单增李斯特菌感染TNF-α人源化小鼠模型的建立与应用

Establishment and application of a TNF-α humanized mouse model of Listeria monocytogenes infection

目的评价TNF-α单抗药物干预后宿主对单增李斯特菌感染的易感性变化。方法动物分为C57BL/6小鼠感染对照组,TNF-α人源化小鼠感染对照组,TNF-α人源化小鼠阿达木单抗(adalimumab)干预组(n=6)。对照组小鼠感染前24 h静脉注射生理盐水200μL,adalimumab组小鼠按照10 mg/kg在感染前24 h静脉注射阿达木单抗200μL。经腹腔接种感染单增李斯特菌1×10~4CFU,检测肝脏及脾脏组织荷菌量,病理变化以及免疫细胞分布,统计对照组与抗体干预组间的差异。结果感染单增李斯特菌4 d后,相对于对照组小鼠,抗体干预组小鼠肝脏中微脓肿面积显著增大(P<0.05),脾脏和肝脏组织荷菌量显著升高(P<0.01),而巨噬细胞和B细胞的分布没有显著变化。结论 TNF-α对于宿主抵抗单增李斯特菌的免疫具有重要作用,TNF-α单抗干预后宿主疾病进展显著加重。

Objective TNF-α monoclonal antibody drugs are widely used to treat conditions such as rheumaticarthritis and ankylosing spondylitis. On the other hand, it is also a wide concern that the application of these drugs mayincrease the susceptibility of patients to infections such as tuberculosis and listeriosis. The aim of this study was to establisha mouse model of Listeria monocytogenes infection and to evaluate the effect of TNF-α monoclonal antibody on the hostsusceptibility to this infection. Methods Six SPF 14-week old female C57BL/ 6 mice and 12 SPF 14-week old femaleTNF-α humanized mice were injected with saline or adalimumab intravenously, and challenged with intraperitoneal injectionof 104CFU Listeria monocytogenes 24 h later. After one day or 4 days, the mice were sacrificed to examine the pathologicallesions and the bacterial load in the spleen and liver. Results Four days after infection, the area of microabscess in the liver tissues was significantly increased in the adalimumab-treated group. The bacterial load in the spleen and liver tissuesof the adalimumab-treated group was significantly higher than that of the C57BL/ 6 mouse control group and TNF-αhumanized mouse control group （P 〈 0. 05）. However, the distribution of macrophages in the liver tissues and B cells inthe spleen tissues were similar among groups. Conclusions TNF-α plays an important role in the host immune responsesto Listeria monocytogenes infection. After the intervention with TNF-α monoclonal antibody, the progress of host disease issignificantly exacerbated.