Successful expression of human factor IX following repeat administration of adenoviral vector in mice.
Successful expression of human factor IX following repeat administration of adenoviral vector in mice.
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在小鼠中重复施用腺病毒载体后成功表达人因子 IX。
DOI：
10.1073/pnas.93.7.3056
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发表时间：
1996
影响因子：
11.1
通讯作者：
High,KA
中科院分区：
文献类型：
--
作者：
Walter,J;You,Q;Hagstrom,JN;Sands,M;High,KA
腺病毒载体可以指导转基因的高水平表达，但是，由于宿主对腺病毒抗原的免疫应答，表达的持续时间有限，并且重复施用通常不成功。在新生儿期开始暴露于外源蛋白可能会改变或消除免疫反应。我们给成年和新生（免疫活性）CD-1小鼠静脉注射表达人凝血因子IX的腺病毒载体。在两组小鼠中，人因子IX的表达持续了12-16周。然而，在最初作为成年人注射的小鼠中，重复施用载体导致转基因的不可检测的表达，而在最初在新生儿期注射的小鼠中，重复施用导致人因子IX的高水平表达。我们发现，动物未能表达转基因重复管理已开发出高滴度的中和抗体腺病毒，而那些表达因子IX没有。该实验模型表明，新生小鼠可以耐受腺病毒载体，并表明，至少一个重复注射的腺病毒载体是可能的，该模型将是有用的，在阐明免疫学机制成功的腺病毒载体的重复管理。
Adenoviral vectors can direct high-level expression of a transgene, but, due to a host immune response to adenoviral antigens, expression is of limited duration, and repetitive administration has generally been unsuccessful. Exposure to foreign proteins beginning in the neonatal period may alter or ablate the immune response. We injected adult and neonatal (immunocompetent) CD-1 mice intravenously with an adenoviral vector expressing human blood coagulation factor IX. In both groups of mice, expression of human factor IX persisted for 12-16 weeks. However, in mice initially injected as adults, repeat administration of the vector resulted in no detectable expression of the transgene, whereas in mice initially injected in the neonatal period, repeat administration resulted in high-level expression of human factor IX. We show that animals that fail to express the transgene on repeat administration have developed high-titer neutralizing antibodies to adenovirus, whereas those that do express factor IX have not. This experimental model suggests that newborn mice can be tolerized to adenoviral vectors and demonstrates that at least one repeat injection of the adenoviral vector is possible; the model will be useful in elucidating the immunologic mechanisms underlying successful repeat administration of adenoviral vectors.