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¹ MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, ² Leukocyte Biology Section, ³ Lung Immunology Group, and ⁴ Allergy and Clinical Immunology, National Heart and Lung Institute and ⁵ Infectious Diseases Department, Investigative Sciences, Faculty of Medicine, Imperial College, London SW7 2 AZ, UK
⁶ University of Massachusetts Medical School, Worcester, MA 01655
⁷ Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet and University Hospital, Stockholm S-171 76, Sweden
⁸ Sir William Dunn School of Pathology, Oxford OX1 3RE, UK
⁹ Department of Medicine, Firestone Institute for Respiratory Health, McMaster University, Hamilton, Ontario L8N 4A6, Canada

CORRESPONDENCE Clare M. Lloyd: c.lloyd{at}imperial.ac.uk

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.

Abbreviations used: AHR, airway hyperreactivity; BAL, bronchoalveolar lavage; i.d., intradermal(ly); i.n., intranasal(ly); PE, phycoerythrin.

© 2009 Campbell et al.
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