| Project/Area Number |
17591363
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | Fukuoka University |
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Principal Investigator |
NAKANO Masashiko Fukuoka University, School of Medicine, Research Associate, 医学部, 助手 (90389354)
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| Co-Investigator(Kenkyū-buntansha) |
YASUNAMI Yohichi Fukuoka University, School of Medicine, Associate Professor, 医学部, 助教授 (00166521)
ONO Junko Fukuoka University, School of Medicine, Professor, 医学部, 教授 (40108692)
HABE Shigehisa Fukuoka University, School of Medicine, Lecturer, 医学部, 講師 (70037430)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | islet transplantation / diabetes mellitus / activated protein C / tissue factor / graft failure / pro-inflammatory cytokine / blood coagulation / 膵島移植 / 活性化プロテインC / 凝固系 |
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| Research Abstract |
The inability of producing successful islet transplantation from one donor to one recipient has been a major obstacle facing clinical islet transplantation (Tx). To overcome this, one way is to find a novel procedure to prevent islet graft failure in association with engraftments. In the present study, we focus on a role of coagulation represented by tissue factor (TF) expression in destruction of islet grafts. STZ-diabetic mice (B6, n=10) receiving intrahepatic 200 syngenic islets, the equivalent number of islets isolated from a single donor, remained hyperglycemic (>400mg/dl) at 60 days after Tx. In marked contrast, all diabetic mice (n=7) with 200 islets and treated with activated protein C (human APC, 4Oug, iv at 0, 2 and 4 hrs after Tx) became normoglycemic (<200mg/dl). Addition of anti-endothelial protein C receptor (EPCR) ab (100 ug, ip) abolished the effect of APC, indicating the effect is mediated by its ligand, EPCR. Histologically, TF was found to be induced in the liver receiving islets and treated with saline and localized in neutrophils infiltrated into islets at 24 hrs after Tx. In contrast, TF expression was inhibited in the liver treated with APC having significant increase in number of islet grafts. FACS analysis disclosed that Gr-1+CD11b+cells (neutrophils and macrophages) with high production of IFN-g were accumulated in the liver of control mice with the peak at 6 hrs after Tx. In mice received with islets and treated with APC, the production of IFN-g in these cells was down-regulated without affecting their number. The beneficial effect of APC was seen in islet allografts when rejection was prevented by anti-CD4 antibody. These findings demonstrate that the coagulation cascades is activated to produce pro-inflammatory cytokines and that APC has a beneficial effect on prevention of islet graft failure.
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