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Am J Physiol Gastrointest Liver Physiol 283: G996-G1003, 2002. First published June 5, 2002; doi:10.1152/ajpgi.00136.2002
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Vol. 283, Issue 4, G996-G1003, October 2002

Intestinal digestive resistance of immunodominant gliadin peptides

Felix Hausch1, Lu Shan1, Nilda A. Santiago1, Gary M. Gray2, and Chaitan Khosla1,3,4

Departments of 1 Chemical Engineering, 2 Medicine, 3 Chemistry, and 4 Biochemistry, Stanford University, Stanford, California 94305-5025

Two recently identified immunodominant epitopes from alpha -gliadin account for most of the stimulatory activity of dietary gluten on intestinal and peripheral T lymphocytes in patients with celiac sprue. The proteolytic kinetics of peptides containing these epitopes were analyzed in vitro using soluble proteases from bovine and porcine pancreas and brush-border membrane vesicles from adult rat intestine. We showed that these proline-glutamine-rich epitopes are exceptionally resistant to enzymatic processing. Moreover, as estimated from the residual peptide structure and confirmed by exogeneous peptidase supplementation, dipeptidyl peptidase IV and dipeptidyl carboxypeptidase I were identified as the rate-limiting enzymes in the digestive breakdown of these peptides. A similar conclusion also emerged from analogous studies with brush-border membrane from a human intestinal biopsy. Supplementation of rat brush-border membrane with trace quantities of a bacterial prolyl endopeptidase led to the rapid destruction of the immunodominant epitopes in these peptides. These results suggest a possible enzyme therapy strategy for celiac sprue, for which the only current therapeutic option is strict exclusion of gluten-containing food.

celiac sprue; brush-border membrane; peptidase; prolyl endopeptidase; kinetics


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