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Articles in PresS, published online ahead of print June 5, 2002
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00136.2002
Submitted on April 9, 2002
Accepted on May 9, 2002
1 Department of Chemical Engineering, Stanford University, Stanford, CA, USA
2 Department of Medicine, Stanford University, Stanford, CA, USA
3 Department of Chemical Engineering, Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University, Stanford, CA, USA; Department of Biochemistry, Stanford University, Stanford, CA, USA
* To whom correspondence should be addressed. E-mail: ck{at}chemeng.stanford.edu.
Two recently identified immunodominant epitopes from a-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.
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