Carlo Catassi; Alessio Fasano

Disclosures

Curr Opin Gastroenterol. 2008;24(6):687-691. 

In This Article

Potential New Therapies: A Future Without Gluten-free Diet?

The problems related to gluten thresholds outlined above and the major progress achieved during the last decade in the understanding of the cellular and molecular basis of celiac disease led to the identification of potential targets for novel therapies alternative to the GFD.

Enzyme Therapy

It has been shown that because of the high proline content, gliadin peptides are highly resistant to digestive processing by pancreatic and brush border proteases.[19] Enzyme supplement therapy with the use of bacterial prolyl endopeptidases has been proposed to promote complete digestion of cereal proteins and thus destroy T-cell multipotent epitopes.[20,21•] It remains to be assessed to what extent such intraluminal digestion may detoxify peptides particularly active in the most proximal part of the small intestine. An alternative approach to reduce gluten toxicity is based on a pretreatment of whole gluten or gluten-containing food with bacterial-derived peptidase.

Engineered Grains and Inhibitory Gliadin Peptides

Either breeding programs or transgenic technology or both may lead to production of wheat that is devoid of biologically active peptide sequences. Site-directed mutagenesis of wheat, which would not affect the baking properties, has also been proposed, although the number and the repetition of such sequences in wheat render this approach difficult. The identification of specific epitopes may also provide a target for immunomodulation of antigenic peptides by engineering peptide analogues of gliadin epitope(s) with antagonistic effects of native peptide(s).

Immunomodulatory Strategies

The autoantigenic tTG is mainly expressed in the lamina propria and its expression is upregulated by various stimuli, such as mechanical stress or bacterial/viral infection, during active celiac disease. Although the precise molecular details of this interaction in vivo remain unclear, selective inhibition of tTG in the small intestine might represent a therapeutically useful strategy for countering the immunotoxic response to dietary gluten in celiac disease. Other immunomodulatory targets, including IL-10, are possible alternative tools for promoting tolerance. However, evidence that gluten toxicity is not dependent only on T-cell recognition is growing. Activation of innate immunity has been demonstrated, and antibodies to IL-15 have been proposed, particularly in the treatment of refractory sprue because of the intraepithelial-lymphocyte-activating role of IL-15.[22] Nevertheless, one should realize that treated celiac disease is a benign condition and dietary treatment is safe, although strenuous. Therefore, any immunomodulatory approach must have a safety profile equivalent to that of the GFD, but with the advantage of increased compliance.

Correction of the Intestinal Barrier Defect

The ability of the intestinal mucosa to regulate the trafficking of macromolecules between the environment and the host is an extremely important function of the intestine. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to nonself antigens. When the finely tuned trafficking of macromolecules is dysregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune disorders can occur.[23] This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on either molecular mimicry or the bystander effect or both, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing the intestinal barrier function. Indeed, in many cases, increased intestinal permeability seems to precede disease and causes an abnormality in antigen delivery that triggers the multiorgan process leading to the autoimmune response.[23] Therefore, correction of the intestinal barrier defects may represent an innovative therapeutic alternative to the treatment of autoimmune diseases, including celiac disease.

The inhibition of zonulin, a modulator of intestinal permeability, has been already successfully explored in an animal model of autoimmunity.[24] More recently, the zonulin inhibitor AT-1001 has been tested in an inpatient, double-blind, randomized placebo-controlled human clinical trial to determine its safety, tolerability, and preliminary efficacy.[25••] Following acute gluten exposure, a 70% increase in intestinal permeability was detected in the placebo group, whereas no changes were seen in the AT-1001 group.[25••] Gastrointestinal symptoms were significantly more frequent among patients of the placebo group as compared with the AT-1001 group.[25••] Combined, these data suggest that AT-1001 is well tolerated and appears to reduce gluten-induced intestinal barrier dysfunction, proinflammatory cytokine production, and gastrointestinal symptoms in celiac patients.

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