Antagonists and non-toxic variants of the dominant wheat gliadin T cell epitope in coeliac disease
Background: Coeliac disease (CD) is due to an inappropriate T cell mediated response to specific gluten peptides. Measured by interferon γ (IFN-γ) ELISPOT, about half of the gliadin specific T cells induced with in vivo wheat gluten exposure in HLA-DQ2+ CD are specific for an α/β-gliadin peptide (p5...
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Published in | Gut Vol. 55; no. 4; pp. 485 - 491 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
England
BMJ Publishing Group Ltd and British Society of Gastroenterology
01.04.2006
BMJ Publishing Group LTD BMJ Group |
Subjects | |
Online Access | Get full text |
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Summary: | Background: Coeliac disease (CD) is due to an inappropriate T cell mediated response to specific gluten peptides. Measured by interferon γ (IFN-γ) ELISPOT, about half of the gliadin specific T cells induced with in vivo wheat gluten exposure in HLA-DQ2+ CD are specific for an α/β-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-γ stimulatory capacity but capable of antagonising IFN-γ 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-γ ELISPOT response. Among 131 partial agonists identified, 45 produced statistically significant inhibition of IFN-γ ELISPOT responses when cocultured in fivefold excess with p57–73 QE65 (n = 10). Four substituted variants of p57–73 QE65 were inactive by IFN-γ ELISPOT but consistently antagonised IFN-γ 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 α/β-gliadins could abolish their capacity to stimulate IFN-γ from CD4 T cells and also have anti-inflammatory or protective effects in HLA-DQ2+ CD. |
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Bibliography: | local:0550485 istex:C4FA0F0D0E9F255A7838967975A6786B1672C077 Correspondence to: Dr R P Anderson Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute, c/o Post Office RMH, Victoria, Australia 3050; banderson@wehi.edu.au href:gutjnl-55-485.pdf PMID:16299041 ark:/67375/NVC-WS3TW71B-Q ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0017-5749 1468-3288 |
DOI: | 10.1136/gut.2005.064550 |