Pathogenesis of inflammatory arthropathy developed in HTLV-I transgenic mice

HTLV-I 转基因小鼠炎症性关节病的发病机制

• 批准号: 04454198
• 负责人: IWAKURA Yoichiro
• 金额: $ 4.16万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04454198/
• 关键词: HTLV-I; Arthritis; Transgenic mouse; Autoimmune; Inflammation; Cytokine; Tax; Disease model; HTLV-I; Cytekine; 関節リウマチ; トランスジェニックマウス; 自己免疫; サイトカイン; 関節炎; 自己免疫疾患; 自己抗体; 成人T細胞白血病ウイルス(HTLV-I)

We have recently reported on an inflammatory arthropathy resembling rheumatoid arthritis that develops in high incidence among transgenic mice that carry the env-pX region of the human T-cell leukemia virus type-1 (HTLV-1) genome (Iwakura et al., Science, 1991). The pathology was very similar to that of rheumatoid arthritis with synovial cell overgrowth, inflammatory cell infiltration, bone and cartilage erosion, and pannus formation (Rheum. Arth. 36,1612,1993), and moreover, a large proportion of the complex-type carbohydrate chains of the immunoglobulins lacked the terminal galactose residue (BBRC,192,1004,1993). In an effort to elucidate the pathogenesis of this disease, we found that genes for inflammatory cytokines including IL-1alpha, IL-1beta, IL-2, IL-6, TNF-alpha, and IFN-gamma as well as MHC genes were activated in the transgenic joints (submitted). Interestingly, these mice produced antibodies against IgG,type II collagen (IIC), and heat shock proteins (HSPs) accompanied by IgG hypergammaglobulinemia. Thus, it was shown that HTLV-I can cause autoimmunity. Since development of arthritis was greatly affected by the genetic background of the mice, involvement of autoimmunity in the pathogenesis was suggested. These observations show that these mice are useful not only to analyze pathogenicity of rheumatoid arthritis but also to study pathogenicity of autoimmunity and roles of cytokines in its development. We are now studying retrovirus-host interactions in details using this transgenic mouse system.

我们最近报道了一种类似于类风湿性关节炎的炎性关节病，其在携带人T细胞白血病病毒1型（HTLV-1）基因组env-pX区域的转基因小鼠中发生率很高（Iwakura等人，Science，1991）。病理学与类风湿性关节炎的病理学非常相似，具有滑膜细胞过度生长、炎性细胞浸润、骨和软骨侵蚀以及血管翳形成（Rheum.阿尔斯。36，1612，1993），而且，免疫球蛋白的大部分复合型碳水化合物链缺乏末端半乳糖残基（BBRC，192，1004，1993）。为了阐明这种疾病的发病机制，我们发现，包括IL-1 α、IL-1 β、IL-2、IL-6、TNF-α和IFN-γ在内的炎性细胞因子基因以及MHC基因在转基因关节中被激活（已提交）。有趣的是，这些小鼠产生了抗IgG、II型胶原（IIC）和热休克蛋白（HSP）的抗体，并伴有IgG高丙种球蛋白血症。因此，显示HTLV-I可引起自身免疫。由于关节炎的发生受小鼠遗传背景的影响很大，因此认为其发病机制与自身免疫有关。这些结果表明，这些小鼠不仅是有用的分析类风湿关节炎的致病性，而且还研究自身免疫的致病性和细胞因子在其发展中的作用。我们现在正在使用这种转基因小鼠系统详细研究逆转录病毒与宿主的相互作用。

项目成果

岩倉 洋一郎(分担執筆): "有用トランスジェニック動物" 生殖系列:親から子への生命の流れ-第7回大学と科学公開シンポジウム組織委員会編集. 190-199 (1993)

Yoichiro Iwakura（贡献者）：“有用的转基因动物”生殖系：从亲代到后代的生命流 - 由第七届大学和科学公共研讨会组织委员会编辑 190-199（1993）。

岩倉洋一郎(分担執筆): "生体防御機能の分子機構:阿蘇シンポジウム1992" 南山堂, 47-56 (1993)

岩仓洋一郎（撰稿人）：“生物防御功能的分子机制：阿苏研讨会 1992” Nanzando，47-56（1993）

Iwakura, Y., Saijo, S., Nakayama, J., Yoshida, E., Itagaki, K., and Tosu, M.: "Augmentation of protooncogene and cytokine gene expression in transgenic mice carrying the HTLV-I tax gene and its relation to the development of tumors and inflammatory arthri

Iwakura, Y.、Saijo, S.、Nakayama, J.、Yoshida, E.、Itagaki, K. 和 Tosu, M.：“携带 HTLV-Itax 基因的转基因小鼠中原癌基因和细胞因子基因表达的增强和

Yamamoto, H., Sekiguchi, T., and Iwakura, Y.: "Polyarthritis in mice transgenic for human T-cell leukemia virus Type-I (HTLV-I). I.Histopathological characteristics of joints." Arth.Rheum.36. 1612-1620 (1993)

Yamamoto, H.、Sekiguchi, T. 和 Iwakura, Y.：“人类 T 细胞白血病病毒 I 型 (HTLV-I) 转基因小鼠的多关节炎。I. 关节的组织病理学特征。”

Iwakura, Y.: "Useful transgenic animals-Germ line transmission of the life from parents to child (in Japanese)." In "The Proceedings of The 7th University and Science Symposium", Kuba Pro.190-199 (1993)

Iwakura, Y.：“有用的转基因动物——生命从父母到孩子的生殖系传播（日语）。”