Identification of the inflammatory signaling in intestinal epithelial cells involved

2012 Fiscal Year Final Research Report

• Project/Area Number: 22590696
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NAGANUMA Makoto 東京医科歯科大学, 医学部, 非常勤講師 (00265810)
• Co-Investigator(Kenkyū-buntansha): NAGISHI Takashi 東京医科歯科大学, 医学部附属病院, 助教 (60447464) ; WATANABE Mamoru 東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (10175127)
• Project Period (FY): 2010 – 2012
• Keywords: 炎症性腸疾患 / 炎症性発癌 / 新規治療法 / 粘膜免疫 / MLCK

Research Abstract

Treatment with anti-tumor necrosis factor (TNF) mAb has been accepted as a successful therapy for patients with inflammatory bowel diseases (IBD). It has been recently reported that blockade of TNF receptor (TNFR) signaling in infiltrating hematopoietic cells may prevents the development of colitis-associated cancer (CAC). However, it remains unclear whether the TNF signaling in the epithelial cells is also involved in the development of CAC. To investigate this, we studied the effects of anti-TNF mAb in animal models of colitis and CAC. Our studies suggest that the TNFR signaling in intestinal epithelial cells may be directly involved in the development of CAC with persistent colitis, and imply that the maintenance therapy with anti-TNF mAb may prevent the development of CAC in patients with IBD.

Research Products

• [Journal Article] Incidence and characteristics of the 2009 influenza (H1N1) infections in inflammatory bowel disease patients (2013)
  • Author(s): Naganuma M, Fujii T, Kunisaki R, Yoshimura N, Takazoe M, Takeuchi Y, Saito E, Nagahori M, Asakura K, Takebayashi T, Watanabe M
  • Journal Title: J Crohns Colitis Volume: 7 Pages: 308-313
  • DOI: doi:10.1016/j.crohns.06.019
  • Peer Reviewed
• [Journal Article] Poor recall of prior exposure to varicella zoster, rubella, measles, or mumps in patients with IBD (2013)
  • Author(s): Naganuma M, Nagahori M, Fujii T, Morio J, Saito E, Watanabe M
  • Journal Title: Inflamm Bowel Dis Volume: 19 Pages: 418-422
  • DOI: doi:10.1002/ibd.23027
  • Peer Reviewed
• [Journal Article] The short isoform of the CEACAM1 receptor in intestinal T cells regulates mucosal immunity and homeostasis via Tfh cell induction (2012)
  • Author(s): Chen L, Chen Z, Baker K, Halvorsen EM, da Cunha AP, Flak MB, Gerber G, Huang YH, Hosomi S, Arthur JC, Dery KJ, Nagaishi T, Beauchemin N, Holmes KV, Ho JW, Shively JE, Jobin C, Onderdonk AB, Bry L, Weiner HL, Higgins DE, Blumberg RS
  • Journal Title: Immunity Volume: 37 Pages: 930- 946
  • DOI: doi:10.1016/j.immuni.2012.07.016
  • Peer Reviewed
• [Journal Article] Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+stem cell (2012)
  • Author(s): Yui S, Nakamura T, Sato T, Nemoto Y, Mizutani T, Zheng X, Ichinose S, Nagaishi T, Okamoto R, Tsuchiya K, Clevers H, Watanabe M
  • Journal Title: Nature Medicine Volume: 18 Pages: 618-623
  • DOI: doi:10.1038/nm.2695
  • Peer Reviewed
• [Journal Article] Real-time analysis of P-glycoprotein-mediated drug transport across primary intestinal epithelium three-dimensionally cultured in vitro (2012)
  • Author(s): Mizutani T, Nakamura T, Morikawa R, Fukuda M, Mochizuki W, Yamauchi Y, Nozaki K, Yui S, Nemoto Y, Nagaishi T, Okamoto R, Tsuchiya K, Watanabe M
  • Journal Title: Biochem Biophys Res Commun Volume: 419 Pages: 238-243
  • DOI: doi:10.1016/j.bbrc.2012.01.155
  • Peer Reviewed
• [Journal Article] The development of colitogenic CD4+T cells is regulated by IL-7 in collaboration with natural killer cell function in a murine model of colitis (2012)
  • Author(s): Yamaji O, Nagaishi T, Totsuka T, Onizawa M, Suzuki M, Tsuge N, Hasegawa A, Okamoto R, Tsuchiya K, Nakamura T, Arase H, Kanai T, Watanabe M
  • Journal Title: J Immunol Volume: 188 Pages: 2524-2536
  • DOI: doi:10.4049/jimmunol .1100371
  • Peer Reviewed
• [Journal Article] IBDモデルにおける病原性T細胞の分化増殖はIL-7とNK細胞によって制御される (2012)
  • Author(s): 永石宇司、渡辺守、他
  • Journal Title: 消化器と免疫 Volume: 49 Pages: 35-38
• [Journal Article] IBDとサイトカイン-ケモカイン (2012)
  • Author(s): 鈴木雅博、永石宇司、渡辺守
  • Journal Title: G.I.Research Volume: 20(5) Pages: 53-64
• [Journal Article] Magnetic resonance enterocolonography is useful for simultaneous evaluation of small and large intestinal lesions in Crohn's disease (2011)
  • Author(s): Hyun SB, Kitazume Y, Nagahori M, Toriihara A, Fujii T, Tsuchiya K, Suzuki S, Okada E, Araki A, Naganuma M, Watanabe M
  • Journal Title: Inflamm Bowel Dis Volume: 17 Pages: 1063-1072
  • DOI: doi:10.1002/ibd.21510
  • Peer Reviewed
• [Journal Article] Conception and pregnancy outcome in women with inflammatory bowel disease: A multicentre study from Japan (2011)
  • Author(s): Naganuma M, Kunisaki R, Yoshimura N, Nagahori M, Yamamoto H, Kimura H, Sako M, Kawaguchi T, Takazoe M, Yamamoto S, Matsui T, Hibi T, Watanabe M
  • Journal Title: J Crohns Colitis Volume: 5 Pages: 317-323
  • DOI: doi:10.1016/j.crohns.2011.02.003
  • Peer Reviewed
• [Journal Article] The use of traditional and newer calcineurin inhibitors in inflammatory bowel disease (2011)
  • Author(s): Naganuma M, Fujii T, Watanabe M
  • Journal Title: J Gastroenterol Volume: 46 Pages: 129-137
  • DOI: doi:10.1007/s00535-010-0352-z
  • Peer Reviewed
• [Journal Article] Safety and usefulness of balloon endoscopy in Crohn's disease patients with postoperative ileal lesions (2011)
  • Author(s): Naganuma M, Watanabe M, Hibi T
  • Journal Title: J Crohns Colitis Volume: 5 Pages: 73-74
  • DOI: doi:10.1016/j.crohns.2010.10.003
  • Peer Reviewed
• [Journal Article] ここまでわかった自己免疫疾患-Crohn 病・潰瘍性大腸炎 (2011)
  • Author(s): 鈴木雅博、永石宇司、渡辺守
  • Journal Title: 臨床検査臨時増刊号 Volume: 55(11) Pages: 1258-1264
• [Journal Article] 分泌メディエーターはヒトマクロファージにおけるNod2誘導性寛容を調節する (2011)
  • Author(s): 永石宇司、渡辺守
  • Journal Title: Review of Gastroenterology & Clinical Gastroenterology and Hepatology Volume: 6(2) Pages: 12-16
• [Journal Article] 腹部症状発現メカニズム解明への臨床的アプローチ:腸内細菌、炎症と腹部症状 (2011)
  • Author(s): 永石宇司、山地統、渡辺守
  • Journal Title: Modern Physician Volume: 31 Pages: 310-313
• [Journal Article] Prevalence of metabolic syndrome is comparable between inflammatory bowel disease patients and the general population (2010)
  • Author(s): Nagahori M, Hyun SB, Totsuka T, Okamoto R, Kuwahara E, Takebayashi T, Naganuma M, Watanabe M
  • Journal Title: J Gastroenterol Volume: 45 Pages: 1008-1013
  • DOI: doi:10.1007/s00535-010-0247-z
  • Peer Reviewed
• [Journal Article] Novel endoscopic activity index is useful for choosing treatment in severe active ulcerative colitis patients (2010)
  • Author(s): Naganuma M, Ichikawa H, Inoue N, Kobayashi T, Okamoto S, Hisamatsu T, Kanai T, Ogata H, Iwao Y, Hibi T
  • Journal Title: J Gastroenterol Volume: 45 Pages: 936-943
  • DOI: doi:10.1007/s00535-010-0244-2
  • Peer Reviewed
• [Presentation] Natural killer cells regulate the early stage of pathogenic T cell development in a murine model of colitis (2013)
  • Author(s): Nagaishi T, Watanabe M et al
  • Organizer: Immuno 2013
  • Place of Presentation: Barcelona
  • Year and Date: 2013-03-11
• [Presentation] Natural killer cells suppress an animal model of colitis by targeting the early stage of pathogenic T cell development (2012)
  • Author(s): Nagaishi T, Watanabe M et al
  • Organizer: 日本免疫学会総会2012
  • Place of Presentation: Kobe
  • Year and Date: 2012-12-05
• [Presentation] Natural killer cells suppress an animal model of IBD by targeting the early stage of pathogenic T cell development (2012)
  • Author(s): Nagaishi T, Watanabe M et al
  • Organizer: Asian IBD Symposium 2012
  • Place of Presentation: Seoul
  • Year and Date: 2012-11-03
• [Presentation] Natural killer cells suppress an animal model of IBD by targeting the early stage of pathogenic T cell development (2012)
  • Author(s): 永石宇司, 渡辺守、他
  • Organizer: 日本臨床免疫学会総会2012
  • Place of Presentation: 東京
  • Year and Date: 2012-09-27
• [Presentation] 慢性大腸炎モデルにおける腸炎惹起性T細胞の増殖はIL-7とNK細胞により制御される (2012)
  • Author(s): 永石宇司, 渡辺守、他
  • Organizer: 日本消化器免疫学会総会2011
  • Place of Presentation: 鹿児島
  • Year and Date: 2012-07-06
• [Presentation] Natural killer cells regulate colitis by targeting the early stage of pathogenic T cell development (2012)
  • Author(s): Nagaishi T, Watanabe M et al
  • Organizer: Federation of Clinical Immunology Societies 2012
  • Place of Presentation: Vancouver
  • Year and Date: 2012-06-22
• [Presentation] Regeneration of damaged colon epithelium by transplanted colon Lgr5+stem cells maintained and expanded in vitro (2012)
  • Author(s): Yui S, Nakamura T, Nagaishi T, Watanabe M et al
  • Organizer: 幹細胞シンポジウム
  • Place of Presentation: Awajishima
  • Year and Date: 2012-06-01
• [Presentation] Serological test and vaccinations for Measles, Mumps, Rubella, and Varicella Zoster deserve considerations as early as possible after diagnosis of Inflammatory Bowel Disease (2011)
  • Author(s): Naganuma M, Watanabe M et al
  • Organizer: UEGW
  • Place of Presentation: ストックホルム
  • Year and Date: 2011-10-25
• [Presentation] マウス腸炎モデルにおける腸炎惹起性CD4+T細胞の増殖はIL-7とNK細胞により制御される (2011)
  • Author(s): 山地統、永石宇司、渡辺守、ほか
  • Organizer: 日本消化器病学会大会
  • Place of Presentation: 福岡
  • Year and Date: 2011-10-20
• [Presentation] Natural killer cells suppress a murine model of colitis by targeting the early stage of T cell development (2011)
  • Author(s): Nagaishi T, Yamaji O, Watanabe M, et al
  • Organizer: 国際粘膜免疫学会議
  • Place of Presentation: パリ
  • Year and Date: 2011-07-07
• [Presentation] Regeneration of damaged colonic tissue by transplanted colonic epithelial stem cells maintained and expanded in vitro (2011)
  • Author(s): Yui S, Nakamura T, Nagaishi T, Watanabe M, et al
  • Organizer: GI Research Academy
  • Place of Presentation: 京都
  • Year and Date: 2011-06-17
• [Presentation] 本邦におけるIBD患者の妊娠・出産の転帰に関する検討 (2011)
  • Author(s): 長沼誠、渡辺守他
  • Organizer: 日本消化器病学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-05-14
• [Presentation] 免疫調節薬・抗体製剤使用IBD患者におけるインフルエンザ感染症の現状 (2011)
  • Author(s): 長沼誠、渡辺守他
  • Organizer: 日本消化器病学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-05-13
• [Presentation] Regeneration of damaged colonic tissue by transplantation of colonic epithelial stem cells maintained and expanded in vitro (2011)
  • Author(s): Yui S, Nakamura T, Nagaishi T, Okamoto R, Watanabe M, et al
  • Organizer: アメリカ消化器病学会
  • Place of Presentation: シカゴ
  • Year and Date: 2011-05-07
• [Presentation] NK cells regulate CD62L-CD44-T cell subset in the development of pathogenic T cells in a murine model of colitis (2011)
  • Author(s): Yamaji Y, Nagaishi T, Watanabe M, et al
  • Organizer: アメリカ消化器病学会
  • Place of Presentation: シカゴ
  • Year and Date: 2011-05-07
• [Presentation] TNF-α/NF-кB pathways in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis (2010)
  • Author(s): Onizawa M, Nagaishi T, Watanabe M, e tal
  • Organizer: The 4^<th> Japan and US Collaboration Conference in Gastroenterology
  • Place of Presentation: 東京
  • Year and Date: 2010-11-18
• [Presentation] A well-defined culture system for colonic epithelial cells that allows efficient enrichment of LGR5+stem cells (2010)
  • Author(s): Yui S, Nagaishi T, Okamoto R, Watanabe M, et al
  • Organizer: The 1^<st> JSGE International Topic Conference-Stem cells in digestive organs
  • Place of Presentation: 鎌倉
  • Year and Date: 2010-09-26
• [Presentation] TNF path-way in intestinal epithelial cells may be directly involved in colitis-associated carcino-genesis (2010)
  • Author(s): Onizawa M, Nagaishi T, Watanabe M, et al
  • Organizer: 国際免疫学会議
  • Place of Presentation: 神戸
  • Year and Date: 2010-08-25
• [Presentation] Myosin light chain kinase is associated with disruption of epithelial tight junction in an animal model of colitis-associated tumor (2010)
  • Author(s): Onizawa M, Nagaishi T, Watanabe M, et al
  • Organizer: アメリカ臨床免疫学会
  • Place of Presentation: ボストン
  • Year and Date: 2010-06-25
• [Presentation] Myosin light chain kinase is associated with disruption of epithelial tight junction in colitisassociated tumor (2010)
  • Author(s): Onizawa M, Nagaishi T, Watanabe M, et al
  • Organizer: アメリカ消化器病学会
  • Place of Presentation: ニューオリンズ(国内学会)
  • Year and Date: 2010-05-02
• [Book] 炎症性腸疾患:腸管粘膜免疫の特殊性 (2010)
  • Author(s): 永石宇司、渡辺守
  • Total Pages: 267-282
  • Publisher: 医学書院
• [Book] 臨床粘膜免疫学:潰瘍性大腸炎 (2010)
  • Author(s): 永石宇司、渡辺守
  • Total Pages: 218-232
  • Publisher: シナジー
• [Remarks]
  • URL: http://www.tmd.ac.jp/grad/gast/index.html
• [Patent(Industrial Property Rights)] 大腸上皮幹細胞の単離・培養技術とこ (2011)
  • Inventor(s): 渡辺 守・中村哲也
  • Industrial Property Rights Holder: 国立大学法人東京医科歯科大学
  • Industrial Property Number: 特願、2011-236469
  • Filing Date: 2011-10-27