title: Peptide immunotherapy in allergic asthma generates IL-10-dependent immunological tolerance associated with linked epitope suppression.
abstract: Treatment of patients with allergic asthma using low doses of peptides containing T cell epitopes from Fel d 1, the major cat allergen, reduces allergic sensitization and improves surrogate markers of disease. Here, we demonstrate a key immunological mechanism, linked epitope suppression, associated with this therapeutic effect. Treatment with selected epitopes from a single allergen resulted in suppression of responses to other ("linked") epitopes within the same molecule. This phenomenon was induced after peptide immunotherapy in human asthmatic subjects and in a novel HLA-DR1 transgenic mouse model of asthma. Tracking of allergen-specific T cells using DR1 tetramers determined that suppression was associated with the induction of interleukin (IL)-10(+) T cells that were more abundant than T cells specific for the single-treatment peptide and was reversed by anti-IL-10 receptor administration. Resolution of airway pathophysiology in this model was associated with reduced recruitment, proliferation, and effector function of allergen-specific Th2 cells. Our results provide, for the first time, in vivo evidence of linked epitope suppression and IL-10 induction in both human allergic disease and a mouse model designed to closely mimic peptide therapy in humans.
authors.affiliation: MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, London SW7 2 AZ, UK.
authors.forename: John D
authors.initials: JD
authors.lastname: Campbell
authors.forename: Karen F
authors.initials: KF
authors.lastname: Buckland
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: McMillan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kearley
authors.forename: William L G
authors.initials: WL
authors.lastname: Oldfield
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Stern
authors.forename: Hans
authors.initials: H
authors.lastname: Grönlund
authors.forename: Marianne
authors.initials: M
authors.lastname: van Hage
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Reynolds
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Boyton
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Cobbold
authors.forename: A Barry
authors.initials: AB
authors.lastname: Kay
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Altmann
authors.forename: Clare M
authors.initials: CM
authors.lastname: Lloyd
authors.forename: Mark
authors.initials: M
authors.lastname: Larché
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000628:therapy; D016535:Bronchial Hyperreactivity / Q000276:immunology; D002415:Cats; D003888:Desensitization, Immunologic; D004195:Disease Models, Animal; D004311:Double-Blind Method; D000939:Epitopes / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology; D005802:Genes, MHC Class II; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology; D015798:HLA-DR1 Antigen / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000276:immunology / Q000627:therapeutic use; D010919:Placebos; D016032:Randomized Controlled Trials as Topic; D053701:Receptors, Interleukin-10 / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology
chemical_list: D000485:Allergens; D000939:Epitopes; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006023:Glycoproteins; D015798:HLA-DR1 Antigen; D010455:Peptides; D010919:Placebos; D053701:Receptors, Interleukin-10; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; C059296:Fel d 1 protein, Felis domesticus