目的 對小鼠重復(fù)給予擴增活化的淋巴細胞EAL，考察其毒性反應(yīng)，為臨床應(yīng)用提供安全性依據(jù)。方法 采用C57BL/6小鼠，設(shè)A、B兩大項目組，每個大項目組均設(shè)置陰性對照組、溶媒對照組、低劑量（1.5×10⁶/只）及高劑量（1×10⁷/只）組。A項每組36只，進行常規(guī)毒性檢測、血清生化測定、血液學(xué)測定、外周血T淋巴細胞亞群分布測定、大體病理學(xué)及組織病理學(xué)檢查；B項每組24只，進行免疫學(xué)測定，包括γ-干擾素（IFN-γ）水平和外周血T淋巴細胞亞群分布測定。所有組別均雌雄各半，靜脈注射給藥，每周1次，共17次，恢復(fù)期為28 d。結(jié)果 重復(fù)給予EAL可能會使C57BL/6小鼠體質(zhì)量和攝食量增加（P<0.05）。IFN-γ檢測結(jié)果顯示給藥組動物個別時間點IFN-γ水平升高。組織病理學(xué)檢查結(jié)果顯示給予供試品會加重低劑量組、高劑量組動物脾臟生發(fā)中心明顯及易染體巨噬細胞增多的病變程度和/或病變頻度。供試品未對其他評價指標(biāo)產(chǎn)生明顯影響。結(jié)論 C57BL/6小鼠重復(fù)給予EAL，可能會引起動物體質(zhì)量、攝食量的增加以及脾臟生發(fā)中心明顯和易染體巨噬細胞增多，未見其他相關(guān)的毒理學(xué)反應(yīng)。該結(jié)果為EAL進入臨床試驗奠定了基礎(chǔ)。

Objective EAL was repeatedly administered to mice to investigate its toxicity and provide a safety basis for clinical application. Methods C57BL/6 mice are randomized into two parts, A and B. Each part including negative control group, the vehicle control group, low dose group (1.5×10⁶ cells per mouse) and high dose group (1×10⁷ 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 C57BL/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 C57BL/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.

十二五國家科技重大專項“生物大分子藥物特殊評價關(guān)鍵技術(shù)研究”（2015ZX09501007-004）；細胞治療產(chǎn)品臨床前安全性評價關(guān)鍵技術(shù)的建立（2015X1）