Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration
Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration
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DOI：
10.1089/hum.1997.8.1-37
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发表时间：
1997-01-01
影响因子：
4.2
通讯作者：
Crystal, RG
中科院分区：
文献类型：
--
作者：
Worgall, S;Wolff, G;Crystal, RG
为了评估宿主防御的先天免疫成分在体内给药后清除腺病毒（Ad）载体基因组中的贡献，Ad载体AdCMV。-gal（表达-半乳糖苷酶）或AdCMV。将空（不表达基因）静脉注射到免疫正常或免疫缺陷的小鼠中，并对肝脏中载体基因组的数量进行量化。引人注目的是，90%的载体DNA在24小时内被消除，在此期间其他组织中的载体DNA没有增加，这表明载体基因组的快速清除是由局部降解引起的。重要的是，早期阶段（0-24小时）载体DNA的清除与转基因无关，在免疫正常动物和裸动物中相似，这些观察结果表明Ad载体的消除有两个阶段：先前已认识到的晚期免疫相关消除，以及本研究中描述的早期先天免疫消除，到目前为止，载体丢失的早期阶段是主要机制，这一观察结果对在体内基因治疗后开发维持新转移基因持续表达的策略具有重要意义。
To evaluate the contribution of the innate immune component of host defense in clearing the genome of adenovirus (Ad) vectors following in vivo administration, the Ad vectors AdCMV.beta gal (expressing beta-galactosidase) or AdCMV.Null (expressing no gene) were administered intravenously to immunocompetent or immunodeficient mice, and the amount of vector genome was quantified in the liver, Strikingly, 90% of vector DNA was eliminated within 24 hr, There was no increase in vector DNA in other tissues over this period, suggesting that rapid clearance of vector genome resulted from local degradation, After 24 hr, vector elimination was slow, with only 9% of the initial amount of vector genome cleared over the subsequent 3 weeks, Importantly, early phase (0-24 hr) elimination of vector DNA was independent of the transgene and similar in immunocompetent and nude animals, These observations suggest two phases of Ad vector elimination: a previously recognized late, immune-related elimination, and the early, innate immune elimination described in the present study, The early phase of vector loss is, by far, the dominant mechanism, an observation that has implications in developing strategies to maintain persistent expression of the newly transferred gene following in vivo gene therapy.