Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3)

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 2; pp. 500 - 510.e11
• Main Authors: Syed, Aleena, Garcia, Marco A., Lyu, Shu-Chen, Bucayu, Robert, Kohli, Arunima, Ishida, Satoru, Berglund, Jelena P., Tsai, Mindy, Maecker, Holden, O’Riordan, Gerri, Galli, Stephen J., Nadeau, Kari C.
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.02.2014; Elsevier; Elsevier Limited
• Subjects: Administration, Oral; Adolescent; Adult; Allergic diseases; Allergies; allergy; Allergy and Immunology; Antigens - immunology; Arachis - adverse effects; Arachis - immunology; Arachis hypogaea; Biological and medical sciences; Child; Child, Preschool; Children & youth; Dendritic Cells - immunology; Dermatitis; desensitization; Desensitization, Immunologic; Digestive allergic diseases; Double-Blind Method; Drug therapy; epigenetics; Female; Food allergies; Food allergy; forkhead box protein 3; Forkhead Transcription Factors - immunology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immune Tolerance - immunology; Immunoglobulin E - blood; Immunoglobulin G - blood; Immunopathology; Male; Medical sciences; Methylation; Middle Aged; oral immunotherapy; peanut; Peanut Hypersensitivity - immunology; Peanut Hypersensitivity - therapy; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; T-Lymphocytes, Regulatory - immunology; tolerance; T regulatory cells; Young Adult; CD40L; Food allergy; ns-Treg; iTreg; NT; oral immunotherapy; OFC; epigenetics; ai-Treg; MFI; SPT; nTreg; peanut; T regulatory cells; tolerance; LAG3; Treg; allergy; CFSE; IT; FOXP3; desensitization; forkhead box protein 3; TR1; APC; Teff; OIT; DBPCFC; DC; Nonspecific regulatory T; Lymphocyte activation gene 3; Type 1 regulatory T; Nontolerant; T R1; Natural regulatory T; Regulatory T; Antigen-presenting cell; Induced regulatory T; Dendritic cell; Oral food challenge; Double-blind, placebo-controlled food challenge; Mean fluorescence intensity; Antigen-induced regulatory T; Skin prick test; Effector CD4 + T; Carboxyfluorescein succinimidyl ester; Immune tolerant; CD40 ligand; Peanut; Immunopathology; T regulatory cell; Desensitization; Oral administration; Tolerance; Protein; Antigen; Immunology; Treatment; T regulatory cells; Immunotherapy; T-Lymphocyte; Epigenetics; Digestive diseases; Methylation; Regulatory cell; Transcription factor FOXP3; Groundnut; Forkhead box protein 3; T(R)1; Oral immunotherapy; Effector CD4(+) T
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2013.12.1037

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. 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. 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). 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. 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.