New Therapeutic Strategies for Coeliac Disease: Tissue Transglutaminase as a Target

Abstract

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.

Transglutaminase 2 is expressed and active on the surface of human monocyte-derived dendritic cells and macrophages

“…Our observation that LPS-stimulated dendritic cells have increased csTG supports the suggestion that in an initial inflammatory response to gluten can accelerate this process [31]. Inhibition of TG2 with antibodies or selective inhibitors, therefore, can be a valid approach to palliate celiac disease [58,59].…”

Celiac Disease in Pediatric Patients with Autoimmune Hepatitis

“…[62][63][64][65][66] 3. tTG blockade: tTG is a promising target for therapeutic intervention in CD. [67] KCC009 inhibits intestinal tTG2 when given orally, is well tolerated by rodents, has a short serum half-life, and looks promising for further evaluation. [68] Since tTG2 is involved in major biologic pathways such as apoptosis, cell adhesion, signal transduction, collagen assembly, and wound repair mechanisms, its systemic inhibition could be harmful.…”

“…[68] Since tTG2 is involved in major biologic pathways such as apoptosis, cell adhesion, signal transduction, collagen assembly, and wound repair mechanisms, its systemic inhibition could be harmful. [67] 4. HLA-DQ groove blockade: The known sequence of the immunogenic gliadin epitopes provides the opportunity to immunomodulate those immune peptides.…”

Enzymatic Strategies to Detoxify Gluten: Implications for Celiac Disease

“…In order to restrain the T cell-mediated immune response to dietary gluten, a different approach could be to consider tTG as a potential therapeutic target [69]. The inhibition of the tTG-catalyzed deamidation of specific glutamine residues within naturally digested gluten peptides might not generate negatively charged amino acid residues and therefore might not increase the binding to the HLA-DQ2/DQ8 molecules (thus potentiating T cell activation).…”