Chen Jian, Wang John, Li Jun, Wu Qi, Chu Lim Fei, Yang Pingar, Hsu Hui-Chen, Curiel David T, Mountz John D
1Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Mol Ther. 2008 Aug;16(8):1500-6. doi: 10.1038/mt.2008.121. Epub 2008 Jun 10.
A decrease in the expression of Th1 cytokines has been associated with age-related decrease in cytotoxic T-lymphocyte (CTL) function. We utilized an E1-deleted adenovirus (Ad) vector to deliver the murine interleukin-12 (IL-12) gene in order to enhance the antivirus CTL response. Wild-type (WT) Ad was administered 3 days after AdIL-12 treatment, when IL-12 production was at its peak and the anti-Ad antibody response had not yet begun to develop. Before receiving AdIL-12 treatment, aged (18 month old) mice exhibited a 58% decrease in the number of virus-specific CTLs, and a 30% decrease in in vivo CTL activity as compared to young (2 month old) mice. After AdIL-12 treatment, aged mice displayed a greater increase in IL-12 expression and endogenous production of interferon-gamma than observed in young mice. When infected with WT Ad, these AdIL-12-treated aged mice exhibited an increased in vivo CTL response and an in vitro proliferative response that was similar to those in young mice. The frequencies of occurrence of D(b)-E1Bp(+)CD8(+) T cells in the spleen, liver, and lung in aged mice were higher than the corresponding values in young mice. These results indicate that IL-12 treatment significantly promotes the virus-specific CTL response in aged mice and, more importantly, specifically targets the virally infected organs, such as the liver and lung, promoting enhanced CTL activity against the virus.
Th1细胞因子表达的降低与细胞毒性T淋巴细胞（CTL）功能随年龄增长而下降有关。我们利用一种缺失E1的腺病毒（Ad）载体来递送小鼠白细胞介素-12（IL-12）基因，以增强抗病毒CTL反应。在AdIL-12治疗3天后给予野生型（WT）Ad，此时IL-12产生达到峰值，且抗Ad抗体反应尚未开始发展。在接受AdIL-12治疗前，与年轻（2个月大）小鼠相比，老年（18个月大）小鼠的病毒特异性CTL数量减少了58%，体内CTL活性降低了30%。AdIL-12治疗后，老年小鼠的IL-12表达和干扰素-γ的内源性产生比年轻小鼠有更大的增加。当感染WT Ad时，这些接受AdIL-12治疗的老年小鼠表现出体内CTL反应增强和体外增殖反应，与年轻小鼠相似。老年小鼠脾脏、肝脏和肺中D(b)-E1Bp(+)CD8(+) T细胞的出现频率高于年轻小鼠的相应值。这些结果表明，IL-12治疗显著促进老年小鼠的病毒特异性CTL反应，更重要的是，特异性靶向病毒感染的器官，如肝脏和肺，促进针对病毒的CTL活性增强。
