Are Transglutaminase 2 Inhibitors Able to Reduce Gliadin-Induced Toxicity Related to Celiac Disease? A Proof-of-Concept Study
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Celiac disease is an autoimmune-mediated enteropathy characterized by adaptive and innate immune responses to dietary gluten in wheat, rye and barley in genetically susceptible individuals. Gluten-derived gliadin peptides are deamidated by transglutaminase 2 (TG2), leading to an immune response in the small-intestinal mucosa. TG2 inhibitors have therefore been suggested as putative drugs for celiac disease. In this proof-of-concept study we investigated whether two TG2 inhibitors, cell-impermeable R281 and cell-permeable R283, can prevent the toxic effects of gliadin in vitro and ex vivo.
Intestinal epithelial Caco-2 cells were treated with peptic-tryptic-digested gliadin (PT-gliadin) with or without TG2 inhibitors and thereafter direct toxic effects (transepithelial resistance, cytoskeletal rearrangement, junction protein expression and phoshorylation of extracellular-signal-regulated kinase 1/2) were determined. In an organ culture of celiac-patient-derived small-intestinal biopsies we measured secretion of TG2-autoantibodies into the culture medium and the densities of CD25- and interleukin (IL) 15-positive cells, forkhead box P3 (FOXP3)-positive regulatory T cells (Tregs) and Ki-67-positive proliferating crypt cells.
Both TG2 inhibitors evinced protective effects against gliadin-induced detrimental effects in Caco-2 cells but the cell-impermeable R281 seemed slightly more potent. In addition, TG2 inhibitor R281 modified the gluten-induced increase in CD25- and IL15-positive cells, Tregs and crypt cell proliferation, but had no effect on antibody secretion in celiac-patient-derived biopsies.
Our results suggest that TG2 inhibitors are able to reduce certain gliadin-induced effects related to responses in vitro and ex vivo.
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- Are Transglutaminase 2 Inhibitors Able to Reduce Gliadin-Induced Toxicity Related to Celiac Disease? A Proof-of-Concept Study
Journal of Clinical Immunology
Volume 33, Issue 1 , pp 134-142
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- Springer US
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- Celiac disease
- transglutaminase 2 inhibitor
- small intestine
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- Author Affiliations
- 1. Pediatric Research Center, University of Tampere and Tampere University Hospital, Tampere, 33014, Finland
- 2. Division of Pharmacology and Toxicology, University of Helsinki, Helsinki, Finland
- 3. School of Life and Health Sciences, Aston University, Birmingham, UK
- 4. Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and School of Medicine, University of Tampere, Tampere, Finland