Journal of Clinical Immunology

, Volume 33, Issue 1, pp 134–142

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

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

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.

Keywords

Celiac disease gliadin transglutaminase 2 inhibitor small intestine 

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Tiina Rauhavirta
    • 1
  • Mikko Oittinen
    • 1
  • Rami Kivistö
    • 2
  • Pekka T. Männistö
    • 2
  • J. Arturo Garcia-Horsman
    • 2
  • Zhuo Wang
    • 3
  • Martin Griffin
    • 3
  • Markku Mäki
    • 1
  • Katri Kaukinen
    • 4
  • Katri Lindfors
    • 1
  1. 1.Pediatric Research CenterUniversity of Tampere and Tampere University HospitalTampereFinland
  2. 2.Division of Pharmacology and ToxicologyUniversity of HelsinkiHelsinkiFinland
  3. 3.School of Life and Health SciencesAston UniversityBirminghamUK
  4. 4.Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and School of MedicineUniversity of TampereTampereFinland

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