Tumor necrosis factor α plays a central role in immune-mediated clearance of adenoviral vectors
Tumor necrosis factor α plays a central role in immune-mediated clearance of adenoviral vectors
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肿瘤坏死因子α在免疫介导的腺病毒载体清除中发挥核心作用
DOI：
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
E. Falck
中科院分区：
文献类型：
--
作者：
K. Elkon;Chau‐Ching Liu;J. Gall;J. Trevejo;M. Marino;K. Abrahamsen;Xin Song;J. Zhou;L. Old;R. Crystal;E. Falck
腺病毒（Ad）基因转移载体在小鼠中从感染的肝细胞中快速清除。为了确定哪些效应机制负责消除Ad载体，我们用Ad载体Ad 5-氯霉素乙酰转移酶（CAT）感染免疫效应途径[穿孔素、Fas或肿瘤坏死因子α（TNF-α）]遗传受损的小鼠。在感染后7-60天处死小鼠，并通过定量酶分析测定肝脏中CAT表达水平。感染后28天取肝组织，CAT表达水平显示，对Ad载体清除最重要的效应因子为TNF-α > Fas >穿孔素。TNF-α对感染的肝细胞没有疗效，因为对感染的重度联合免疫缺陷小鼠或感染的体外培养物给予TNF-α对病毒持久性没有特异性影响。然而，TNF-α缺陷小鼠在感染早期表现出白细胞浸润的显著减少，表明TNF-α缺陷导致炎症细胞向炎症部位的募集受损。此外，TNF缺陷小鼠对病毒感染的体液免疫应答显著降低。这些结果表明TNF-α在消除Ad基因转移载体中起主导作用。这一结果特别重要，因为使TNF-α功能丧失的病毒蛋白已从大多数Ad载体中去除，使它们对TNF-α介导的消除高度敏感。
Adenovirus (Ad) gene transfer vectors are rapidly cleared from infected hepatocytes in mice. To determine which effector mechanisms are responsible for elimination of the Ad vectors, we infected mice that were genetically compromised in immune effector pathways [perforin, Fas, or tumor necrosis factor α (TNF-α)] with the Ad vector, Ad5-chloramphenicol acetyl transferase (CAT). Mice were sacrificed at 7–60 days postinfection, and the levels of CAT expression in the liver determined by a quantitative enzymatic assay. When the livers of infected mice were harvested 28 days postinfection, the levels of CAT expression revealed that the effectors most important for the elimination of the Ad vector were TNF-α > Fas > perforin. TNF-α did not have a curative effect on infected hepatocytes, as the administration of TNF-α to infected severe combined immunodeficient mice or to infected cultures in vitro had no specific effect on virus persistence. However, TNF-α-deficient mice demonstrated a striking reduction in the leukocytic infiltration early on in the infection, suggesting that TNF-α deficiency resulted in impaired recruitment of inflammatory cells to the site of inflammation. In addition, the TNF-deficient mice had a significantly reduced humoral immune response to virus infection. These results demonstrate a dominant role of TNF-α in elimination of Ad gene transfer vectors. This result is particularly important because viral proteins that disable TNF-α function have been removed from most Ad vectors, rendering them highly susceptible to TNF-α-mediated elimination.
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发育阶段、给药途径和免疫系统对腺病毒介导的基因转移的影响。
影响因子：
5.1
作者：
Kass-Eisler,A;Falck-Pedersen,E;Elfenbein,DH;Alvira,M;Buttrick,PM;Leinwand,LA
通讯作者：
Leinwand,LA
影响因子：
4.2
作者：
LI, QT;KAY, MA;WOO, SLC
通讯作者：
WOO, SLC
DOI：
10.1073/pnas.90.24.11498
发表时间：
1993-12-15
影响因子：
11.1
作者：
KASSEISLER, A;FALCKPEDERSEN, E;LEINWAND, LA
通讯作者：
LEINWAND, LA
影响因子：
4.2
作者：
Worgall, S;Wolff, G;Crystal, RG
通讯作者：
Crystal, RG
DOI：
10.1073/pnas.93.10.4589
发表时间：
1996-05-14
影响因子：
11.1
作者：
Guidotti, LG;Borrow, P;Chisari, FV
通讯作者：
Chisari, FV