Coeliac disease is a T-cell-mediated chronic inflammatory disorder with an autoimmune component. Altered processing by intraluminal enzymes, changes in intestinal permeability and activation of innate immunity mechanisms seem to precede the activation of the adaptive response. Significant progress has been made in the understanding of the cellular and molecular basis of coeliac disease and in the consequent identification of potential targets for therapy. Recently, it has been shown that gliadin peptides are highly resistant to digestive processing by pancreatic and brush border proteases. Enzyme supplement therapy using bacterial prolyl endopeptidases has been proposed to destroy T-cell multipotent epitopes. The identification of T-cell stimulatory gliadin sequences is important. Breeding programmes and/or transgenic technology may lead to the production of wheat that is devoid of biologically active peptide sequences. The identification of specific epitopes may also provide a target for immunomodulation of antigenic peptides. Other promising areas include preventing gliadin presentation to T cells by blocking HLA binding sites, use of tTG inhibitors, and assessing IL-10 as a tool 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 proposed, particularly in refractory sprue because of the intra-epithelial lymphocyte-activating role of IL-15. However, one should realise that coeliac disease is a benign disease and dietary treatment is safe, although strenuous. An immunomodulatory approach will need to have a safety profile equivalent to that of the gluten-free diet, but with the advantage of increased compliance.
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