重组人白细胞介素-12对食蟹猴的反复给药毒性研究

目的:观察重组人白细胞介素-12(rhIL-12)对食蟹猴的长期毒性。方法:食蟹猴皮下注射给予rhIL-12,剂量分别为0.5,5和40μg·kg-1,每周3次,共13周。检测指标包括临床症状、血液学、血生化、免疫、血清抗体和组织病理学检查。结果:rhIL-12给药后导致动物出现腹泻、面部及眼睑部肿胀、腹股沟淋巴结肿大、溃疡、及注射局部红斑和硬结等临床症状,并出现贫血和白细胞分类异常,血液生化指标出现肝脏转氨酶升高,免疫学指标出现外周血总T淋巴细胞比例增加,CD4细胞百分率下降,CD8细胞百分率增加。第7次给药后,给药组动物产生了rhIL-12抗体。结论:食蟹猴皮下注射给予rhIL-12,毒性靶器官和组织为血液系统、肝脏、心脏、肾脏和淋巴结等免疫调节系统,其安全剂量为0.5μg·kg-1。

Repeated dose toxicity study of recombinant human interleukin-12 in cynomolgus monkeys

Objective: To assess the long-term toxicity of recombinant human interleukin-12(rhIL-12) in cynomolgus monkeys.Methods: Cynomolgus monkeys were randomly administered with subcutaneous injection of 0.5,5,or 40 μg·kg-1 rhIL-12,three times a week for 13 weeks.Each group had three male and three female monkeys.The clinical signs,hematological,biochemical,urinary,and immunological parameters and the serum antibody were measured,organ masses were weighed,and the bone marrow and tissue pathology were observed.Results: Diarrhea,facial and eyelids swelling,inguinal lymph node,ulcer and local erythema were observed after dosing.Anemia and abnormal WBC classification were detected.Biochemical examinations revealed increases in serum alanine aminotransferase and aspartate aminotransferase.Immunological detection showed increases in total T cell ratio and CD8 cell percentage in peripheral blood,and decreases in CD8 cell percentage.The antibodies for the rhIL-12 were detected after the seventh dosing in all three dosing groups.The antibody levels showed increase after the last dosing and then a gradual decline in the 4-week recovery period.Conclusion: The target toxicity organs and systems for rhIL-12 in cynomolgus monkeys are blood,liver,cardiac,kidney and immune system.The damages are reversible and the no-toxic-effect dosage is 0.5 μg·kg-1.