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Departments of 1 Chemical Engineering, 2 Medicine, 3 Chemistry, and 4 Biochemistry, Stanford University, Stanford, California 94305-5025
Two recently identified immunodominant
epitopes from 
-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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