PMID- 24258832
OWN - NLM
STAT- MEDLINE
DCOM- 20140429
LR  - 20220129
IS  - 1468-3296 (Electronic)
IS  - 0040-6376 (Print)
IS  - 0040-6376 (Linking)
VI  - 69
IP  - 4
DP  - 2014 Apr
TI  - 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.
PG  - 335-45
LID - 10.1136/thoraxjnl-2013-204324 [doi]
AB  - 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.
FAU - Till, Stephen J
AU  - Till SJ
AD  - 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.
FAU - Raynsford, Eleanor J
AU  - Raynsford EJ
FAU - Reynolds, Catherine J
AU  - Reynolds CJ
FAU - Quigley, Kathryn J
AU  - Quigley KJ
FAU - Grzybowska-Kowalczyk, Agnieszka
AU  - Grzybowska-Kowalczyk A
FAU - Saggar, Lavina R
AU  - Saggar LR
FAU - Goldstone, Andrea
AU  - Goldstone A
FAU - Maillere, Bernard
AU  - Maillere B
FAU - Kwok, William W
AU  - Kwok WW
FAU - Altmann, Daniel M
AU  - Altmann DM
FAU - Durham, Stephen R
AU  - Durham SR
FAU - Boyton, Rosemary J
AU  - Boyton RJ
LA  - eng
GR  - G1000758/MRC_/Medical Research Council/United Kingdom
GR  - G108/495/MRC_/Medical Research Council/United Kingdom
GR  - HHSN272200700046C/AI/NIAID NIH HHS/United States
GR  - HHSN272200900046C/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131120
PL  - England
TA  - Thorax
JT  - Thorax
JID - 0417353
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Allergens)
RN  - 0 (Cblb protein, mouse)
RN  - 0 (HLA-DR1 Antigen)
RN  - 0 (Immunodominant Epitopes)
RN  - 0 (PHLPVI protein, Phleum pratense)
RN  - 0 (Plant Proteins)
RN  - EC 2.3.2.26 (Itch protein, mouse)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-cbl)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*physiology
MH  - Adult
MH  - Allergens/*immunology
MH  - Animals
MH  - CD4-Positive T-Lymphocytes/*immunology
MH  - Female
MH  - HLA-DR1 Antigen/*immunology
MH  - Humans
MH  - Immunity, Cellular
MH  - Immunodominant Epitopes/*immunology
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Microarray Analysis
MH  - Middle Aged
MH  - Phleum/immunology
MH  - Plant Proteins/*immunology
MH  - Pollen/*immunology
MH  - Proto-Oncogene Proteins c-cbl/*physiology
MH  - Real-Time Polymerase Chain Reaction
MH  - Rhinitis, Allergic, Seasonal/*immunology
MH  - Ubiquitin-Protein Ligases/*physiology
MH  - United Kingdom
MH  - Young Adult
PMC - PMC4368902
MID - NIHMS617087
OTO - NOTNLM
OT  - Allergic lung disease
OT  - Lymphocyte Biology
COIS- Competing interests SRD reports grants and personal fees from (ALK)-Abello, 
      grants and personal fees from Merck, personal fees from Circassia, outside the 
      submitted work; Dr Till reports grants from ALK-Abello, outside the submitted 
      work; the rest of the authors declare that they have no conflict of interest.
EDAT- 2013/11/22 06:00
MHDA- 2014/04/30 06:00
PMCR- 2015/04/01
CRDT- 2013/11/22 06:00
PHST- 2013/11/22 06:00 [entrez]
PHST- 2013/11/22 06:00 [pubmed]
PHST- 2014/04/30 06:00 [medline]
PHST- 2015/04/01 00:00 [pmc-release]
AID - thoraxjnl-2013-204324 [pii]
AID - 10.1136/thoraxjnl-2013-204324 [doi]
PST - ppublish
SO  - Thorax. 2014 Apr;69(4):335-45. doi: 10.1136/thoraxjnl-2013-204324. Epub 2013 Nov 
      20.