Liver Toxicities typically induced by first-generation adenoviral vectors can be reduced by use of E1, E2b-deleted adenoviral vectors
Liver Toxicities typically induced by first-generation adenoviral vectors can be reduced by use of E1, E2b-deleted adenoviral vectors
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DOI：
10.1089/104303403322611737
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发表时间：
2003-12-01
影响因子：
4.2
通讯作者：
Amalfitano, A
中科院分区：
文献类型：
--
作者：
Everett, RS;Hodges, BL;Amalfitano, A
已知E1区域缺失的腺病毒载体（[E1（-）] Ad）在全身递送后会诱导强烈的免疫反应。在这项研究中，我们评估了C57 BL/6、BALB/c和SCID小鼠静脉注射高剂量[E1（-）]或修饰的[E1（-）、E2 b（-）] Ad载体（均表达细菌β-半乳糖苷酶[lacZ]标记基因）后小鼠的肝脏毒性。我们的数据表明，在所有测试的小鼠品系中，使用[E1（-），E2 b（-）]修饰的载体，最大肝毒性和病理学（通常在注射后21天观察到）显著降低。我们的数据还表明，尽管使用[E1（-），E2 b（-）] Ad载体，仍然观察到显著的肝毒性。为了解决这一问题以及lacZ基因在免疫活性C57 BL/6和BALB/c小鼠中被视为外源抗原的事实，我们类似地注射了LacZ耐受小鼠（lacZ-TG）。与我们在C57 BL/6和BALB/c小鼠中的研究相反，LacZ-TG小鼠在静脉内注射[E1（-），E2 b（-）]载体后几乎没有表现出肝毒性的证据，这与使用[E1（-）] Ad载体相反。我们的研究结果表明，[E1-，E2 b（-）] Ad载体类可以减少肝毒性，通常归因于Ad载体介导的基因转移后，转移的高度免疫原性或外源基因，而转移的转基因，被认为是非外来的主机可以交付几乎没有毒性的证据。在仔细回顾文献的基础上，这些载体安全性的改善与迄今为止描述的其他更显著修饰的Ad载体相媲美。
Adenoviral vectors from which the E1 region has been deleted ([E1(-)] Ad) are known to induce strong immune responses after systemic delivery. In this study we have evaluated liver toxicities in mice after intravenous injection with high doses of [E1(-)] or modified [E1(-), E2b(-)] Ad vectors (both expressing the bacterial beta-galactosidase [lacZ] marker gene) in C57BL/6, BALB/c, and SCID mice. Our data demonstrate a marked reduction in maximal liver toxicities and pathologies (typically noted at 21 days postinjection) with the use of the [E1(-), E2b(-)] modified vector in all strains of mice tested. Our data also demonstrated that despite the use of the [E1(-), E2b(-)] Ad vector, significant liver toxicities were still observed. To address this issue and the fact that the lacZ gene was perceived as a foreign antigen in the immune-competent C57BL/6 and BALB/c mice, we similarly injected mice tolerant of LacZ (lacZ-TG). In contrast to our studies in C57BL/6 and BALB/c mice, LacZ-TG mice exhibited virtually no evidence of hepatotoxicity after intravenous injection with the [E1(-), E2b(-)] vector, in contrast to use of the [E1(-)] Ad vector. Our results demonstrate that the [E1-, E2b(-)] Ad vector class can reduce liver toxicities typically ascribed to Ad vector-mediated gene transfer after transfer of a highly immunogenic or foreign gene, whereas transfer of a transgene that is perceived as nonforeign by the host can be delivered with virtually no evidence of toxicity. On the basis of a careful review of the literature, these improvements in vector safety rival those noted with other, more significantly modified Ad vectors described to date.