rhIL-1Ra对恒河猴肾脏毒性的病理组织学观察

Histopathological observation of renal toxicity of recombinant human interleukin-1Ra in normal rhesus monkeys

目的观察重组人白介素-1受体拮抗剂(rhIL-1Ra)的毒性靶器官及毒性的严重程度。方法32只成年恒河猴分为rhIL-1Ra 2mg/(kg·d)(n=6)、10mg/(kg·d)(n=6)和50mg/(kg·d)(n=6)连续给药90天组,10mg/(kg·d)(n=4)连续给药30天组,正常对照组(n=5)和溶剂对照组(n=5)。rhIL-1Ra为皮下注射给药,每日1次。观察指标包括一般药物反应、尿八项、心电图、眼底检查、外周血细胞计数及白细胞分类、凝血时间、血清生化、外周血T细胞亚群和猴抗rhIL-1Ra抗体测定、脏器重量和脏器系数、常规病理组织学检查。结果给药后30天各给药组动物血清非特异性抗体明显升高。rhIL-1Ra 2mg/(kg·d)组其他检测指标均未见明显地改变。rhIL-1Ra 10mg/(kg·d)组给药后90天肾小球毛细血管基底膜明显增厚,但此剂量给药时间为30天时未见任何异常。rhIL-1Ra 50mg/(kg·d)组肾小球及肾小管中蛋白性液体量多,小球毛细血管基底膜增厚更为严重,且停药30天后基底膜增厚程度仍未见明显减轻或改善。结论rhIL-1Ra的主要毒性靶器官为肾脏。2mg/(kg·d)为安全剂量,10mg/(kg·d)给药30天时为安全剂量,给药90天为恒河猴中毒性剂量,而50mg/(kg·d)为明显的毒性反应剂量,可产生难以恢复的肾脏纤维化。

Objective In order to find the toxic-related organ with treating by rhlL 1Ra. Methods 32 adult rhesus monkeys （average body weight 2. 65±0. 54kg） were divided into normal control group （n=5）, placebo control group（n=5）, rhIL-1Ra 2（n=6）, 10（n= 6）, 50（n=6） rng/（kg · d） groups with consecutive administration for 90 days and rhIL-1Ra 10rng/（kg · d） group with consecutive administration for 30 days. rhIL-1Ra was administered subcutaneously to the animals once per day. The observed indexes included general drug reaction, 8 items from urine, electrocardiogram, fundus examination, peripheral blood count and WBC differential count, clotting time test, biochemistry in serum, peripheral T cell subtype and monkey anti rhIL-1Ra antibody, organ weight and organ index, histopathological observation. Results Nonspecific antibody increased distinguishingly in each groups after drug treatment 30 days, but all tested indexes showed no anycbange in 2mg/（kg · d） group. Glomerular basement membrane became thick in 10mg/（kg · d） group after drug treatment 90 days, but it showed normal when treatment time was shorten to 30 days. The thickness of glomerular basement membrane was very serious in in 50mg/（kg · d） group and liquid containing protein was found increasing in glomerular and tubular. The thickness of glomerular basement membrane didn＇t ameliorate after stopping drug 30 days. Conclusion The result showed that the main toxic organ of rhIL-1Ra was kidney. Dosage below 2rng/（kg · d） is safe dosage. Dosage of 10mg/（kg · d） for treatment 30 days was safe, but for treatment 90days was toxic. Clear toxic reaction was observed in dosage of 50mg/（kg·d）, which resulted irreversible renal fibrosis.