白消安预处理及人外周血单个核细胞移植量对aGVHD小鼠模型的影响  

Effects of busulfan pre⁃conditioning and hPBMC transplantation levels on aGVHD mouse model

作　　者：王雁 吴晓倩 王统治 陈志勇 张红琴 侯敏博 赵俊 李华 马璟 WANG Yan;WU Xiao-qian;WANG Tong-zhi;CHEN Zhi-yong;ZHANG Hong-qin;HOU Min-bo;ZHAO Jun;LI Hua;MA Jing(Shanghai InnoStar Bio-Tech Co.,Ltd.,Shanghai 201203,China;China State Institute of Pharmaceutical Industry,Shanghai 201203,China)

机构地区：[1]上海益诺思生物技术股份有限公司,上海201203 [2]中国医药工业研究总院,上海201203

出　　处：《中国新药杂志》2024年第1期73-78,共6页Chinese Journal of New Drugs

基　　金：国家重点研发计划“干细胞及转化研究”专项资助项目(2020YFA0112600)。

摘　　要：目的:研究白消安(busulfan,BS)预处理方案和人外周血单个核细胞(hPBMC)移植量对hPBMC诱导的重度免疫缺陷鼠M-NSG小鼠人源化急性移植物抗宿主病(acute graft-versus-host disease,aGVHD)模型的影响。方法:分别用BS预处理方案和1×10^(7),5×10^(7)cells·只^(-1)的hPBMC的移植量诱导重度免疫缺陷鼠M-NSG小鼠人源化急性移植物抗宿主病模型,观察移植后动物临床征状、生存率、人源T细胞嵌合率和靶器官损伤情况,比较BS预处理方案和hPBMC移植量对人源化aGVHD小鼠模型建立的影响。结果:hPBMC移植各剂量组组织病理学检查均可见aGVHD典型的靶器官组织病理学改变;hPBMC移植量为5×10^(7)cells·只^(-1)时,与未预处理组相比,BS预处理对动物整体生存期、临床征状、体重改变无明显影响;hPBMC移植量为1×10^(7)cells·只^(-1)时,经过BS处理后aGVHD模型生存期明显缩短,出现aGVHD征状和体重下降时间均更早或程度更严重;BS预处理对人源T细胞在M-NSG小鼠外周血的浸润百分比无明显影响;M-NSG小鼠生存期、临床征状、体重改变、人源T细胞CD_(3)^(+)CD_(8)^(+)嵌合率均与hPBMC移植量有明显的关系。结论:hPBMC移植量和BS预处理方案均可以加重人源化aGVHD小鼠模型的表现。因此使用BS结合较低剂量的hPBMC可以提高人源化aGVHD小鼠模型建立的成功率,从而为后续研究aGVHD发生相关机制提供可靠的临床前研究模型。Objective:To study the effects of busulfan(BS)pre⁃conditioning regimen and hPBMC transplantation amount on the humanized M⁃NSG mouse model of acute graft versus host disease(aGVHD).Methods:The humanized aGVHD model of immune⁃deficient mice,M⁃NSG mice,was induced by BS pre⁃conditioning and the transplantation amount of 1×10^(7) cells/mouse and 5×10^(7) cells/mouse,respectively.The clinical signs,survival rate,chimerism rate of human T cells,and target organ injury were observed.The effects of BS pre⁃conditioning and the transplantation amount of hPBMC on the established humanized aGVHD mouse model were compared.Results:The typical histopathological changes of target organs of aGVHD were found in the histopathological examination of each dose group of hPBMC transplantation.When the transplantation level of hPBMC 5×10^(7) cells/animal was used,no significant effect was found in the overall survival period,clinical signs and body weight changes among the animals with BS pre⁃conditioning as compared to the non⁃conditioning group.When the transplantation level of hPBMC 1×10^(7) cells/animal was used,the survival period of aGVHD model was significantly shortened in animals with BS pre⁃conditioning,and the appearance time of aGVHD⁃related clinical signs and body weight loss were earlier and more serious,respectively.No significant changes were found in the infiltration percentage of human T cells in peripheral blood of M⁃NSG mice with BS pre⁃conditioning.The survival period of M⁃NSG mice,clinical signs,body weight changes,and the chimerism rate of human T cells(CD_(3)^(+) CD_(8)^(+))were significantly correlated to the amount of hPBMC transplanted.Conclusion:Both the amount of hPBMC transplanted and BS pre⁃conditioning regimen can aggravate the performance of the humanized aGVHD mouse model.Therefore,the use of BS combined with lower dose hPBMC can realize the establishment of humanized aGVHD mouse model,which provides a reliable preclinical model for the study of the mechanism of aGVHD.

关 键 词：人源化急性移植物抗宿主病模型 白消安 人外周血单个核细胞 

分 类 号：R965.1[医药卫生—药理学]