Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation

Background: The immunologic mechanisms underlying sublingual immunotherapy (SLIT) are still unclear, particularly the role of regulatory T cells. Objective: We sought to characterize allergen-specific T-cell responses during successful birch pollen SLIT. Methods: Proliferation of PBMCs and PBMCs depleted of CD25(+) cells obtained from 9 patients before, after 4 weeks. and after 52 weeks of SLIT was assessed in response to the major birch pollen allergen Bet v 1, the homologous apple allergen Mal d 1, or tetanus toxoid. Allergen-induced cytokine responses and FoxP3 expression of T cells were analyzed by using real-time PCR. The role of IL-10 for regulatory activity of T cells was investigated. Results: After 4 weeks, higher frequencies of circulating CD4(+)CD25(+) T cells were detected together with increased FoxP3 and IL-10 and reduced IL-4 and IFN-gamma mRNA expression levels compared with those before SLIT. Proliferation to all 3 antigens was markedly reduced but increased significantly after depletion of CD25(+) cells or addition of anti-IL-10 antibodies. After 52 weeks, proliferation in response to Mal d I or tetanus toxoid returned to pre-SLIT levels, whereas Bet v I-induced proliferation remained significantly suppressed and was enhanced by neither depletion of CD25(+) cells nor addition of anti-IL-10 antibodies. In parallel, increased IFN-gamma and reduced IL-4, IL-10, and FoxP3 mRNA expression was detected. Neither TGF-beta levels nor cell-cell contact-mediated suppression of CD4(+)CD25(+) cells changed during the course of SLIT. Conclusion: SLIT induces regulatory T-cell suppression through IL-10 during the early phase and specific nonreactivity and immune deviation of allergen-specific T cells during the later phase of therapy. Clinical implications: SLIT induces immune mechanisms comparable with subcutaneous specific immunotherapy.