Are transglutaminase 2 inhibitors able to reduce gliadin-induced toxicity related to celiac disease? A proof-of-concept study

Research output: Contribution to journalArticle

View graph of relations Save citation

Authors

  • Tiina Rauhavirta
  • Mikko Oittinen
  • Rami Kivistö
  • Pekka T. Männistö
  • J. Arturo Garcia-Horsman
  • Zhuo Wang
  • Martin Griffin
  • Markku Mäki
  • Katri Kaukinen
  • Katri Lindfors

Research units

Abstract

Purpose 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. Methods 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 celiacpatient- 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 Tcells (Tregs) and Ki-67- positive proliferating crypt cells. Results Both TG2 inhibitors evinced protective effects against gliadin-induced detrimental effects in Caco-2 cells but the cellimpermeableR281seemedslightlymorepotent. Inaddition,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. Conclusions Our results suggest that TG2 inhibitors are able to reduce certain gliadin-induced effects related to responses in vitro and ex vivo.

Request a copy

Request a copy

Details

Original languageEnglish
Pages (from-to)134-142
Number of pages9
JournalJournal of Clinical Immunology
Volume33
Issue number1
Early online date10 Aug 2012
DOIs
Publication statusPublished - Jan 2013

    Keywords

  • celiac disease, gliadin, small intestine, transglutaminase 2 inhibitor

Employable Graduates; Exploitable Research

Copy the text from this field...