Use of a liver-specific promoter reduces immune response to the transgene in adenoviral vectors
Use of a liver-specific promoter reduces immune response to the transgene in adenoviral vectors
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DOI：
10.1089/10430349950017455
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发表时间：
1999-07-20
影响因子：
4.2
通讯作者：
Beaudet, AL
中科院分区：
文献类型：
--
作者：
Pastore, L;Morral, N;Beaudet, AL
先前的研究使用在普遍存在的启动子（RSV、mPGK）控制下表达人α（1）-抗胰蛋白酶（hAAT）的腺病毒（Ad）载体，在一些小鼠品系（C3WHeJ）和BALB/c）中引发了针对hAAT的抗体的产生，但在其他品系（C57BL/6J）中则没有。相反，当所有病毒编码序列均被删除的辅助依赖性Ad载体（AdSTK109）和使用用内源启动子从人类基因组DNA表达hAAT时，C3H/HeJ小鼠未能产生抗体并表现出长期表达。这些结果表明启动子的选择和/或载体本身的特性可能会影响宿主对转基因产物的免疫反应。直接比较从普遍存在的小鼠 PGK 启动子而不是从肝脏特异性小鼠白蛋白启动子表达 hAAT cDNA 的第一代载体表明，在 C3WHeJ 小鼠中，针对 hAAT 的抗体反应发生在 mPGK 启动子而非白蛋白启动子上。正如预期的那样，两种载体均未在 C57BL/6J 小鼠中引发抗体反应。将含有 mPGK 和白蛋白启动子的两个第一代载体共同注射到 C3WHeJ 小鼠中诱导了抗体反应，导致注射小鼠血清中可检测到的 hAAT 在 3-4 周内消失。从这些数据中，我们得出结论，在某些条件下，启动子及其相关肝脏特异性表达的选择可以独立于病毒骨架调节宿主对转基因的免疫反应。
Previous studies using adenoviral (Ad) vectors expressing human alpha(1)-antitrypsin (hAAT) under the control of ubiquitous promoters (RSV, mPGK) elicited the production of antibodies to hAAT in some mouse strains (C3WHeJ) and BALB/c) but not in others (C57BL/6J), In contrast, when a helper-dependent Ad vector (AdSTK109) with all viral coding sequences deleted and expressing hAAT from human genomic DNA with the endogenous promoter was used, C3H/HeJ mice failed to develop antibodies and demonstrated long-term expression. These results suggested that promoter choice and/or properties of the vector itself might influence the host immune response to the transgene product. Direct comparison of first-generation vectors expressing the hAAT cDNA from a ubiquitous mouse PGK promoter rather than from a liver-specific mouse albumin promoter demonstrated that an antibody response to hAAT occurred with the mPGK promoter but not with the albumin promoter in C3WHeJ mice. As expected, neither vector elicits an antibody response in C57BL/6J mice. Coinjection of the two first-generation vectors containing the mPGK and albumin promoter in C3WHeJ mice induced an antibody response with resulting loss of detectable hAAT from the sera of the injected mice in 3-4 weeks. From these data, we conclude that under certain conditions, the choice of promoter with its associated liver-specific expression can modulate the host immune response to the transgene independent of viral backbone.