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Published in: Seminars in Immunopathology 4/2012

01-07-2012 | Research Article

Animal models to study gluten sensitivity

Authors: Eric V. Marietta, Joseph A. Murray

Published in: Seminars in Immunopathology | Issue 4/2012

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Abstract

The initial development and maintenance of tolerance to dietary antigens is a complex process that, when prevented or interrupted, can lead to human disease. Understanding the mechanisms by which tolerance to specific dietary antigens is attained and maintained is crucial to our understanding of the pathogenesis of diseases related to intolerance of specific dietary antigens. Two diseases that are the result of intolerance to a dietary antigen are celiac disease (CD) and dermatitis herpetiformis (DH). Both of these diseases are dependent upon the ingestion of gluten (the protein fraction of wheat, rye, and barley) and manifest in the gastrointestinal tract and skin, respectively. These gluten-sensitive diseases are two examples of how devastating abnormal immune responses to a ubiquitous food can be. The well-recognized risk genotype for both is conferred by either of the HLA class II molecules DQ2 or DQ8. However, only a minority of individuals who carry these molecules will develop either disease. Also of interest is that the age at diagnosis can range from infancy to 70–80 years of age. This would indicate that intolerance to gluten may potentially be the result of two different phenomena. The first would be that, for various reasons, tolerance to gluten never developed in certain individuals, but that for other individuals, prior tolerance to gluten was lost at some point after childhood. Of recent interest is the concept of non-celiac gluten sensitivity, which manifests as chronic digestive or neurologic symptoms due to gluten, but through mechanisms that remain to be elucidated. This review will address how animal models of gluten-sensitive disorders have substantially contributed to a better understanding of how gluten intolerance can arise and cause disease.
Literature
2.
go back to reference Fry L (2002) Dermatitis herpetiformis: problems, progress and prospects. Eur J Dermatol: EJD 12:523–531PubMed Fry L (2002) Dermatitis herpetiformis: problems, progress and prospects. Eur J Dermatol: EJD 12:523–531PubMed
3.
go back to reference March JB (2003) High antigliadin IgG titers in laboratory rabbits fed a wheat-containing diet: a model for celiac disease? Dig Dis Sci 48:608–610PubMedCrossRef March JB (2003) High antigliadin IgG titers in laboratory rabbits fed a wheat-containing diet: a model for celiac disease? Dig Dis Sci 48:608–610PubMedCrossRef
6.
go back to reference van der Kolk JH, van Putten LA, Mulder CJ, Grinwis GC, Reijm M, Butler CM, von Blomberg BM (2012) Gluten-dependent antibodies in horses with inflammatory small bowel disease (ISBD). Vet Q. doi:10.1080/01652176.2012.675636 van der Kolk JH, van Putten LA, Mulder CJ, Grinwis GC, Reijm M, Butler CM, von Blomberg BM (2012) Gluten-dependent antibodies in horses with inflammatory small bowel disease (ISBD). Vet Q. doi:10.​1080/​01652176.​2012.​675636
7.
go back to reference Batt RM, Carter MW, McLean L (1984) Morphological and biochemical studies of a naturally occurring enteropathy in the Irish setter dog: a comparison with coeliac disease in man. Res Vet Sci 37:339–346PubMed Batt RM, Carter MW, McLean L (1984) Morphological and biochemical studies of a naturally occurring enteropathy in the Irish setter dog: a comparison with coeliac disease in man. Res Vet Sci 37:339–346PubMed
8.
go back to reference Hall EJ, Batt RM (1992) Dietary modulation of gluten sensitivity in a naturally occurring enteropathy of Irish setter dogs. Gut 33:198–205PubMedCrossRef Hall EJ, Batt RM (1992) Dietary modulation of gluten sensitivity in a naturally occurring enteropathy of Irish setter dogs. Gut 33:198–205PubMedCrossRef
9.
go back to reference Polvi A, Garden OA, Houlston RS, Maki M, Batt RM, Partanen J (1998) Genetic susceptibility to gluten sensitive enteropathy in Irish setter dogs is not linked to the major histocompatibility complex. Tissue Antigens 52:543–549PubMedCrossRef Polvi A, Garden OA, Houlston RS, Maki M, Batt RM, Partanen J (1998) Genetic susceptibility to gluten sensitive enteropathy in Irish setter dogs is not linked to the major histocompatibility complex. Tissue Antigens 52:543–549PubMedCrossRef
10.
go back to reference Hall EJ, Carter SD, Barnes A, Batt RM (1992) Immune responses to dietary antigens in gluten-sensitive enteropathy of Irish setters. Res Vet Sci 53:293–299PubMedCrossRef Hall EJ, Carter SD, Barnes A, Batt RM (1992) Immune responses to dietary antigens in gluten-sensitive enteropathy of Irish setters. Res Vet Sci 53:293–299PubMedCrossRef
13.
go back to reference Sestak K, Mazumdar K, Midkiff CC, Dufour J, Borda JT, Alvarez X (2011) Recognition of epidermal transglutaminase by IgA and tissue transglutaminase 2 antibodies in a rare case of <em> rhesus</em> dermatitis. J Visualized Exp: JoVE. doi:10.3791/3154 Sestak K, Mazumdar K, Midkiff CC, Dufour J, Borda JT, Alvarez X (2011) Recognition of epidermal transglutaminase by IgA and tissue transglutaminase 2 antibodies in a rare case of <em> rhesus</em> dermatitis. J Visualized Exp: JoVE. doi:10.​3791/​3154
14.
go back to reference Powrie F, Leach MW, Mauze S, Menon S, Caddle LB, Coffman RL (1994) Inhibition of Th1 responses prevents inflammatory bowel disease in SCID mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1:553–562PubMedCrossRef Powrie F, Leach MW, Mauze S, Menon S, Caddle LB, Coffman RL (1994) Inhibition of Th1 responses prevents inflammatory bowel disease in SCID mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1:553–562PubMedCrossRef
15.
go back to reference Freitag TL, Rietdijk S, Junker Y, Popov Y, Bhan AK, Kelly CP, Terhorst C, Schuppan D (2009) Gliadin-primed CD4+ CD45RBlowCD25− T cells drive gluten-dependent small intestinal damage after adoptive transfer into lymphopenic mice. Gut 58:1597–1605. doi:10.1136/gut.2009.186361 PubMedCrossRef Freitag TL, Rietdijk S, Junker Y, Popov Y, Bhan AK, Kelly CP, Terhorst C, Schuppan D (2009) Gliadin-primed CD4+ CD45RBlowCD25− T cells drive gluten-dependent small intestinal damage after adoptive transfer into lymphopenic mice. Gut 58:1597–1605. doi:10.​1136/​gut.​2009.​186361 PubMedCrossRef
17.
go back to reference Black KE, Murray JA, David CS (2002) HLA-DQ determines the response to exogenous wheat proteins: a model of gluten sensitivity in transgenic knockout mice. J Immunol 169:5595–5600PubMed Black KE, Murray JA, David CS (2002) HLA-DQ determines the response to exogenous wheat proteins: a model of gluten sensitivity in transgenic knockout mice. J Immunol 169:5595–5600PubMed
18.
go back to reference Verdu EF, Huang X, Natividad J, Lu J, Blennerhassett PA, David CS, McKay DM, Murray JA (2008) Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice. Am J Physiol Gastrointest Liver Physiol 294:G217–G225. doi:10.1152/ajpgi.00225.2007 PubMedCrossRef Verdu EF, Huang X, Natividad J, Lu J, Blennerhassett PA, David CS, McKay DM, Murray JA (2008) Gliadin-dependent neuromuscular and epithelial secretory responses in gluten-sensitive HLA-DQ8 transgenic mice. Am J Physiol Gastrointest Liver Physiol 294:G217–G225. doi:10.​1152/​ajpgi.​00225.​2007 PubMedCrossRef
19.
go back to reference de Kauwe AL, Chen Z, Anderson RP, Keech CL, Price JD, Wijburg O, Jackson DC, Ladhams J, Allison J, McCluskey J (2009) Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressing specific anti-gliadin CD4+ T cells. J Immunol 182:7440–7450. doi:10.4049/jimmunol.0900233 PubMedCrossRef de Kauwe AL, Chen Z, Anderson RP, Keech CL, Price JD, Wijburg O, Jackson DC, Ladhams J, Allison J, McCluskey J (2009) Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressing specific anti-gliadin CD4+ T cells. J Immunol 182:7440–7450. doi:10.​4049/​jimmunol.​0900233 PubMedCrossRef
20.
go back to reference Hovhannisyan Z, Weiss A, Martin A, Wiesner M, Tollefsen S, Yoshida K, Ciszewski C, Curran SA, Murray JA, David CS, Sollid LM, Koning F, Teyton L, Jabri B (2008) The role of HLA-DQ8 beta57 polymorphism in the anti-gluten T-cell response in coeliac disease. Nature 456:534–538. doi:10.1038/nature07524 PubMedCrossRef Hovhannisyan Z, Weiss A, Martin A, Wiesner M, Tollefsen S, Yoshida K, Ciszewski C, Curran SA, Murray JA, David CS, Sollid LM, Koning F, Teyton L, Jabri B (2008) The role of HLA-DQ8 beta57 polymorphism in the anti-gluten T-cell response in coeliac disease. Nature 456:534–538. doi:10.​1038/​nature07524 PubMedCrossRef
21.
go back to reference Vader W, Kooy Y, Van Veelen P, De Ru A, Harris D, Benckhuijsen W, Pena S, Mearin L, Drijfhout JW, Koning F (2002) The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides. Gastroenterology 122:1729–1737PubMedCrossRef Vader W, Kooy Y, Van Veelen P, De Ru A, Harris D, Benckhuijsen W, Pena S, Mearin L, Drijfhout JW, Koning F (2002) The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides. Gastroenterology 122:1729–1737PubMedCrossRef
22.
go back to reference Korponay-Szabo IR, Halttunen T, Szalai Z, Laurila K, Kiraly R, Kovacs JB, Fesus L, Maki M (2004) In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies. Gut 53:641–648PubMedCrossRef Korponay-Szabo IR, Halttunen T, Szalai Z, Laurila K, Kiraly R, Kovacs JB, Fesus L, Maki M (2004) In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies. Gut 53:641–648PubMedCrossRef
23.
go back to reference Esposito C, Paparo F, Caputo I, Rossi M, Maglio M, Sblattero D, Not T, Porta R, Auricchio S, Marzari R, Troncone R (2002) Anti-tissue transglutaminase antibodies from coeliac patients inhibit transglutaminase activity both in vitro and in situ. Gut 51:177–181PubMedCrossRef Esposito C, Paparo F, Caputo I, Rossi M, Maglio M, Sblattero D, Not T, Porta R, Auricchio S, Marzari R, Troncone R (2002) Anti-tissue transglutaminase antibodies from coeliac patients inhibit transglutaminase activity both in vitro and in situ. Gut 51:177–181PubMedCrossRef
24.
go back to reference Zone JJ, Egan CA, Taylor TB, Meyer LJ (2004) IgA autoimmune disorders: development of a passive transfer mouse model. J invest Dermatol Symp Proc / Soc Invest Dermatol, Inc [and] Eur Soc Dermatol Res 9:47–51. doi:10.1111/j.1087-0024.2004.00840.x Zone JJ, Egan CA, Taylor TB, Meyer LJ (2004) IgA autoimmune disorders: development of a passive transfer mouse model. J invest Dermatol Symp Proc / Soc Invest Dermatol, Inc [and] Eur Soc Dermatol Res 9:47–51. doi:10.​1111/​j.​1087-0024.​2004.​00840.​x
25.
go back to reference Zone JJ, Taylor TB, Kadunce DP, Meyer LJ (1990) Identification of the cutaneous basement membrane zone antigen and isolation of antibody in linear immunoglobulin A bullous dermatosis. J Clin Invest 85:812–820. doi:10.1172/JCI114508 PubMedCrossRef Zone JJ, Taylor TB, Kadunce DP, Meyer LJ (1990) Identification of the cutaneous basement membrane zone antigen and isolation of antibody in linear immunoglobulin A bullous dermatosis. J Clin Invest 85:812–820. doi:10.​1172/​JCI114508 PubMedCrossRef
26.
go back to reference Zone JJ, Schmidt LA, Taylor TB, Hull CM, Sotiriou MC, Jaskowski TD, Hill HR, Meyer LJ (2011) Dermatitis herpetiformis sera or goat anti-transglutaminase-3 transferred to human skin-grafted mice mimics dermatitis herpetiformis immunopathology. J Immunol 186:4474–4480. doi:10.4049/jimmunol.1003273 PubMedCrossRef Zone JJ, Schmidt LA, Taylor TB, Hull CM, Sotiriou MC, Jaskowski TD, Hill HR, Meyer LJ (2011) Dermatitis herpetiformis sera or goat anti-transglutaminase-3 transferred to human skin-grafted mice mimics dermatitis herpetiformis immunopathology. J Immunol 186:4474–4480. doi:10.​4049/​jimmunol.​1003273 PubMedCrossRef
27.
go back to reference Sardy M, Karpati S, Merkl B, Paulsson M, Smyth N (2002) Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med 195:747–757PubMedCrossRef Sardy M, Karpati S, Merkl B, Paulsson M, Smyth N (2002) Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis. J Exp Med 195:747–757PubMedCrossRef
28.
go back to reference Di Niro R, Ziller F, Florian F, Crovella S, Stebel M, Bestagno M, Burrone O, Bradbury AR, Secco P, Marzari R, Sblattero D (2007) Construction of miniantibodies for the in vivo study of human autoimmune diseases in animal models. BMC Biotechnol 7:46. doi:10.1186/1472-6750-7-46 PubMedCrossRef Di Niro R, Ziller F, Florian F, Crovella S, Stebel M, Bestagno M, Burrone O, Bradbury AR, Secco P, Marzari R, Sblattero D (2007) Construction of miniantibodies for the in vivo study of human autoimmune diseases in animal models. BMC Biotechnol 7:46. doi:10.​1186/​1472-6750-7-46 PubMedCrossRef
31.
go back to reference Yokoyama S, Watanabe N, Sato N, Perera PY, Filkoski L, Tanaka T, Miyasaka M, Waldmann TA, Hiroi T, Perera LP (2009) Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes. Proc Natl Acad Sci USA 106:15849–15854. doi:10.1073/pnas.0908834106 PubMedCrossRef Yokoyama S, Watanabe N, Sato N, Perera PY, Filkoski L, Tanaka T, Miyasaka M, Waldmann TA, Hiroi T, Perera LP (2009) Antibody-mediated blockade of IL-15 reverses the autoimmune intestinal damage in transgenic mice that overexpress IL-15 in enterocytes. Proc Natl Acad Sci USA 106:15849–15854. doi:10.​1073/​pnas.​0908834106 PubMedCrossRef
35.
go back to reference Dubois PC, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A, Zhernakova A, Heap GA, Adany R, Aromaa A, Bardella MT, van den Berg LH, Bockett NA, de la Concha EG, Dema B, Fehrmann RS, Fernandez-Arquero M, Fiatal S, Grandone E, Green PM, Groen HJ, Gwilliam R, Houwen RH, Hunt SE, Kaukinen K, Kelleher D, Korponay-Szabo I, Kurppa K, MacMathuna P, Maki M, Mazzilli MC, McCann OT, Mearin ML, Mein CA, Mirza MM, Mistry V, Mora B, Morley KI, Mulder CJ, Murray JA, Nunez C, Oosterom E, Ophoff RA, Polanco I, Peltonen L, Platteel M, Rybak A, Salomaa V, Schweizer JJ, Sperandeo MP, Tack GJ, Turner G, Veldink JH, Verbeek WH, Weersma RK, Wolters VM, Urcelay E, Cukrowska B, Greco L, Neuhausen SL, McManus R, Barisani D, Deloukas P, Barrett JC, Saavalainen P, Wijmenga C, van Heel DA (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42:295–302. doi:10.1038/ng.543 PubMedCrossRef Dubois PC, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A, Zhernakova A, Heap GA, Adany R, Aromaa A, Bardella MT, van den Berg LH, Bockett NA, de la Concha EG, Dema B, Fehrmann RS, Fernandez-Arquero M, Fiatal S, Grandone E, Green PM, Groen HJ, Gwilliam R, Houwen RH, Hunt SE, Kaukinen K, Kelleher D, Korponay-Szabo I, Kurppa K, MacMathuna P, Maki M, Mazzilli MC, McCann OT, Mearin ML, Mein CA, Mirza MM, Mistry V, Mora B, Morley KI, Mulder CJ, Murray JA, Nunez C, Oosterom E, Ophoff RA, Polanco I, Peltonen L, Platteel M, Rybak A, Salomaa V, Schweizer JJ, Sperandeo MP, Tack GJ, Turner G, Veldink JH, Verbeek WH, Weersma RK, Wolters VM, Urcelay E, Cukrowska B, Greco L, Neuhausen SL, McManus R, Barisani D, Deloukas P, Barrett JC, Saavalainen P, Wijmenga C, van Heel DA (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42:295–302. doi:10.​1038/​ng.​543 PubMedCrossRef
36.
go back to reference Ludvigsson JF, Ludvigsson J, Ekbom A, Montgomery SM (2006) Celiac disease and risk of subsequent type 1 diabetes: a general population cohort study of children and adolescents. Diabetes Care 29:2483–2488. doi:10.2337/dc06-0794 PubMedCrossRef Ludvigsson JF, Ludvigsson J, Ekbom A, Montgomery SM (2006) Celiac disease and risk of subsequent type 1 diabetes: a general population cohort study of children and adolescents. Diabetes Care 29:2483–2488. doi:10.​2337/​dc06-0794 PubMedCrossRef
37.
go back to reference Barera G, Bonfanti R, Viscardi M, Bazzigaluppi E, Calori G, Meschi F, Bianchi C, Chiumello G (2002) Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study. Pediatrics 109:833–838PubMedCrossRef Barera G, Bonfanti R, Viscardi M, Bazzigaluppi E, Calori G, Meschi F, Bianchi C, Chiumello G (2002) Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospective longitudinal study. Pediatrics 109:833–838PubMedCrossRef
38.
go back to reference Maki M, Hallstrom O, Huupponen T, Vesikari T, Visakorpi JK (1984) Increased prevalence of coeliac disease in diabetes. Arch Dis Child 59:739–742PubMedCrossRef Maki M, Hallstrom O, Huupponen T, Vesikari T, Visakorpi JK (1984) Increased prevalence of coeliac disease in diabetes. Arch Dis Child 59:739–742PubMedCrossRef
39.
go back to reference Maurano F, Mazzarella G, Luongo D, Stefanile R, D'Arienzo R, Rossi M, Auricchio S, Troncone R (2005) Small intestinal enteropathy in non-obese diabetic mice fed a diet containing wheat. Diabetologia 48:931–937. doi:10.1007/s00125-005-1718-2 PubMedCrossRef Maurano F, Mazzarella G, Luongo D, Stefanile R, D'Arienzo R, Rossi M, Auricchio S, Troncone R (2005) Small intestinal enteropathy in non-obese diabetic mice fed a diet containing wheat. Diabetologia 48:931–937. doi:10.​1007/​s00125-005-1718-2 PubMedCrossRef
41.
go back to reference Jabri B, Sollid LM (2006) Mechanisms of disease: immunopathogenesis of celiac disease. Nat Clin Pract Gastroenterol Hepatol 3:516–525PubMedCrossRef Jabri B, Sollid LM (2006) Mechanisms of disease: immunopathogenesis of celiac disease. Nat Clin Pract Gastroenterol Hepatol 3:516–525PubMedCrossRef
43.
go back to reference Fox CJ, Paterson AD, Mortin-Toth SM, Danska JS (2000) Two genetic loci regulate T cell-dependent islet inflammation and drive autoimmune diabetes pathogenesis. Am J Hum Genet 67:67–81. doi:10.1086/302995 PubMedCrossRef Fox CJ, Paterson AD, Mortin-Toth SM, Danska JS (2000) Two genetic loci regulate T cell-dependent islet inflammation and drive autoimmune diabetes pathogenesis. Am J Hum Genet 67:67–81. doi:10.​1086/​302995 PubMedCrossRef
44.
go back to reference Rajagopalan G, Mangalam AK, Sen MM, Cheng S, Kudva YC, David CS (2007) Autoimmunity in HLA-DQ8 transgenic mice expressing granulocyte/macrophage-colony stimulating factor in the beta cells of islets of Langerhans. Autoimmunity 40:169–179. doi:10.1080/08916930701201083 PubMedCrossRef Rajagopalan G, Mangalam AK, Sen MM, Cheng S, Kudva YC, David CS (2007) Autoimmunity in HLA-DQ8 transgenic mice expressing granulocyte/macrophage-colony stimulating factor in the beta cells of islets of Langerhans. Autoimmunity 40:169–179. doi:10.​1080/​0891693070120108​3 PubMedCrossRef
45.
go back to reference Fox CJ, Danska JS (1998) Independent genetic regulation of T-cell and antigen-presenting cell participation in autoimmune islet inflammation. Diabetes 47:331–338PubMedCrossRef Fox CJ, Danska JS (1998) Independent genetic regulation of T-cell and antigen-presenting cell participation in autoimmune islet inflammation. Diabetes 47:331–338PubMedCrossRef
46.
go back to reference Marietta E, Black K, Camilleri M, Krause P, Rogers RS 3rd, David C, Pittelkow MR, Murray JA (2004) A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice. J Clin Invest 114:1090–1097. doi:10.1172/JCI21055 PubMed Marietta E, Black K, Camilleri M, Krause P, Rogers RS 3rd, David C, Pittelkow MR, Murray JA (2004) A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice. J Clin Invest 114:1090–1097. doi:10.​1172/​JCI21055 PubMed
47.
go back to reference Sababi M, Hallgren A, Nylander O (1996) Interaction between prostanoids, NO, and VIP in modulation of duodenal alkaline secretion and motility. Am J Physiol 271:G582–G590PubMed Sababi M, Hallgren A, Nylander O (1996) Interaction between prostanoids, NO, and VIP in modulation of duodenal alkaline secretion and motility. Am J Physiol 271:G582–G590PubMed
48.
go back to reference Nylander O, Hallgren A, Sababi M (2001) COX inhibition excites enteric nerves that affect motility, alkaline secretion, and permeability in rat duodenum. Am J Physiol Gastrointest Liver Physiol 281:G1169–G1178PubMed Nylander O, Hallgren A, Sababi M (2001) COX inhibition excites enteric nerves that affect motility, alkaline secretion, and permeability in rat duodenum. Am J Physiol Gastrointest Liver Physiol 281:G1169–G1178PubMed
52.
go back to reference de Koning BA, van Dieren JM, Lindenbergh-Kortleve DJ, van der Sluis M, Matsumoto T, Yamaguchi K, Einerhand AW, Samsom JN, Pieters R, Nieuwenhuis EE (2006) Contributions of mucosal immune cells to methotrexate-induced mucositis. Int Immunol 18:941–949. doi:10.1093/intimm/dxl030 PubMedCrossRef de Koning BA, van Dieren JM, Lindenbergh-Kortleve DJ, van der Sluis M, Matsumoto T, Yamaguchi K, Einerhand AW, Samsom JN, Pieters R, Nieuwenhuis EE (2006) Contributions of mucosal immune cells to methotrexate-induced mucositis. Int Immunol 18:941–949. doi:10.​1093/​intimm/​dxl030 PubMedCrossRef
53.
go back to reference DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, Marietta EV, Kasarda DD, Waldmann TA, Murray JA, Semrad C, Kupfer SS, Belkaid Y, Guandalini S, Jabri B (2011) Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471:220–224. doi:10.1038/nature09849 PubMedCrossRef DePaolo RW, Abadie V, Tang F, Fehlner-Peach H, Hall JA, Wang W, Marietta EV, Kasarda DD, Waldmann TA, Murray JA, Semrad C, Kupfer SS, Belkaid Y, Guandalini S, Jabri B (2011) Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471:220–224. doi:10.​1038/​nature09849 PubMedCrossRef
54.
go back to reference Zanzi D, Stefanile R, Santagata S, Iaffaldano L, Iaquinto G, Giardullo N, Lania G, Vigliano I, Vera AR, Ferrara K, Auricchio S, Troncone R, Mazzarella G (2011) IL-15 interferes with suppressive activity of intestinal regulatory T cells expanded in Celiac disease. Am J Gastroenterol 106:1308–1317. doi:10.1038/ajg.2011.80 PubMedCrossRef Zanzi D, Stefanile R, Santagata S, Iaffaldano L, Iaquinto G, Giardullo N, Lania G, Vigliano I, Vera AR, Ferrara K, Auricchio S, Troncone R, Mazzarella G (2011) IL-15 interferes with suppressive activity of intestinal regulatory T cells expanded in Celiac disease. Am J Gastroenterol 106:1308–1317. doi:10.​1038/​ajg.​2011.​80 PubMedCrossRef
55.
go back to reference Galipeau HJ, Rulli NE, Jury J, Huang X, Araya R, Murray JA, David CS, Chirdo FG, McCoy KD, Verdu EF (2011) Sensitization to gliadin induces moderate enteropathy and insulitis in nonobese diabetic-DQ8 mice. J Immunol 187:4338–4346. doi:10.4049/jimmunol.1100854 PubMedCrossRef Galipeau HJ, Rulli NE, Jury J, Huang X, Araya R, Murray JA, David CS, Chirdo FG, McCoy KD, Verdu EF (2011) Sensitization to gliadin induces moderate enteropathy and insulitis in nonobese diabetic-DQ8 mice. J Immunol 187:4338–4346. doi:10.​4049/​jimmunol.​1100854 PubMedCrossRef
56.
go back to reference Fehniger TA, Suzuki K, Ponnappan A, VanDeusen JB, Cooper MA, Florea SM, Freud AG, Robinson ML, Durbin J, Caligiuri MA (2001) Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J Exp Med 193:219–231PubMedCrossRef Fehniger TA, Suzuki K, Ponnappan A, VanDeusen JB, Cooper MA, Florea SM, Freud AG, Robinson ML, Durbin J, Caligiuri MA (2001) Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J Exp Med 193:219–231PubMedCrossRef
57.
go back to reference Ohta N, Hiroi T, Kweon MN, Kinoshita N, Jang MH, Mashimo T, Miyazaki J, Kiyono H (2002) IL-15-dependent activation-induced cell death-resistant Th1 type CD8 alpha beta + NK1.1+ T cells for the development of small intestinal inflammation. J Immunol 169:460–468PubMed Ohta N, Hiroi T, Kweon MN, Kinoshita N, Jang MH, Mashimo T, Miyazaki J, Kiyono H (2002) IL-15-dependent activation-induced cell death-resistant Th1 type CD8 alpha beta + NK1.1+ T cells for the development of small intestinal inflammation. J Immunol 169:460–468PubMed
58.
go back to reference Yokoyama S, Takada K, Hirasawa M, Perera LP, Hiroi T (2011) Transgenic mice that overexpress human IL-15 in enterocytes recapitulate both B and T cell-mediated pathologic manifestations of celiac disease. J Clin Immunol 31:1038–1044. doi:10.1007/s10875-011-9586-7 PubMedCrossRef Yokoyama S, Takada K, Hirasawa M, Perera LP, Hiroi T (2011) Transgenic mice that overexpress human IL-15 in enterocytes recapitulate both B and T cell-mediated pathologic manifestations of celiac disease. J Clin Immunol 31:1038–1044. doi:10.​1007/​s10875-011-9586-7 PubMedCrossRef
59.
go back to reference Du Pre MF, Kozijn AE, van Berkel LA, ter Borg MN, Lindenbergh-Kortleve D, Jensen LT, Kooy-Winkelaar Y, Koning F, Boon L, Nieuwenhuis EE, Sollid LM, Fugger L, Samsom JN (2011) Tolerance to ingested deamidated gliadin in mice is maintained by splenic, type 1 regulatory T cells. Gastroenterology 141:610–620. doi:10.1053/j.gastro.2011.04.048, 620 e611-612PubMedCrossRef Du Pre MF, Kozijn AE, van Berkel LA, ter Borg MN, Lindenbergh-Kortleve D, Jensen LT, Kooy-Winkelaar Y, Koning F, Boon L, Nieuwenhuis EE, Sollid LM, Fugger L, Samsom JN (2011) Tolerance to ingested deamidated gliadin in mice is maintained by splenic, type 1 regulatory T cells. Gastroenterology 141:610–620. doi:10.​1053/​j.​gastro.​2011.​04.​048, 620 e611-612PubMedCrossRef
60.
go back to reference Collado MC, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y (2008) Imbalances in faecal and duodenal Bifidobacterium species composition in active and non-active coeliac disease. BMC Microbiol 8:232. doi:10.1186/1471-2180-8-232 PubMedCrossRef Collado MC, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y (2008) Imbalances in faecal and duodenal Bifidobacterium species composition in active and non-active coeliac disease. BMC Microbiol 8:232. doi:10.​1186/​1471-2180-8-232 PubMedCrossRef
62.
63.
go back to reference Di Cagno R, De Angelis M, De Pasquale I, Ndagijimana M, Vernocchi P, Ricciuti P, Gagliardi F, Laghi L, Crecchio C, Guerzoni ME, Gobbetti M, Francavilla R (2011) Duodenal and faecal microbiota of celiac children: molecular, phenotype and metabolome characterization. BMC Microbiol 11:219. doi:10.1186/1471-2180-11-219 PubMedCrossRef Di Cagno R, De Angelis M, De Pasquale I, Ndagijimana M, Vernocchi P, Ricciuti P, Gagliardi F, Laghi L, Crecchio C, Guerzoni ME, Gobbetti M, Francavilla R (2011) Duodenal and faecal microbiota of celiac children: molecular, phenotype and metabolome characterization. BMC Microbiol 11:219. doi:10.​1186/​1471-2180-11-219 PubMedCrossRef
64.
go back to reference Hoorfar J, Buschard K, Dagnaes-Hansen F (1993) Prophylactic nutritional modification of the incidence of diabetes in autoimmune non-obese diabetic (NOD) mice. Br J Nutr 69:597–607PubMedCrossRef Hoorfar J, Buschard K, Dagnaes-Hansen F (1993) Prophylactic nutritional modification of the incidence of diabetes in autoimmune non-obese diabetic (NOD) mice. Br J Nutr 69:597–607PubMedCrossRef
65.
go back to reference Beales PE, Elliott RB, Flohe S, Hill JP, Kolb H, Pozzilli P, Wang GS, Wasmuth H, Scott FW (2002) A multi-centre, blinded international trial of the effect of A(1) and A(2) beta-casein variants on diabetes incidence in two rodent models of spontaneous Type I diabetes. Diabetologia 45:1240–1246. doi:10.1007/s00125-002-0898-2 PubMedCrossRef Beales PE, Elliott RB, Flohe S, Hill JP, Kolb H, Pozzilli P, Wang GS, Wasmuth H, Scott FW (2002) A multi-centre, blinded international trial of the effect of A(1) and A(2) beta-casein variants on diabetes incidence in two rodent models of spontaneous Type I diabetes. Diabetologia 45:1240–1246. doi:10.​1007/​s00125-002-0898-2 PubMedCrossRef
67.
go back to reference Funda DP, Kaas A, Bock T, Tlaskalova-Hogenova H, Buschard K (1999) Gluten-free diet prevents diabetes in NOD mice. Diabetes Metab Res Rev 15:323–327. doi:10.1002/(SICI)1520-7560(199909/10)15:5<323::AID-DMRR53>3.0.CO;2-PPubMedCrossRef Funda DP, Kaas A, Bock T, Tlaskalova-Hogenova H, Buschard K (1999) Gluten-free diet prevents diabetes in NOD mice. Diabetes Metab Res Rev 15:323–327. doi:10.1002/(SICI)1520-7560(199909/10)15:5<323::AID-DMRR53>3.0.CO;2-PPubMedCrossRef
68.
go back to reference Karges W, Hammond-McKibben D, Cheung RK, Visconti M, Shibuya N, Kemp D, Dosch HM (1997) Immunological aspects of nutritional diabetes prevention in NOD mice: a pilot study for the cow's milk-based IDDM prevention trial. Diabetes 46:557–564PubMedCrossRef Karges W, Hammond-McKibben D, Cheung RK, Visconti M, Shibuya N, Kemp D, Dosch HM (1997) Immunological aspects of nutritional diabetes prevention in NOD mice: a pilot study for the cow's milk-based IDDM prevention trial. Diabetes 46:557–564PubMedCrossRef
70.
go back to reference Hummel S, Pfluger M, Hummel M, Bonifacio E, Ziegler AG (2011) Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care 34:1301–1305. doi:10.2337/dc10-2456 PubMedCrossRef Hummel S, Pfluger M, Hummel M, Bonifacio E, Ziegler AG (2011) Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care 34:1301–1305. doi:10.​2337/​dc10-2456 PubMedCrossRef
71.
go back to reference Scott FW, Rowsell P, Wang GS, Burghardt K, Kolb H, Flohe S (2002) Oral exposure to diabetes-promoting food or immunomodulators in neonates alters gut cytokines and diabetes. Diabetes 51:73–78PubMedCrossRef Scott FW, Rowsell P, Wang GS, Burghardt K, Kolb H, Flohe S (2002) Oral exposure to diabetes-promoting food or immunomodulators in neonates alters gut cytokines and diabetes. Diabetes 51:73–78PubMedCrossRef
72.
go back to reference Visser J, Hillebrands JL, Boer MW, Bos NA, Rozing J (2009) Prevention of diabetes by a hydrolysed casein-based diet in diabetes-prone biobreeding rats does not involve restoration of the defective natural regulatory T cell function. Diabetologia 52:1445–1447. doi:10.1007/s00125-009-1370-3 PubMedCrossRef Visser J, Hillebrands JL, Boer MW, Bos NA, Rozing J (2009) Prevention of diabetes by a hydrolysed casein-based diet in diabetes-prone biobreeding rats does not involve restoration of the defective natural regulatory T cell function. Diabetologia 52:1445–1447. doi:10.​1007/​s00125-009-1370-3 PubMedCrossRef
73.
go back to reference Visser J, Brugman S, Klatter F, Vis L, Groen H, Strubbe J, Rozing J (2003) Short-term dietary adjustment with a hydrolyzed casein-based diet postpones diabetes development in the diabetes-prone BB rat. Metab: Clin Exp 52:333–337. doi:10.1053/meta.2003.50052 CrossRef Visser J, Brugman S, Klatter F, Vis L, Groen H, Strubbe J, Rozing J (2003) Short-term dietary adjustment with a hydrolyzed casein-based diet postpones diabetes development in the diabetes-prone BB rat. Metab: Clin Exp 52:333–337. doi:10.​1053/​meta.​2003.​50052 CrossRef
74.
go back to reference MacFarlane AJ, Burghardt KM, Kelly J, Simell T, Simell O, Altosaar I, Scott FW (2003) A type 1 diabetes-related protein from wheat (Triticum aestivum). cDNA clone of a wheat storage globulin, Glb1, linked to islet damage. J Biol Chem 278:54–63. doi:10.1074/jbc.M210636200 PubMedCrossRef MacFarlane AJ, Burghardt KM, Kelly J, Simell T, Simell O, Altosaar I, Scott FW (2003) A type 1 diabetes-related protein from wheat (Triticum aestivum). cDNA clone of a wheat storage globulin, Glb1, linked to islet damage. J Biol Chem 278:54–63. doi:10.​1074/​jbc.​M210636200 PubMedCrossRef
75.
go back to reference Loit E, Melnyk CW, MacFarlane AJ, Scott FW, Altosaar I (2009) Identification of three wheat globulin genes by screening a Triticum aestivum BAC genomic library with cDNA from a diabetes-associated globulin. BMC Plant Biol 9:93. doi:10.1186/1471-2229-9-93 PubMedCrossRef Loit E, Melnyk CW, MacFarlane AJ, Scott FW, Altosaar I (2009) Identification of three wheat globulin genes by screening a Triticum aestivum BAC genomic library with cDNA from a diabetes-associated globulin. BMC Plant Biol 9:93. doi:10.​1186/​1471-2229-9-93 PubMedCrossRef
76.
go back to reference Sapone A, de Magistris L, Pietzak M, Clemente MG, Tripathi A, Cucca F, Lampis R, Kryszak D, Carteni M, Generoso M, Iafusco D, Prisco F, Laghi F, Riegler G, Carratu R, Counts D, Fasano A (2006) Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes 55:1443–1449PubMedCrossRef Sapone A, de Magistris L, Pietzak M, Clemente MG, Tripathi A, Cucca F, Lampis R, Kryszak D, Carteni M, Generoso M, Iafusco D, Prisco F, Laghi F, Riegler G, Carratu R, Counts D, Fasano A (2006) Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes 55:1443–1449PubMedCrossRef
77.
go back to reference Smecuol E, Sugai E, Niveloni S, Vazquez H, Pedreira S, Mazure R, Moreno ML, Label M, Maurino E, Fasano A, Meddings J, Bai JC (2005) Permeability, zonulin production, and enteropathy in dermatitis herpetiformis. Clin Gastroenterol Hepatol: Off Clin Pract J Am Gastroenterol Assoc 3:335–341 Smecuol E, Sugai E, Niveloni S, Vazquez H, Pedreira S, Mazure R, Moreno ML, Label M, Maurino E, Fasano A, Meddings J, Bai JC (2005) Permeability, zonulin production, and enteropathy in dermatitis herpetiformis. Clin Gastroenterol Hepatol: Off Clin Pract J Am Gastroenterol Assoc 3:335–341
78.
go back to reference Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN, Fasano A (2008) Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology 135:194–204. doi:10.1053/j.gastro.2008.03.023 PubMedCrossRef Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN, Fasano A (2008) Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology 135:194–204. doi:10.​1053/​j.​gastro.​2008.​03.​023 PubMedCrossRef
80.
go back to reference Sonier B, Strom A, Wang GS, Patrick C, Crookshank JA, Mojibian M, MacFarlane AJ, Scott FW (2011) Antibodies from a patient with type 1 diabetes and celiac disease bind to macrophages that express the scavenger receptor CD163. J Can Gastroenterol 25:327–329 Sonier B, Strom A, Wang GS, Patrick C, Crookshank JA, Mojibian M, MacFarlane AJ, Scott FW (2011) Antibodies from a patient with type 1 diabetes and celiac disease bind to macrophages that express the scavenger receptor CD163. J Can Gastroenterol 25:327–329
81.
go back to reference Huibregtse IL, Marietta EV, Rashtak S, Koning F, Rottiers P, David CS, van Deventer SJ, Murray JA (2009) Induction of antigen-specific tolerance by oral administration of Lactococcus lactis delivered immunodominant DQ8-restricted gliadin peptide in sensitized nonobese diabetic Abo Dq8 transgenic mice. J Immunol 183:2390–2396. doi:10.4049/jimmunol.0802891 PubMedCrossRef Huibregtse IL, Marietta EV, Rashtak S, Koning F, Rottiers P, David CS, van Deventer SJ, Murray JA (2009) Induction of antigen-specific tolerance by oral administration of Lactococcus lactis delivered immunodominant DQ8-restricted gliadin peptide in sensitized nonobese diabetic Abo Dq8 transgenic mice. J Immunol 183:2390–2396. doi:10.​4049/​jimmunol.​0802891 PubMedCrossRef
82.
go back to reference Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F, Falk W, Fiers W, Remaut E (2000) Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 289:1352–1355PubMedCrossRef Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F, Falk W, Fiers W, Remaut E (2000) Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 289:1352–1355PubMedCrossRef
83.
86.
go back to reference Endo H, Higurashi T, Hosono K, Sakai E, Sekino Y, Iida H, Sakamoto Y, Koide T, Takahashi H, Yoneda M, Tokoro C, Inamori M, Abe Y, Nakajima A (2011) Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low-dose aspirin users: a pilot randomized controlled study. J Gastroenterol 46:894–905. doi:10.1007/s00535-011-0410-1 PubMedCrossRef Endo H, Higurashi T, Hosono K, Sakai E, Sekino Y, Iida H, Sakamoto Y, Koide T, Takahashi H, Yoneda M, Tokoro C, Inamori M, Abe Y, Nakajima A (2011) Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low-dose aspirin users: a pilot randomized controlled study. J Gastroenterol 46:894–905. doi:10.​1007/​s00535-011-0410-1 PubMedCrossRef
87.
go back to reference Keech CL, Dromey J, Chen ZJ, Anderson RP, McCluskey J (2009) Immune tolerance induced by peptide immunotherapy in an HLA Dq2-dependent mouse model of gluten immunity. Gastroenterology 136:A57–A57CrossRef Keech CL, Dromey J, Chen ZJ, Anderson RP, McCluskey J (2009) Immune tolerance induced by peptide immunotherapy in an HLA Dq2-dependent mouse model of gluten immunity. Gastroenterology 136:A57–A57CrossRef
88.
go back to reference Senger S, Luongo D, Maurano F, Mazzeo MF, Siciliano RA, Gianfrani C, David C, Troncone R, Auricchio S, Rossi M (2003) Intranasal administration of a recombinant alpha-gliadin down-regulates the immune response to wheat gliadin in DQ8 transgenic mice. Immunol Lett 88:127–134PubMedCrossRef Senger S, Luongo D, Maurano F, Mazzeo MF, Siciliano RA, Gianfrani C, David C, Troncone R, Auricchio S, Rossi M (2003) Intranasal administration of a recombinant alpha-gliadin down-regulates the immune response to wheat gliadin in DQ8 transgenic mice. Immunol Lett 88:127–134PubMedCrossRef
90.
go back to reference Malamut G, El Machhour R, Montcuquet N, Martin-Lanneree S, Dusanter-Fourt I, Verkarre V, Mention JJ, Rahmi G, Kiyono H, Butz EA, Brousse N, Cellier C, Cerf-Bensussan N, Meresse B (2010) IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest 120:2131–2143. doi:10.1172/JCI41344 PubMedCrossRef Malamut G, El Machhour R, Montcuquet N, Martin-Lanneree S, Dusanter-Fourt I, Verkarre V, Mention JJ, Rahmi G, Kiyono H, Butz EA, Brousse N, Cellier C, Cerf-Bensussan N, Meresse B (2010) IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest 120:2131–2143. doi:10.​1172/​JCI41344 PubMedCrossRef
91.
go back to reference Drago S, El Asmar R, Di Pierro M, Grazia Clemente M, Tripathi A, Sapone A, Thakar M, Iacono G, Carroccio A, D'Agate C, Not T, Zampini L, Catassi C, Fasano A (2006) Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol 41:408–419. doi:10.1080/00365520500235334 PubMedCrossRef Drago S, El Asmar R, Di Pierro M, Grazia Clemente M, Tripathi A, Sapone A, Thakar M, Iacono G, Carroccio A, D'Agate C, Not T, Zampini L, Catassi C, Fasano A (2006) Gliadin, zonulin and gut permeability: effects on celiac and non-celiac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol 41:408–419. doi:10.​1080/​0036552050023533​4 PubMedCrossRef
93.
go back to reference Gopalakrishnan S, Durai M, Kitchens K, Tamiz AP, Somerville R, Ginski M, Paterson BM, Murray JA, Verdu EF, Alkan SS, Pandey NB (2012) Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides. doi:10.1016/j.peptides.2012.02.015 Gopalakrishnan S, Durai M, Kitchens K, Tamiz AP, Somerville R, Ginski M, Paterson BM, Murray JA, Verdu EF, Alkan SS, Pandey NB (2012) Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides. doi:10.​1016/​j.​peptides.​2012.​02.​015
94.
go back to reference Bergamo P, Maurano F, Mazzarella G, Iaquinto G, Vocca I, Rivelli AR, De Falco E, Gianfrani C, Rossi M (2011) Immunological evaluation of the alcohol-soluble protein fraction from gluten-free grains in relation to celiac disease. Mol Nutr Food Res 55:1266–1270. doi:10.1002/mnfr.201100132 PubMedCrossRef Bergamo P, Maurano F, Mazzarella G, Iaquinto G, Vocca I, Rivelli AR, De Falco E, Gianfrani C, Rossi M (2011) Immunological evaluation of the alcohol-soluble protein fraction from gluten-free grains in relation to celiac disease. Mol Nutr Food Res 55:1266–1270. doi:10.​1002/​mnfr.​201100132 PubMedCrossRef
Metadata
Title
Animal models to study gluten sensitivity
Authors
Eric V. Marietta
Joseph A. Murray
Publication date
01-07-2012
Publisher
Springer-Verlag
Published in
Seminars in Immunopathology / Issue 4/2012
Print ISSN: 1863-2297
Electronic ISSN: 1863-2300
DOI
https://doi.org/10.1007/s00281-012-0315-y

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