| Project/Area Number |
16390368
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Hokkaido University |
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Principal Investigator |
FURUKAWA Hiroyuki Hokkaido University, Graduate School of Medicine, Professor, 大学院医学研究科, 特任教授 (70292026)
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| Co-Investigator(Kenkyū-buntansha) |
TODO Satoru Hokkaido University, Graduate School of Medicine, Professor, 大学院医学研究科, 教授 (60136463)
UEDA Toshimitsu Hokkaido University, Institute for Genetic Medicine, Professor, 遺伝子病制御研究所, 教授 (00160185)
SHIMAMURA Tsuyoshi Hokkaido University, Hokkaido University Hospital, Associate Professor, 病院・助教授 (00333617)
OZAKI Michitaka Hokkaido University, Graduate School of Medicine, Associate Professor, 大学院医学研究科, 特任助教授 (80256510)
YAMASHITA Kenichiro Hokkaido University, Hokkaido University Hospital, Instructor, 病院・医員 (00399940)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,200,000 (Direct Cost: ¥14,200,000)
Fiscal Year 2006: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2005: ¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 2004: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Keywords | Small bowel transplantation / Gene therapy / Costimulatory signals / Immunosuppression / Ischemia / reperfusion / NF-kB / Adeno virus / DHMEQ / 拒絶反応 / マウス / 小腸 / 虚血再灌流障害 / ラット / CTLA4Ig / CD40Ig |
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| Research Abstract |
Advances in both surgical techniques and immunosuppression have made small bowel transplantation (SBTx) as an established treatment for patients with irreversible intestinal failure. However, further refinements in immunosuppression and graft preservation including protection against ischemia/reperfusion (IR) injury are necessary to improve SBTx patient survival and their quality of life. In this study, we aimed to establish a new strategy for SBTx based on a gene therapy. In rats, blockade of CD80/86-CD28 and/or CD4O-CD154 costimulatory signals by applying the adenoviral vector coding CTLA4Ig or CD40Ig markedly prolonged a fully MHC mismatched small intestinal allograft. Most of these allografts survived for over 300 days, however, progression of chronic rejection was inevitable. Despite the success of this gene therapy based costimulation blockade in SBTx, adeno-virus mediated gene therapy became unpractical because serious side-effects occurred following such therapy during its clinical trials. The event has led us to reconsider the approaches to accomplish our aim of this study. We have examined the immunosuppressive properties of new Leflunomide derivatives, FK778/FK779 and a novel NF-kB inhibitor, DHMEQ in rodent transplantation models, and demonstrated that these newly developed agents have a significant ability to prevent acute cellular rejection and to prolong allograft survival. Also in this study, we have shown that a degree of lipid peroxidation within the organ correlates with severity of I/R, injury, and that the free radical scavenging agent, Edaravone and NF-kB inhibitor DHMEQ ameliorate FR injury in dogs and rats. Although further studies are warranted to establish a new strategy in SBTx, we conclude that especially, costimulatory signal blockers and NF-kB inhibitor are effective agents for preventing small bowel allograft rejection and preservation/IR injuries that seems to be potential candidates for clinical use in SBTx.
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