Clinical outcome and IL-17, IL-23, IL-27 and FOXP3 expression in peripheral blood mononuclear cells of pollen-allergic children during sublingual immunotherapy

Abstract

Induction of allergen-specific, tolerogenic, IL-10 and/or TGF-β-producing T-regulatory (Treg) cells that express transcription factor FOXP3 is considered as one of the key mechanisms of allergen-specific immunotherapy. However, little is known of the induction of FOXP3 expression in children during sublingual immunotherapy (SLIT). Recently, also, a novel subgroup of T-helper (Th) cells, the Th17 cells, secreting predominantly IL-17 (IL-17A), was identified. The expressions of IL-17 or the Th17-regulating cytokines IL-23 and IL-27 during SLIT are currently completely unexplored. This randomized, placebo-controlled dose-response study was performed to analyze the effects of SLIT on FOXP3, IL-17, IL-23, and IL-27 expressions in peripheral blood mononuclear cells (PBMC) of children with allergic rhinitis and their associations with clinical outcome. Thirty children were included: ten received SLIT with a glycerinated mixture of birch, hazel and alder with a cumulative weekly dose of 24,000 SQ-U, 10 with dose 200,000 SQ-U/wk, and ten received placebo. Cytokine and FOXP3 mRNA expressions in allergen-, purified protein derivative-stimulated and non-stimulated PBMC were determined at 0, 1 and 2 yr of SLIT by real-time RT-PCR (TaqMan). Symptoms and medications were recorded using diary cards. Allergen-induced IL-17 mRNA expression was significantly increased in the study subjects with elevated combined Symptom Medication Score (SMS) after 2 yr. There was also a significant positive correlation between the allergen-induced IL-17 and SMS in whole study group (r = 0.38, p = 0.039) and especially the 200,000 SQ-U dose-treated group (r = 0.74, p = 0.027) at 2 yr. Allergen-induced FOXP3 mRNA expression was significantly increased in the 200,000 SQ-U dose-treated children after two study years as compared with baseline (p = 0.016) and placebo-treated children (p = 0.028). The changes in FOXP3 mRNA expression positively correlated with IL-10 and TGF-β mRNAs during SLIT in whole study population. Increased allergen-induced IL-17 responses during SLIT are associated with elevated SMS. Increased tolerogenic, allergen-specific Treg responses are also observed in children during SLIT.