Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity

Background: Grass pollen immunotherapy is an effective treatment for seasonal allergic rhinitis that provides the opportunity to study the induction and maintenance of allergen-specific immune tolerance. Objectives: We investigated the relationship between clinical responsiveness, regulatory cytokine production, and antibody responses to allergen during 1 year of immunotherapy. Methods: Eighteen subjects with severe seasonal allergic rhinitis were randomized double-blind to receive active or placebo injections of an alum-adsorbed grass pollen vaccine (Alutard SQ). Subjects underwent repeated testing of early- and late-phase skin responses to intradermal allergen, and cellular responses to grass pollen allergen were tested. Sera were tested for allergen-specific IgG4, IgA, and inhibitory activity in biologic assays of IgE responses. Results: Grass pollen immunotherapy was effective in reducing overall symptom scores (P <.05) and conjunctival reactivity (P <.05). In the active group significant IL-10 production occurred early at low allergen doses and at a similar time as inhibition of late skin responses at 2 to 4 weeks. Serum allergen-specific IgG4, IgA, and inhibitory antibody activity for basophil histamine release and IgE-facilitated allergen binding to B cells occurred later, at 6 to 12 weeks, at higher allergen doses and preceded inhibition of early skin responses. Conclusion: IL-10 responses occur early but at immunotherapy doses that are not clinically effective. Later induction of inhibitory antibodies, including IgG4 and IgA, might be required for efficacy through modulation of IgE-mediated events.