Prolyl endopeptidase-mediated destruction of T cell epitopes in whole gluten: chemical and immunological characterization.
Celiac Sprue is a widely prevalent immune disease of the small intestine induced by dietary gluten intake in genetically susceptible individuals. It has been suggested that prolyl endopeptidases (PEPs) may be useful catalysts for gluten detoxification. We have investigated this hypothesis using food-grade gluten as the target antigen, and a combination of mass spectrometry and patient-derived T cells as quantitative assay systems. Spectrometric characterization of physiologically proteolyzed gluten revealed a number of 10 to 50 residue peptides containing known T cell epitopes involved in Celiac Sprue pathogenesis. Several of these peptides were multivalent, suggesting they may be potent triggers of the inflammatory response to gluten in celiac patients. Treatment of proteolyzed gluten with recombinant bacterial PEP decreased the number of potentially immunostimulatory peptides. Substantially reduced immunogenicity was also quantified in 12 of 14 intestinal polyclonal T cell lines from celiac patients. Kinetic investigations using eight T cell clones showed rapid destruction of alpha-gliadin epitopes, but less complete processing of gamma-gliadin epitopes. Given the difficulty associated with a strict lifelong gluten-exclusion diet, the ability of a single enzyme to greatly reduce the antigenic burden of grocery store gluten reinforces the case for developing oral peptidase therapy against Celiac Sprue.
Marti
Thomas
T
Celiac Sprue Research Foundation, 3181 Porter Dr., Palo Alto, CA 94304, USA.
Molberg
Oyvind
O
Li
Qing
Q
Gray
Gary M
GM
Khosla
Chaitan
C
Sollid
Ludvig M
LM
D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D000939:Epitopes / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D005903:Gliadin / Q000276:immunology; D005983:Glutens / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D010455:Peptides / Q000032:analysis; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000378:metabolism*; D013601:T-Lymphocytes
D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D010455:Peptides; D005983:Glutens; D005903:Gliadin; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases