Peptide immunotherapy in allergic asthma generates IL-10–dependent immunological tolerance associated with linked epitope suppression

• Published in: The Journal of experimental medicine Vol. 206; no. 7; pp. 1535 - 1547
• Main Authors: Campbell, John D., Buckland, Karen F., McMillan, Sarah J., Kearley, Jennifer, Oldfield, William L.G., Stern, Lawrence J., Grönlund, Hans, van Hage, Marianne, Reynolds, Catherine J., Boyton, Rosemary J., Cobbold, Stephen P., Kay, A. Barry, Altmann, Daniel M., Lloyd, Clare M., Larché, Mark
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 06.07.2009
• Subjects: Allergens - immunology; Animals; Asthma - immunology; Asthma - therapy; Bronchial Hyperreactivity - immunology; Cats; Desensitization, Immunologic; Disease Models, Animal; Double-Blind Method; Epitopes - immunology; Forkhead Transcription Factors - immunology; Genes, MHC Class II; Glycoproteins - genetics; Glycoproteins - immunology; HLA-DR1 Antigen - immunology; Humans; Immune Tolerance - immunology; Interleukin-10 - immunology; Lung - cytology; Lung - immunology; Lung - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptides - immunology; Peptides - therapeutic use; Placebos; Randomized Controlled Trials as Topic; Receptors, Interleukin-10 - immunology; Th2 Cells - immunology; Transforming Growth Factor beta - immunology
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20082901

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.