Development of rheumatoid arthritis models using transgenic technique

利用转基因技术开发类风湿性关节炎模型

• 批准号: 10558120
• 负责人: IWAKURA Yoichiro
• 金额: $ 8.38万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10558120/
• 关键词: Rheumatoid arthritis; transgenic mice; knockout mice; HTLV-I; IL-1; IL-6; antoimmune disease; model mice; 疾患モデル; サイトカイン; HTLV-I-Tgマウス; コンジェニック; IL-1レセプターアンタゴニスト

Disease models are important to analyze pathogenesis of the disease and to develop effective medication. It is important for the disease models to represent faithfully the symptoms of the disease. Thus, to develop disease model, it is important to characterize the pathogenesity of the disease in order to show similarity to human cases. Previously, we reported that HTLV-I-Tg mice developed rheumatoid-like inflammatory arthropathy, and suggested involvement of autoimmunity in the pathogenesity. In this report, to elucidate pathogenesis of arthritis, we produced Tg mice that expressed tax gene in T cell or macrophage by constructing DNAs that express the tax gene alone under the control of either CD4 enhancer/promoter or c-fms promoter. The tax gene was expressed in T cells and in macrophages in CD4-tax-Tg mice, and these mice developed not only arthritis, but also autoimmunity. On the other hand, the transgene was determined in macrophages in fms-tax mice, and 100% of the mice developed arthritis at the age of 2 months. Transplantation of bone marrow cells from these mice could induce arthritis in wild type mice suggesting that the synovial cells that originated from bone marrow cells are abnormal in these Tg mice. Thus, it is shown that not only LTR-pX mice, but also fms-tax mice are both valuable models for human rheumatoid arthritis.

疾病模型对于分析疾病的发病机制和开发有效的药物治疗具有重要意义。对于疾病模型来说，忠实地表现疾病的症状是很重要的。因此，为了开发疾病模型，重要的是表征疾病的致病性以显示与人类病例的相似性。以前，我们报道HTLV-I-Tg小鼠发生类风湿样炎性关节病，并建议参与自身免疫的发病机制。在本报告中，为了阐明关节炎的发病机制，我们通过构建在CD 4增强子/启动子或c-fms启动子的控制下单独表达tax基因的DNA，产生了在T细胞或巨噬细胞中表达tax基因的Tg小鼠。tax基因在CD 4-tax-Tg小鼠的T细胞和巨噬细胞中表达，这些小鼠不仅发生关节炎，而且发生自身免疫。另一方面，在fms-tax小鼠的巨噬细胞中确定了转基因，并且100%的小鼠在2个月大时发生了关节炎。这些小鼠的骨髓细胞移植可诱导野生型小鼠的关节炎，表明这些Tg小鼠中源自骨髓细胞的滑膜细胞异常。因此，表明不仅LTR-pX小鼠，而且fms-tax小鼠都是人类类风湿性关节炎的有价值的模型。

项目成果

Tagawa, Y., Matthys, P., Heremans, H., Dillen, C., Zaman, Z., Iwakura, Y., and Billiau, A.: "Bimodal role of endogenous interleukin-6 in concanavalin A-induced hepatitis in mice"J.Leukocyte Biology.. 67. 90-96 (2000)

Takawa, Y.、Matthys, P.、Heremans, H.、Dillen, C.、Zaman, Z.、Iwakura, Y. 和 Billiau, A.：“内源性白细胞介素 6 在刀豆球蛋白 A 诱导的肝炎中的双峰作用

Sasaki, S., Nishikawa, S., Miura, T., Mizuki, M., Yamada, K., Madarame, H., Tagawa, Y., Iwakura, Y., and Nakane, A.: "Interleukin-4 and interleukin-10 are involved in host resistance to Staphylococcus aureus infection through regulation of gamma interfero

Sasaki, S.、Nishikawa, S.、Miura, T.、Mizuki, M.、Yamada, K.、Madarame, H.、Takawa, Y.、Iwakura, Y. 和 Nakane, A.：“Interleukin-4

Seino, K., Muramoto, K., Yanagisawa, K., Oyama, K., Iwakura, Y., Van Kaer, L., Takeda, K., Nakayama, T., Taniguchi, M., Bashuda, H., Yagita, H., Okumura, K., and Fukao, K.: "Requirement for NKT cells in the induction of allograft tolerance."Proc.Natl.Acad

Seino，K.，Muramoto，K.，Yanagisawa，K.，Oyama，K.，Iwakura，Y.，Van Kaer，L.，Takeda，K.，Nakayama，T.，Taniguchi，M.，Bashuda，H.

Igarashi, I., Asaba, U., Xuan, X., Omata, Y., Saito, A., Nagasawa, H., Fujisaki, K., Suzuki, N., Iwakura, Y., and Mikami, T.: "Immunization with recombinant surface antigens p26 with Freund's adjuvants against Babesia rodhaini infection"J.Vet.Med.Sci.. 62

五十岚 I.、浅羽 U.、轩 X.、大俣 Y.、斋藤 A.、长泽 H.、藤崎 K.、铃木 N.、岩仓 Y. 和三上 T.

Ishii, T., Serizawa, S., Kohda, A., Nakatani, H., Shiroishi, T., Okumura, K., Iwakura, Y., Nagawa, F., Tsuboi, A., and Sakano, H.: "Projection of three subsets of olfactory neurons expressing the odorant receptor transgene and the two cognate endogenous a

石井 T.、芹泽 S.、幸田 A.、中谷 H.、白石 T.、奥村 K.、岩仓 Y.、长川 F.、坪井 A. 和坂野 H.