Intranasal administration of a novel synthetic TLR4 agonist suppresses allergen-specific Th2 responses in mice

Abstract

Abstract Allergen-agnostic immunotherapies to treat seasonal allergic rhinitis are not currently available. Antihistamines are the most common form of seasonal allergic rhinitis treatment – minimizing symptoms instead of addressing underlying immune dysfunction. Allergen specific immunotherapies (AIT) are also available for seasonal allergic rhinitis but require a known allergen and long-term treatment regiments that can be costly and take several years to complete. Here we report a novel synthetic TLR4 agonist that prevented Th2 allergic responses in an OVA-sensitized mouse model. This novel synthetic TLR4 agonist has improved stability compared to other TLR4 agonists used as vaccine adjuvants or immunotherapeutics. After sensitizing Balb/c mice to OVA using IP injections of OVA + alum, intranasal treatment with the novel TLR4 agonist at one, three, or seven days prior to intranasal OVA challenge reduced or ameliorated OVA-specific Th2 allergic responses. Specifically, intranasal TLR4 agonist treatment reduced OVA-induced airway hypersensitivity, eosinophil influx, and Th2 T cell cytokine secretion – hallmarks of Th2 allergic immune responses. Additionally, we have identified a particular formulation of our novel synthetic TLR4 agonist which has shown greater efficacy, stability, and reduced toxicity profile compared to initial formulations. These data suggest this novel synthetic TLR4 agonist can potentially treat the underlying immune dysfunction associated with allergic responses for a durable cure of seasonal allergic rhinitis. Supported by NIH contract HHSN272201800036C