The effects of clinically relevant reference agents in a mouse model of severe asthma

Le résumé fourni par la source

Severe asthma is not controlled by normal doses of inhaled or oral corticosteroids. Patients need high dose oral steroids and there is an unmet medical need for new therapies. Neutrophilic airway inflammation, mediated by Th17 cytokines, has been associated with corticosteroid insensitivity in this population. We investigated the effect of Dexamethasone (DEX), Roflumilast (ROF), Montelukast (MONT) and an IL-17 monoclonal antibody (mAb) in a severe asthma model. BALB/c mice were sensitised with 100µg house dust mite (HDM) in Complete Freunds Adjuvant. Fourteen days later, they were challenged with intranasal HDM. Animals were orally pre-treated with DEX (0.3, 1, 3mg/kg), ROF (10mg/kg) or MONT (10mg/kg), or with anti-IL-17 mAb (200µg/mouse i.p.), prior to challenge. HDM-challenge significantly increased lung inflammation, comprised of neutrophils (1.0±0.5x106 vs 0.1±0.04x106) and eosinophils (0.25±0.1x106 vs 0.003±0.003x106). ROF, MONT and low doses of DEX, failed to inhibit the inflammation. High dose DEX (3mg/kg) significantly inhibited both the neutrophilia (0.25±0.1x106 vs 1.0±0.5x106; p<0.0001, 75% inhibition) and eosinophilia (0.04±0.04x106 vs 0.25±0.1x106; p<0.0001, 85% inhibition). Anti-IL-17 significantly inhibited the HDM-induced airway neutrophilia (0.56 ± 0.1 x 106 vs. 0.98 ± 0.2 x 106; p<0.0001, 43% inhibition) but not the eosinophilia. The CFA/HDM asthma model is insensitive to normal doses of oral steroids, ROF and MONT but sensitive to high dose oral steroid. The neutrophilic inflammation is inhibited by anti-IL-17. This model mimics human severe asthma and these data suggest that novel therapeutics targeting IL-17 may prove beneficial in the treatment of phentoypes of this disease.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.