Readministration of helper-dependent adenoviral vectors to mouse airway mediated via transient immunosuppression
Readministration of helper-dependent adenoviral vectors to mouse airway mediated via transient immunosuppression
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DOI：
10.1038/gt.2010.125
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发表时间：
2011-02-01
期刊：
影响因子：
5.1
通讯作者：
Hu, J.
中科院分区：
文献类型：
--
作者：
Cao, H.;Yang, T.;Hu, J.
腺病毒介导的基因治疗的功效被宿主对载体和转基因产物的免疫应答减弱。即使对于所有病毒编码序列缺失的辅助依赖性腺病毒（HD-Ad）载体，病毒衣壳蛋白仍然引起免疫反应。为了提高转基因表达的效率，在HD-Ad载体再施用期间，我们施用环磷酰胺来瞬时调节小鼠免疫系统。我们将高剂量（每只小鼠5 × 10（10）载体颗粒（vp））的空HD-Ad递送至小鼠气道以诱导初始免疫应答。4周后，用含有报告基因LacZ或人囊性纤维化跨膜传导调节因子（CFTR）基因的HD-Ad载体（每只小鼠1.5 × 10（10）vp）重新接种小鼠。我们发现，这两个转基因的表达大大提高了环磷酰胺的管理时，在小鼠的表达相比，没有免疫抑制药物。我们还发现，鼻内给予高剂量的空HD-Ad载体不会诱导急性全身免疫应答，但它确实引起促炎细胞因子产生的急性局部应答。在载体中加入环磷酰胺后，抗Ad载体的抗体（包括中和抗体）大大降低。此外，环磷酰胺减少炎症细胞的浸润，包括总白细胞、淋巴细胞、CD 4+和CD 8 + T细胞。这些结果表明，免疫抑制剂的瞬时施用可用于延长转基因表达以及减弱气道再施用中对HD-Ad载体的免疫原性。Gene Therapy（2011）18，173-181; doi：10.1038/gt.2010.125; 2010年9月30日在线发表
The efficacy of adenovirus-mediated gene therapy is attenuated by the host immune responses to both vector and transgene products. Even for helper-dependent adenoviral (HD-Ad) vectors, which have all viral-coding sequences deleted, the viral capsid proteins still cause immune reactions. In order to improve the efficiency in transgene expression during HD-Ad vector readministration, we administered cyclophosphamide to transiently modulate the mouse immune system. We delivered a high dose (5x10(10) vector particles (vp) per mouse) of empty HD-Ad to the mouse airway to induce an initial immune response. After 4 weeks, the mice were readministered with an HD-Ad vector containing either the reporter gene, LacZ, or the gene for the human cystic fibrosis transmembrane conductance regulator (CFTR) (1.5x10(10) vp per mouse). We found that the expression of both transgenes was greatly improved by the administration of cyclophosphamide when compared with the expression in mice without the immunosuppressing drug. We also found that the high dose of the empty HD-Ad vector administered intranasally does not induce an acute systemic immune response, but it does elicit an acute local response of proinflammatory cytokine production. Antibodies against Ad vector, including the neutralizing antibodies, were greatly reduced by the presence of cyclophosphamide in vector readministratiton. Moreover, cyclophosphamide reduced the infiltration of inflammatory cells, including total leukocytes, lymphocytes, CD4+ and CD8+ T cells. These results indicate that transient administration of immunosuppressive agent can be used to extend transgene expression as well as attenuating immunogenicity to HD-Ad vectors in airway readministration. Gene Therapy (2011) 18, 173-181; doi:10.1038/gt.2010.125; published online 30 September 2010