New Therapy with CXCL16 Blocking for Inflammatory Bowel Disease

• Project/Area Number: 18590677
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: NAKASE Hiroshi Kyoto University, Graduate School of Medicine, Department of Gastroenterology & Hepatology, Assistant Professor (60362498)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,630,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥330,000); Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: Inflammatory bowel disease / CXCL16 / Chemokine / Dendritic cells

Research Abstract

(Background &Aim) CXCL16 is selectively expressed on only APC such as dendritic cells and macrophages. CXCL16 supports binding and phagocytosis of both gram-positive and negative bacteria through the chemokine-domain, suggesting that it may be involved in facilitating uptake of various pathogens and APC-T cell interactions in initiation of immune response. In this regard, it may be interesting to speculate that the interaction between APC and T cells through CXCL16 in response to various stimuli such as luminal bacteria components is involved in the pathophysiology of IBD. Therefore, the aim of the present study is to examine whether or not regulation of CXCL16 is effective for inflammatory bowel disease. (Methods) We generate CXCL16 knock out mice and anti-CXCL16mAbIgG1 and anti-human CXCL16mAbs. Induction of Colitis: To induce colitis, C57BL/6 mice are given 3%DSS (mol wt, 36-50 kilodaltons) in their drinking water for 5 days (from day 0 to 4). TNBS colitis is induced in SJL/J mice by using a modification of the method described by Neurath et. Al. Clinical evaluation after treatment by anti-CXCL16mAb: After induction of colitis, mice are injected with 500μg anti-CXCL16mAb or control rat IgG. For 5 days. (Results) Administration of anti-CXCL16 antibody dramatically decreased the severity of colonic inflammation in both DSS and TNBS colitis models. Production of both TNF-α and IFN-γ from mesenteric lymph node cells will be significantly lower in the group treated with anti-CXCL16 antibody than in non-treated group. The number of lymphocytes of CD4^+ CD69^+ T cells from the MLN in the mice treated with anti-CXCL16 was significantly lower than those in non-treated group. These finding suggested that CXCL16 is one of the most important chemokines, which is involved in the intestinal inflammation. (Conclusion) This data demonstrate the first evidence that dysregulation of CXCL16 activity is one of the important pathogenetic factor for human IBD.

Research Products

• [Journal Article] Clinical features of Japanese patients with colonic angiodysplasia. (2008)
  • Author(s): Ueno S, Nakase H, et. al.
  • Journal Title: J Gastroenterol Hepatol. (in press)
  • Peer Reviewed
• [Journal Article] Open label trial of Clarithromycin therapy in Japanese patients with Crohn's disease. (2007)
  • Author(s): Inoue S, Nakase H, et. al.
  • Journal Title: J Gastroenterol Hepatol. 22 Pages: 984-988
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Usefulness of quantitative real-time PCR assay for early detection of cytomegalovirus infection in patients with ulcerative colitis refractory to immunosuppressive therapies. (2007)
  • Author(s): Yoshino T, Nakase H, et. al.
  • Journal Title: Inflamm Bowel Dis. 13 Pages: 1516-1521
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A case of ileal heterotopic pancreas with repeated melena (2007)
  • Author(s): Endo, Y, Yazumi, S, Kimura, Y, Uza, N, Matsuura, M, Kodama, Y, Nakase, H, Chiba, T
  • Journal Title: Gastrointest Endosc 65 Pages: 156-157
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of cytomegalovirus infection in the ileal lesions of the patient with Behhet's disease (2007)
  • Author(s): Mikami, S, Nakase, H, Ueno, S, Matsuura, M, Sakurai, T, Chiba, T
  • Journal Title: Inflamm Bowel Dis 13 Pages: 802-803
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Magnifying endoscopic view of primary follicular lymphoma at duodenal papilla (2007)
  • Author(s): Nakase, H, Matsuura, M, Mikami, S, Chiba, T
  • Journal Title: Intern Med 46 Pages: 141-142
  • NAID: 130000078579
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hemosuccus pancreaticus (2007)
  • Author(s): Maruyama, J, Nakase, H, Chiba, T
  • Journal Title: J Gastroenterol Hepatol 22 Pages: 446-446
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pneumatosis cystoides intestinalis at ascending colon (2007)
  • Author(s): Mikami, S, Nakase, H, Sakurai, T, Chiba, T, Shimizu, S
  • Journal Title: J Gastroenterol Hepatol 22 Pages: 760-760
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Rescue therapy with tacrolimus for a patient with severe ulcerative colitis refractory to combination leukocytapheresis and high dose of corticosteroid therapy (2007)
  • Author(s): Nakase, H, Mikami, S, Matsuura, M, Ueno, S, Inoue, S, Kitamura, H, Kasahara, K, Yoshino, T, Takeda, Y, Chiba, T
  • Journal Title: Intern Med 46 Pages: 717-720
  • NAID: 130000076720
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Localized cytomegalovirus reactivation after radiotherapy for high grade gastric lymphoma (2007)
  • Author(s): Saga, K, Fukui, T, Kato, Y, Komeda, T, Nakase, H, Watanabe, N, Nishio, A, Chiba, T
  • Journal Title: Gastrointest Endosc 65 Pages: 545-547
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Education and Imaging. Gastrointestinal : ileal ulcers induced by non-steroidal anti-inflammatory drugs (2007)
  • Author(s): H.,Matsuura, M, Nakase, H, Nakamura, F, Yoshihide, Ueda, Y, Mikami S, Yoshino, T, Ueno, S, Uza, N, Chiba, T
  • Journal Title: J Gastroenterol Hepatol 22 Pages: 1346-1346
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clincal Challenge and Image in GI : Unique gastrointestinal involvement in a patient with Henoch-Schonlein purpura (2007)
  • Author(s): Ueo, T, Nakase, H, Chiba, T
  • Journal Title: Gastroenterology 133
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Image of Month : Ileal polyposis caused by follicular lymphoma (2007)
  • Author(s): Matsuura, M, Nakase, H, Mochizuki, N
  • Journal Title: Clin Gastroenterol Hepatol 5
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Image of Month : Follicular Lymphoma with Small Intestinal Involvement Detected by Double-Balloon Enteroscopy (2007)
  • Author(s): Yamamoto, S, Nakase, H, Kawanami, C
  • Journal Title: Clin Gastroenterol Hepatol 5
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Administration of PEG-interferon to a patient with ulcerative colitis and chronic hepatitis C correlated with reduced colonic inflammation and reversal of peripheral Th1/Th2 ratios (2007)
  • Author(s): Kasahara, K, Nakase, H, Uza, N, Ueno, S, Matsuura, M, Mikami, S, Inoue, S, Chiba, T
  • Journal Title: Case Reports in Gastroenterology 1 Pages: 157-161
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Importance of early detection of cytomegalovirus infection in refractory inflammatory bowel disease (2007)
  • Author(s): Nakase, H, Yoshino, T, Ueno, S, Uza, N, Mikami, S, Matsuura, M, Chiba, T
  • Journal Title: Inflamm Bowel Dis 13 Pages: 364-364
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Diagnosis and treatment of obscure GI bleeding with double balloon endoscopy (2007)
  • Author(s): Nakase, H, Matsuura, M, Mikami, S, Chiba, T
  • Journal Title: Gastrointest Endosc 66(3 Suppl)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Open label trial of Clarithromycin therapy in Japanese patients with Crohn's disease (2007)
  • Author(s): Inoue, S, Nakase, H, Matsuura, M, Ueno, S, Uza, N, Kitamura, H, Mikami, S, Tamaki, H, Kasahara, K, Chiba, T
  • Journal Title: J Gastroenterol Hepatol 22 Pages: 984-988
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cross-Primed CD8(+) Cytotoxic T cells Induce Severe Helicobacter-associated Gastritis in the Absence of CD4(+) T cells (2007)
  • Author(s): Fukui, T, Nishio, A, Okazaki, K, Kasahara, K, Saga, K, Tanaka, J, Uza, N, Ueno, S, Kido, M, Ohashi, S, Asada, M, Nakase, H, Watanabe, N, Chiba, T
  • Journal Title: Helicobacter 12 Pages: 486-97
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Usefulness of quantitative real-time PCR assay for early detection of cytomegalovirus infection in patients with ulcerative colitis refractory to immunosuppressive therapies (2007)
  • Author(s): Yoshino, T, Nakase, H, Ueno, S, Uza, N, Inoue, S, Mikami, S, Matsuura, M, Oomori, K, Sakurai, T, Nagayama, S, Hasegawa, S, Sakai, Y, Chiba, T
  • Journal Title: Inflamm Bowel Dis 13 Pages: 1516-1521
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Importance of early detection of cytomegalovirus infection in refractory inflammatory bowel disease. (2007)
  • Author(s): Nakase H, et al.
  • Journal Title: Inflamm Bowel Dis 13 Pages: 364-364
• [Journal Article] Magnified endoscopic view of primary follicular lymphoma at the duodenal papilla (2007)
  • Author(s): Nakase H, et al.
  • Journal Title: Intern Med 46 Pages: 141-142
  • NAID: 130000078579
• [Journal Article] Caecal cancer associated with longstanding Crohn's disease (2006)
  • Author(s): Uza, N, Nakase, H, Kuwabara, Y, Fujii, S, Chiba, T
  • Journal Title: Lancet 368(9549) Pages: 1842-1842
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cytomegalovirus infection in patients with ulcerative colitis diagnosed by quantitative real-time PCR analysis (2006)
  • Author(s): Kou, T, Nakase, H, Tamaki, H, Kudo, T, Nishio, A, Chiba, T
  • Journal Title: Dig Dis Sci 51 Pages: 1052-1055
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human Thioredoxin-I Ameliorates Experimental Murine Colitis in Association with Suppressed Macrophage Inhibitory Factor Production (2006)
  • Author(s): Tamaki, H, Nakamura, H, Nishio, A, Nakase, H, Ueno, S, Uza, N, Kido, M, Inoue, S, Mikami, S, Asada, M, Kiriya, K, Kitamura, H, Ohashi, S, Fukui, T, Kawasaki, K, Matsuura, M, Ishii, Y, Okazaki, K, Yodoi, J, Chiba, T
  • Journal Title: Gastroenterology 131 Pages: 1110-1121
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Caecal cancer associated with longstanding Crohn's disease (2006)
  • Author(s): Uza N, Nakase H, et al.
  • Journal Title: Lancet 368 Pages: 1842-1842
• [Journal Article] Clinical challenges and images in GI. Meckel's diverticulum with an enterolith (2006)
  • Author(s): Uza N, Nakase H, et al.
  • Journal Title: Gastroenterology 131
• [Journal Article] Cytomegalovirus infection in patients with ulcerative colitis diagnosed by quantitative real-time PCR analysis. (2006)
  • Author(s): Kou T, Nakase H, et al.
  • Journal Title: Dig Dis Sci 51 Pages: 1052-1055
• [Journal Article] Human Thioredoxin-1 Ameliorates Experimental Murine Colitis in Association with Suppressed Macrophage Inhibitory Factor (2006)
  • Author(s): Tamaki H, Nakase H, et al.
  • Journal Title: Gastroenterology 131 Pages: 1110-1121
• [Journal Article] Clinical features of Japanese patients with colonic angiodysplasia.
  • Author(s): Ueno S, Nakase H, et. al.
  • Journal Title: J Gastroenterol Hepatol. (in press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Possible link between ulcerative colitis and in situ adenocarcinoma of an appendiceal mucocele-Importanceof inflammation in the appendiceal orifice related to ulcerative colitis
  • Author(s): Takeda, Y, Nakase, H, Mikami, S, Inoue, T, Satou, S, Sakai, Y, Chiba, T
  • Journal Title: Inflamm Bowel Dis (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The importance of diagnosis of concomitant cytomegalovirus infection in patients with intestinal Bechet's disease
  • Author(s): Yoshino, T, Nakase, H, Mikami, S, Nio, M, Ueno, S, Uza, N, Ohmori, K, Manabe, T, Chiba, 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 features of Japanese patients with colonic angiodysplasia
  • Author(s): Ueno, S, Nakase, H, Kasahara, K, Uza, N, Kitamura, H, Inoue, S, Mikami, S, Matsuura, M, Chiba, T
  • Journal Title: J Gastroenterol Hepatol (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The effect of medical treatment on patients with fistulizing Crohn's Disease : Our experience with a retrospective study
  • Author(s): Uza, N, Nakase, H, Ueno, S, Inoue, S, Mikami, S, Tamaki, H, Matsuura, M, Chiba, T
  • Journal Title: Intern Med (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The critical involvement of cytomegalovirus infection in inflammatory bowel disease refractory to conventional therapies-How to diagnose at early stage? (2007)
  • Author(s): Nakase H
  • Organizer: The 3rd Annual meeting of the Japanese Gastroenterological Association
  • Place of Presentation: 東京
  • Year and Date: 2007-02-02
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] The Critical role of Heat Shock Protein 47 in intestinal Fibrosis associated with inflammatory bowel disease (2007)
  • Author(s): Kitamura, H, Nakase, H, et. al.
  • Organizer: Digestive Disease Week
  • Place of Presentation: USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The Usefulness of quantitative real-time PCR assay for early detection of cytomegalovirus in patients with UC refractory to immunosuppressive therapies (2007)
  • Author(s): Yoshino, T, Nakase, H, et. al.
  • Organizer: Digestive Disease Week
  • Place of Presentation: USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Ectopic expression of activation-induced cytidine deaminase in ulcerative colitis-associated colorectal cancers (2007)
  • Author(s): Kou, T, Marusawa, H, Endo, Y, Nakase, H, et. al.
  • Organizer: Digestive Disease Week
  • Place of Presentation: USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The Usefulness of quantitative real-time PCR assay for early detection of cytomegalovirus in patients with UC refractory to immunosuppressive therapies (2007)
  • Author(s): Nakase, H, et. al.
  • Organizer: UEGW
  • Place of Presentation: France
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Rescue therapy with leukocytapheresis for patients with ulcerative colitis refractory to immunomodulators by alternation of CXCR4 expression on T cells and Thl/Th2 balance (2007)
  • Author(s): Nakase, H, et. al.
  • Organizer: UEGW
  • Place of Presentation: France
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Modulation of Heat shock protein 47 in intestinal fibrosis of inflammatory bowel disease regulated by interleukin-10 (2007)
  • Author(s): Kitamura, H, Nakase, H, et. al.
  • Organizer: 13th ICMI
  • Place of Presentation: Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The Usefulness of quantitative real -time PCR assay for early detection of cytomegalovirus in patients with UC refractory to immunosuppressive therapies (2007)
  • Author(s): Yoshino, T, Nakase, H, et. al.
  • Organizer: 13th ICMI
  • Place of Presentation: Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Bifidobacterium logum(BB536) therapy shifts cytokine profile toward T-helper 1 by up-regulation of T-bet and enhances mucosal barrier function (2007)
  • Author(s): Inoue, S, Nakase, H, et. al.
  • Organizer: 13th ICMI
  • Place of Presentation: Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Basic fibroblast growth factor-induced multidrug resistance 1 expression plays an important role in the protective effect on intestinal epithelial injury (2006)
  • Author(s): Matsuura, M, Nakase, H, Masuda, S, Tabata, Y, Chiba, T
  • Organizer: Digestive Disease Week
  • Place of Presentation: USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Critical role of CXCL12-CXCR4 interaction in the pathophysiology of inflammatory bowel disease (2006)
  • Author(s): Mikami, S, Nakase, H, Nagasawa, T, Chiba, T
  • Organizer: Digestive Disease Week
  • Place of Presentation: USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Maintenance therapy with tacrolimus in patients with Crohn's disease refractory to Azathiopurine : 2 year trial (2006)
  • Author(s): Nakase, H, et. al.
  • Organizer: Digestive Disease Week
  • Place of Presentation: USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Novel maintenance therapy with tacrolimus in patients with Crohn's disease refractory to Azathioprine (2006)
  • Author(s): Nakase, H, et. al.
  • Organizer: UEGW
  • Place of Presentation: Germany
  • Description: 「研究成果報告書概要(欧文)」より