Inhibition of tumor necrosis factor alpha decreases inflammation and prolongs adenovirus gene expression in lung and liver.
Inhibition of tumor necrosis factor alpha decreases inflammation and prolongs adenovirus gene expression in lung and liver.
复制标题
抑制肿瘤坏死因子α可减少炎症并延长肺和肝中腺病毒基因的表达。
DOI：
10.1089/hum.1998.9.13-1875
复制
发表时间：
1998
影响因子：
4.2
通讯作者：
Mountz,JD
中科院分区：
文献类型：
--
作者：
Zhang,HG;Zhou,T;Yang,P;Edwards3rd,CK;Curiel,DT;Mountz,JD
腺病毒基因治疗的临床应用目前受到宿主对病毒的强烈免疫反应的阻碍，这限制了其作用的持续时间。在这些研究中，我们研究了TNF-α和可溶性TNF受体（TNF-bp）在小鼠肝和肺中表达alacz的腺病毒（AdCMVlacZ）的炎症反应和表达中的作用。通过测定重组腺病毒acz基因产物的活性，研究了重组腺病毒在小鼠肝脏和肺中的表达。经静脉或鼻内给药后不同时间的单核细胞炎症反应进行组织学测定。测定细胞毒性T细胞和抗体对腺病毒的反应。用TNF-bp治疗可降低循环中TNF-α的水平，大大降低炎症反应，并导致静脉或鼻内给药腺病毒后肝脏和肺中flacz的表达延长长达30天。在AdCMVlacZ治疗30天后，TNF-bp对抗腺病毒抗体和诱导细胞毒性T细胞没有影响。这些结果表明，TNF-α是驱动早期炎症反应的主要因素，导致肝脏和肺部腺病毒感染细胞的消除，而TNF-bp能够抑制这些作用。
The clinical application of adenoviral gene therapy currently is impeded by the potent host immune response to the virus, which limits the duration of its effects. In these studies, we investigated the role of TNF-αand of a soluble TNF receptor (TNF-bp) in the inflammatory response and expression of alacZ-expressing adenovirus (AdCMVlacZ) in the liver and lung of mice. The expression of the recombinant adenovirus was studied in mouse liver and lung by determining the activity of thelacZgene product of the adenovirus. The mononuclear cell inflammatory response was determined histologically at different times after intravenous or intranasal administration of AdCMVlacZ. The cytotoxic T cell and antibody response to the adenovirus was determined. Treatment with TNF-bp reduced circulating levels of TNF-α, greatly reduced the inflammatory response, and resulted in prolonged expression oflacZfor up to 30 days in the liver and lung after either intravenous or intranasal administration of adenovirus. Treatment with TNF-bp had no effect on anti-adenovirus antibodies and induction of cytotoxic T cells 30 days after administration of AdCMVlacZ. These results indicate that TNF-αis the primary factor driving the early inflammatory response leading to elimination of adenovirus-infected cells in the liver and lung and that TNF-bp is capable of inhibiting these effects.