Immunosuppressive role of TGF-β1 against autoimmune destruction of islet β cells and a basic study on islet β cells of NOD-RGP-TGF-β1 Tg

TGF-β1对胰岛β细胞自身免疫破坏的免疫抑制作用及NOD-RGP-TGF-β1 Tg对胰岛β细胞的基础研究

基本信息

批准号：
11671090
负责人：
ITAKURA Mitsuo
金额：
$ 1.28万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Type 1 diabetes is a major public health problem. To determine the immunosuppressive role of TGF-β1 for autoimmune destruction of islet β cells, we used the animal model of NOD-RGP-TGF-β1 transgenic mice(Tg). Qur findings are as follows ;1)NOD-RGP-TGF-β1(homo)Tg showed impaired glucose tolerance, low serum insulin levels, small islet sizes compared with those of NOD-RGP-TGF-β1(hemi)and littermates. These findings suggest that overexpression of constitutively active TGF-β1 severely impaired the development of islet β cells. It is suggested that a modest TGF-β1 signaling plays an important role for the early stage islet development.2)To identify the susceptibility genes for diabetes, we performed genome-wide quantitative trait loci(QTL)analysis, using NOD-RGP-TGF-β1 in NOD background which were crossed to C3H genetic background. F2 intercrosses between NOD-RGP-TGF-β1 and C3H strain demonstrated a wide variety of diabetes-related parameters including, plasma insulin concentration, glucose tolerance, and islet morphology. We are performing genome-wide QTL analysis using F2 generation.3)To determine the immunosuppressive roles of islet β cells in NOD-RGP-TGF-β1(hemi)transgenic mice against autoimmune destrunction, we analysed the model of syngenic islet transplantation to diabetic NOD mice. Immunohistochemical examination of islet cell graft showed the long survival of graft, but syngenic islet cell graft was not protected in diabetic NOD mice. The number of islet cells for trasplantation or other factors have to be examined. We are performing this points.

1型糖尿病是一个主要的公共卫生问题。为了确定TGF-β1在胰岛β细胞自身免疫性破坏中的免疫抑制作用，我们使用了NOD-RGP-TGF-TGF-β1转基因小鼠（TG）的动物模型。古兰经的发现如下：1）与NOD-RGP-RGP-TGF-β1（Hemi）和同窝鼠相比，NOD-RGP-TGF-β1（HOMO）TG显示出葡萄糖耐受性受损，低血清胰岛素水平，小胰岛尺寸。这些发现表明，组成性活性TGF-β1的过表达严重损害了胰岛β细胞的发展。有人提出，适度的TGF-β1信号传导对于早期胰岛发展起着重要作用。2）为了鉴定糖尿病的易感基因，我们使用NOD-RGP-TGF-β1在NOD背景中使用NOD-RGP-TGF-β进行了与C3H遗传背景交叉的NOD-RGP-TGF-β。 F2 NOD-RGP-TGF-β1和C3H菌株之间的F2间交叉表现出了各种各样的糖尿病相关参数，包括血浆胰岛素浓度，葡萄糖耐受性和胰岛形态。我们正在使用F2 Generation进行全基因组QTL分析。3）为了确定NOD-RGP-TGF-β1（HEMI）转基因小鼠在自身免疫性破坏的NOD-RGP-TGF-β1（HEMI）转基因小鼠中的免疫抑制作用，我们分析了旋律胰岛移植到糖尿病NOD小鼠的模型。胰岛细胞移植物的免疫组织化学检查显示了移植物的长期存活，但是在糖尿病NOD小鼠中未受保护的胰岛细胞移植物受到保护。必须检查用于trasplantation或其他因素的胰岛细胞的数量。我们正在执行这一点。