Single-chain recombinant HLA-DQ2.5/peptide molecules block α2-gliadin-specific pathogenic CD4+ T-cell proliferation and attenuate production of inflammatory cytokines: a potential therapy for celiac disease.
Celiac disease (CD) is a disorder of the small intestine caused by intolerance to wheat gluten and related proteins in barley and rye. CD4(+) T cells have a central role in CD, recognizing and binding complexes of HLA-DQ2.5 bearing gluten peptides that have survived digestion and that are deamidated by tissue transglutaminase (TG2), propagating a cascade of inflammatory processes that damage and eventually destroy the villous tissue structures of the small intestine. In this study, we present data showing that recombinant DQ2.5-derived molecules bearing covalently tethered α2-gliadin-61-71 peptide have a remarkable ability to block antigen-specific T-cell proliferation and inhibited proinflammatory cytokine secretion in human DQ2.5-restricted α2-gliadin-specific T-cell clones obtained from patients with CD. The results from our in vitro studies suggest that HLA-DQ2.5-derived molecules could significantly inhibit and perhaps reverse the intestinal pathology caused by T-cell-mediated inflammation and the associated production of proinflammatory cytokines.
Huan
J
J
Department of Neurology, Oregon Health and Science University, Portland, Oregon, USA.
Meza-Romero
R
R
Mooney
J L
JL
Vandenbark
A A
AA
Offner
H
H
Burrows
G G
GG
D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002446:Celiac Disease / Q000276:immunology / Q000628:therapy; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis*; D019204:GTP-Binding Proteins; D005903:Gliadin / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D005983:Glutens / Q000276:immunology; D006683:HLA-DQ Antigens / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011994:Recombinant Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism
D016207:Cytokines; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D010446:Peptide Fragments; D011994:Recombinant Proteins; D005983:Glutens; D005903:Gliadin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins