Grass tablet sublingual immunotherapy downregulates the TH2 cytokine response followed by regulatory T-cell generation

Background: Sublingual administration of Phleum pratense allergen immunotherapy (SLIT) tablets is a clinically efficient treatment for grass pollen-induced rhinoconjunctivitis. This immunotherapy downregulates T(H)2 immune responses, induces tolerogenic pathways, and increases regulatory T cells. However, associated immune response markers of allergen desensitization remain undefined. Objective: We sought to characterize the kinetics of individual changes in the immunologic response to grass tablet SLIT. Methods: We evaluated the systemic effects of SLIT in a longitudinal analysis of humoral and cellular immune parameters in peripheral blood samples. Results: Grass tablet SLIT administration induced a 2-phase systemic humoral and cellular response. The T(H)2 response was initially exacerbated and detected as increased allergen-specific IgE (sIgE) and IgG(4) (sIgG(4)) levels and an increase in IL-4-producing cells, followed by downregulation of the T(H)2 response with a shift toward a T(H)1 cytokine profile. T cells with a regulatory phenotype were also elicited. Statistical correlations between immunologic measurements for each patient throughout therapy indicated that T(H)2 response downregulation and reduction of the immediate SLIT-induced IgE response were associated with increased allergen-specific IgG(4) synthesis early in therapy. T(H)2 response downregulation by month 4 correlated with increased frequency of CD4(+) T cells with a regulatory phenotype by 12 months. Conclusion: Changes in sIgE levels after therapy were linked to a specific IgG(4) response, and production of blocking antibodies correlated with T(H)2 response downregulation. Reduced IL-4(+) cell frequency was linked to an increase in the frequency of CD4(+) T cells with a regulatory phenotype. Changes in sIgE levels and reduced IL-4 and blocking antibody levels could thus be used as indicators of a patient's immune response to therapy.