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Modification of donor MHC antigens with ribozyme RNA transfer to prevent rejection of graft liver

Research Project

Project/Area Number 14571179
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionCHIBA UNIVERSITY

Principal Investigator

SHIMIZU Hiroaki  Chiba University, University Hospital, Lecturer, 医学部附属病院, 講師 (80272318)

Co-Investigator(Kenkyū-buntansha) OHTSUKA Masayuki  Chiba University, University Hospital, Assistant, 医学部附属病院, 助手 (90334185)
ITO Hiroshi  Chiba University, Graduate School of Medicine, Associate Professor, 大学院・医学研究院, 助教授 (00232463)
MIYAZAKI Masaru  Chiba University, Graduate School of Medicine, Professor, 大学院・医学研究院, 教授 (70166156)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2003: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsRibozyme / MHC antigen / Acute rejection / Angiogeneic factor / VEGF / Angiopoietin / Sinusoidal endothelial cell / 急性拒絶反応
Research Abstract

In our first study, we examined whether insertion of ribozyme RNA into the allograft could down-regulate the expression of the target antigens and prevent the rejection of transplanted organs. However, at present, significant down-regulation of donor MHC class I antigen expression on the donor vascular endothelial cells was not observed after insertion of ribozyme RNA even in vitro. Therefore, immunological response to these cells was not significantly reduced. Probably, structure of ribozyme RNA was not suitable for these target antigens. Now we are developing new ribozyme RNA to provide for efficient gene therapy.
In our second study, we investigated the expression of angiopoietin (Ang)-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) in both regenerating liver tissue and isolated liver cells after 70% hepatectomy in rats. Proliferation and apoptosis of sinusoidal endothelial cells (SECs) were also evaluated with proliferating cell nuclear antigen (PCNA) and TUNEL staining, respectively. Results : Expression of VEGF rRNA increased, with a peak at 72 h after hepatectomy, decreasing thereafter. Ang-1 mRNA was present at detectable levels before hepatectomy and increased slowly with a peak at 96 h. Meanwhile, Ang-2 mRNA was hardly detected before hepatectomy, but increased remarkably at 120 h. In isolated cells, VEGF mRNA expression was limited to hepatocytes, but Ang-2 mRNA was found in sinusoidal cells, mainly in hepatic stellate cells (HSCs). The PCNA labeling index of SECs increased slowly, reaching a peak at 72 h, whereas apoptotic SECs were detected at 120 h. Conclusions : VEGF secreted by hepatocytes may play a key role in SEC proliferation, followed by increased Ang-1, presumably promoting sinusoidal maturation. Thereafter, Ang-2 mainly released from HSCs in the absence of VEGF may contribute to apoptosis of superfluous SECs for cessation of regenerative process.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] Mitsuhashi N, Shimizu H, et al.: "Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellular carcinoma."Hepatology. 37. 1105-1113 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kataoka M, Shimizu H, et al.: "Effect o cold ischemia time on C-X-C chemokine expression and neutrophil accumulation in the graft liver after orthotopic liver transplantation in rat"Transplantation. 73. 1730-1735 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimizu H, et al.: "Decreased cell-mediated immune status in colorectal cancer patients with hepatic metastasis"Hepato-Gastroenterol. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimizu H, Kataoka M, et al.: "Extended cold preservation of the graft liver enhances neutrophil-mediated pulmonary injury after liver"Hepato-Gastroenterol. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimizu H, Ito H, Kimura F, Togawa A, Yoshidome H, Ohtsuka M, Kato A, Nukui Y, Miyazaki M.: "Decreased cell-mediated immune status in colorectal cancer patients with hepatic metastasis."Hepatogastroenterol. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimizu H, Kataoka M, Ohtsuka M, Ito H, Kimura F, Togawa A, Yoshidome H, Kato A, Miyazaki M.: "Extended cold preservation of the graft liver enhances neutrophil-mediated pulmonary injury after liver transplantation."Hepatogastroenterol. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mitsuhashi N, Shimizu H, Ohtsuka M, Wakabayashi Y, Ito H, Kimura F, Yoshidome H, Kato A, Nukui Y, Miyazaki M.: "Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellular carcinoma."Hepatology. 37. 1105-1113 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kataoka M, Shimizu H, Mitsuhashi N, Ohtsuka M, Wakabayashi Y, Ito H, Nakagawa K, Yoshidome H, Kataoka, M., Miyazaki, M.: "Effect of cold ischemia time on C-X-C chemokine expression and neutrophil accumulation in the graft liver after orthotopic liver transplantation in rat."Transplantation. 73. 1730-1735 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Shimizu H, et al.: "Decreased cell-mediated immune status in colorectal cancer patients with hepatic metastasis"Hepato-Gastroenterol. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Mitsuhashi N, Shiinizu H, et al.: "Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellular carcinoma"Hepatology. 37. 1105-1113 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kataoka M, Shimizu H, et al.: "Effect o cold ischemia time on C-X-C chemokine expression and neutrophil accumulation in the graft liver after orthotopic liver transplantation in rat"Transplantation. 73. 1730-1735 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimizu H, Kataoka M, et al.: "Extended cold preservation of the graft liver enhances neutrophil-mediated pulmonary injury after liver"Hepato-Gastroenterol. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimizu H, et al.: "Decreased cell-mediated immune status in colorectal cancer patients with hepatic metastasis"Hepato-Gastroenterol. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Mitsuhashi N, Shimizu H, et al.: "Clinical significance of angiopoietins and Tie-2 Expression in human hepatocellular carcinoma : Implication for angiopoietin-2 expression in tumor angiogenesis and progression"Hepatology. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Kataoka M, Shimizu H, et al.: "Effect o cold ischemia time on C-X-C chemokine expression and neutrophil accumulation in the graft liver after orthotopic liver transplantation in rat"Transplantation. 73. 1730-1735 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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