Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 206, Issue 7, Pages 1535-1547Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20082901
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Funding
- Medical Research Council (MRC) [G0100509]
- National Institutes of Health [R01-AI48833]
- Canada Research Chairs program
- Canadian Foundation for Innovation
- Wellcome Trust [057704]
- Swedish Research Council, and Asthma UK [05/045]
- Asthma UK Senior Research Fellow [2001-2006]
- BBSRC CASE
- MRC [G0700153, G108/495] Funding Source: UKRI
- Medical Research Council [G0400503B, G0700153, G108/495] Funding Source: researchfish
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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.
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