扩增活化的淋巴细胞EAL在C57BL/6小鼠中的重复给药毒性研究  

Toxicity investigation of Expanded Activated Lymphocytes in C57BL/6 mice

作　　者：黄瑛[1] 高阳 霍艳[1] 张澄[1] 姜华[1] 王超[1] 张永华 王歈 王军志[1] HUANG Ying;GAO Yang;HUO Yan;ZHANG Cheng;JIANG Hua;WANG Chao;ZHANG Yonghua;WANG Yu;WANG Junzhi(National Center for Safety Evaluation of Drugs,National Institutes for Food and Drug Control,The Beijing Key Lab for Pre clinical Safety Evaluation of Drugs,Beijing 100176,China;Immunotech Applied Science Limited,Beijing 101111,China)

机构地区：[1]中国食品药品检定研究院国家药物安全评价监测中心药物非临床安全评价研究北京市重点实验室,北京100176 [2]北京永泰生物制品有限公司,北京101111

出　　处：《药物评价研究》2019年第10期1968-1974,共7页Drug Evaluation Research

基　　金：十二五国家科技重大专项“生物大分子药物特殊评价关键技术研究”（2015ZX09501007-004）;细胞治疗产品临床前安全性评价关键技术的建立（2015X1）

摘　　要：目的对小鼠重复给予扩增活化的淋巴细胞EAL,考察其毒性反应,为临床应用提供安全性依据。方法采用C57BL/6小鼠,设A、B两大项目组,每个大项目组均设置阴性对照组、溶媒对照组、低剂量(1.5×10~6/只)及高剂量(1×10~7/只)组。A项每组36只,进行常规毒性检测、血清生化测定、血液学测定、外周血T淋巴细胞亚群分布测定、大体病理学及组织病理学检查;B项每组24只,进行免疫学测定,包括γ-干扰素(IFN-γ)水平和外周血T淋巴细胞亚群分布测定。所有组别均雌雄各半,静脉注射给药,每周1次,共17次,恢复期为28 d。结果重复给予EAL可能会使C57BL/6小鼠体质量和摄食量增加(P<0.05)。IFN-γ检测结果显示给药组动物个别时间点IFN-γ水平升高。组织病理学检查结果显示给予供试品会加重低剂量组、高剂量组动物脾脏生发中心明显及易染体巨噬细胞增多的病变程度和/或病变频度。供试品未对其他评价指标产生明显影响。结论 C57BL/6小鼠重复给予EAL,可能会引起动物体质量、摄食量的增加以及脾脏生发中心明显和易染体巨噬细胞增多,未见其他相关的毒理学反应。该结果为EAL进入临床试验奠定了基础。Objective EAL was repeatedly administered to mice to investigate its toxicity and provide a safety basis for clinical application. Methods C57 BL/6 mice are randomized into two parts, A and B. Each part including negative control group, the vehicle control group, low dose group(1.5×10~6 cells per mouse) and high dose group(1×10~7 cells per mouse). 36 mice in each group of part A and 24 mice in each group of part B. All animals were administered by intravenous injection of EAL for seventeen times with 28-day recovery. For A groups, mortality, clinical signs, body weights, food consumption were measured, and hematology,clinical chemistry analysis, T lymphocyte subset assay in peripheral blood and grossly pathological and histopathological examination were conducted at terminal and recovery necropsy respectively. IFN-γ level and T lymphocyte phenotypes in peripheral blood were measured for satellite animals in B groups. Results Following repeated administration of different doses of EAL, it was found that body weight and food consumption were markedly elevated in C57 BL/6 mice(P < 0.05). Histopathological examination showed that the extent and/or frequency of the lesions in the low-dose group and the high-dose group were aggravated by the administration of the test product. The test products had no significant impact on other evaluation indicators. Conclusion Repeated EAL administration in C57 BL/6 mice may increase animal body weight, food intake, spleen germinal center and dyeable macrophages. No other related toxicological reactions were observed. The results laid a foundation for EAL to enter clinical trials.

关 键 词：细胞治疗 EAL C57BL/6小鼠 安全性 

分 类 号：R944[医药卫生—药剂学]