Establishment of the anti-IL-6 receptor therapy for refractory autoimmune diseases

我们已经证实了抗白细胞介素6(IL-6)受体抗体tocilizumab对类风湿性关节炎(RA)和全身性幼年特发性关节炎(SoJIA)的疗效。IL-6阻断可提高血清雄激素水平，对类风湿关节炎具有抗炎作用。IL-6阻断也延缓了关节损伤的进展，远期疗效可通过TOCILIZUMA治疗后前3个月血清中MMP3、CRP和PIIANP的下降来预测。在SoJIA患者中，对mRNA表达的详尽DNA微阵列分析显示，与健康捐赠者相比，有24个分子表达存在差异。这些包括与先天免疫、信号转导和细胞生长相关的分子。基因本体论和网络通路分析也揭示了干扰素-γ、肿瘤坏死因子在SOJIA和多关节JIA中的刺激作用。只有SoJIA中的ATP合成相关基因表达下调。这些分子可能在SoJIA中起病理作用。我们现在正在研究与IL-6有关的病理作用。在系统性红斑狼疮中，基因芯片分析鉴定了24个分子，其中包括9个干扰素-α诱导基因和3个防御素-α。我们还建立了新的IL-6受体抑制物(NRI)，可以用于基因治疗。它们的体内功能正在研究中。

We have confirmed the efficacy of an anti-Interleukin-6 (IL-6) receptor antibody, tocilizumab, for rheumatoid arthritis (RA) and systemic-onset juvenile idiopathic arthritis (soJIA). IL-6 blockade increased serum androgen which has anti-inflammatory effect for RA. IL-6 blockade also retarded the progression of joint damage and the long-term efficacy was predicted by the decrease in the serum MMP-3, CRP and PIIANP in the first 3 months after the start of tocilizumab. In the patients with soJIA, an exhaustive DNA microarray analysis of mRNA expression revealed 24 molecules differentially expressed compared to healthy donors. Those included the molecules related to innate immunity, signal transduction and cell growth. Gene Ontology and Network, Pathway analysis also revealed the stimulation of IFN-γ, TNF cascades in both soJIA and polyarticular JIA. ATP synthesis related genes were down-regulated only in soJIA. These molecules might play a pathological role in soJIA. We are now studying a pathological role in relation to IL-6. In systemic lupus erythematosus (SLE), DNA microarray analysis identified 24 molecules which include 9 IFN-α-inducible genes and defensin-α3. We have also established new receptor inhibitor of IL-6 (NRI) which is feasible to gene therapy.We have identified several candidate molecules which play pathological roles in these autoimmune diseases. The in vivo functions of them are being studied.