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.
Highlights
Allergic immune responses in the lung to common environmental antigens lead to the development of atopic asthma
To determine the effects the different Toll-like receptor (TLR)-agonists had on the development of OVA-specific Th2 responses the different ligands were applied together with OVA/alum on day 0, 14 and 21
When the mice were challenged with OVA, only the OVA/TLR-agonist treated group and not the PBS/TLRagonist group showed an increase in neutrophils. This clearly suggests that the observed neutrophilia was OVA specific and due to an altered immune response towards OVA since it was not observed in the OVA only treated mice
Summary
Allergic immune responses in the lung to common environmental antigens lead to the development of atopic asthma. Anti IgE therapy is used to treat patients with severe atopic asthma. None of these drugs show any disease-modifying effects in asthma or other atopic diseases [1,2] and need to be taken continuously. The only well-established disease-modifying treatment available for allergy sufferers is the allergen-specific immunotherapy (SIT) [3]. This involves the subcutaneous (SCIT) or sublingual (SLIT) application of increasing doses of different allergens (usually standardised extracts of the allergen) over a period of up to 3 - 5 years [4,5]. In particular if the patient is allergic to numerous allergens
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