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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 nonoral routes, such as the skin, may be more effective for the development of maintained tolerance to food allergens. OBJECTIVE:We sought to determine the efficacy and mechanism of tolerance induced by epicutaneous immunotherapy (EPIT) 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 oral immunotherapy using OVA. Mice were orally challenged with OVA to induce anaphylaxis. Antigen-specific regulatory T (Treg)-cell induction was assessed by flow cytometry using a transgenic T-cell transfer model. RESULTS:By using an adjuvant-free model of food allergy generated by epicutaneous sensitization and reactions triggered by oral allergen challenge, we found that EPIT induced sustained protection against anaphylaxis. We show that the gastrointestinal tract is deficient in de novo generation of Treg cells in allergic mice. This defect was tissue-specific, and epicutaneous application of antigen generated a population of gastrointestinal-homing LAP+Foxp3- Treg cells. The mechanism of protection was found to be a novel pathway of direct TGF-?-dependent Treg-cell suppression of mast cell activation, in the absence of modulation of T- or B-cell responses. CONCLUSIONS:Our data highlight the immune communication between skin and gastrointestinal tract, and identifies novel mechanisms by which epicutaneous tolerance can suppress food-induced anaphylaxis.

SUBMITTER: Tordesillas L

PROVIDER: S-EPMC5149454 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Epicutaneous immunotherapy induces gastrointestinal LAP<sup>+</sup> regulatory T cells and prevents food-induced anaphylaxis.

Tordesillas Leticia L Mondoulet Lucie L Blazquez Ana Belen AB Benhamou Pierre-Henri PH Sampson Hugh A HA Berin M Cecilia MC

The Journal of allergy and clinical immunology 20160611 1

<h4>Background</h4>The attempt to induce oral tolerance as a treatment for food allergy has been hampered by a lack of sustained clinical protection. Immunotherapy by nonoral routes, such as the skin, may be more effective for the development of maintained tolerance to food allergens.<h4>Objective</h4>We sought to determine the efficacy and mechanism of tolerance induced by epicutaneous immunotherapy (EPIT) in a model of food-induced anaphylaxis.<h4>Methods</h4>C3H/HeJ mice were sensitized to ov ...[more]

PMID: 27417020

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Project description:BackgroundConsortium for Food Allergy Research investigators previously reported 52-week outcomes from a randomized controlled trial of peanut epicutaneous immunotherapy, observing modest and statistically significant induction of desensitization, highest in children ages 4 to 11 years.ObjectiveWe sought to evaluate changes in efficacy, safety, and mechanistic parameters following extended open-label peanut epicutaneous immunotherapy.MethodsPeanut-allergic participants (4-25 years) received 52 weeks of placebo (PLB), Viaskin Peanut 100 μg (VP100) or 250 μg (VP250), and then crossed over to VP250 for PLB (PLB-VP250) and VP100 (VP100-VP250) participants and continued treatment for VP250 participants (total = 130 weeks of active epicutaneous immunotherapy). Efficacy was assessed by double-blind, placebo-controlled food challenge (5044 mg peanut protein), and adherence, safety, and mechanistic parameters were evaluated.ResultsAt week 130, desensitization success was achieved in 1 of 20 (5%) PLB-VP250, 5 of 24 (20.8%) VP100-VP250, and 9 of 25 (36%) VP250 participants, with median successfully consumed dose change from baseline of 11.5 mg, 141.5 mg, and 400 mg, respectively. Median age (years) for week 130 desensitization success was 6.2 years (interquartile range, 5.2-9.1) versus 9.4 years (interquartile range, 7.6-12.8) for failures (P < .001). Adherence was 96%. Adverse reactions were predominantly local patch-site reactions. Significant increases in peanut- and Ara h2-specific IgG4 observed at week 52 persisted to week 130. By a post hoc analysis, there were no statistically significant increases from week 52 to week 130 in either desensitization success or successfully consumed dose.ConclusionsExtended treatment with VP250 was well tolerated, and desensitization observed at week 52 persisted between weeks 52 and 130. Treatment success was observed predominantly in younger participants, with younger age at initiation of active therapy an important predictor of success.

Dataset Information

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

Publications

Epicutaneous immunotherapy induces gastrointestinal LAP<sup>+</sup> regulatory T cells and prevents food-induced anaphylaxis.

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