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Celiac Disease: A Future Without Gluten-free Diet?

Gastroenterology, Oct 2003, Vol 125, No 4, p1264-67

Celiac.com 10/08/2003 - An article by Vader et al. published in the October 2003 edition of the journal Gastroenterology discusses recent insights into celiac disease pathogenesis, and the possibility of detoxifying gluten for celiacs. After describing the toxic process of gluten peptides in celiacs in some detail, Vader et al. examined the possibility of detoxifying gluten in the wheat kernel: "The effect of comparable substitutions in the immunodominant 9-gliadin epitope. One mutation, consisting in the substitution of a glutamine (residue) by a proline residue, decreased T cell recognition. Further: "Interestingly, given the similarities between the respective codons for glutamine and proline, this substitution was achieved by changing a single nucleotide at the DNA level. This mutation, resulting in an exchange between the 2 most frequent amino acids in prolamins, suggests that detoxification of gluten might be achievable by site-directed mutagenesis of wheat without affecting the unique baking properties of gluten." They go on by emphasizing that due to the complexity of the amino acid sequences found in wheat, achieving a detoxified wheat using this method would be difficult.

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Later in the article Shan et al. propose detoxifying gluten in the intestine of a celiac with "a peptidase therapy based on the use of a bacterial endoprolyl protease." Although this therapy has been tested as effective in rats, it has not yet been tested in humans. Further: "Using intestinal biopsies mounted in Using chambers, we have observed that several gliadin-derived peptides, including the 33 mer, can be efficiently degraded into amino acids during their epithelial transport and processing in control patients and in patients on a gluten-free diet, arguing against a major intrinsic intestinal defect of proteolysis of proline-rich peptides. The situation was different in patients with active disease in which a significant amount of peptide entered undigested into the mucosa. In the latter cases, however, it remains unclear whether entrance of the intact peptides was related only to altered epithelial processing or favored by a more active mechanism that remains to be elucidated." So this also may not be an effective way to detoxify gluten.

Finally the article explores the possibility of treating the disease using vaccinotherapy which would be based on the central role of the adaptive antigluten T-cell response: "Senger et al. observed that intranasal administration of whole gliadin or of one of its isoforms could partially inhibit the systemic T-cell response to the parenteral challenge by whole gliadins in HLA-DQ8-transgenic mice." Further: "Using unmodified gluten, however, entails an important risk of enhancing immunization. An alternative strategy might be to develop peptide analogues able to interfere with HLA-class II binding and T-cell activation and to redirect the immune response toward tolerance. This approach has been successful in several experimental models of autoimmune diseases and has provided encouraging results in patients with multiple sclerosis." These type of therapies, however, run the risk of enhancing immunization instead of promoting tolerance.

The article concludes in a hopeful tone: "Although the ultimate goal of producing wheat deprived of toxicity remains remote and perhaps inaccessible, our broadening knowledge of celiac disease pathogenesis offers a growing number of alternative strategies to the gluten-free diet. Much work, hopefully soon supported by the development of an accurate animal model, is needed to evaluate the feasibility, efficiency, and risks of these approaches. In the vast majority of cases, celiac disease is a benign disease. Its current treatment, although constraining, is safe and efficient, and the cost and benefits of any other treatment will require a thorough appraisal. Furthermore, one unresolved key issue is to simply define who deserves treatment. The wide clinical spectrum of the disease might reflect a wide level of individual sensitivity, some of which could be compatible with a normal diet. Epidemiologic studies providing a precise appraisal of the risk of complications are therefore needed to substantiate the need of a treatment in individuals with silent or pauci-symptomatic disease determined by serologic studies."

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