New therapeutic strategies for coeliac disease: tissue transglutaminase as a target

Coeliac disease is a multifactorial disease characterized by a dysregulated immune response to ingested wheat gluten and related cereal proteins. With an incidence of about 1% of the general population, it is considered the most common food intolerance disorder. The mainstay of coeliac disease treatment is strict lifelong adherence to a gluten-free diet. Elimination of gluten and related proteins from the diet leads to clinical and histological improvement. However, some patients do not respond to dietary therapy and others have poor dietary compliance. This has prompted the search for a therapy alternative to a gluten-free diet. Tissue transglutaminase is a crucial factor in coeliac disease because it promotes the gluten-specific T-cell response and is also the target of the autoimmune response. Tissue transglutaminase induces changes in gluten, which in turn, cause the generation of a series of gluten peptides that bind to HLA-DQ2 or DQ8 molecules with high affinity. The resulting HLA-DQ2 (DQ8)-gluten peptide interaction triggers the proinflammatory T cell response. Tissue transglutaminase is also involved in other non-T-cell-mediated biological activities of gliadin peptides. For these reasons, tissue transglutaminase is a potential target for therapeutic intervention. In this paper we review the state-of-the-art of tissue transglutaminase inhibition, and examine known and new-generation inhibitors and their activity in in vitro and in vivo models. We also examine their potential as therapeutic tools for coeliac disease.