目的本实验使用Wistar大鼠进行单次尾静脉注射,给予鼠源和人源细胞治疗产品APC,观察大鼠由供试品引起的死亡情况、毒性反应及其严重程度,为评价供试品在临床研究中的应用提供临床前数据支持。方法实验共使用175只大鼠,其中105只雄性大鼠作为供体大鼠,用来采血处理成鼠源供试品;人源供试品由人血处理得来。另外70只大鼠作为主实验大鼠(受体大鼠),雌雄各半,设置7个组别,包括溶媒对照组、鼠源供试品低、中、高各3个组和人源供试品低、中、高各3个组(低、中、高剂量分别为2×106/鼠、6×106/鼠和20×106/鼠)。供体大鼠入室后检疫3天,检疫期间进行常规检疫观察,检疫第4天取血处理,供体动物采血当天安乐死。主实验组动物(受体大鼠)入室后检疫21 d,期间对动物进行症状观察、称量动物体重,给药前随机分为7组,单次尾静脉注射给予鼠源及人源供试品,给药体积为1 ml/只。动物给药后观察14 d,第15天对动物剖检观察,对有大体病理学改变的组织进行病理学检查。结果整个观察期间未见与供试品相关的动物死亡和异常临床症状。供试品给药给药后第1天以及给药后第7天、14天测定体重,与溶媒对照组比较未见显著差异。给药后14 d,大体病理学检查发现人源中剂量组肠系膜淋巴结体积增大(2只动物),颌下淋巴结体积增大(1只动物),其余各组动物均未见大体病理学改变。组织病理学检查发现上述动物相应的出现肠系膜淋巴结和颌下淋巴结副皮质区淋巴细胞数量增多,认为上述淋巴结副皮质区淋巴细胞数量中度增多与静脉注射细胞治疗产品有关。结论大鼠静脉注射鼠源APC和人源APC,最大耐受量为20×106/鼠(人源产品最大耐受量排除淋巴结副皮质区淋巴细胞数量中度增多)。 Objective In this experiment, a single tail vein injection was performed in Wistar rats, APCs were treated with both murine and human-derived cells, and the mortality, toxicity and severity of rats induced by the test substance were observed. Clinical studies provide preclinical data support. Methods A total of 175 rats were used in this experiment. 105 male rats were used as donor rats to collect blood for the test. The human test sample was obtained from human blood. Another 70 rats as the main experimental rats (recipient rats), male and female, set seven groups, including the vehicle control group, the mouse for the test low, medium and high each of the three groups and human source Low, medium and high each of the three test groups (low, medium and high doses were 2 × 106 / mouse, 6 × 106 / mouse and 20 × 106 / mouse). The donor rats were quarantined for 3 days after entering the house. During the quarantine period, routine quarantine inspection was carried out. On the 4th day of quarantine, the blood was taken for treatment and the donor animals were euthanized on the same day. The main experimental group of animals (rats) after admission into the hospital quarantine 21 d, the animals were observed during the symptoms, weighed animals, pre-dose randomized divided into 7 groups, single tail vein injection of mice and human-derived test Product, dosing volume of 1 ml / only. The animals were observed for 14 days after administration, the animals were dissected on the 15th day, and the pathological examination was performed on the tissues with the gross pathological changes. Results No animal deaths and abnormal clinical symptoms were observed during the entire observation period. The test product administration after administration of the first day and 7 days after administration, 14 days determination of body weight, compared with the vehicle control group no significant difference. At 14 days after administration, gross pathological examination revealed that the volume of mesenteric lymph nodes increased (2 animals) and the size of submandibular lymph nodes increased (1 animal) in the middle-dose group, while no changes in gross pathology were observed in the other groups . Histopathological examination revealed that the number of lymphocytes in the mesenteric lymph nodes and the para-cortex of the submandibular lymph nodes corresponding to the above animals was increased, and the moderate increase in lymphocyte numbers in the para-cortical lymph nodes was considered to be related to the product for intravenous injection of cells. Conclusion The rats were injected intravenously with APC and APC, the maximum tolerated dose was 20 × 106 / mouse (the maximum tolerated dose of human product excluded the moderate increase of lymphocytes in para-cortex of lymph node).