Antagonists and non-toxic variants of the dominant wheat gliadin T cell epitope in coeliac disease.
Gut
; 55(4): 485-91, 2006 Apr.
Article
de 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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Fragments peptidiques
/
Triticum
/
Maladie coeliaque
/
Interféron gamma
/
Déterminants antigéniques des lymphocytes T
/
Gliadine
Limites:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Langue:
En
Journal:
Gut
Année:
2006
Type de document:
Article
Pays d'affiliation:
Australie