Epicutaneous immunotherapy induces gastrointestinal LAP + regulatory T cells and prevents food-induced anaphylaxis

Abstract

Background The attempt to induce oral tolerance as a treatment for food allergy has been hampered by a lack of sustained clinical protection. Immunotherapy by non-oral routes, such as the skin, may be more effective for the development of maintained tolerance to food allergens. Objective To determine the efficacy and mechanism of tolerance induced by epicutaneous immunotherapy in a model of food-induced anaphylaxis. Methods C3H/HeJ mice were sensitized to ovalbumin (OVA) orally or through the skin and treated with EPIT using OVA-Viaskin® patches or OIT using OVA. Mice were orally challenged with OVA to induce anaphylaxis. Antigen-specific Treg induction was assessed by flow cytometry using a transgenic T cell transfer model. Results Using an adjuvant-free model of food allergy generated by epicutaneous sensitization and reactions triggered by oral allergen challenge, we found that epicutaneous immunotherapy induced sustained protection against anaphylaxis. We show that the gastrointestinal tract is deficient in de novo generation of Tregs in allergic mice. This defect was tissue-specific, and epicutaneous application of antigen generated a population of gastrointestinal-homing LAP+Foxp3− Tregs. The mechanism of protection was found to be a novel pathway of direct TGF-β-dependent Treg suppression of mast cell activation, in the absence of modulation of T or B cell responses. Conclusions Our data highlights the immune communication between skin and gastrointestinal tract, and identifies novel mechanisms by which epicutaneous tolerance can suppress food-induced anaphylaxis.

Epicutaneous Tolerance Induction to a Bystander Antigen Abrogates Colitis and Ileitis in Mice

“…The colonic production of TNF-α, IFN-γ and IL-17 was significantly reduced compared to untreated mice (Fig 5D). Consistent with previous data using Viaskin-OVA for food allergy, 22 ET was associated with a significant increase in mRNA expression of Foxp3, TGF-β1, and TGFβ2 in the colonic tissue, but no change in IL-10 (Fig 5E). By flow cytometry, we also identified a significant increase in CD4 + CD25 + Foxp3 + as well as CD4 + CD25 + LAP + Tregs within the colonic lamina propria of ET-treated mice (Fig 4F).…”

“…LAP + Tregs have also been shown to contribute to suppression of food allergy in ET-treated mice. 22 Additional studies are needed to determine the duration of the protective effect, as well as the mechanism of bystander suppression by Tregs of ET treated mice.…”

Deciphering the black box of food allergy mechanisms

“…Interestingly, these Tregs did not suppress IgE but directly suppressed mast cell activation. 30 Epigenetic modifications with increased methylation of the GATA-3 promoter region has also been observed. 31 …”

Allergen-Specific Immunotherapy for Food Allergy: Latest Advances in Vaccines

“…Great efforts are being made to develop novel strategies in animal models exploring combination of mucosal routes [54], bioadhesive carrier systems [34,55], novel immunomodulatory and/or tolerogenic adjuvants [9,10,55,56], immunological drugs to expand Tregs [12] and nanoparticles [56] to prevent or revert food allergy. These finding will undoubtedly provide new parameters to analyze the induction of novel regulatory cell subsets, and cellular and molecular biomarkers for regulatory cell activation, with a direct impact in the design of safer and more effective treatments.…”