conclusions: Our dog allergen-induced murine model of asthma mirrors the steroid-insensitive traits of human severe T2^low asthma with AR, making it a relevant tool for identifying novel therapeutic targets in this orphan asthma subset.