Antagonists and non-toxic variants of the dominant wheat gliadin T cell epitope in coeliac disease

Anderson, RP; van Heel, DA; Tye-Din, JA; Jewell, DP; Hill, AVS

Author(s): Anderson, RP; van Heel, DA; Tye-Din, JA; Jewell, DP; Hill, AVS;
Details: Publication Year 2006-04,Volume 55,Issue #4,Page 485-491
Journal Title: GUT
Publication Type: Journal Article
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 regionp 60-71 (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.
Publisher: B M J PUBLISHING GROUP
Keywords: SEQUENCE-SPECIFIC PRIMERS; ALTERED PEPTIDE LIGAND; MULTIPLE-SCLEROSIS; TISSUE TRANSGLUTAMINASE; CEREAL TOXICITY; PCR-SSP; ENCEPHALOMYELITIS; CHALLENGE; HLA-DQB1; TRIAL
Publisher's Version: https://doi.org/10.1136/gut.2005.064550
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2006-04-01 12:00:00