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01-01-2013 | Original Research

Are Transglutaminase 2 Inhibitors Able to Reduce Gliadin-Induced Toxicity Related to Celiac Disease? A Proof-of-Concept Study

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

Published in: Journal of Clinical Immunology | Issue 1/2013

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 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.

Results

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.

Conclusions

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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Title: Are Transglutaminase 2 Inhibitors Able to Reduce Gliadin-Induced Toxicity Related to Celiac Disease? A Proof-of-Concept Study
Authors: Tiina Rauhavirta
Mikko Oittinen
Rami Kivistö
Pekka T. Männistö
J. Arturo Garcia-Horsman
Zhuo Wang
Martin Griffin
Markku Mäki
Katri Kaukinen
Katri Lindfors
Publication date: 01-01-2013
Publisher: Springer US
Published in: Journal of Clinical Immunology / Issue 1/2013
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-012-9745-5

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