Ｆｉｂｒｏｃｙｔｅ浸潤による腸管線維化機序の解明と新規治療標的の探索

2012 Fiscal Year Annual Research Report

• Project/Area Number: 24659374
• Research Institution: Keio University
• Principal Investigator: 日比 紀文 慶應義塾大学, 医学部, 教授 (50129623)
• Project Period (FY): 2012-04-01 – 2013-03-31
• Keywords: クローン病 / 腸管線維化 / fibrocyte

Research Abstract

クローン病は徐々に腸管障害が蓄積する進行性疾患であり、腸管の線維化に伴う狭窄が手術理由の多くを占める。腸管線維化のよる狭窄への進展メカニズムは解明されておらず、適切な薬物治療や進行予防策は見出されていない。我々は末梢血fibrocyteに着目した。Fibrocyteは骨髄から供給される未分化細胞の一つで末梢血中ではCD34陽性細胞集団の一部として存在する。Fibrocyteは末梢血中からケモカインのシステムなどにより障害組織や炎症局所に浸潤し、その過程でfibroblastなどの局所に定着したコラーゲン産生細胞へと分化していく。我々はこの１年間でクローン病患者末梢血中にfibrocyteが増加していることを見出した。現在、患者背景因子と末梢血fibrocyteの相関を解析し線維化リスク因子の割り出しに着手している。さらにfibrocyteを標的とした線維化予防治療の開発のため腸管線維化モデルの開発に着手した。すでに慢性DSS誘発性腸炎において末梢血中にfibrocyteが出現し、その後腸管線維化が始まるという事実をつかんでいる。末梢血fibrocyteのダイナミクスをより詳細に解析するためcollagen-GFPマウスをすでに手に入れており、今後DSS腸炎での末梢血fibrocyteの可視化を試みるとともに、isolationしてその機能解析に取り組む予定である。またよりクローン病に近いモデルとしてTNF αAREマウスをギリシアから入手しており、同マウスにおいてcollagen産生fibrocyteの動態が他のモデルとどう異なっているのかを解析している。さらにfibrocyteのホーミング機能やcollagen産生性成熟細胞への分化メカニズムの研究成果をもとにそれらを抑制する低分子化合物のスクリーニングを開始すべく準備を始めている。

Research Products

• [Journal Article] CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion. (2013)
  • Author(s): Nakamura Y, Hibi T,et al.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: 304(8) Pages: G700-7
  • DOI: doi: 10.1152/ajpgi.00318.2012.
  • Peer Reviewed
• [Journal Article] Dendritic cells administered intrarectally penetrate the intestinal barrier to break intestinal tolerance via Th2-medeiated colitis in mice. (2013)
  • Author(s): Handa T, Kanai T, Sato T, Mikami Y, Sujino T, Hayashi A, Mizuno S, Matsumoto A, Hisamatsu T, Hibi T.
  • Journal Title: Immunol Lett. Volume: 150(1-2) Pages: 123-9
  • DOI: 10.1016/j.imlet.2013.01.010.
  • Peer Reviewed
• [Journal Article] Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells. (2012)
  • Author(s): Nishida A, Nagahama K, Imaeda H, Ogawa A, Lau CW, Kobayashi T, Hisamatsu T, Preffer FI, Mizoguchi E, Ikeuchi H, Hibi T, Fukuda M, Andoh A, Blumberg RS, Mizoguchi A.
  • Journal Title: J Exp Med. Volume: 209(13) Pages: 2383-94
  • DOI: doi: 10.1084/jem.20112631.
  • Peer Reviewed
• [Journal Article] TGR5 signaling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn’s disease. (2012)
  • Author(s): Yoneno K, Hisamatsu T, Shimamura K, Kamada N, Ichikawa R, Kitazume MT, Mori M, Uo M, Namikawa Y, Matsuoka K, Sato T, KoganeiK, Sugita A, Kanai T and Hibi T
  • Journal Title: Immunology. Volume: 139(1) Pages: 19-29
  • DOI: 10.1111/imm.12045.
  • Peer Reviewed
• [Journal Article] Anticoagulation therapy dramatically improved severe sigmoiditis with findings resembling inflammatory bowel disease, which was caused by mesenteric venous thrombosis. (2012)
  • Author(s): Mikami Y, Kanai T, Iwasaki E, Naganuma M, Yamagishi Y, Shimoda M, Matsuoka K, Hisamatsu T, Iwao Y, Ogata H, Nakatsuka S, Mukai M, Hibi T.
  • Journal Title: Clinical Journal of Gastroenterology. Volume: 5 Pages: 377-382
  • DOI: 0.1007/s12328-012-0340-3
  • Peer Reviewed
• [Journal Article] Immune aspects of the pathogenesis of inflammatory bowel disease. (2012)
  • Author(s): Hisamatsu T, Kanai T, Yohei Mikami, Yoneno K, Matsuoka K, Hibi T.
  • Journal Title: Pharmacol Ther. Volume: 137(3) Pages: 283-97
  • DOI: 10.1016/j.pharmthera.2012.10.008.
  • Peer Reviewed
• [Journal Article] Activated Hepatic Stellate Cells Mediate the Differentiation of Macrophages. (2012)
  • Author(s): Chang J, Hisamatsu T, Shimamura K, Yoneno K, Adachi M, Naruse H, Igarashi T, Higuchi H, Matsuoka K, Kitazume MT, Ando S, Kamada N, Kanai T, and Hibi T.
  • Journal Title: Hepatology Research. Volume: Epub ahead of print Pages: Epub ahead
  • DOI: 10.1111/j.1872-034X.2012.01111.x.
  • Peer Reviewed
• [Journal Article] Dysregulated balance of retinoid-related orphan receptor γt-dependent innate lymphoid cells is involved in the pathogenesis of chronic DSS-induced colitis. (2012)
  • Author(s): Kimura K, Kanai T, Hayashi A, Mikami Y, Sujino T, Mizuno S, Handa T, Matsuoka K, Hisamatsu T, Sato T Hibi T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 427(4) Pages: 694-700
  • DOI: 10.1016/j.bbrc.2012.09.091.
  • Peer Reviewed
• [Journal Article] Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcγR-mediated CD14+ macrophage activation. (2012)
  • Author(s): Uo M, Hisamatsu T, Miyoshi J, Kaito D, Yoneno K, Kitazume MT, Mori M, Sugita A, Koganei K,Matsuoka K, Kanai T, Hibi T.
  • Journal Title: Gut. Volume: Epub ahead of print Pages: Epub ahead
  • Peer Reviewed
• [Journal Article] A Case of Intestinal Behçet's Disease Treated with Infliximab Monotherapy Who Successfully Maintained Clinical Remission and Complete Mucosal Healing for Six Years. (2012)
  • Author(s): Maruyama Y, Hisamatsu T, Matsuoka K, Naganuma M, Inoue N, Ogata H, Iwao Y, Kanai T, Hibi T.
  • Journal Title: Intern Med. Volume: 51(16) Pages: 2125-9
  • Peer Reviewed
• [Journal Article] T-helper 17 and Interleukin-17-Producing Lymphoid Tissue Inducer-Like T Cells Make Different Contributions to Colitis in Mice. (2012)
  • Author(s): Ono Y, Kanai T, Sujino T, Nemoto Y, Kanai Y, Mikami Y, Hayashi A, Matsumoto A, Takaishi H, Ogata H, Matsuoka K, Hisamatsu T, Watanabe M, Hibi T.
  • Journal Title: Gastroenterology. Volume: 143(5) Pages: 1288-97
  • DOI: 10.1053/j.gastro.2012.07.108.
  • Peer Reviewed
• [Presentation] Early normalization of C-reactive protein (CRP)by infliximab is a predictive factor of sustained long-term clinical efficacy in crohn’s disease. (2012)
  • Author(s): 26. Kimura K, Matsuoka K, Kanai T, Okamoto S, Hisamatsu T, Inoue N, Yajima T, Ogata H, Iwao Y, Hibi T
  • Organizer: The 14th Meeting of International Conference on Ulcer Research.
  • Place of Presentation: Tokyo
  • Year and Date: 20120712-20120714