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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.

我们通过在抗关节炎的 C57BL/6 背景下杂交两种 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。这些小鼠自发地发展出严重的关节炎，其发病时间比gp130^<F759/F759>小鼠早得多，并且发病率比pX-Tg小鼠高得多。 gp130^<F759/F759>小鼠的症状，包括淋巴结肿大、脾肿大、高γ-球蛋白血症、自身抗体产生、外周淋巴器官中记忆/活化T细胞和粒细胞的增加以及II类MHC^<bright>CD11c^+群体的减少，在双倍实验中得到增强。突变体。免疫组织化学分析揭示了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 STAT3 的核转位。 CD4^+ T 细胞与滑膜中 CD11b^+ 细胞表达的 II 类 MHC 分子紧密相连。在三突变体IL-6^-/->/gp130^<F759/F759>/pX-Tg中观察到发病率、严重程度和免疫学异常显着降低，表明双突变体中的关节炎是IL-6依赖性的。 IL-6/STAT3 信号对树突状细胞成熟的抑制作用在体内和体外均得到证实。骨髓移植实验表明，gp130^<F759/F759>突变和pX基因在非造血细胞中而非造血细胞中的过度表达是关节炎发生的必要条件。