Study for molecular and gene therapy of rheumatoid arthritis by targeting IL-6 signal transduction.

1.结论：1.抗白细胞介素-6受体抗体（anti-IL-6 R Ab）对小鼠和类似小鼠胶原诱导的关节炎和关节破坏有抑制作用.人源化抗IL-6 R抗体被证明对难治性类风湿关节炎（RA）患者有效，从而证实IL-6在RA病理学中起主要作用。提示IL-6信号阻断可能成为RA治疗的新途径. IL-6在可溶性IL-6 R（sIL-6 R）存在下抑制滑膜细胞的生长。TNFα诱导的IL-6可能是TNFα诱导RA滑膜细胞增殖的负反馈因子. IL-6阻断剂的治疗作用是通过清除穿透RA滑膜组织的炎性细胞，抑制血管生成和破骨细胞形成. STATs诱导的STATs抑制因子-1及其家族分子SSI-3作为胞浆内IL-6信号转导的负反馈因子可能参与RA的慢性炎症状态.这些结果表明，RA的病理生理基础上，通过阻断IL-6信号转导的新的治疗方法的可能性。

1. Inhibitory effects of anti-interleukin-6 receptor antibody (anti-IL-6R Ab) against murine and similar collagen-induced arthritis and joint destruction were elucidated.2. Humanized anti-IL-6R Ab was proven to be effective to patients with refractory rheumatoid arthritis (RA) and thus confirming that IL-6 plays a major role in the RA pathology. It also shows IL-6 signal blocking can be a new therapy for RA.3. IL-6 in the presence of soluble IL-6R (sIL-6R) inhibits the growth of synovial cells. TNFα-induced IL-6 can be a negative feedback factor of TNFα-induced synovial cell proliferation in RA.4. Therapeutic effects of IL-6 blockade were through elimination of inflammatory cell penetrating the RA synovial tissue and also through inhibition of angiogenesis and osteoclast formation.5. STATs-induced STATs inhibitor-1 and its family molecule SSI-3 as negative feed back factors of intracytoplasmic IL-6 signaling may be involved in the chronic inflammatory status of RA.6. These results indicate the possibility of new therapeutic approach for RA by blocking IL-6 signaling based on the pathophysiology of RA.