Adjuvant effects of different TLR agonists on the induction of allergen-specific Th2 responses

Abstract

Currently different Toll-like receptor (TLR) agonists are tested in humans for their ability to enhance the efficacy of specific immunotherapy (SIT). Recent clinical data suggest that this may be achieved by increasing allergen-specific Th1 responses. However, it is not clear which TLR agonist is best suited to be used in combination with SIT. We tested the ability of five TLR agonists, LTA, poly(I:C), LPS, R848, and CpG-ODN, activating TLR2, 3, 4, 7, and 9, to induce allergen-specific Th1 and suppress allergen-specific Th2 responses in a preclinical setting. Mice were immunized by intraperitoneal injection of ovalbumin (OVA)/Al(OH) 3 together with different doses (0.0025, 0.025, 0.25, and 2.5 mg/kg) of agonists followed by two OVA aerosol challenges. The results of these experiments showed, that the suppression of allergen-specific Th2 responses and the induction of Th1 responses dependedon the dose and the agonists used. All TLR agonists increased allergen-specific IgG2a, and with the exception of poly(I:C), reduced allergen-specific IgE levels in the serum. Allergic cutaneous anaphylaxis was also suppressed in mice when LPS or CpG was given together with OVA/alum. The strongest Th1 responses were induced by CpG and poly(I:C), characterized by the presence of IFN-g in the BAL and the highest OVA-specific IgG2a levels in the serum. This study suggests that the TLR9 agonist CpG-ODN and TLR4 agonist LPS have the strongest suppressive effects on the development of aller-gen-specific Th2 responses in mice and CpG-ODN induces the strongest allergen-specific Th1 responses. Therefore these two TLR agonists may be good candidates to combine with allergen in novel SIT formulations in humans.