title: Epicutaneous immunotherapy induces gastrointestinal LAP+regulatory T cells and prevents food-induced anaphylaxis.
abstract: 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.
  
  
  
  We sought to determine the efficacy and mechanism of tolerance induced by epicutaneous immunotherapy (EPIT) in a model of food-induced anaphylaxis.
  
  
  
  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.
  
  
  
  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-β-dependent Treg-cell suppression of mast cell activation, in the absence of modulation of T- or B-cell responses.
  
  
  
  Our data highlight the immune communication between skin and gastrointestinal tract, and identifies novel mechanisms by which epicutaneous tolerance can suppress food-induced anaphylaxis.
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Leticia
authors.initials: L
authors.lastname: Tordesillas
authors.affiliation: DBV Technologies, Bagneux, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Mondoulet
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Ana Belen
authors.initials: AB
authors.lastname: Blazquez
authors.affiliation: DBV Technologies, Bagneux, France.
authors.forename: Pierre-Henri
authors.initials: PH
authors.lastname: Benhamou
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Sampson
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address: cecilia.berin@mssm.edu.
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Berin
mesh_terms: D000279:Administration, Cutaneous; D000485:Allergens / Q000276:immunology; D000707:Anaphylaxis / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D000818:Animals; D010367:Arachis / Q000276:immunology; D002772:Cholera Toxin / Q000276:immunology; D003888:Desensitization, Immunologic / Q000379:methods*; D005512:Food Hypersensitivity / Q000097:blood / Q000276:immunology / Q000628:therapy*; D051858:Forkhead Transcription Factors / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D010047:Ovalbumin / Q000276:immunology; D010455:Peptides / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology
chemical_list: D000485:Allergens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007074:Immunoglobulin G; D010455:Peptides; D016212:Transforming Growth Factor beta; D010047:Ovalbumin; D002772:Cholera Toxin
keywords: Epicutaneous immunotherapy; food allergy; mast cells; oral immunotherapy; regulatory T cells