摘要
目的探讨应用抗白细胞介素18抗体(IL-18Ab)中和内源性IL-18活性对阿霉素(ADR)小鼠微小病变型肾病综合征(MCNS)的治疗作用。方法雄性昆明种小鼠,一次性尾静脉注射ADR7.5mg/kg建立MCNS模型,对照组注射同等容量的生理盐水。给予ADR后第5、7、12及21天模型组小鼠分别注射IL-18Ab(10μg/只,IL-18Ab组)或等容量PBS(非治疗组)。于实验第1、14、28及42天检测尿蛋白水平,第42天处死小鼠,常规方法测血清总蛋白(TP)、白蛋白(Alb)、总胆固醇(TC)、甘油三酯(TG)及IL-4、IL-18、IFN-γ和TNF-α水平,电镜观察肾脏组织病理改变。结果注射阿霉素后,小鼠均出现肾病综合征表现,以大量蛋白尿、低蛋白血症、高胆固醇血症为特征。大量蛋白尿于实验第2周出现,第4周达到高峰。对照组、非治疗组及IL-18Ab组分别为(3.13±0.82)mg/24h、(34.27±5.16)mg/24h及(27.51±3.34)mg/24h(P<0.01),第7周非治疗组尿蛋白水平为(30.45±2.13)mg/24h,IL-18Ab治疗组尿蛋白水平明显降低为(21.83±2.67)mg/24h(P<0.01)。非治疗组及IL-18Ab组TC分别为(6.51±0.23)mmol/L及(5.15±0.9)mmol/L(P<0.01),TG为(3.31±0.32)mmol/L及(1.67±0.17)mmol/L(P<0.01),Alb分别为(15.99±0.89)g/L及(19.23±1.53)g/L(P<0.05)。电镜显示:非治疗组肾脏上皮细胞足突广泛融合,而IL-18Ab组肾脏组织学改变显著减轻,仅有部分足突融合。与正常对照组相比,非治疗组血清IL-18、IFN-γ和TNF-α显著增高。而IL-18Ab治疗后上述细胞因子均明显降低(P<0.01)。结论IL-18Ab对ADR诱导的MCNS的治疗作用可能与中和内源性IL-18活性、抑制Th1细胞介导的免疫反应有关,抑制或中和内源性IL-18的释放及活性,有可能成为MCNS治疗的新途径。
Objectives To investigate the therapeutic effect of neutralizing endogenous IL-18 activity by anti-IL-18 antibody （IL-18Ab） in ardriamycin （ADR） -induced model of MCNS. Methods All experiments were performed on male kungmin mice, MCNS was induced in mice by single injection of ADR （7.5 mg/kg） intravenously. The mice injected with saline were used as normal control. MCNS mice were then treated with IL-18Ab or PBS on day 5, 7,12 and 21 after ADR administration. The protein in urine was measured on day 1, 14, 28 and 42. Serum total protein, albumin, cholesterol, ereatinine, IL-4, TNF-α and INF-γ were analyzed, the renal histological changes were observed under electron microscope when mice were sacrificed. Results All ADR-miee developed nephropathy eharacterized by proteinuria, hypoalbuminemia, hypercholasterolnemia, and progressive renal injury. Overt proteinuria appeared at second week with peak at fourth week. However, the proteinurine and clinical severity in mice undergoing MCNS were significantly reduced ＇after treatment with IL-18Ab. At fourth week of the experiment, the protein levels in urine were （3.13 ± 0.82） mg/24 h, （34.27 ± 5.16） mg,/24 h and （27.51 ± 3.34） mg/24 h in normal control, MCNS miee and IL-18Ab-treated MCNS mice respectively. At the seventh week, the protein levels of urine were 30.45 mg/24 h and 21.83 mg/24 h （P 〈 0.01） , serum cholesterol was （6.51 ± 0.23） mmol/L and （5.15 ± 0.9） mmol/L （P 〈0.01）, serum protein levels were （15.99 ± 0.89） g/L and （19.23 g ± 1.53） g/L （P〈 0.05） in MCNS mice and IL-1BAh-treated MCNS mice respectively. The attenuation of the disease was associated with reduced renal histopathologie injury. Ultrastructeral examination demonstrated wide fusion of foot processes of glomerular epithelial cells in MCNS mice. However, only focal and significantly reduced fusion of foot processes was observed in MCNS mice treated with IL-18Ab. In addition, the production of IL-18, IFN-γ and TNF-α in MCNS mice were markedly increased as compared to normal control mice. Treatment with IL-18Ab led to decreased production of IL-18, IFN-γ, TNF-α. Conclusions IL-18Ab may decreased both proteinurine and histopathological injury of kidney in the mice model of MCNS induced by ADR. This therapeutic effect correlated with an attenuation of Thl to Th2 immune response. IL-18 may be a new target molecule for the MCNS treatment.
出处
《临床儿科杂志》
CAS
CSCD
北大核心
2008年第7期617-620,共4页
Journal of Clinical Pediatrics
基金
贵州省科学技术基金项目(No.黔科合J2005-2043号)
