Development of novel mouse model of human Crohn's disease

• Project/Area Number: 15590684
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: INOUE Nagamu Keio University, Department of Medicine, Instructor, 医学部, 助手 (00232546)
• Co-Investigator(Kenkyū-buntansha): HIBI Toshifumi Keio University, Department of Medicine, Professor, 医学部, 教授 (50129623) ; ISHIKAWA Hiromichi Keio University, Department of Medicine, Professor, 医学部, 教授 (20051667) ; YAJIMA Tomoharu Keio University, Department of Medicine, Instructor, 医学部, 所長 (70306710) ; NOMURA Tatsuji Central Laboratories for Experimental Animals, Director, 所長 (10072399)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2003: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: Crohn's disease / NOG mice / intestinal microflora / disease model mice / inflammatory bowel disease / stem cell

Research Abstract

Inflammatory bowel disease(IBD) is a chronic inflammation of the gastrointestinal tract and its prevalence has been increasing in Japan. However, no fundamental therapy has been established because the etiology of IBD remains obscure in spite of extensive pathophysiological researches. Recent advances in the understanding of the pathophysiological conditions of IBD have provided new immune system modulators as therapeutic tools. Animal models, such as dextran sulfate sodium(DSS)-indeced colitis, interleukin-10 deficient(IL-10-/-) mice and CD4^+CD45^<RBhigh> transfer model, have been widely used for studying the intestinal inflammation and testing therapeutic effect of newly-developed drugs. However, there has not been established ideal animal models resembling the pathogenesis of human IBD including intestinal microflora which plays an important role for inducing and perpetuating the intestinal inflammation.
At First, we crossed NOD-SCID mice with IL-2Rγc knock out mice and obtained NOD/SCID×IL-2RγcKO(NOG) mice which completely deficient immnocompetent cells and is ideal for the recipient of transplant experiment. We already established stable supply of the NOG mice for the present study.
Next, we studied the importance of intestinal microfolora in the intestinal inflammation using human flora associated(HFA) mice. Results of flora analysis indicated that derangement of intestinal flora with ulcerative colitis(UC) was reproduced in HFA mice model. However, intestinal inflammation was not induced by administration of UC flora in wild-type mice. In contrast, mice colonized with UC flora presented severe inflammation compared with mice colonized with healthy control(HC) flora upon DSS administration. Moreover, in IL-10-/- mice, several inflammatory parameters were also severer in UC flora mice than those in HC flora mice. These results suggested that breakdown of intestinal bacterial balance increased the susceptibility of intestinal inflammatory stimuli.

Research Products

• [Journal Article] Non-pathogenic Escherichia coil strain Nissle 1917 prevents murine acute and chronic colitis. (2005)
  • Author(s): Kamada N, Inoue N, et al.
  • Journal Title: Inflamm Bowel Dis (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Non-pathogenic Escherichia coli strain Nissle 1917 prevents murine acute and chronic colitis. (2005)
  • Author(s): Kamada N, Jnoue N, Hisamatsu T, Okamoto S, Matsuoka K, Sato T, Chinen H, Hong KS, Yamada T, Suzuki Y, Suzuki T, Watanabe N, Tsuchimoto K, Hibi T
  • Journal Title: Inflamm Bowel Dis (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical significance of microsatellite instability in the inflamed mucosa for the prediction of colonic neoplasms in patients with ulcerative colitis. (2005)
  • Author(s): Tahara T, Inoue N, et al.
  • Journal Title: J Gastroenterol Hepatol (in press)
• [Journal Article] Non-pathogenic Escherichia coli strain Nissle 1917 prevents murine acute and chronic colitis. (2005)
  • Author(s): Kamada N, Inoue N, et al.
  • Journal Title: Inflamm Bowel Dis (in press)
• [Journal Article] T-bet up-regulation and subsequent interleukin 12 stimulation are essential for the induction of Th1 mediated immunopathology in Crohn's disease. (2004)
  • Author(s): Matsuoka K, Inoue N, et al.
  • Journal Title: GUT 53 Pages: 1303-1308
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Human intestinal epithelial cell-derived interleukin (IL)-18, along with IL-2, IL-7 and IL-15, is a potent synergistic factor for the proliferation of intraepithelial lymphocytes. (2004)
  • Author(s): Okazawa A, Inone N, et al.
  • Journal Title: Clin Exp Immunol 136 Pages: 269-276
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Hyperexpression of inducible costimulator and its contribution on lamina propria T cells in inflammatory bowel disease. (2004)
  • Author(s): Sato T, Inoue N, et al.
  • Journal Title: Gastroenterology 126 Pages: 829-839
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] T-bet up-regulation and subsequent interleukin 12 stimulation are essential for the induction of Th1 mediated immunopathology in Crohn's disease. (2004)
  • Author(s): Matsuoka K, Inoue N, Sato T, Okamoto S, Hisamatsu T, Kishi Y, Sakuraba A, Hitotsumatsu O, Fukushima T, Kanai T, Watanabe M, Ishii H, Hibi T
  • Journal Title: Gut 53(9) Pages: 1303-1308
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human intestinal epithelial cell-derived interleukin(IL)-18, along with IL-2, IL-7 and IL-15, is a potent synergistic factor for the proliferation of intraepithelial lymphocytes. (2004)
  • Author(s): Okazawa A, Kanai T, Nakamaru K, Sato T, Jnoue N, Ogata H, Iwao Y, Ikeda M, Kawamura T, Makita S, Uraushihara K, Okamoto H, Yamazaki M, Kurimoto M, Ishii H, Watanabe M, Hibi T
  • Journal Title: Clin Exp Immunol 136(2) Pages: 269-276
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hyperexpression of inducible costimulator and its contribution on lamina propria T cells in inflammatory bowel disease. (2004)
  • Author(s): Sato T, Kanai T, Watanabe M, Sakuraba A, Okamoto 5, Nakai T, Okazawa A, Inoue N, Totsuka T, Yamazaki M, Kxoczek RA, Fukushima T, Ishii H, Hibi T
  • Journal Title: Gastroenterology 126(3) Pages: 829-839
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Granulocytapheresis is useful as an alterative therapy in patients with steroid-refractory or-dependent ulcerative colitis. (2004)
  • Author(s): Naganuma M, Inoue N, et al.
  • Journal Title: Inflamm Bowel Dis 10・3 Pages: 251-257
• [Journal Article] T-bet up-regulation and subsequent interleukin 12 stimulation are essential for the induction of Th1 mediated immunopathology in Crohn's disease. (2004)
  • Author(s): Matsuoka K, Inoue N, et al.
  • Journal Title: GUT 53・9 Pages: 1303-1308
• [Journal Article] Human intestinal epithelial cell-derived interleukin(IL)-18, along with IL-2, IL-7 and IL-15, is a potent synergistic factor for the proliferation of intraepithelial lymphocytes. (2004)
  • Author(s): Okazawa A, Inoue N, et al.
  • Journal Title: Clin Exp Immunol 136・2 Pages: 269-276
• [Journal Article] Hyperexpression of inducible costimulator and its contribution on lamina propria T cells in inflammatory bowel disease. (2004)
  • Author(s): Sato T, Inoue N, et al.
  • Journal Title: Gastroenterology 126・3 Pages: 829-839
• [Journal Article] Contrasting action of IL-12 and IL-18 in the development of dextran sodium sulphate colitis in mice. (2003)
  • Author(s): Takagi H, Inoue N, et al.
  • Journal Title: Scand J Gastroenterol 38 Pages: 837-844
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A specific genetic alteration on chromosome 6 in ulcerative colitis-associated colorectal cancers. (2003)
  • Author(s): Ezaki T, Inoue N, et al.
  • Journal Title: Cancer Res 63 Pages: 3747-3749
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Contrasting action of IL-12 and IL-18 in the development of dextran sodium sulfate colitis in mice. (2003)
  • Author(s): Takagi T, Kanai T, Okazawa A, Sato T, Takaishi H, Inoue N, Ogata H, Hoshino K, Takeda K, Akira S, Watanabe M, Ishii H, Hibi T
  • Journal Title: Scand J Gastroenterol 38(8) Pages: 837-844
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A specific genetic alteration on chromosome 6 in ulcerative colitis-associated colorectal cancers. (2003)
  • Author(s): Ezaki T, Watanabe M, Inoue N, Kanai T, Ogata H, Iwao Y, Ishii H, Hibi T
  • Journal Title: Cancer Res 63(13) Pages: 3747-3749
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sato T, et al.: "Hyperexpression of Inducible Costimulator and Its Contribution on Lamina Propria T cells in Inflammatory Bowel Disease."Gastroenterology. 126(3). 829-839 (2004)
• [Publications] Takagi H, et al.: "Contrasting action of IL-12 and IL-18 in the development of dextran sodium sulphate colitis in mice."Scand J Gastroenterol. 38(8). 837-844 (2003)
• [Publications] Yamazaki M, et al.: "Mucosal T cells expressing high levels of IL-7 receptor are potential targets for treatment of chronic colitis."J Immunol. 171(3). 1556-1563 (2003)
• [Publications] Ezaki T, et al.: "A specific genetic alteration on chromosome 6 in ulcerative colitis-associated colorectal cancers."Cancer Res. 63(13). 3747-3749 (2003)
• [Publications] Kanai T, et al.: "Macrophage-derived IL-18 targeting for the treatment of Crohn's disease."Curr Drug Targets Inflamm Allergy. 2(2). 131-136 (2003)
• [Publications] Hibi T, et al.: "Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis."J Gastroenterol. 38(8). 740-746 (2003)