Modulation of Lung Inflammation and Airway Hypereactivity By the Toll-like Receptor 4 (TLR4) Agonist Glucopyranosyl Lipid a (GLA) in a Mouse Model of Airway Allergy

Rationale:  The pathogenic mechanisms underlying a range of allergies involve aberrant Th2 immune responses to normally innocuous antigens. The synthetic TLR4 agonist Glucopyranosyl Lipid A (GLA) is an immunomodulator that has the potential to reprogram pathogenic Th2 responses in an antigen-specific manner. The aim of this study was to assess the therapeutic efficacy of intranasal instillation of GLA alone and in combination with ovalbumin (OVA) on allergic lung inflammation and airway hyperreactivity in OVA-sensitized and -challenged BALB/c mice.

Methods:  Male BALB/c mice were systemically immunized and challenged with OVA to induce lung inflammation and airway hyperreactivity. GLA-AF (2 μg aqueous formulation) was instilled by intranasal administration on day 14 either alone or in combination with OVA.

Results:  Sensitization and repeated challenge with OVA resulted in an increase in airway resistance and dynamic lung compliance that were significantly inhibited by GLA-AF instillation. This inhibitory effect was more pronounced when GLA-AF was administered with ovalbumin. OVA-induced airway hyperreactivity was also associated with a significant increase in the release of IL-4 in bronchoalveolar lavage fluid. This increase was significantly inhibited when GLA-AF was co-administered with ovalbumin. OVA-sensitization and challenge were also associated with increased serum antigen-specific IgE levels compared to saline-challenged animals. GLA-AF treatment reduced OVA-specific IgE serum levels, and this effect was enhanced when GLA-AF was co-administered with ovalbumin.

Conclusions:  Therapeutic administration of GLA-AF was efficacious in a mouse OVA­induced airway hyperreactivity model, and this was further potentiated when GLA was co-administered with the eliciting antigen.