| Project/Area Number |
13854019
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| Research Category |
Grant-in-Aid for Scientific Research (S)
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| Allocation Type | Single-year Grants |
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| Research Field |
General surgery
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| Research Institution | HOKKAIDO UNIVERSITY |
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Principal Investigator |
TODO Satoru Hokkaido Univ., Grad.School of Med., Professor, 大学院・医学研究科, 教授 (60136463)
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| Co-Investigator(Kenkyū-buntansha) |
UEDE Toshimitsu Hokkaido Univ., Institute for Genetic Medicine Grad. School of Med., Professor, 遺伝子病制御研究所, 教授 (00160185)
FUJITA Hiroyoshi Hokkaido Univ., Grad.School of Med., Professor, 大学院・医学研究科, 教授 (60142931)
MATSUSHITA Michiaki Hokkaido Univ., School of Med., Professor, 医学部保健学科, 教授 (20250425)
FURUKAWA Hiroyuki Hokkaido Univ., Grad.School of Med., Adjunct Professor, 大学院・医学研究科, 寄附講座教員 (70292026)
SHIMAMURA Tsuyoshi Hokkaido Univ., Hokkaido University Hospital, Assistant Professor, 助教授 (00333617)
陳 孟鳳 北海道大学, 大学院・医学研究科, 寄附講座教員 (40333603)
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| Project Period (FY) |
2001 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥122,850,000 (Direct Cost: ¥94,500,000、Indirect Cost: ¥28,350,000)
Fiscal Year 2005: ¥21,580,000 (Direct Cost: ¥16,600,000、Indirect Cost: ¥4,980,000)
Fiscal Year 2004: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000)
Fiscal Year 2003: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000)
Fiscal Year 2002: ¥14,950,000 (Direct Cost: ¥11,500,000、Indirect Cost: ¥3,450,000)
Fiscal Year 2001: ¥48,880,000 (Direct Cost: ¥37,600,000、Indirect Cost: ¥11,280,000)
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| Keywords | Transplantation / Gene therapy / Adenovirus / Costimulatory signal / Rejection / Tolerance / Rodents / Monkey / costimulatory signal / NF-κB / DHMEQ / CD40 / anti-human monoclonal antibody / 4D11 / Kidney transplantation / 臓器移植 / 遺伝子治療 / 免疫抑制療法 / CTLA4Ig / CD40Ig / SDF-1 / HO-1 / モノクローナル抗体 / Leflunomide / FK779 / 異種心移植 / AdCD40Ig / AdCTLA4Ig / FK778 / タクロリムス / プログラフ / 腎移植 / 免疫寛容 / MHCクラス2抗原 / 副刺激経路 / anergy / 肝臓移植 / 小腸移植 |
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| Research Abstract |
In this project, we aimed to develop a strategy to achieve potent immunosuppression and to induce tolerance in organ transplantation by applying a gene therapy. We examined the effect of B7-CD28 and CD40-CD154 costimulatory signaling blockades by using adenoviral vectors coding such as CTLA4Ig and CD40Ig genes, and found that a single gene therapy is potent enough to induce antigen specific tolerance in liver transplantation using a rat model. Although such gene therapies also allowed long-term acceptance of heart and small intestinal allografts in rats, progression of chronic rejection was not fully abrogated in these transplants. The mechanism of tolerance induction by CD40Ig gene therapy was exploited, and we found that CD40Ig enhances IL-2 production in CD4^+ T cells and generates CD4^+CD25^+ regulatory T cells. Concomitant use of calcineurin inhibitors did not abolish tolerance induction by the CD40Ig gene therapy, while some treatment strategy together with calcineurin inhibition
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have accelerated chronic allograft rejection in rodent heart transplantation models. To develop a suitable adjunct therapy for the gene therapy, effects of SDF-1/CXCR4 signaling blockade, a new pirimidine synthesis inhibitor Malononitrilamides and NF-κB inhibitor DHMEQ was further examined in this study. Due to the severe side-effects of viral mediated gene therapy noted in clinical trials, we developed several ways to reduce the amount of viral vector use and also applied cre/loxP system. We also tried non-viral gene transduction by utilizing an electroporation method; however, we found that it is not practical. We therefore examined the effect of a new human CD40 monoclonal antibody, 4D11 in sub-human primate kidney transplantation. Treatment with 4D11 (10-40 mg/kg) for one or 2.5 months allowed long-term renal allograft survival, without showing adverse effects such as thromboembolism or infection, which indicating 4D11 as a promising candidate for clinical use to block CD40-CD154 interactions. Less
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