title: Specific immunotherapy modifies allergen-specific CD4(+) T-cell responses in an epitope-dependent manner.
abstract: BACKGROUND
  Understanding the mechanisms by which the immune system induces and controls allergic inflammation at the T-cell epitope level is critical for the design of new allergy vaccine strategies.
  
  
  OBJECTIVE
  We sought to characterize allergen-specific T-cell responses linked with allergy or peripheral tolerance and to determine how CD4(+) T-cell responses to individual allergen-derived epitopes change over allergen-specific immunotherapy.
  
  
  METHODS
  Timothy grass pollen (TGP) allergy was used as a model for studying grass pollen allergies. The breadth, magnitude, epitope hierarchy, and phenotype of the DR04:01-restricted TGP-specific T-cell responses in 10 subjects with grass pollen allergy, 5 nonatopic subjects, and 6 allergy vaccine-treated subjects was determined by using an ex vivo peptide-MHC class II tetramer approach.
  
  
  RESULTS
  CD4(+) T cells in allergic subjects are directed to a broad range of TGP epitopes characterized by defined immunodominance hierarchy patterns and with distinct functional profiles that depend on the epitope recognized. Epitopes that are restricted specifically to either TH2 or TH1/TR1 responses were identified. Allergen-specific immunotherapy was associated with preferential deletion of allergen-specific TH2 cells and without a significant change in the frequency of TH1/TR1 cells.
  
  
  CONCLUSIONS
  Preferential allergen-specific TH2 cell deletion after repeated high-dose antigen stimulation can be another independent mechanism to restore tolerance to allergen during immunotherapy.
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Wash.
authors.forename: Erik
authors.initials: E
authors.lastname: Wambre
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Wash.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: DeLong
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Wash.
authors.forename: Eddie A
authors.initials: EA
authors.lastname: James
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Wash.
authors.forename: Nadia
authors.initials: N
authors.lastname: Torres-Chinn
authors.affiliation: Department of Dermatology and Allergology, University Medical Center, Marburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Pfützner
authors.affiliation: Department of Dermatology and Allergology, University Medical Center, Marburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Möbs
authors.affiliation: Department of Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College, London, United Kingdom.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Durham
authors.affiliation: Allergy, Asthma and Lung Biology, King's College London, London, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Till
authors.affiliation: Virginia Mason Medical Center, Seattle, Wash.
authors.forename: David
authors.initials: D
authors.lastname: Robinson
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Wash; Department of Medicine, University of Washington, Seattle, Wash. Electronic address: bkwok@benaroyaresearch.org.
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
mesh_terms: D000485:Allergens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003888:Desensitization, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D031784:Phleum / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis
chemical_list: D000485:Allergens; D018984:Epitopes, T-Lymphocyte; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
keywords: CD4; Immunotherapy; T cells; allergy; epitope; ex vivo; peptide–MHC class II tetramer; peripheral tolerance; pollen