title: Regulation of IgE production and airway reactivity by CD4⁻CD8⁻ regulatory T cells.
abstract: The mechanisms of tolerance induction occurring in the course of allergen-specific immunotherapy have not been elucidated in full detail. Our study aimed to characterize high zone tolerance in mouse models of type I allergy and of allergic airway inflammation induced by subcutaneous sensitization of mice with high doses of the model allergen ovalbumin (OVA) without the use of adjuvant. Mice were immunized by subcutaneous injection of high doses (HD) of OVA or, for comparison, low doses (LD) of OVA in saline. HD-mice showed lower specific IgE, but augmented IgG in sera than LD-mice. Pre-treatment of mice with HD-OVA antigen-specifically inhibited IgE production subsequently induced by LD-OVA. OVA-restimulated splenocytes from HD-mice revealed hypoproliferation and impaired production of Th2-associated cytokines. HD-mice exhibited lower airway reactivity, goblet cell hyperplasia and mucus production, as well as IL-5 and IL-13 production in the lungs than LD-mice following local provocation. Recruitment of inflammatory cells into the airways was comparable, while the number of eosinophils in the bronchoalveolar lavage was substantially higher in HD-mice. Adoptive transfer of dnTC from HD-mice into naïve mice, which were subsequently sensitized with LD-OVA, suppressed IgE production in the recipients. The number of dnTC was higher in the spleens of HD-mice than LD-mice. In conclusion, our study demonstrates that subcutaneous sensitization of mice with high doses of allergen in the absence of adjuvant results in attenuated airway reactivity as compared with LD-sensitization and induces CD4(-)CD8(-) dnTC with regulatory function on IgE production.
authors.affiliation: Clinical Research Unit Allergology, Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Germany. Electronic address: rakerv@uni-mainz.de.
authors.forename: Verena
authors.initials: V
authors.lastname: Raker
authors.affiliation: Clinical Research Unit Allergology, Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Stein
authors.affiliation: Clinical Research Unit Allergology, Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Montermann
authors.affiliation: Asthma Core Facility, I. Medical Clinic, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Maxeiner
authors.affiliation: University Leiden Medical Center, Department of Pulmonology, Leiden, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Taube
authors.affiliation: Clinical Research Unit Allergology, Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
authors.forename: Angelika B
authors.initials: AB
authors.lastname: Reske-Kunz
authors.affiliation: Clinical Research Unit Allergology, Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Sudowe
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D007114:Immunization; D007073:Immunoglobulin E / Q000096:biosynthesis* / Q000276:immunology*; D056747:Immunomodulation; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D051379:Mice; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D016692:Receptors, Antigen, T-Cell, gamma-delta; D007073:Immunoglobulin E; D010047:Ovalbumin
keywords: Airway hyperreactivity; Allergy; Antigen dose; CD4−CD8− double-negative T cells; Immunoglobulin (Ig)E; Mouse model; Ovalbumin