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Modification of donor MHC antigens with antisense gene transfer to prevent rejection of transplanted organ, and mechanism of hepatic sinusoidal endothelial cell proliferation during regeneration after partial hepateclomy.

通过反义基因转移修饰供体 MHC 抗原以防止移植器官排斥，以及部分肝切除后再生过程中肝窦内皮细胞增殖的机制。

基本信息

批准号：
12671204
负责人：
SHIMIZU Hiroaki
金额：
$ 2.11万
依托单位：
CHIBA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671204/
关键词：
Sinusoidal endothelial cello Liver regeneration VEGF Hepatocyte Antisense gene MHC antigen Liver transplantation

项目摘要

In our first study, we examined whether insertion of an antisense vector into the allograft could down-regulate the expression of the target antigens and to prevent the rejection of transplanted organs. Down-regulation of' donor MHC class I antigen expression on the donor cells Was observed after transfection of plasmid vector containing antisense of donor target antigen in vitro, and also immunological response to these cells decreased. However, in vivo, efficient transfection of plasmid vector containing antisense to the donor graft liver during cold preservation periods was verry difficult at present. Now we are developing new technology to provide for efficient in vivo transfection.In our second study, We investigated expressions of vascular endothelial cell growth factor (VEGF) and its receptors, flt-1 and -KDR/flk-1 in regenerating liver after 70 % hepatectomy. Proliferation of both hepatocytes and SECs was also monitored by evaluating proliferating cell nuclear antigen (PCNA) labeling index. The expression of VEGF mRNA was increased markedly between 48 and 72 hr after hepatectomy. The immunohistochemical staining revealed that expression of VEGF started to increase 24 hr after hepatectomy, with a peak at 72 hr, and the majority of the VEGF-positive cells were hepatocytes. Meanwhile, expression of flt-1 and KDR/flk-1 was observed along the sinusoids even before hepatectomy, but was increased between 72 and 120 hr. These results strongly suggest that VEGF secreted by proliferating hepatocytes may represent an important stimulator of SEC proliferation.

在我们的第一项研究中，我们检查了在同种异体移植物中插入反义载体是否可以下调靶抗原的表达，并防止移植器官的排斥反应。体外转染含反义供体靶抗原的载体后，供体细胞表面供体MHC-I类抗原表达下调，对供体细胞的免疫应答也降低。然而，在体内，目前还很难将含有反义基因的质粒载体在冷保存期间有效地转移到供体肝上。在我们的第二个研究中，我们研究了血管内皮细胞生长因子及其受体Flt-1和-KDR/Flk-1在70%肝切除后再生肝中的表达。用增殖细胞核抗原标记指数监测肝细胞和SECs的增殖情况。肝切除后48~72h，血管内皮细胞生长因子mRNA的表达显著增加。免疫组织化学染色显示，肝切除后24小时血管内皮生长因子表达开始增加，72小时达高峰，阳性细胞以肝细胞为主。同时，甚至在肝切除前，Flt-1和KDR/Flk-1就在肝窦中观察到表达，但在72-120小时后表达增加。提示增殖期肝细胞分泌的血管内皮生长因子可能是SEC增殖的重要刺激因子。