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）受体抗体托珠单抗（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阻断剂可提高血清雄激素水平，对RA有抗炎作用。IL-6阻断剂也延缓了关节损伤的进展，长期疗效通过托珠单抗治疗开始后前3个月血清MMP-3、CRP和PIIANP的降低来预测。在soJIA患者中，mRNA表达的详尽DNA微阵列分析显示，与健康供体相比，有24种分子差异表达。这些分子包括与先天免疫、信号转导和细胞生长相关的分子。基因本体论和网络、通路分析也揭示了在soJIA和多关节JIA中IFN-γ、TNF级联反应的刺激。ATP合成相关基因仅在soJIA中表达下调。这些分子可能在soJIA中发挥病理作用。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（SLE）中，DNA微阵列分析鉴定了24种分子，包括9种IFN-α诱导基因和防御素-α3。我们还建立了新的IL-6受体抑制剂（NRI），为基因治疗提供了新的途径，并鉴定了几个在这些自身免疫性疾病中起病理作用的候选分子。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.