Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy

Abstract

Background Allergen-specific immunotherapy is the only mode of therapy that has been demonstrated to offer a cure in patients with IgE-mediated respiratory allergies. Objective We sought to demonstrate the safety and efficacy of timothy grass (TG) and dust mite (DM) dual sublingual immunotherapy (SLIT) and to begin to investigate the immune mechanisms involved in successful immunotherapy with multiple allergens. Methods The safety and efficacy of dual SLIT with TG and DM in children and adults with demonstrated allergies to TG and DM were investigated in a single-center, randomized, double-blind, controlled phase I study. Thirty subjects received either TG and DM dual SLIT (n = 20) or placebo (n = 10). Immune parameters were evaluated for differentiation of desensitized subjects from control subjects. Results Subjects treated with dual SLIT had decreased rhinoconjunctivitis scores (P < .001) and medication use scores (P < .001) and reduced responses to TG and DM allergen based on results of skin prick tests or nasal disk challenges (P < .01 and P < .001, respectively) compared with placebo-treated control subjects. An increase in TG- and DM-specific IgG4 levels, reduced allergen-specific IgE levels, and subsequent basophil activation were observed in the active treatment group. Dual SLIT promoted allergen-specific suppressive CD4+CD25highCD127lowCD45RO+ forkhead box protein 3 (Foxp3)+ memory regulatory T cells with reduced DNA methylation of CpG sites within the Foxp3 locus. Conclusion The results of this pilot study suggest that dual SLIT could be an effective means to treat subjects with sensitivities to a variety of allergens and that long-term tolerance might be induced by epigenetic modifications of Foxp3 in memory regulatory T cells.

Sublingual Immunotherapy for Asthma: Affects T-Cells but Does not Impact Basophil Activation

“…35 On the other hand, Swamy et al observed a decrease of basophil activation after stimulation with specific allergens in a group of patients receiving dual SLIT (house dust mite and timothy grass) for 2 years. 36 Lack of changes in basophil sensitivity to specific allergens after 1 year of SLIT is thought to be associated with high affinity IgE receptor (FceRI) expression on the surface of basophils. It is postulated that B-cells primarily react to SLIT by increasing asIgE production.…”

EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis

“…142 A small study in children demonstrated efficacy using a mixture of grass pollen and HDM SLIT. 143 SLIT drops that employed a monomeric Phleum pratense grass pollen extract was more effective when given alone compared to when given in an equivalent dose as part of a combination with a 9-pollen, multi-allergen, sublingual extract. 100 There are a number of potential drawbacks of mixing allergens including a dilutional effect, potential allergen degradation due to enzymatic activity of some allergens and the difficulties of adequately demonstrating efficacy of a high number of allergen combinations and/or different products.…”

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

“…4 T H 2 response downregulation, immunologic switch to T H 1 responses, or both suggest induction of tolerogenic pathways, 7-9 suppression of allergic inflammation, and generation of regulatory T (Treg) cells. 6,8,[10][11][12] Treg cells have multiple effects in controlling allergen-specific immune and IgE-mediated allergic inflammation. 13 These cells can induce dendritic cells that support further Treg cell generation and suppress effector T-cell differentiation 14 ; they also suppress T H 1 and T H 2 cells and induce IgG 4 , IgA, or both.…”