非T细胞结合肽(FNS007)对小鼠胶原性关节炎的抑制作用及其机制

摘要

Aim To investigate the effect of non-T cell binding peptide(FNS007)on collagen type Ⅱ-induced arthritis(CIA)in mice and the possible mechanisms.Methods The CIA model was induced by intradermal injection of bovine CⅡ+Freunds adjuvant.At the clinical onset of CIA,mice were randomly divided into 6 groups: blank control group(Control),model group,ORENCIA(abatacept)group,FNS007 low dose(1.2 mg·kg-1)group,FNS007 middle dose(2.4 mg·kg-1)group and FNS007 high dose(4.8 mg·kg-1)group.FNS007 was given by intravenous injection on the first day of arthritis and every other day until the study was terminated on d 28 after injection of the drug.The paw thickness and the ankle joint width were measured,and the arthritis scores were recorded.At termination,interferon-γ(IFN-γ),tumor necrosis factor-α(TNF-α),interleukin-6(IL-6)and level of anti-CⅡ antibody in serum were examined by enzyme-linked immunosorbent assay(ELISA).Bone injury was analyzed by X-ray imaging,and HE staining was conducted to observe the histopathologic changes and pathological score of ankle tissues.Results CIA models were successfully induced.Compared with CIA group,FNS007 high dose significantly reduced the paw thickness and the ankle joint left-right diameter,lowered arthritis scores in CIA mice,reduced serum concentrations of IFN-γ,IL-6 and anti-CⅡ antibodies,and lowered the radiographic and histologic scores.Compared with CIA group,FNS007 middle dose group showed marked reduction in the arthritis scores,IL-6 content in serum,and inhibion in the radiographic and histologic scores.The arthritis scores,concentration of IFN-γ,the radiographic and histologic scores were significantly reduced in FNS007 low dose group compared with those in model group.Conclusion FNS007 can effectively inhibit the progression of CIA through inhibiting T-cell activation and reducing inflammatory cytokines,anti-CⅡ antibodies,and histoclasia and bone destruction.%目的 研究非T细胞结合肽(FNS007,又称NTAP)对小鼠Ⅱ型胶原(CⅡ)诱导的关节炎(CIA)的抑制作用及其机制.方法 牛CⅡ加弗氏佐剂诱导小鼠胶原性关节炎动物模型.发病小鼠随机分为6组:空白对照组、模型组、阳性药(阿巴西普)组、FNS007 低剂量(1.2 mg·kg-1)、中剂量(2.4 mg·kg-1)和高剂量(4.8 mg·kg-1)治疗组,发病入组当天尾静脉注射给药,以后隔天1次,直至治疗结束.给药后d 28处死小鼠.给药期间测量小鼠爪厚度和踝关节宽度;关节评分法检测关节炎发生情况;实验结束后,酶联免疫吸附法(ELISA)测定小鼠血清中干扰素-γ(IFN-γ)、肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)和抗CⅡ抗体水平;X线分析FNS007对CIA小鼠4爪骨损伤的作用;对小鼠踝关节进行组织病理学检查.结果 与模型组比较,FNS007给药后能明显抑制CIA小鼠的爪厚度和踝关节宽度,明显降低小鼠的关节炎症评分,明显降低血清IFN-γ、IL-6及抗CⅡ抗体水平,小鼠X线评分降低,踝关节的病理损伤明显减轻.结论 FNS007对CⅡ诱导的小鼠胶原性关节炎有明显抑制作用,其机制为竞争抑制T细胞活化,抑制CIA小鼠体内致炎性细胞因子的分泌,抑制抗CⅡ抗体的产生,减轻组织损伤和骨破坏,从而对小鼠CIA发挥治疗作用.