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

由于Th1细胞参与了类风湿关节炎的免疫病理过程，因此需要了解Th1fTh2分化的分子机制，以开发治疗类风湿关节炎的新疗法。Th1和Th2细胞来源于CD4阳性的初始T细胞。由于CD4阳性的初始T细胞需要与抗原提呈细胞间结合才能分化为辅助性T细胞，因此我们研究了CD4阳性的初始T细胞表面的细胞间黏附分子是否在辅助T细胞分化的初始触发中起重要作用。加入抗IL-12中和抗体不能抑制LFA-1诱导的Th1分化。这些结果表明，LFA-1介导的Th1分化不依赖IL-12。此外，我们发现慢病毒载体介导的突变(Y-F^&322&gt；)CD226转移到初始的CD4^+辅助T细胞可以抑制CD3和LFA-1连接启动的IL-12非依赖的Th1分化。这些结果表明，CD226参与了LFA-1介导的共刺激信号，从而触发了NAVE辅助T细胞的分化。今后，我们将利用类风湿关节炎的小鼠模型，研究LFA-1/CD226介导的Th1分化与类风湿关节炎免疫病理的关系

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