Antagonists and non-toxic variants of the dominant wheat gliadin T cell epitope in coeliac disease.
Gut
; 55(4): 485-91, 2006 Apr.
Article
em En
| MEDLINE
| ID: mdl-16299041
ABSTRACT
BACKGROUND:
Coeliac disease (CD) is due to an inappropriate T cell mediated response to specific gluten peptides. Measured by interferon gamma (IFN-gamma) ELISPOT, about half of the gliadin specific T cells induced with in vivo wheat gluten exposure in HLA-DQ2+ CD are specific for an alpha/beta-gliadin peptide (p57-73 QE65; QLQPFPQPELPYPQPQS) that includes two overlapping T cell epitopes (PFPQPELPY and PQPELPYPQ).AIM:
To define minimally substituted variants of p57-73 QE65 universally devoid of IFN-gamma stimulatory capacity but capable of antagonising IFN-gamma secretion from polyclonal T cells specific for p57-73 QE65.METHODS:
Peripheral blood mononuclear cells collected from 75 HLA-DQ2+ CD patients after in vivo gluten challenge were used in overnight ELISPOT assays to screen 218 single or double substituted variants of p57-73 QE65 for cytokine stimulatory and antagonist activity.RESULTS:
The region p60-71 (PFPQPELPYPQP) and especially p64-67 (PELP) was sensitive to substitution. Twelve substitutions in p64-67 stimulated no IFN-gamma ELISPOT response. Among 131 partial agonists identified, 45 produced statistically significant inhibition of IFN-gamma ELISPOT responses when cocultured in fivefold excess with p57-73 QE65 (n = 10). Four substituted variants of p57-73 QE65 were inactive by IFN-gamma ELISPOT but consistently antagonised IFN-gamma ELISPOT responses to p57-73 QE65, and also retained interleukin 10 stimulatory capacity similar to p57-73 QE65.CONCLUSIONS:
Altered peptide ligands of p57-73 QE65, identified using polyclonal T cells from multiple HLA-DQ2+ CD donors, have properties in vitro that suggest that a single substitution to certain alpha/beta-gliadins could abolish their capacity to stimulate IFN-gamma from CD4 T cells and also have anti-inflammatory or protective effects in HLA-DQ2+ CD.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Triticum
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Doença Celíaca
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Interferon gama
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Epitopos de Linfócito T
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Gliadina
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article