PROLONGED AND EFFECTIVE BLOCKADE OF TUMOR-NECROSIS-FACTOR ACTIVITY THROUGH ADENOVIRUS-MEDIATED GENE-TRANSFER
PROLONGED AND EFFECTIVE BLOCKADE OF TUMOR-NECROSIS-FACTOR ACTIVITY THROUGH ADENOVIRUS-MEDIATED GENE-TRANSFER
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DOI：
10.1073/pnas.91.1.215
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发表时间：
1994-01-04
影响因子：
11.1
通讯作者：
BEUTLER, B
中科院分区：
文献类型：
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作者：
KOLLS, J;PEPPEL, K;BEUTLER, B
一种能够结合和中和肿瘤坏死因子（TNF）和光毒蛋白的嵌合蛋白质在小鼠中表达，该小鼠用一种复制缺陷型腺病毒载体转导，该载体中已经改造了TNF抑制剂基因。在注射10（9）个感染性颗粒后3天内，TNF抑制剂浓度超过1 mg/ml血浆;该表达水平维持至少4周，并且在注射重组病毒后6周测量可检测的TNF抑制活性。引入人工基因产生的表型效应与55 kDa TNF受体的纯合缺失相当，因为动物对单核细胞增生李斯特菌感染高度敏感，而接受编码β-半乳糖苷酶的复制缺陷型病毒的对照动物能够抵抗李斯特菌的攻击。腺病毒介导的编码TNF抑制剂的基因的转移提供了一种用于研究和治疗目的的在体内施加有效的、长期的TNF活性阻断的实用手段。
A chimeric protein capable of binding and neutralizing tumor necrosis factor (TNF) and lymphotoxin was expressed in mice transduced with a replication-incompetent adenoviral vector into which a TNF inhibitor gene had been engineered. Within 3 days following the injection of 10(9) infectious particles, the TNF inhibitor concentration exceeded 1 mg/ml of plasma; this level of expression was maintained for at least 4 weeks, and detectable TNF inhibitory activity was measured 6 weeks after injection of the recombinant virus. Introduction of the artificial gene produced a phenotypic effect comparable to homozygous deletion of the 55-kDa TNF receptor, in that animals were rendered highly susceptible to infection by Listeria monocytogenes, whereas control animals receiving a replication-incompetent virus coding for beta-galactosidase were capable of resisting Listeria challenge. Adenovirus-mediated transfer of a gene encoding a TNF inhibitor offers a practical means of imposing effective, long-term blockade of TNF activity in vivo for investigational and therapeutic purposes.