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Pathogenesis of immune-mediated cholangiopathy

Research Project

Project/Area Number 11670473
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionTohoku University

Principal Investigator

UENO Yoshiyuki  Tohoku University Hospital, Research Associate, 医学部・附属病院, 助手 (70282126)

Co-Investigator(Kenkyū-buntansha) MANO Yutaka  Tohoku University Hospital, Research Associate, 医学部・附属病院, 助手 (50302120)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥2,600,000 (Direct Cost: ¥2,600,000)
KeywordsBile Duct Epithelial Cells / Apoptosis / Fas (CD95) / Fas ligand (FasL) / GVHD / Fas / FasL / 胆管炎 / TUNEL / MRL(lpr / lpr)
Research Abstract

Bile duct injury observed in hepatic graft versus host disease (GVHD) is regarded as an immune-mediated injury, although its precise mechanism is unclear. However, recent studies have suggested the involvement of Fas-mediated cell death in this immune-mediated cholangiopathy. In this study, we first demonstrated the constitutive expression of Fas receptor by cholangiocytes in situ from normal BALB/c mice, which was upregulated in GVHD mice. Also, we confirmed the Fas protein expression in the isolated cholangiocytes from normal BALB/c mice by immunocytochemistry and immunoblotting. Furthermore, the addition of agonistic Fas antibody (Jo2) induced cholangiocyte apoptosis confirmed by DNA-ladder formation and annexin V staining. Cholangiocytes from Fas-deficient mice (MRL lpr/lpr) did not show Jo2-induced apoptosis. Interferon γ augmented Fas expression and Fas-mediated cell death, respectively. Following these observations, experimental GVHD was induced by transfer of splenocytes from B10.D2 mice to irradiated (800 rad) BALB/c mice. Liver infiltrating lymphocytes from the recipient showed dose-dependent cytotoxicity against ^<51>Cr-labeled cholangiocytes isolated from BALB/c mice. Moreover, the addition of blocking Fas-Fc fusion protein reduced this cytotoxicity to 44.7%. Finally, administration of this Fas-Fc protein to the BALB/c mice, which had been adoptively transferred with splenocytes of B10.D2 mice, prevented the development of hepatic GVHD in vivo. These results demonstrated the involvement of Fas-mediated cell death in cholangiopathy observed in GVHD, and a soluble Fas-Fc protein may have a therapeutic potential for hepatic GVHD.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Ueno Y,Ishii M,Yahagi et al: "Fas-mediated cholangiopathy in the murine model of graft versus host disease."Hepatology. 31. 966-974 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ueno Y,Yahagi K,Mano et.al: "Protective effects of ursodeoxycholic acid (UDCA) for bile duct cells are not enhanced with colchicine in a murine model of experimental cholestasis."Hepatology. 32. 496A (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Alpini G,Glaser SS,Ueno Y, et al: "Bile acid feeding induces cholangiocytes proliferation and secretion"Gastroenterology. 116. 179-186 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ueno Y,Ishii M,Yahagi K, et.al: "Persistent Cholangitis and delayed apoptosis of cholangiocytes observed in Fas-deficient mice"Hepatology. 30. 388A (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ueno Y, Ishii M, Yahagi K, Mano Y, Kisara N, Nakamura N, et al. (total 9, first): "Fas-mediated cholangiopathy in the murine model of graft versus host disease."Hepatology. 31(4). 966-74 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ueno Y, Yahagi K, Mano Y, Kobayashi Y, Kida M, Shimosegawa T.: "Protective effects of ursodeoxycholic acid (UDCA) for bile duct cells are not enhanced with colchicine in a murine model of experimental cholestasis."Hepatology. 32. 496A (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Alpini G, Glaser SS, Ueno Y, Rodgers R, Phinizy JL, Francis H, Baiocchi L, Holcomb LA, Caligiuri A, and LeSage GD.: "Bile acid feeding induces cholangiocyte proliferation and secretion : evidence for bile acid-regulated ductal secretion."Gastroenterolgy. 116(1). 179-86 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kobayashi N, Ishii M, Ueno Y, Kisara N, Chida N, Iwasaki T, and Toyota T.: "Co-expressi on of Bcl-2 protein and vascular endothelial growth factor in hepatocellular carcinomas treat ed by chemoembolization."Liver. 19(1). 25-31 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ueno Y,Ishii M,Yahagi et al: "Fas-mediated cholangiopathy in the murine model of graft versus host disease."Hepatology. 31. 966-974 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ueno Y,Yahagi K,Mano et.al: "Protective effects of ursodeoxycholic acid (UDCA) for bile duct cells are not enhanced with colchicine in a murine model of experimental cholestasis."Hepatology. 32. 496A (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Alpini G,Glaser SS,Ueno Y, et al: "Bile acid feeding induces cholangiocytes proliferation and secretion"Gastroenterology. 116. 179-186 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ueno Y,Ishii M,Yahagi K, et.al: "Persistent Cholangitis and delayed apoptosis of cholangiocytes observed in Fas-deficient mice"Hepatology. 30. 388A (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Alpini G.,Glaser SS.,Ueno Y.et al.: "Bile acid feeding induces cholangiocytes prolireferation and secretion"Gastroenterology. 116. 179-186 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ueno Y.,Ishii M.,Yahagi K.et al.: "Persistent Cholangitis and delayed apoptosis of cholangiocytes observed in Fas-deficient mice"Hepatology. 30. 388A (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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