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
| Autor: | Stephen J. Till, Rosemary J. Boyton, Agnieszka Grzybowska-Kowalczyk, Catherine J. Reynolds, Bernard Maillere, William W. Kwok, Eleanor J. Raynsford, Stephen R. Durham, Andrea Goldstone, Kathryn J. Quigley, Lavina R Saggar, Daniel M. Altmann |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Adult
CD4-Positive T-Lymphocytes Male Pulmonary and Respiratory Medicine Allergy Ubiquitin-Protein Ligases Mice Transgenic Human leukocyte antigen Biology Real-Time Polymerase Chain Reaction medicine.disease_cause Article Epitope Phleum Mice Young Adult Allergen Immunity otorhinolaryngologic diseases medicine Animals Humans Proto-Oncogene Proteins c-cbl Adaptor Proteins Signal Transducing Plant Proteins Immunity Cellular Immunodominant Epitopes Microarray analysis techniques HLA-DR1 Antigen Rhinitis Allergic Seasonal Allergens Middle Aged Microarray Analysis biology.organism_classification medicine.disease United Kingdom Epitope mapping Immunology Pollen Female |
| Zdroj: | Thorax. 69:335-345 |
| ISSN: | 1468-3296 0040-6376 |
| DOI: | 10.1136/thoraxjnl-2013-204324 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|