Polymeric Binders Suppress Gliadin-Induced Toxicity in the Intestinal Epithelium
Received 22 February 2008; accepted 11 September 2008. published online 22 September 2008.
Background & Aims
Celiac disease is a prevalent immune disorder caused by the ingestion of gliadin-containing grains. We investigated the ability of a polymeric binder to reverse the toxic effects induced by gliadin in human intestinal cells and gliadin-sensitive HCD4-DQ8 mice.
Methods
Gliadin was neutralized by complexation to a linear copolymer of hydroxyethylmethacrylate (HEMA) and sodium 4-styrene sulfonate (SS). The ability of the polymeric binder to abrogate the damaging effect of gliadin on cell-cell contact was investigated in IEC-6, Caco-2/15, and primary cultured differentiated enterocytes. The efficacy of the polymeric binder in preventing gliadin-induced intestinal barrier dysfunction was assessed using gliadin-sensitive HLA-HCD4/DQ8 transgenic mice.
Results
Poly(hydroxyethylmethacrylate-co-styrene sulfonate) [P(HEMA-co-SS)] complexed with gliadin in a relatively specific fashion. Intestinal cells exposed to gliadin underwent profound alterations in morphology and cell-cell contacts. These changes were averted by complexing the gliadin with P(HEMA-co-SS). More importantly, the P(HEMA-co-SS) hindered the digestion of gliadin by gastrointestinal enzymes, thus minimizing the formation of immunogenic peptides. Coadministration of P(HEMA-co-SS) with gliadin to HLA-HCD4/DQ8 mice attenuated gliadin-induced changes in the intestinal barrier and reduced intraepithelial lymphocyte and macrophage cell counts.
Conclusions
Polymeric binders can prevent in vitro gliadin-induced epithelial toxicity and intestinal barrier dysfunction in HCD4/DQ8 mice. They have a potential role in the treatment of patients with gluten-induced disorders.
⁎Faculty of Pharmacy, University of Montreal, Montreal, Canada
‡Intestinal Disease Research Programme, Faculty of Health Sciences, McMaster University, Hamilton, Canada
§Department of Immunology, Mayo Clinic, Rochester, New York
∥CIHR Team in Digestive Epithelium, Department of Anatomy and Cellular Biology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Canada
Address requests for reprints to: Jean–Christophe Leroux, Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada. fax: (514) 343-6455
The authors disclose the following: Supported by the Canadian Celiac Association, Fonds Québécois de la Recherche sur la Nature et les Technologies, Canadian Institutes of Health Research (to N.R.), National Institutes of Health DK 071003 (to C.S.D.), CAG/CIHR New Investigator Establishment Award (to E.F.V.), and the Canada Research Chair program.
ABSTRACT