Development of a novel molecular therapy for rheumatoid arthritis by regulation of Th1/Th2 differentiation

通过调节 Th1/Th2 分化开发治疗类风湿性关节炎的新型分子疗法

• 批准号: 14370167
• 负责人: SHIBUYA Kazuko
• 金额: $ 8.58万
• 依托单位: University of Tsukuba (2003)The Institute of Physical and Chemical Research (2002)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370167/
• 关键词: autoimmune response; rheumatoid arthritis; Th1 cells; Th2 cells; differentiation of Th1; independency of cytokines; LFA-1; CD226; Th 1細胞; Th 2細胞

Because Th1 cells are implicated in the immunopathology of rheumatoid arthritis, an understanding of molecular mechanisms of Th1fTh2 differentiation is required for development of a new therapy for rheumatoid arthritis, Th1 and Th2 cells are derived from CD4 positive naive T cells. Because CD4 positive naive T cells require intercellular binding with antigen presenting cells for differentiation of helper T cells, we investigated whether intercellular adhesion molecules on CD4 positive naive T cells may play an important role for initial triggering of differentiation of helper T cellsHere, we report that cross-linking of LFA-1 and CD3 drives Th1 differentiation from CD4 positive naive T cells from peripheral blood or cord blood cells. Addition of anti-IL-12 neutrarizing antibody did not inhibit the Th1 differentiation induced by stimulation of LFA-1. These results indicate that Th1 differentiation mediated by LFA-1 is independent on IL-12. Furthermore, we, show that lentiviral vector-mediated mutant (Y-F^<322>) CD226 transfer into naive CD4^+ helper T cells inhibited IL-12-independent Th1 differentiation initiated by CD3 and LFA-1 ligations. These results suggest that CD226 is involved in LFA-1-mediated costimulatory signals for triggering nave T helper cell differentiationIn future, we will investigate the relationship between LFA-1/CD226-mediated Th1 differentiation and the immunopathology of rheumatoid arthritis using mice with the collaoen-induced arthritis, a model for rheumatoid arthritis

由于Th 1细胞与类风湿关节炎的免疫病理学有关，因此需要了解Th 1/Th 2分化的分子机制以开发治疗类风湿关节炎的新疗法，Th 1和Th 2细胞来源于CD 4阳性幼稚T细胞。由于CD 4阳性初始T细胞需要与抗原呈递细胞细胞细胞间结合以分化辅助T细胞，我们研究了CD 4阳性初始T细胞上的细胞间粘附分子是否可能在初始触发辅助T细胞分化中起重要作用。我们报道了LFA-1和CD 3的交联驱动来自外周血或脐带血细胞的CD 4阳性初始T细胞的Th 1分化。添加抗IL-12中和抗体不抑制由LFA-1刺激诱导的Th 1分化。这些结果表明，由LFA-1介导的Th 1分化不依赖于IL-12。此外，我们发现慢病毒载体介导的突变型（Y-F^<322>）CD 226转移到初始CD 4 ^+辅助性T细胞中抑制了由CD 3和LFA-1连接启动的IL-12非依赖性Th 1分化。这些结果表明，CD 226参与了LFA-1介导的共刺激信号，触发了原始T辅助细胞分化。未来，我们将利用胶原诱导的关节炎小鼠模型，研究LFA-1/CD 226介导的Th 1分化与类风湿关节炎免疫病理学的关系

项目成果

Yoh K.: "Transgenic Overexpression of GATA-3 in T Lymphocytes Improves Autoimmune Glomerulonephritis in BXSB/MpJ-Yaa Genetic Background Mice."J.Am.Soc.Nephrol.. 14. 2494-2502 (2003)

Yoh K.：“T 淋巴细胞中 GATA-3 的转基因过度表达可改善 BXSB/MpJ-Yaa 遗传背景小鼠的自身免疫性肾小球肾炎。”J.Am.Soc.Nephrol.. 14. 2494-2502 (2003)

Kojima H.: "CD226 mediated platelet and megakaryocytic cell adhesion to vascular endothelial cells."J.Biol.Chem.. 278. 36748-36753 (2003)

Kojima H.：“CD226 介导血小板和巨核细胞与血管内皮细胞的粘附。”J.Biol.Chem.. 278. 36748-36753 (2003)

Shibuya K.: "CD226 (DNAM-1) is involved in LEA-1 costimulatory signal for naive T cell differentiation and proliferation."J.Exp.Med.. 198. 1829-1839 (2003)

Shibuya K.：“CD226 (DNAM-1) 参与幼稚 T 细胞分化和增殖的 LEA-1 共刺激信号。”J.Exp.Med.. 198. 1829-1839 (2003)

Iwama A.: "Reciprocal roles for C/EBP and PU.I transcription factors in Langerhans cell commitment"J.Exp.Med.. 195. 547-558 (2002)

Iwama A.：“C/EBP 和 PU.I 转录因子在朗格汉斯细胞定型中的相互作用”J.Exp.Med.. 195. 547-558 (2002)

Yoh K.: "Transgenic Overexpression of DATA-3 in T Lymphocytes Improves Autoimmune Glomerulonephritis in BXSB/MpJ-Yaa Genetic Background Mice"J.Am.Soc.Nephrol.. 14. 2494-2502 (2003)

Yoh K.：“T 淋巴细胞中 DATA-3 的转基因过度表达可改善 BXSB/MpJ-Yaa 遗传背景小鼠的自身免疫性肾小球肾炎”J.Am.Soc.Nephrol.. 14. 2494-2502 (2003)