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Are Transglutaminase 2 Inhibitors Able to Reduce Gliadin-Induced Toxicity Related to Celiac Disease? A Proof-of-Concept Study.
MedLine Citation:
PMID:  22878839     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Tiina Rauhavirta; Mikko Oittinen; Rami Kivistö; Pekka T Männistö; J Arturo Garcia-Horsman; Zhuo Wang; Martin Griffin; Markku Mäki; Katri Kaukinen; Katri Lindfors
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-8-10
Journal Detail:
Title:  Journal of clinical immunology     Volume:  -     ISSN:  1573-2592     ISO Abbreviation:  J. Clin. Immunol.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-8-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8102137     Medline TA:  J Clin Immunol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Pediatric Research Center, University of Tampere and Tampere University Hospital, Tampere, 33014, Finland.
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