Glucopyranosyl Lipid a (GLA) a Toll-like Receptor 4 (TLR4) Agonist for Use As an Adjuvant in Combination with Peanut Allergen Immunotherapy

The efficacy, safety and durability of peanut allergen immunotherapy may be improved by the addition of an adjuvant with immunomodulatory and allergen dose-sparing properties. We investigated whether GLA, a TLR4 agonist, could attenuate allergen-induced immune responses in: 1) a non-human primate (NHP) model of natural allergy; 2) a mouse model of peanut allergy and; 3) PBMC from peanut allergic (PA) individuals. NHPs allergic to Ascaris suum were administered (intranasal) Ascaris with or without GLA (10μg) once weekly for four weeks. Ascaris induced nasal congestion was measured using acoustic rhinometery one day, two weeks and four weeks after treatment. C3H/HeOuJ mice sensitized with peanut extract (PE) were administered (sublingual) PE with and without GLA (2μg), once weekly for four weeks. Allergic responses to PE were assessed by anaphylaxis scoring after systemic allergen challenge. PBMC from peanut allergic individuals were labeled with CellTrace Dye, incubated with PE and GLA (30μg/ml-3ng/ml) and CD4+T cell proliferation was measured by FACS. In NHPs, intranasal administration of GLA and Ascaris, but not Ascaris alone, attenuated allergen-induced nasal congestion for up to one month after the last treatment (2-way ANOVA, p=0.0003). In mice, sublingual administration of GLA and PE but not PE alone attenuated anaphylaxis relative to mice treated with vehicle (Wilcox two-tailed; p = 0.0394). In human PA PBMC, GLA inhibited peanut allergen specific T cell proliferation in a dose dependent manner. GLA durably attenuates allergen induced immune responses and may be a promising new therapeutic approach to peanut allergen immunotherapy.