title: IL-10 and regulatory T cells cooperate in allergen-specific immunotherapy to ameliorate allergic asthma.
abstract: Human studies demonstrated that allergen-specific immunotherapy (IT) represents an effective treatment for allergic diseases. IT involves repeated administration of the sensitizing allergen, indicating a crucial contribution of T cells to its medicinal benefit. However, the underlying mechanisms of IT, especially in a chronic disease, are far from being definitive. In the current study, we sought to elucidate the suppressive mechanisms of IT in a mouse model of chronic allergic asthma. OVA-sensitized mice were challenged with OVA or PBS for 4 wk. After development of chronic airway inflammation, mice received OVA-specific IT or placebo alternately to airway challenge for 3 wk. To analyze the T cell-mediated mechanisms underlying IT in vivo, we elaborated the role of T-bet-expressing Th1 cells, T cell-derived IL-10, and Ag-specific thymic as well as peripherally induced Foxp3(+) regulatory T (Treg) cells. IT ameliorated airway hyperresponsiveness and airway inflammation in a chronic asthma model. Of note, IT even resulted in a regression of structural changes in the airways following chronic inhaled allergen exposure. Concomitantly, IT induced Th1 cells, Foxp3(+), and IL-10-producing Treg cells. Detailed analyses revealed that thymic Treg cells crucially contribute to the effectiveness of IT by promoting IL-10 production in Foxp3-negative T cells. Together with the peripherally induced Ag-specific Foxp3(+) Treg cells, thymic Foxp3(+) Treg cells orchestrate the curative mechanisms of IT. Taken together, we demonstrate that IT is effective in a chronic allergic disease and dependent on IL-10 and thymic as well as peripherally induced Ag-specific Treg cells.
authors.affiliation: Institute for Immunology, University Medical Center Mainz, 55131 Mainz, Germany;
authors.forename: Livia
authors.initials: L
authors.lastname: Böhm
authors.affiliation: Institute for Immunology, University Medical Center Mainz, 55131 Mainz, Germany;
authors.forename: Joachim
authors.initials: J
authors.lastname: Maxeiner
authors.affiliation: Department of Pulmonary Medicine, III Medical Clinic, University Medical Center Mainz, 55131 Mainz, Germany;
authors.forename: Helen
authors.initials: H
authors.lastname: Meyer-Martin
authors.affiliation: Department of Pulmonary Medicine, III Medical Clinic, University Medical Center Mainz, 55131 Mainz, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Reuter
authors.affiliation: Institute of Molecular Pneumology, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany; and.
authors.forename: Susetta
authors.initials: S
authors.lastname: Finotto
authors.affiliation: Institute for Immunology, University Medical Center Mainz, 55131 Mainz, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Klein
authors.affiliation: Institute for Immunology, University Medical Center Mainz, 55131 Mainz, Germany;
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.affiliation: Institute for Immunology, University Medical Center Mainz, 55131 Mainz, Germany;
authors.forename: Edgar
authors.initials: E
authors.lastname: Schmitt
authors.affiliation: Institute for Immunology, University Medical Center Mainz, 55131 Mainz, Germany;
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
authors.affiliation: Department of Pulmonology, University Medical Center Leiden, 2333 ZA Leiden, the Netherlands C.Taube@lumc.nl.
authors.forename: Christian
authors.initials: C
authors.lastname: Taube
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003888:Desensitization, Immunologic; D004195:Disease Models, Animal; D005260:Female; D020397:Goblet Cells / Q000473:pathology; D007073:Immunoglobulin E / Q000276:immunology; D056747:Immunomodulation; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008679:Metaplasia; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000009:adverse effects; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D016753:Interleukin-10; D007073:Immunoglobulin E; D010047:Ovalbumin