title: Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3).
abstract: BACKGROUND
  The mechanisms contributing to clinical immune tolerance remain incompletely understood. This study provides evidence for specific immune mechanisms that are associated with a model of operationally defined clinical tolerance.
  
  
  OBJECTIVE
  Our overall objective was to study laboratory changes associated with clinical immune tolerance in antigen-induced T cells, basophils, and antibodies in subjects undergoing oral immunotherapy (OIT) for peanut allergy.
  
  
  METHODS
  In a phase 1 single-site study, we studied participants (n = 23) undergoing peanut OIT and compared them with age-matched allergic control subjects (n = 20) undergoing standard of care (abstaining from peanut) for 24 months. Participants were operationally defined as clinically immune tolerant (IT) if they had no detectable allergic reactions to a peanut oral food challenge after 3 months of therapy withdrawal (IT, n = 7), whereas those who had an allergic reaction were categorized as nontolerant (NT; n = 13).
  
  
  RESULTS
  Antibody and basophil activation measurements did not statistically differentiate between NT versus IT participants. However, T-cell function and demethylation of forkhead box protein 3 (FOXP3) CpG sites in antigen-induced regulatory T cells were significantly different between IT versus NT participants. When IT participants were withdrawn from peanut therapy for an additional 3 months (total of 6 months), only 3 participants remained classified as IT participants, and 4 participants regained sensitivity along with increased methylation of FOXP3 CpG sites in antigen-induced regulatory T cells.
  
  
  CONCLUSIONS
  In summary, modifications at the DNA level of antigen-induced T-cell subsets might be predictive of a state of operationally defined clinical immune tolerance during peanut OIT.
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Aleena
authors.initials: A
authors.lastname: Syed
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Garcia
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Lyu
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Robert
authors.initials: R
authors.lastname: Bucayu
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Arunima
authors.initials: A
authors.lastname: Kohli
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Satoru
authors.initials: S
authors.lastname: Ishida
authors.affiliation: Duke Translational Medicine Institute, Regulatory Affairs, Durham, NC.
authors.forename: Jelena P
authors.initials: JP
authors.lastname: Berglund
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Mindy
authors.initials: M
authors.lastname: Tsai
authors.affiliation: Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Holden
authors.initials: H
authors.lastname: Maecker
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Gerri
authors.initials: G
authors.lastname: O'Riordan
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, Calif; Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, Calif.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Galli
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif. Electronic address: knadeau@stanford.edu.
authors.forename: Kari C
authors.initials: KC
authors.lastname: Nadeau
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000941:Antigens / Q000276:immunology; D010367:Arachis / Q000009:adverse effects / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000276:immunology; D003888:Desensitization, Immunologic; D004311:Double-Blind Method; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D008745:Methylation; D008875:Middle Aged; D021183:Peanut Hypersensitivity / Q000276:immunology* / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D055815:Young Adult
chemical_list: D000941:Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007074:Immunoglobulin G; D007073:Immunoglobulin E
keywords: APC; Antigen-induced regulatory T; Antigen-presenting cell; CD40 ligand; CD40L; CFSE; Carboxyfluorescein succinimidyl ester; DBPCFC; DC; Dendritic cell; Double-blind, placebo-controlled food challenge; Effector CD4(+) T; FOXP3; Food allergy; Forkhead box protein 3; IT; Immune tolerant; Induced regulatory T; LAG3; Lymphocyte activation gene 3; MFI; Mean fluorescence intensity; NT; Natural regulatory T; Nonspecific regulatory T; Nontolerant; OFC; OIT; Oral food challenge; Oral immunotherapy; Regulatory T; SPT; Skin prick test; T(R)1; Teff; Treg; Type 1 regulatory T; T regulatory cells; ai-Treg; allergy; desensitization; epigenetics; forkhead box protein 3; iTreg; nTreg; ns-Treg; oral immunotherapy; peanut; tolerance