Advertisement

The Copolymer P(HEMA-co-SS) Binds Gluten and Reduces Immune Response in Gluten-Sensitized Mice and Human Tissues

Published:November 11, 2011DOI:https://doi.org/10.1053/j.gastro.2011.10.038

      Background & Aims

      Copolymers of hydroxyethyl methacrylate and styrene sulfonate complex with isolated gliadin (the toxic fraction of gluten) and prevent damage to the intestinal barrier in HLA-HCD4/DQ8 mice. We studied the activity toward gluten and hordein digestion and biologic effects of poly(hydroxyethyl methacrylate-co-styrene sulfonate (P(HEMA-co-SS)). We also investigated the effect of gliadin complex formation in intestinal biopsy specimens from patients with celiac disease.

      Methods

      We studied the ability of P(HEMA-co-SS) to reduce digestion of wheat gluten and barley hordein into immunotoxic peptides using liquid chromatography–mass spectrometry. The biodistribution and pharmacokinetic profile of orally administered P(HEMA-co-SS) was established in rodents using tritium-labeled polymer. We assessed the capacity of P(HEMA-co-SS) to prevent the immunologic and intestinal effects induced by a gluten-food mixture in gluten-sensitized HLA-HCD4/DQ8 mice after short-term and long-term administration. We measured the effects of gliadin complex formation on cytokine release ex vivo using intestinal biopsy specimens from patients with celiac disease.

      Results

      P(HEMA-co-SS) reduced digestion of wheat gluten and barley hordein in vitro, thereby decreasing formation of toxic peptides associated with celiac disease. After oral administration to rodents, P(HEMA-co-SS) was predominantly excreted in feces, even in the presence of low-grade mucosal inflammation and increased intestinal permeability. In gluten-sensitized mice, P(HEMA-co-SS) reduced paracellular permeability, normalized anti-gliadin immunoglobulin A in intestinal washes, and modulated the systemic immune response to gluten in a food mixture. Furthermore, incubation of P(HEMA-co-SS) with mucosal biopsy specimens from patients with celiac disease showed that secretion of tumor necrosis factor-α was reduced in the presence of partially digested gliadin.

      Conclusions

      The copolymer P(HEMA-co-SS) reduced digestion of wheat gluten and barley hordein and attenuated the immune response to gluten in a food mixture in rodents. It might be developed to prevent or reduce gluten-induced disorders in humans.

      Keywords

      Abbreviations used in this paper:

      BSA (bovine serum albumin), GFD (gluten-free diet), HD (high dose), IL (interleukin), LC-MS (liquid chromatography–mass spectrometry), LD (low dose), MCP-1 (monocyte chemotactic protein 1), P(HEMA-co-SS) (poly(hydroxyethyl methacrylate-co-styrene sulfonate)), PT (peptic-tryptic), TNF (tumor necrosis factor)
      To read this article in full you will need to make a payment
      AGA Member Login
      Login with your AGA username and password.
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Purchase one-time access:

      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Fasano A.
        • Berti I.
        • Gerarduzzi T.
        • et al.
        Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.
        Arch Intern Med. 2003; 163: 286-292
        • Maki M.
        • Mustalahti K.
        • Kokkonen J.
        • et al.
        Prevalence of celiac disease among children in Finland.
        N Engl J Med. 2003; 348: 2517-2524
        • West J.
        • Logan R.F.
        • Hill P.G.
        • et al.
        Seroprevalence, correlates, and characteristics of undetected coeliac disease in England.
        Gut. 2003; 52: 960-965
        • Sollid L.M.
        Coeliac disease: dissecting a complex inflammatory disorder.
        Nat Rev Immunol. 2002; 2: 647-655
        • Garner C.P.
        • Murray J.
        • Ding Y.C.
        • et al.
        Replication of celiac disease UK genome-wide association study results in US population.
        Hum Mol Genet. 2009; 18: 4219-4225
        • Dubois P.C.A.
        • Trynka G.
        • Franke L.
        • et al.
        Multiple common variants for celiac disease influencing immune gene expression.
        Nat Genet. 2010; 42: 295-302
        • Green P.H.
        • Jabri B.
        Celiac disease.
        Annu Rev Med. 2006; 57: 207-221
        • Verdu E.F.
        • Armstrong D.
        • Murray J.A.
        Between celiac disease and irritable bowel syndrome: the “no man’s land” of gluten sensitivity.
        Am J Gastroenterol. 2009; 104: 1587-1594
        • Ludvigsson J.F.
        • Montgomery S.M.
        • Ekbom A.
        • et al.
        Small-intestinal histopathology and mortality risk in celiac disease.
        JAMA. 2009; 302: 1171-1178
        • Green P.H.R.
        Mortality in celiac disease, intestinal inflammation, and gluten sensitivity.
        JAMA. 2009; 302: 1225-1226
        • Lee A.R.
        • Ng D.L.
        • Zivin J.
        • et al.
        Economic burden of a gluten-free diet.
        J Hum Nutr Diet. 2007; 20: 423-430
        • Niewinski M.M.
        Advances in celiac disease and gluten-free diet.
        J Am Diet Assoc. 2008; 108: 661-672
        • Pinier M.
        • Fuhrmann G.
        • Verdu E.F.
        • et al.
        Prevention measures and exploratory pharmacological treatments of celiac disease.
        Am J Gastroenterol. 2010; 105: 2551-2561
        • Gianfrani C.
        • Siciliano R.A.
        • Facchiano A.M.
        • et al.
        Transamidation of wheat flour inhibits the response to gliadin of intestinal T cells in celiac disease.
        Gastroenterology. 2007; 133: 780-789
        • Van den Broeck H.C.
        • Van Herpen T.W.
        • Schuit C.
        • et al.
        Removing celiac disease-related gluten proteins from bread wheat while retaining technological properties: a study with Chinese Spring deletion lines.
        BMC Plant Biol. 2009; 9: 41-53
        • De Angelis M.
        • Rizzello C.G.
        • Fasano A.
        • et al.
        VSL#3 probiotic preparation has the capacity to hydrolyze gliadin polypeptides responsible for celiac sprue.
        Biochim Biophys Acta. 2006; 1762: 80-93
        • Gass J.
        • Bethune M.T.
        • Siegel M.
        • et al.
        Combination enzyme therapy for gastric digestion of dietary gluten in patients with celiac sprue.
        Gastroenterology. 2007; 133: 472-480
        • Tye-Din J.A.
        • Anderson R.P.
        • Ffrench R.A.
        • et al.
        The effects of ALV003 pre-digestion of gluten on immune response and symptoms in celiac disease in vivo.
        Clin Immunol. 2010; 134: 289-295
        • Fuhrmann G.
        • Leroux J.C.
        In vivo fluorescence imaging of exogenous enzyme activity in the gastrointestinal tract.
        Proc Natl Acad Sci U S A. 2011; 108: 9032-9037
        • Paterson B.M.
        • Lammers K.M.
        • Arrieta M.C.
        • et al.
        The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study.
        Aliment Pharmacol Ther. 2007; 26: 757-766
        • Kelly C.P.
        • Green P.H.
        • Murray J.A.
        • et al.
        Safety, tolerability and effects on intestinal permeability of larazotide acetate in celiac disease: results of a phase IIB 6-week gluten-challenge clinical trial (abstr).
        Gastroenterology. 2009; 136: A-474
        • Huibregtse I.L.
        • Marietta E.V.
        • Rashtak S.
        • et al.
        Induction of antigen-specific tolerance by oral administration of Lactococcus lactis delivered immunodominant DQ8-restricted gliadin peptide in sensitized nonobese diabetic Ab° Dq8 transgenic mice.
        J Immunol. 2009; 183: 2390-2396
        • Schuppan D.
        • Junker Y.
        • Barisani D.
        Celiac disease: from pathogenesis to novel therapies.
        Gastroenterology. 2009; 137: 1912-1933
        • Pardin C.
        • Roy I.
        • Lubell W.D.
        • et al.
        Reversible and competitive cinnamoyl triazole inhibitors of tissue transglutaminase.
        Chem Biol Drug Des. 2008; 72: 189-196
        • Ozaki S.
        • Ebisui E.
        • Hamada K.
        • et al.
        Potent transglutaminase inhibitors, aryl [beta]-aminoethyl ketones.
        Bioorg Med Chem Lett. 2010; 20: 1141-1144
        • Siegel M.
        • Xia J.
        • Khosla C.
        Structure-based design of alpha-amido aldehyde containing gluten peptide analogues as modulators of HLA-DQ2 and transglutaminase 2.
        Bioorg Med Chem. 2007; 15: 6253-6261
        • Dhal P.K.
        • Polomoscanik S.C.
        • Avila L.Z.
        • et al.
        Functional polymers as therapeutic agents: concept to market place.
        Adv Drug Deliv Rev. 2009; 61: 1121-1130
        • Pinier M.
        • Verdu E.F.
        • Nasser-Eddine M.
        • et al.
        Polymeric binders suppress gliadin-induced toxicity in the intestinal epithelium.
        Gastroenterology. 2009; 136: 288-298
        • Black K.E.
        • Murray J.A.
        • David C.S.
        HLA-DQ determines the response to exogenous wheat proteins: a model of gluten sensitivity in transgenic knockout mice.
        J Immunol. 2002; 169: 5595-5600
        • Verdu E.F.
        • Huang X.
        • Natividad J.
        • et al.
        Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice.
        Am J Physiol Gastrointest Liver Physiol. 2008; 294 (G217–G25)
        • Natividad J.M.
        • Huang X.
        • Slack E.
        • et al.
        Host responses to intestinal microbial antigens in gluten-sensitive mice.
        PLoS One. 2009; 4: e6472
        • Maiuri L.
        • Ciacci C.
        • Ricciardelli I.
        • et al.
        Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease.
        Lancet. 2003; 362: 30-37
        • Vader W.
        • Kooy Y.
        • Van Veelen P.
        • et al.
        The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides.
        Gastroenterology. 2002; 122: 1729-1737
        • Tye-Din J.A.
        • Stewart J.A.
        • Dromey J.A.
        • et al.
        Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease.
        Sci Transl Med. 2010; 2: 41ra51
        • Henderson K.N.
        • Tye-Din J.A.
        • Reid H.H.
        • et al.
        A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease.
        Immunity. 2007; 27: 23-34
        • Molberg O.
        • Solheim Flaete N.
        • Jensen T.
        • et al.
        Intestinal T-cell responses to high-molecular-weight glutenins in celiac disease.
        Gastroenterology. 2003; 125: 337-344
        • Vader L.W.
        • Stepniak D.T.
        • Bunnik E.M.
        • et al.
        Characterization of cereal toxicity for celiac disease patients based on protein homology in grains.
        Gastroenterology. 2003; 125: 1105-1113
        • Arentz-Hansen H.
        • Korner R.
        • Molberg O.
        • et al.
        The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase.
        J Exp Med. 2000; 191: 603-612
        • Shan L.
        • Molberg O.
        • Parrot I.
        • et al.
        Structural basis for gluten intolerance in celiac sprue.
        Science. 2002; 297: 2275-2279
        • Shan L.
        • Qiao S.W.
        • Arentz-Hansen H.
        • et al.
        Identification and analysis of multivalent proteolytically resistant peptides from gluten: implications for celiac sprue.
        J Proteome Res. 2005; 4: 1732-1741
        • Lammers K.M.
        • Lu R.
        • Brownley J.
        • et al.
        Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3.
        Gastroenterology. 2008; 135: 194-204
        • Fasano A.
        Physiological, pathological, and therapeutic implications of zonulin-mediated intestinal barrier modulation: living life on the edge of the wall.
        Am J Pathol. 2008; 173: 1243-1252
        • Matysiak-Budnik T.
        • Moura I.C.
        • Arcos-Fajardo M.
        • et al.
        Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease.
        J Exp Med. 2008; 205: 143-154
        • Molberg O.
        • McAdam S.
        • Lundin K.E.
        • et al.
        T cells from celiac disease lesions recognize gliadin epitopes deamidated in situ by endogenous tissue transglutaminase.
        Eur J Immunol. 2001; 31: 1317-1323
        • Freitag T.L.
        • Rietdijk S.
        • Junker Y.
        • et al.
        Gliadin-primed CD4+CD45RBlowCD25- T cells drive gluten-dependent small intestinal damage after adoptive transfer into lymphopenic mice.
        Gut. 2009; 58: 1597-1605
        • Menard S.
        • Cerf-Bensussan N.
        • Heyman M.
        Multiple facets of intestinal permeability and epithelial handling of dietary antigens.
        Mucosal Immunol. 2010; 3: 247-259
        • Zhou Y.F.
        • Kawasaki H.
        • Hsu S.C.
        • et al.
        Oral tolerance to food-induced systemic anaphylaxis mediated by the C-type lectin SIGNR1.
        Nat Med. 2010; 16: 1128-1134
        • Salvati V.M.
        • Mazzarella G.
        • Gianfrani C.
        • et al.
        Recombinant human interleukin 10 suppresses gliadin dependent T cell activation in ex vivo cultured coeliac intestinal mucosa.
        Gut. 2005; 54: 46-53
        • Plone M.A.
        • Petersen J.S.
        • Rosenbaum D.P.
        • et al.
        Sevelamer, a phosphate-binding polymer, is a non-absorbed compound.
        Clin Pharmacokinet. 2002; 41: 517-523
        • Liang L.
        • Pinier M.
        • Leroux J.C.
        • et al.
        Interaction of alpha-gliadin with poly(HEMA-co-SS): structural characterization and biological implication.
        Biopolymers. 2009; 91: 169-178

      Further Reading

        • Ewart J.A.D.
        Isolation of a hordein of low electrophoretic mobility.
        J Sci Food Agr. 1980; 31: 82-85
        • Van den Broeck H.C.
        • America A.H.P.
        • Smulders M.J.M.
        • et al.
        A modified extraction protocol enables detection and quantification of celiac disease-related gluten proteins from wheat.
        J Chromatog B: Anal Tech Biomed Life Sci. 2009; : 975-982
        • Black K.E.
        • Murray J.A.
        • David C.S.
        HLA-DQ determines the response to exogenous wheat proteins: a model of gluten sensitivity in transgenic knockout mice.
        J Immunol. 2002; 169: 5595-5600
        • Diehl K.H.
        • Hull R.
        • Morton D.
        • et al.
        A good practice guide to the administration of substances and removal of blood, including routes and volumes.
        J Appl Toxicol. 2001; 21: 15-23
        • Cinova J.
        • Palova-Jelinkova L.
        • Smythies L.E.
        • et al.
        Gliadin peptides activate blood monocytes from patients with celiac disease.
        J Clin Immunol. 2007; 27: 201-209