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目的:以静脉给予食蟹猴抗表皮生长因子受体(anti-EGFR)单克隆抗体长期毒性研究作为个案分析,探讨药物毒性研究中应激反应造成多器官损伤的组织病理学特征。方法:将食蟹猴随机分为4组,分别为溶媒对照组、低剂量组、中剂量组和高剂量组。静脉推注给予EGFR单抗,每周1次,连续26周,停药后8周的恢复期。中高剂量组因动物状态差处于濒死状态而提前至给药22周解剖,进入恢复期。本研究中10只动物在给药期间死亡,死亡动物和其余动物均进行解剖和组织病理学检查。通过免疫组织化学方法检查所有动物垂体的促肾上腺皮质激素(ACTH)的表达。结果:本实验中给药动物出现不同程度腹泻、稀便、皮肤发红、脱毛、脱屑、溃烂。死亡动物的免疫器官表现出明显萎缩,包括胸腺、脾脏、淋巴结中淋巴细胞数目减少。死亡的雌性动物子宫重量减低,组织病理学表现为子宫萎缩伴纤维组织增生。此外,中高剂量组死亡动物肾上腺表现为皮质束状带细胞肥大。中高剂量组动物垂体ACTH的表达明显高于溶媒对照组。结论:药物毒性研究中应激反应诱导的免疫器官的萎缩,可伴有肾上腺皮质束状带细胞肥大。采用权重法综合分析所有数据,并结合垂体促肾上腺皮质激素的检测,这对于辅助性鉴别诊断应激和直接免疫毒性具有一定的意义。
OBJECTIVE: To study the long-term toxicity of anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies in cynomolgus monkey treated by intravenous injection as a case study to explore the histopathological features of multiple organ damage caused by stress reaction in drug toxicity study. Methods: Cynomolgus monkeys were randomly divided into 4 groups: vehicle control group, low dose group, middle dose group and high dose group. Intravenous injection given EGFR monoclonal antibody once a week for 26 weeks, 8 weeks after withdrawal of the recovery period. The high-dose group was anaesthetized at 22 weeks’ administration due to the animal’s state being in a dying condition, and entered the recovery period. Ten animals in this study died during dosing, and dead animals and other animals were dissected and histopathologically examined. All animal pituitary adrenocorticotropic hormone (ACTH) expression was examined by immunohistochemistry. Results: In this experiment, the animals were given different degrees of diarrhea, loose stools, skin redness, hair removal, scaling and ulceration. Immune organs of the dead animals showed a significant atrophy, including thymus, spleen, lymph node lymphocyte number decreased. Uterine weight loss of females died, histopathology showed uterine atrophy with fibrosis. In addition, the adrenal glands in the medium and high dose groups showed cortical fascicular cells hypertrophy. The expression of ACTH in high and middle dose group was significantly higher than that in vehicle control group. CONCLUSIONS: Stress response-induced atrophy of immune organs in drug toxicity studies may be associated with hypertrophy of adrenal fasciculus. All the data were analyzed by the weight method, and combined with the detection of adrenocorticotropic hormone in the pituitary gland, which has some significance for the differential diagnosis of stress and direct immunotoxicity.