Mechanisms to facilitate the development of autoimmune arthritis by over-expression of HTLV-1pX.

通过 HTLV-1pX 过度表达促进自身免疫性关节炎发展的机制。

基本信息

批准号：
15590439
负责人：
ISHIHARA Katsuhiko
金额：
$ 2.3万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590439/
关键词：
IL-6 gp130 mouse models STAT3 Rheumatoid arthritis HTLV-1 pX dendritic cell ノックインマウス自己免疫疾患マウスモデル HTLV-1pX トランスジェニックマウス

项目摘要

We generated a double-mutant mouse by crossing two murine models of RA, a gp 130 mutant knock-in mouse (gp130^<F759/F759>) and an HTLV-1 pX transgenic mouse (pX-Tg), in a C57BL/6 background, which is resistant to arthritis. The mice spontaneously developed severe arthritis with a much earlier onset than the gp130^<F759/F759> mice and with a much higher incidence than did the pX-Tg mice. The symptoms of gp130^<F759/F759> mice, including lymphoadenopathy, splenomegaly, hyper-γ-globulinemia, autoantibody production, increases in memory/activated T cells and granulocytes in the peripheral lymphoid organs, and a decrease in the class II MHC^<bright> CD11c^+ population, were augmented in the double mutants. Immunohistochemical analyses revealed production of IL-6 and nuclear translocation of phospho-STAT3 in the macrophages and fibroblasts in the synovium of arthritic joints. CD4^+ T cells are closely located to the class II MHC molecules expressed by CD11b^+ cells in the synovium. Marked reductions in incidence, severity, and immunological abnormalities were seen in the triple mutant, IL-6^<-/->/gp130^<F759/F759>/pX-Tg, indicating that the arthritis in the double mutant is IL-6 dependent. Inhibitory effects on the maturation of dendritic cells by IL-6/STAT3 signal were demonstrated in vivo and in vitro. Experiments of bone marrow transfer revealed that both the gp130^<F759/F759> mutation and over-expression of pX gene in the non-hematopoietic cells but not in hematopoietic cells are required for the development of arthritis.

我们通过在 C57BL/ 中杂交两种 RA 小鼠模型，即 gp 130 突变敲入小鼠 (gp130^<F759/F759>) 和 HTLV-1 pX 转基因小鼠 (pX-Tg)，产生了双突变小鼠。 6 背景，对关节炎有抵抗力，小鼠自发地出现严重关节炎，且比 gp130^<F759/F759> 发病早得多。 gp130^<F759/F759> 小鼠的症状，包括淋巴结病、脾肿大、高 γ-球蛋白血症、自身抗体产生、记忆/活化 T 细胞和粒细胞增加。在双突变体中，外周淋巴器官中的表达增加以及 II 类 MHC^<bright>CD11c^+ 群体的减少有所增加。免疫组织化学分析显示，关节炎关节滑膜中巨噬细胞和成纤维细胞中 IL-6 的产生和磷酸化 STAT3 的核转位与滑膜中 CD11b^+ 细胞表达的 II 类 MHC 分子紧密相连。在三重突变体中观察到发病率、严重程度和免疫学异常显着降低， IL-6^<-/->/gp130^<F759/F759>/pX-Tg，表明双突变体中的关节炎是IL-6依赖性的IL-6/STAT3对树突状细胞成熟的抑制作用。体内和体外骨髓移植实验均证实了pX基因的gp130^<F759/F759>突变和过表达。关节炎的发生需要非造血细胞，但造血细胞中不需要。