| Co-Investigator(Kenkyū-buntansha) |
OKADA Hidechika Medical School, Nagoya City University, professor, 医学部, 教授 (30160683)
YOKOYAMA Itsuo Nagoya University, School of Medicine MD, 医学部, 講師 (60240206)
TAKAGI Hiroshi Nagoya University, School of Medicine professor, 医学部, 教授 (70154755)
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| Research Abstract |
Xenotransplantation is an atractive strategy tp compensate the donor shortage. However, hyperacute rejecction, induced by xenoantigen, natural antibody, and complement, is an great barrier for the successful xenotransplantation. In this study, we examined the effect of gene therapeutic technique such as adenovirus-mediated gene transfer on the in hibition of hyperacute, delayayd, and acute rejection in organ xenorransplantation. Adenoviral vectors with DAF and HRF20 genes were trasduced in the livers of mice and pigs. In the livers of mice, the transgene expression was observed in both hepatocytes and endothclial lining cells, although in those of pigs, that was observed in sinusoidal lining cells, especially sinusoidal endothelical cells. In the livers transduced with DAF and HRF20 genes, the depositions of C3, C9, IgG,and IgM after the perfusion of human scra were prominently supperssed due to the inhibition of complement activation. We studied two kinds of strategies such as the tra
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nsductions of antisense ribozymc to a (1.3) galactosyltrsnsferase, and a (1.2) fucosyltransferase to downregulate the expression of GalaGal, which has been reported as a major xenoantigen. Adenoviral vectors with antisense ribozyme and a (1.2) fucosyltransferase successfully inhibited the expression of GalaGal, which was proportional to the inhibition of complement dependent cytotoxicity in vitro. It has been reported that the delayd-typed rejection occurs due to the activation of endothelial cells in the exnogeneic organs. We evaluated the effect of adenovirus-mediated gene transfer with tissue plasminogen activator (TPA) and inteleukin 10 (IL10) genes using ischemia-reperfusion injury of the livers in rats. The transductions of both TPA and IL10 genes significantly inhibited the injury of ischemia-reperfusion in the livers.
Finally we examined the effect of adenovirus-mediated gene transfer with CTLA41g gene on the suppression of acute rejection using liver transplantation model of rat. The transduction of CTLA41g gene prominently prolonged the survival of the rats after liver transplantation. These findings suggest that the gene therapeutic approach such as adenovirus-mediated gene tranfer is effective to inhibit hyperacute, delayd-typed, and acute rejections in organ xenotrasnsplantation. Less
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