Peptide immunotherapy in allergic asthma generates IL-10-dependent immunological tolerance associated with linked epitope suppression.
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.
Campbell
John D
JD
MRC and Asthma UK Centre for Allergic Mechanisms of Asthma, London SW7 2 AZ, UK.
Buckland
Karen F
KF
McMillan
Sarah J
SJ
Kearley
Jennifer
J
Oldfield
William L G
WL
Stern
Lawrence J
LJ
Grönlund
Hans
H
van Hage
Marianne
M
Reynolds
Catherine J
CJ
Boyton
Rosemary J
RJ
Cobbold
Stephen P
SP
Kay
A Barry
AB
Altmann
Daniel M
DM
Lloyd
Clare M
CM
Larché
Mark
M
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
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