title: Peptide-induced immune regulation by a promiscuous and immunodominant CD4T-cell epitope of Timothy grass pollen: a role of Cbl-b and Itch in regulation.
abstract: BACKGROUND
  T-cell targeted peptide epitope tolerogens from grass pollen allergens may be useful in treating seasonal allergic rhinitis, but there is urgent need for optimisation of approaches from improved understanding of mechanism.
  
  
  OBJECTIVE
  We sought to identify human leukocyte antigen (HLA)-DR1-restricted epitopes from the Timothy grass pollen allergen, Phleum pratense, and characterise T-cell immune regulation following intranasal administration of a single, immunodominant epitope.
  
  
  METHODS
  T-cell epitopes within P pratense were identified using HLA-DR1 transgenic mice and tetramer-guided epitope mapping (TGEM) in HLA-DR1-positive individuals with grass allergy. An immunodominant epitope was tested in HLA-DR1 transgenics for impact on responses to whole Phl p5 b or peptide. Microarrays and quantitative PCR were used to characterise T-cell immunity.
  
  
  RESULTS
  Peptide 26 (p26) was identified in HLA-DR1 transgenic mice and by TGEM analysis of HLA-DR1-positive individuals with grass allergy. p26 shows promiscuous binding to a wide range of HLA class II alleles, making it of relevance across immunogenetically diverse patients. The epitope is conserved in rye and velvet grass, making it applicable across a spectrum of grass pollen allergy. Intranasal pretreatment of mice with p26 results in significantly reduced T-cell responses. Transcriptomic array analysis in mice showed T-cell regulation in the intranasal treatment group associated with increased expression of members of the Cbl-b and Itch E3 ubiquitin ligase pathway.
  
  
  CONCLUSIONS
  We defined an immunodominant P pratense epitope, p26, with broad binding across multiple HLA class II alleles. Intranasal treatment of mice with p26 results in T-cell regulation to whole allergen, involving the Cbl-b and Itch regulatory pathway.
authors.affiliation: Department of Asthma, Allergy and Respiratory Science, Division of Asthma, Allergy & Lung Biology, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, , London, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Till
authors.forename: Eleanor J
authors.initials: EJ
authors.lastname: Raynsford
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Reynolds
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Quigley
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Grzybowska-Kowalczyk
authors.forename: Lavina R
authors.initials: LR
authors.lastname: Saggar
authors.forename: Andrea
authors.initials: A
authors.lastname: Goldstone
authors.forename: Bernard
authors.initials: B
authors.lastname: Maillere
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Altmann
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Durham
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Boyton
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000328:Adult; D000485:Allergens / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D015798:HLA-DR1 Antigen / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D016056:Immunodominant Epitopes / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D008875:Middle Aged; D031784:Phleum / Q000276:immunology; D010940:Plant Proteins / Q000276:immunology*; D011058:Pollen / Q000276:immunology*; D050721:Proto-Oncogene Proteins c-cbl / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D006255:Rhinitis, Allergic, Seasonal / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D006113:United Kingdom; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000485:Allergens; C118387:Cblb protein, mouse; D015798:HLA-DR1 Antigen; D016056:Immunodominant Epitopes; C095238:PHLPVI protein, Phleum pratense; D010940:Plant Proteins; C471637:Itch protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases
keywords: Allergic lung disease; Lymphocyte Biology