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.