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

Abstract

Background: Sublingual administration of Phleum pratense allergen immunotherapy (SLIT) tablets is a clinically efficient treatment for grass pollen-induced rhinoconjunctivitis. This immunotherapy downregulates TH2 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 TH2 response was initially exacerbated and detected as increased allergen-specific IgE (sIgE) and IgG4 (sIgG4) levels and an increase in IL-4-producing cells, followed by downregulation of the TH2 response with a shift toward a TH1 cytokine profile. T cells with a regulatory phenotype were also elicited. Statistical correlations between immunologic measurements for each patient throughout therapy indicated that TH2 response downregulation and reduction of the immediate SLIT-induced IgE response were associated with increased allergen-specific IgG4 synthesis early in therapy. TH2 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 IgG4 response, and production of blocking antibodies correlated with TH2 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.

Keywords: Allergen-specific IgE; Allergen-specific IgG; CTLA-4; Cytotoxic T lymphocyte–associated antigen 4; GPS; Grass pollen season; IL-4; IgE; IgE-FAB; IgE-facilitated antigen binding; IgG(4); Induced regulatory T; Regulatory T; SLIT; Sublingual immunotherapy; Treg; allergic rhinitis; iTreg; regulatory T cells; sIgE; sIgG.