Overview of Mouse Models of Inflammatory Bowel Disease and Their Use in Drug Discovery

Joseph R. Maxwell1, Joanne L. Viney1

1 Amgen, Thousand Oaks, California
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 5.57
DOI:  10.1002/0471141755.ph0557s47
Online Posting Date:  December, 2009
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library


Inflammatory bowel disease (IBD), a condition that affects millions of individuals, encompasses two distinct conditions: Crohn's disease (CD) and ulcerative colitis (UC). CD is an inflammatory condition affecting any part of the digestive tract between the mouth and anus, but, most commonly, the ileum and colon. It is distinguished by the presence of granulomas in the mucosal tissue and patchy areas of transmural inflammation. UC is restricted to the colon and is manifest as continuous inflammation starting from the rectum and extending back towards the cecum. Inflammation in UC is primarily restricted to mucosal layers. Research is ongoing to understand the causality of these two diseases, and advances in understanding of their pathology have resulted from the variety of mouse models of IBD that have emerged since the early 1990s. Described in this unit are contemporary mouse models of these conditions and examples of their use in drug discovery. Curr. Protoc. Pharmacol. 47:5.57.1‐5.57.19. © 2009 by John Wiley & Sons, Inc.

Keywords: IBD; mouse; model; colitis

PDF or HTML at Wiley Online Library

Table of Contents

  • Mouse Models of IBD
  • Mouse Models of IBD Have Been Useful for Predicting Clinical Response
  • What Else Do These Models Predict?
  • The Right Model for the Job
  • Literature Cited
  • Figures
  • Tables
PDF or HTML at Wiley Online Library


PDF or HTML at Wiley Online Library



Literature Cited

Literature Cited
   Apostolaki, M., Manoloukos, M., Roulis, M., Wurbel, M.A., Muller, W., Papadakis, K.A., Kontoyiannis, D.L., Malissen, B., and Kollias, G. 2008. Role of beta7 integrin and the chemokine/chemokine receptor pair CCL25/CCR9 in modeled TNF‐dependent Crohn's disease. Gastroenterology 134:2025‐2035.
   Atreya, R., Mudter, J., Finotto, S., Mullberg, J., Jostock, T., Wirtz, S., Schutz, M., Bartsch, B., Holtmann, M., Becker, C., Strand, D., Czaja, J., Schlaak, J.F., Lehr, H.A., Autschbach, F., Schürmann, G., Nishimoto, N., Yoshizaki, K., Ito, H., Kishimoto, T., Galle, P.R., Rose‐John, S., and Neurath, M.F. 2000. Blockade of interleukin 6 trans signaling suppresses T‐cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn disease and experimental colitis in vivo. Nat. Med. 6:583‐588.
   Axelsson, L.G., Landstrom, E., and Bylund‐Fellenius, A.C. 1998. Experimental colitis induced by dextran sulphate sodium in mice: Beneficial effects of sulphasalazine and olsalazine. Aliment. Pharmacol. Ther. 12:925‐934.
   Bamias, G., Martin, C., Mishina, M., Ross, W.G., Rivera‐Nieves, J., Marini, M., and Cominelli, F. 2005. Proinflammatory effects of TH2 cytokines in a murine model of chronic small intestinal inflammation. Gastroenterology 128:654‐666.
   Bamias, G., Okazawa, A., Rivera‐Nieves, J., Arseneau, K.O., De La Rue, S.A., Pizarro, T.T., and Cominelli, F. 2007. Commensal bacteria exacerbate intestinal inflammation but are not essential for the development of murine ileitis. J. Immunol. 178:1809‐1818.
   Berg, D.J., Davidson, N., Kuhn, R., Muller, W., Menon, S., Holland, G., Thompson‐Snipes, L., Leach, M.W., and Rennick, D. 1996. Enterocolitis and colon cancer in interleukin‐10‐deficient mice are associated with aberrant cytokine production and CD4(+) TH1‐like responses. J. Clin. Invest. 98:1010‐1020.
   Boirivant, M., Fuss, I.J., Chu, A., and Strober, W. 1998. Oxazolone colitis: A murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4. J. Exp. Med. 188:1929‐1939.
   Brandwein, S.L., McCabe, R.P., Cong, Y., Waites, K.B., Ridwan, B.U., Dean, P.A., Ohkusa, T., Birkenmeier, E.H., Sundberg, J.P., and Elson, C.O. 1997. Spontaneously colitic C3H/HeJBir mice demonstrate selective antibody reactivity to antigens of the enteric bacterial flora. J. Immunol. 159:44‐52.
   Burns, R.C., Rivera‐Nieves, J., Moskaluk, C.A., Matsumoto, S., Cominelli, F., and Ley, K. 2001. Antibody blockade of ICAM‐1 and VCAM‐1 ameliorates inflammation in the SAMP‐1/Yit adoptive transfer model of Crohn's disease in mice. Gastroenterology 121:1428‐1436.
   Cahill, R.J., Foltz, C.J., Fox, J.G., Dangler, C.A., Powrie, F., and Schauer, D.B. 1997. Inflammatory bowel disease: An immunity‐mediated condition triggered by bacterial infection with Helicobacter hepaticus. Infect. Immun. 65:3126‐3131.
   Cong, Y., Brandwein, S.L., McCabe, R.P., Lazenby, A., Birkenmeier, E.H., Sundberg, J.P., and Elson, C.O. 1998. CD4+ T cells reactive to enteric bacterial antigens in spontaneously colitic C3H/HeJBir mice: Increased T helper cell type 1 response and ability to transfer disease. J. Exp. Med. 187:855‐864.
   Contractor, N.V., Bassiri, H., Reya, T., Park, A.Y., Baumgart, D.C., Wasik, M.A., Emerson, S.G., and Carding, S.R. 1998. Lymphoid hyperplasia, autoimmunity, and compromised intestinal intraepithelial lymphocyte development in colitis‐free gnotobiotic IL‐2‐deficient mice. J. Immunol. 160:385‐394.
   Cooper, H.S., Murthy, S.N., Shah, R.S., and Sedergran, D.J. 1993. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab. Invest. 69:238‐249.
   Daniel, C., Sartory, N.A., Zahn, N., Radeke, H.H., and Stein, J.M. 2008. Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile. J. Pharmacol. Exp. Ther. 324:23‐33.
   Dave, S.H., Tilstra, J.S., Matsuoka, K., Li, F., Karrasch, T., Uno, J.K., Sepulveda, A.R., Jobin, C., Baldwin, A.S., Robbins, P.D., and Plevy, S.E. 2007. Amelioration of chronic murine colitis by peptide‐mediated transduction of the IkappaB kinase inhibitor NEMO binding domain peptide. J. Immunol. 179:7852‐7859.
   Davidson, N.J., Hudak, S.A., Lesley, R.E., Menon, S., Leach, M.W., and Rennick, D.M. 1998. IL‐12, but not IFN‐gamma, plays a major role in sustaining the chronic phase of colitis in IL‐10‐deficient mice. J. Immunol. 161:3143‐3149.
   Dieleman, L.A., Ridwan, B.U., Tennyson, G.S., Beagley, K.W., Bucy, R.P., and Elson, C.O. 1994. Dextran sulfate sodium‐induced colitis occurs in severe combined immunodeficient mice. Gastroenterology 107:1643‐1652.
   Duchmann, R., Schmitt, E., Knolle, P., Meyer zum Buschenfelde, K.H., and Neurath, M. 1996. Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin‐10 or antibodies to interleukin‐12. Eur. J. Immunol. 26:934‐938.
   Elson, C.O., Beagley, K.W., Sharmanov, A.T., Fujihashi, K., Kiyono, H., Tennyson, G.S., Cong, Y., Black, C.A., Ridwan, B.W., and McGhee, J.R. 1996. Hapten‐induced model of murine inflammatory bowel disease: Mucosa immune responses and protection by tolerance. J. Immunol. 157:2174‐2185.
   Elson, C.O., Cong, Y., Weaver, C.T., Schoeb, T.R., McClanahan, T.K., Fick, R.B., and Kastelein, R.A. 2007. Monoclonal anti‐interleukin 23 reverses active colitis in a T cell‐mediated model in mice. Gastroenterology 132:2359‐2370.
   Fichtner‐Feigl, S., Fuss, I.J., Young, C.A., Watanabe, T., Geissler, E.K., Schlitt, H.J., Kitani, A., and Strober, W. 2007. Induction of IL‐13 triggers TGF‐beta1‐dependent tissue fibrosis in chronic 2,4,6‐trinitrobenzene sulfonic acid colitis. J. Immunol. 178:5859‐5870.
   Fiorucci, S., Mencarelli, A., Palazzetti, B., Sprague, A.G., Distrutti, E., Morelli, A., Novobrantseva, T.I., Cirino, G., Koteliansky, V.E., and de Fougerolles, A.R. 2002. Importance of innate immunity and collagen binding integrin alpha1beta1 in TNBS‐induced colitis. Immunity 17:769‐780.
   Fiorucci, S., Wallace, J.L., Mencarelli, A., Distrutti, E., Rizzo, G., Farneti, S., Morelli, A., Tseng, J.L., Suramanyam, B., Guilford, W.J., and Parkinson, J.F. 2004. A beta‐oxidation‐resistant lipoxin A4 analog treats hapten‐induced colitis by attenuating inflammation and immune dysfunction. Proc. Natl. Acad. Sci. U.S.A. 101:15736‐15741.
   Fiorucci, S., Orlandi, S., Mencarelli, A., Caliendo, G., Santagada, V., Distrutti, E., Santucci, L., Cirino, G., and Wallace, J.L. 2007. Enhanced activity of a hydrogen sulphide–releasing derivative of mesalamine (ATB‐429) in a mouse model of colitis. Br. J. Pharmacol. 150:996‐1002.
   Garrett, W.S., Lord, G.M., Punit, S., Lugo‐Villarino, G., Mazmanian, S.K., Ito, S., Glickman, J.N., and Glimcher, L.H. 2007. Communicable ulcerative colitis induced by T‐bet deficiency in the innate immune system. Cell 131:33‐45.
   Gorelik, L. and Flavell, R.A. 2000. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12:171‐181.
   Heller, F., Fuss, I.J., Nieuwenhuis, E.E., Blumberg, R.S., and Strober, W. 2002. Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL‐13‐producing NK‐T cells. Immunity 17:629‐638.
   Hermiston, M.L. and Gordon, J.I. 1995. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N‐cadherin. Science 270:1203‐1207.
   Hue, S., Ahern, P., Buonocore, S., Kullberg, M.C., Cua, D.J., McKenzie, B.S., Powrie, F., and Maloy, K.J. 2006. Interleukin‐23 drives innate and T cell‐mediated intestinal inflammation. J. Exp. Med. 203:2473‐2483.
   Iijima, H., Takahashi, I., Kishi, D., Kim, J.K., Kawano, S., Hori, M., and Kiyono, H. 1999. Alteration of interleukin 4 production results in the inhibition of T helper type 2 cell‐dominated inflammatory bowel disease in T cell receptor alpha chain‐deficient mice. J. Exp. Med. 190:607‐615.
   Ikenoue, Y., Tagami, T., and Murata, M. 2005. Development and validation of a novel IL‐10 deficient cell transfer model for colitis. Int. Immunopharmacol. 5:993‐1006.
   Ito, R., Shin‐Ya, M., Kishida, T., Urano, A., Takada, R., Sakagami, J., Imanishi, J., Kita, M., Ueda, Y., Iwakura, Y., Kataoka, K., Okanoue, T., and Mazda, O. 2006. Interferon‐gamma is causatively involved in experimental inflammatory bowel disease in mice. Clin. Exp. Immunol. 146:330‐338.
   Kang, S.S., Bloom, S.M., Norian, L.A., Geske, M.J., Flavell, R.A., Stappenbeck, T.S., and Allen, P.M. 2008. An antibiotic‐responsive mouse model of fulminant ulcerative colitis. PLoS Med. 5:e41.
   Kato, S., Hokari, R., Matsuzaki, K., Iwai, A., Kawaguchi, A., Nagao, S., Miyahara, T., Itoh, K., Ishii, H., and Miura, S. 2000. Amelioration of murine experimental colitis by inhibition of mucosal addressin cell adhesion molecule‐1. J. Pharmacol. Exp. Ther. 295:183‐189.
   Kawaguchi‐Miyashita, M., Shimada, S., Kurosu, H., Kato‐Nagaoka, N., Matsuoka, Y., Ohwaki, M., Ishikawa, H., and Nanno, M. 2001. An accessory role of TCRgammadelta (+) cells in the exacerbation of inflammatory bowel disease in TCRalpha mutant mice. Eur. J. Immunol. 31:980‐988.
   Kobayashi, M., Kweon, M.N., Kuwata, H., Schreiber, R.D., Kiyono, H., Takeda, K., and Akira, S. 2003. Toll‐like receptor‐dependent production of IL‐12p40 causes chronic enterocolitis in myeloid cell‐specific Stat3‐deficient mice. J. Clin. Invest. 111:1297‐1308.
   Kojima, R., Kuroda, S., Ohkishi, T., Nakamaru, K., and Hatakeyama, S. 2004. Oxazolone‐induced colitis in BALB/C mice: A new method to evaluate the efficacy of therapeutic agents for ulcerative colitis. J. Pharmacol. Sci. 96:307‐313.
   Kojouharoff, G., Hans, W., Obermeier, F., Mannel, D.N., Andus, T., Scholmerich, J., Gross, V., and Falk, W. 1997. Neutralization of tumour necrosis factor (TNF) but not of IL‐1 reduces inflammation in chronic dextran sulphate sodium‐induced colitis in mice. Clin. Exp. Immunol. 107:353‐358.
   Kontoyiannis, D., Pasparakis, M., Pizarro, T.T., Cominelli, F., and Kollias, G. 1999. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU‐rich elements: Implications for joint and gut‐associated immunopathologies. Immunity 10:387‐398.
   Kontoyiannis, D., Boulougouris, G., Manoloukos, M., Armaka, M., Apostolaki, M., Pizarro, T., Kotlyarov, A., Forster, I., Flavell, R., Gaestel, M., Tsichlis, P., Cominelli, F., and Kollias, G. 2002. Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor‐induced Crohn's‐like inflammatory bowel disease. J. Exp. Med. 196:1563‐1574.
   Kosiewicz, M.M., Nast, C.C., Krishnan, A., Rivera‐Nieves, J., Moskaluk, C.A., Matsumoto, S., Kozaiwa, K., and Cominelli, F. 2001. Th1‐type responses mediate spontaneous ileitis in a novel murine model of Crohn's disease. J. Clin. Invest. 107:695‐702.
   Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K., and Muller, W. 1993. Interleukin‐10‐deficient mice develop chronic enterocolitis. Cell 75:263‐274.
   Kullberg, M.C., Rothfuchs, A.G., Jankovic, D., Caspar, P., Wynn, T.A., Gorelick, P.L., Cheever, A.W., and Sher, A. 2001. Helicobacter hepaticus–induced colitis in interleukin‐10‐deficient mice: Cytokine requirements for the induction and maintenance of intestinal inflammation. Infect. Immun. 69:4232‐4241.
   Li, X., Fox, J.G., Whary, M.T., Yan, L., Shames, B., and Zhao, Z. 1998. SCID/NCr mice naturally infected with Helicobacter hepaticus develop progressive hepatitis, proliferative typhlitis, and colitis. Infect. Immun. 66:5477‐5484.
   Maggio‐Price, L., Shows, D., Waggie, K., Burich, A., Zeng, W., Escobar, S., Morrissey, P., and Viney, J.L. 2002. Helicobacter bilis infection accelerates and H. hepaticus infection delays the development of colitis in multiple drug resistance‐deficient (mdr1a−/−) mice. Am. J. Pathol. 160:739‐751.
   Mahler, M., Bristol, I.J., Leiter, E.H., Workman, A.E., Birkenmeier, E.H., Elson, C.O., and Sundberg, J.P. 1998. Differential susceptibility of inbred mouse strains to dextran sulfate sodium‐induced colitis. Am. J. Physiol. 274:G544‐551.
   Mahler, M. and Leiter, E.H. 2002. Genetic and environmental context determines the course of colitis developing in IL‐10‐deficient mice. Inflamm. Bowel Dis. 8:347‐355.
   Mannon, P.J., Fuss, I.J., Mayer, L., Elson, C.O., Sandborn, W.J., Present, D., Dolin, B., Goodman, N., Groden, C., Hornung, R.L., Quezado, M., Neurath, M.F., Salfeld, J., Veldman, G.M., Schwertschlag, U., and Strober, W. 2004. Anti‐interleukin‐12 antibody for active Crohn's disease. N. Engl. J. Med. 351:2069‐2079.
   Marini, M., Bamias, G., Rivera‐Nieves, J., Moskaluk, C.A., Hoang, S.B., Ross, W.G., Pizarro, T.T., and Cominelli, F. 2003. TNF‐alpha neutralization ameliorates the severity of murine Crohn's‐like ileitis by abrogation of intestinal epithelial cell apoptosis. Proc. Natl. Acad. Sci. U.S.A. 100:8366‐8371.
   Matsumoto, S., Okabe, Y., Setoyama, H., Takayama, K., Ohtsuka, J., Funahashi, H., Imaoka, A., Okada, Y., and Umesaki, Y. 1998. Inflammatory bowel disease‐like enteritis and caecitis in a senescence accelerated mouse P1/Yit strain. Gut 43:71‐78.
   Mitsuyama, K., Matsumoto, S., Rose‐John, S., Suzuki, A., Hara, T., Tomiyasu, N., Handa, K., Tsuruta, O., Funabashi, H., Scheller, J., Toyonaga, A., and Sata, M. 2006. STAT3 activation via interleukin 6 trans‐signalling contributes to ileitis in SAMP1/Yit mice. Gut 55:1263‐1269.
   Mizoguchi, A., Mizoguchi, E., Smith, R.N., Preffer, F.I., and Bhan, A.K. 1997. Suppressive role of B cells in chronic colitis of T cell receptor alpha mutant mice. J. Exp. Med. 186:1749‐1756.
   Mizoguchi, A., Mizoguchi, E., and Bhan, A.K. 1999. The critical role of interleukin 4 but not interferon gamma in the pathogenesis of colitis in T‐cell receptor alpha mutant mice. Gastroenterology 116:320‐326.
   Mombaerts, P., Mizoguchi, E., Grusby, M.J., Glimcher, L.H., Bhan, A.K., and Tonegawa, S. 1993. Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell 75:274‐282.
   Murano, M., Maemura, K., Hirata, I., Toshina, K., Nishikawa, T., Hamamoto, N., Sasaki, S., Saitoh, O., and Katsu, K. 2000. Therapeutic effect of intracolonically administered nuclear factor kappa B (p65) antisense oligonucleotide on mouse dextran sulphate sodium (DSS)‐induced colitis. Clin. Exp. Immunol. 120:51‐58.
   Murthy, S.N., Cooper, H.S., Shim, H., Shah, R.S., Ibrahim, S.A., and Sedergran, D.J. 1993. Treatment of dextran sulfate sodium–induced murine colitis by intracolonic cyclosporin. Dig. Dis. Sci. 38:1722‐1734.
   Myers, K.J., Murthy, S., Flanigan, A., Witchell, D.R., Butler, M., Murray, S., Siwkowski, A., Goodfellow, D., Madsen, K., and Baker, B. 2003. Antisense oligonucleotide blockade of tumor necrosis factor‐alpha in two murine models of colitis. J. Pharmacol. Exp. Ther. 304:411‐424.
   Naito, Y., Takagi, T., Uchiyama, K., Kuroda, M., Kokura, S., Ichikawa, H., Yanagisawa, R., Inoue, K., Takano, H., Satoh, M., Yoshida, N., Okanoue, T., and Yoshikawa, T. 2004. Reduced intestinal inflammation induced by dextran sodium sulfate in interleukin‐6‐deficient mice. Int. J. Mol. Med. 14:191‐196.
   Nenci, A., Becker, C., Wullaert, A., Gareus, R., van Loo, G., Danese, S., Huth, M., Nikolaev, A., Neufert, C., Madison, B., Gumucio, D., Neurath, M.F., and Pasparakis, M. 2007. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446:557‐561.
   Neurath, M.F., Fuss, I., Kelsall, B.L., Stuber, E., and Strober, W. 1995. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J. Exp. Med. 182:1281‐1290.
   Neurath, M.F., Pettersson, S., Meyer zum Buschenfelde, K.H., and Strober, W. 1996. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF‐kappa B abrogates established experimental colitis in mice. Nat. Med. 2:998‐1004.
   Neurath, M.F., Fuss, I., Pasparakis, M., Alexopoulou, L., Haralambous, S., Meyer zum Buschenfelde, K.H., Strober, W., and Kollias, G. 1997. Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice. Eur. J. Immunol. 27:1743‐1750.
   Obermeier, F., Kojouharoff, G., Hans, W., Scholmerich, J., Gross, V., and Falk, W. 1999. Interferon‐gamma (IFN‐gamma)‐ and tumour necrosis factor (TNF)‐induced nitric oxide as toxic effector molecule in chronic dextran sulphate sodium (DSS)‐induced colitis in mice. Clin. Exp. Immunol. 116:238‐245.
   Okayasu, I., Hatakeyama, S., Yamada, M., Ohkusa, T., Inagaki, Y., and Nakaya, R. 1990. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98:694‐702.
   Panwala, C.M., Jones, J.C., and Viney, J.L. 1998. A novel model of inflammatory bowel disease: Mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis. J. Immunol. 161:5733‐5744.
   Picarella, D., Hurlbut, P., Rottman, J., Shi, X., Butcher, E., and Ringler, D.J. 1997. Monoclonal antibodies specific for beta 7 integrin and mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4+ T cells. J. Immunol. 158:2099‐2106.
   Powrie, F., Leach, M.W., Mauze, S., Caddle, L.B., and Coffman, R.L. 1993. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B‐17 scid mice. Int. Immunol. 5:1461‐1471.
   Powrie, F., Leach, M.W., Mauze, S., Menon, S., Caddle, L.B., and Coffman, R.L. 1994. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity 1:553‐562.
   Rakoff‐Nahoum, S., Hao, L., and Medzhitov, R. 2006. Role of toll‐like receptors in spontaneous commensal‐dependent colitis. Immunity 25:319‐329.
   Read, S. and Powrie, F. 1999. Induction of inflammatory bowel disease in immunodeficient mice by depletion of regulatory T cells. Curr. Protoc. Immunol. 30:15.13.1‐15.13.10.
   Rijcken, E.M., Laukoetter, M.G., Anthoni, C., Meier, S., Mennigen, R., Spiegel, H.U., Bruewer, M., Senninger, N., Vestweber, D., and Krieglstein, C.F. 2004. Immunoblockade of PSGL‐1 attenuates established experimental murine colitis by reduction of leukocyte rolling. Am. J. Physiol. Gastrointest. Liver Physiol. 287:G115‐G124.
   Rivera‐Nieves, J., Bamias, G., Vidrich, A., Marini, M., Pizarro, T.T., McDuffie, M.J., Moskaluk, C.A., Cohn, S.M., and Cominelli, F. 2003. Emergence of perianal fistulizing disease in the SAMP1/YitFc mouse, a spontaneous model of chronic ileitis. Gastroenterology 124:972‐982.
   Rivera‐Nieves, J., Olson, T., Bamias, G., Bruce, A., Solga, M., Knight, R.F., Hoang, S., Cominelli, F., and Ley, K. 2005. L‐selectin, alpha 4 beta 1, and alpha 4 beta 7 integrins participate in CD4+ T cell recruitment to chronically inflamed small intestine. J. Immunol. 174:2343‐2352.
   Rivera‐Nieves, J., Ho, J., Bamias, G., Ivashkina, N., Ley, K., Oppermann, M., and Cominelli, F. 2006. Antibody blockade of CCL25/CCR9 ameliorates early but not late chronic murine ileitis. Gastroenterology 131:1518‐1529.
   Rudolph, U., Finegold, M.J., Rich, S.S., Harriman, G.R., Srinivasan, Y., Brabet, P., Boulay, G., Bradley, A., and Birnbaumer, L. 1995. Ulcerative colitis and adenocarcinoma of the colon in G alpha i2‐deficient mice. Nat. Genet. 10:143‐150.
   Sadlack, B., Merz, H., Schorle, H., Schimpl, A., Feller, A.C., and Horak, I. 1993. Ulcerative colitis‐like disease in mice with a disrupted interleukin‐2 gene. Cell 75:253‐261.
   Sadlack, B., Lohler, J., Schorle, H., Klebb, G., Haber, H., Sickel, E., Noelle, R.J., and Horak, I. 1995. Generalized autoimmune disease in interleukin‐2‐deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur. J. Immunol. 25:3053‐3059.
   Schreiber, S., Fedorak, R.N., Nielsen, O.H., Wild, G., Williams, C.N., Nikolaus, S., Jacyna, M., Lashner, B.A., Gangl, A., Rutgeerts, P., Isaacs, K., Van Deventer, S.J.H., Koningsberger, J.C., Cohard, M., LeBeaut, A., and Hanauer, S.B. 2000. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Gastroenterology 119:1461‐1472.
   Schultz, M., Tonkonogy, S.L., Sellon, R.K., Veltkamp, C., Godfrey, V.L., Kwon, J., Grenther, W.B., Balish, E., Horak, I., and Sartor, R.B. 1999. IL‐2‐deficient mice raised under germfree conditions develop delayed mild focal intestinal inflammation. Am. J. Physiol. 276:G1461‐1472.
   Shibata, W., Maeda, S., Hikiba, Y., Yanai, A., Ohmae, T., Sakamoto, K., Nakagawa, H., Ogura, K., and Omata, M. 2007. Cutting edge: The IkappaB kinase (IKK) inhibitor, NEMO‐binding domain peptide, blocks inflammatory injury in murine colitis. J. Immunol. 179:2681‐2685.
   Shomer, N.H., Dangler, C.A., Schrenzel, M.D., and Fox, J.G. 1997. Helicobacter bilis–induced inflammatory bowel disease in scid mice with defined flora. Infect. Immun. 65:4858‐4864.
   Singh, B., Read, S., Asseman, C., Malmstrom, V., Mottet, C., Stephens, L.A., Stepankova, R., Tlaskalova, H., and Powrie, F. 2001. Control of intestinal inflammation by regulatory T cells. Immunol. Rev. 182:190‐200.
   Specht, S., Arriens, S., and Hoerauf, A. 2006. Induction of chronic colitis in IL‐10 deficient mice requires IL‐4. Microbes Infect. 8:694‐703.
   Steidler, L., Hans, W., Schotte, L., Neirynck, S., Obermeier, F., Falk, W., Fiers, W., and Remaut, E. 2000. Treatment of murine colitis by Lactococcus lactis secreting interleukin‐10. Science 289:1352‐1355.
   Stevceva, L., Pavli, P., Husband, A., Ramsay, A., and Doe, W.F. 2001. Dextran sulphate sodium‐induced colitis is ameliorated in interleukin 4 deficient mice. Genes Immun. 2:309‐316.
   Sundberg, J.P., Elson, C.O., Bedigian, H., and Birkenmeier, E.H. 1994. Spontaneous, heritable colitis in a new substrain of C3H/HeJ mice. Gastroenterology 107:1726‐1735.
   Takagi, H., Kanai, T., Okazawa, A., Kishi, Y., Sato, T., Takaishi, H., Inoue, N., Ogata, H., Iwao, Y., Hoshino, K., Takeda, K., Akira, S., Watanabe, M., Ishii, H., and Hibi, T. 2003. Contrasting action of IL‐12 and IL‐18 in the development of dextran sodium sulphate colitis in mice. Scand. J. Gastroenterol. 38:837‐844.
   Takahashi, I., Kiyono, H., and Hamada, S. 1997. CD4+ T‐cell population mediates development of inflammatory bowel disease in T‐cell receptor alpha chain‐deficient mice. Gastroenterology 112:1876‐1886.
   Takeda, K., Clausen, B.E., Kaisho, T., Tsujimura, T., Terada, N., Forster, I., and Akira, S. 1999. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10:39‐49.
   te Velde, A.A., Verstege, M.I., and Hommes, D.W. 2006. Critical appraisal of the current practice in murine TNBS‐induced colitis. Inflamm. Bowel Dis. 12:995‐999.
   Torrence, A.E., Brabb, T., Viney, J.L., Bielefeldt‐Ohmann, H., Treuting, P., Seamons, A., Drivdahl, R., Zeng, W., and Maggio‐Price, L. 2008. Serum biomarkers in a mouse model of bacterial‐induced inflammatory bowel disease. Inflamm. Bowel Dis. 14:480‐490.
   Totsuka, T., Kanai, T., Uraushihara, K., Iiyama, R., Yamazaki, M., Akiba, H., Yagita, H., Okumura, K., and Watanabe, M. 2003. Therapeutic effect of anti‐OX40L and anti‐TNF‐alpha MAbs in a murine model of chronic colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 284:G595‐G603.
   Totsuka, T., Kanai, T., Nemoto, Y., Makita, S., Okamoto, R., Tsuchiya, K., and Watanabe, M. 2007. IL‐7 Is essential for the development and the persistence of chronic colitis. J. Immunol. 178:4737‐4748.
   Uhlig, H.H., McKenzie, B.S., Hue, S., Thompson, C., Joyce‐Shaikh, B., Stepankova, R., Robinson, N., Buonocore, S., Tlaskalova‐Hogenova, H., Cua, D.J., and Powrie, F. 2006. Differential activity of IL‐12 and IL‐23 in mucosal and systemic innate immune pathology. Immunity 25:309‐318.
   von Freeden‐Jeffry, U., Davidson, N., Wiler, R., Fort, M., Burdach, S., and Murray, R. 1998. IL‐7 deficiency prevents development of a non‐T cell non‐B cell‐mediated colitis. J. Immunol. 161:5673‐5680.
   Ward, J.M., Anver, M.R., Haines, D.C., Melhorn, J.M., Gorelick, P., Yan, L., and Fox, J.G. 1996. Inflammatory large bowel disease in immunodeficient mice naturally infected with Helicobacter hepaticus. Lab. Anim. Sci. 46:15‐20.
   Watanabe, M., Ueno, Y., Yajima, T., Okamoto, S., Hayashi, T., Yamazaki, M., Iwao, Y., Ishii, H., Habu, S., Uehira, M., Nishimoto, H., Ishikawa, H., Hata, J., and Hibi, T. 1998. Interleukin 7 transgenic mice develop chronic colitis with decreased interleukin 7 protein accumulation in the colonic mucosa. J. Exp. Med. 187:389‐402.
   Wilk, J.N., Bilsborough, J., and Viney, J.L. 2005. The mdr1a−/− mouse model of spontaneous colitis: A relevant and appropriate animal model to study inflammatory bowel disease. Immunol. Res. 31:151‐159.
   Wirtz, S., Finotto, S., Kanzler, S., Lohse, A.W., Blessing, M., Lehr, H.A., Galle, P.R., and Neurath, M.F. 1999. Cutting edge: Chronic intestinal inflammation in STAT‐4 transgenic mice: Characterization of disease and adoptive transfer by TNF‐ plus IFN‐gamma‐producing CD4+ T cells that respond to bacterial antigens. J. Immunol. 162:1884‐1888.
   Wirtz, S., Neufert, C., Weigmann, B., and Neurath, M.F. 2007. Chemically induced mouse models of intestinal inflammation. Nat. Protoc. 2:541‐546.
   Yamazaki, M., Yajima, T., Tanabe, M., Fukui, K., Okada, E., Okamoto, R., Oshima, S., Nakamura, T., Kanai, T., Uehira, M., Takeuchi, T., Ishikawa, H., Hibi, T., and Watanabe, M. 2003. Mucosal T cells expressing high levels of IL‐7 receptor are potential targets for treatment of chronic colitis. J. Immunol. 171:1556‐1563.
   Yen, D., Cheung, J., Scheerens, H., Poulet, F., McClanahan, T., McKenzie, B., Kleinschek, M.A., Owyang, A., Mattson, J., Blumenschein, W., Murphy, E., Sathe, M., Cua, D.J., Kastelein, R.A., and Rennick, D. 2006. IL‐23 is essential for T cell‐mediated colitis and promotes inflammation via IL‐17 and IL‐6. J. Clin. Invest. 116:1310‐1316.
PDF or HTML at Wiley Online Library