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

1型糖尿病是一个主要的公共卫生问题。为了确定转化生长因子-β1对胰岛β细胞自身免疫破坏的免疫抑制作用，我们采用了NOD-RGP-转化生长因子-β1转基因小鼠(TG)的动物模型。研究结果如下：1)NOD-RGP-转化生长因子-β1(HOMO)TG与NOD-RGP-转化生长因子-β1(HMO)组和同胎组相比，表现为糖耐量减低、血清胰岛素水平降低、胰岛体积变小。这些结果表明，过度表达具有结构性活性的转化生长因子-β-1严重损害了胰岛β细胞的发育。为了确定糖尿病的易感基因，我们利用NOD背景中的NOD-β-β1与C3H遗传背景杂交，进行了全基因组的数量性状分析。NOD-RGP-转化生长因子-β1与C3H株的F2杂交显示了广泛的糖尿病相关参数，包括血浆胰岛素浓度、糖耐量和胰岛形态。3)为了确定NOD-RGP-β-β1(HMI)转基因小鼠中胰岛细胞对自身免疫功能丧失的免疫抑制作用，我们分析了同基因胰岛移植给糖尿病NOD小鼠的模型。免疫组织化学检测显示胰岛细胞移植物存活时间较长，但同基因胰岛细胞移植物对糖尿病NOD小鼠无保护作用。移植胰岛细胞的数量或其他因素必须进行检查。我们正在执行这几点。

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.