Walter J, You Q, Hagstrom J N, Sands M, High K A
Children's Hospital of Phildelphia, PA 19104, USA.
Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):3056-61. doi: 10.1073/pnas.93.7.3056.
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.
腺病毒载体可指导转基因的高水平表达，但由于宿主对腺病毒抗原产生免疫反应，其表达持续时间有限，且重复给药通常不成功。从新生儿期开始接触外来蛋白质可能会改变或消除免疫反应。我们给成年和新生（具有免疫能力）的CD-1小鼠静脉注射了一种表达人凝血因子IX的腺病毒载体。在两组小鼠中，人因子IX的表达均持续了12 - 16周。然而，在最初作为成年小鼠注射的小鼠中，重复给予该载体未检测到转基因的表达，而在最初在新生儿期注射的小鼠中，重复给药导致人因子IX的高水平表达。我们发现，重复给药时未能表达转基因的动物已产生了针对腺病毒的高滴度中和抗体，而那些确实表达因子IX的动物则没有。这个实验模型表明新生小鼠可以对腺病毒载体产生耐受，并证明至少可以重复注射一次腺病毒载体；该模型将有助于阐明腺病毒载体成功重复给药背后的免疫机制。
