Wild-type adenoviruses from groups A-F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent
Wild-type adenoviruses from groups A-F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent
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DOI：
10.1038/gt.2008.18
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发表时间：
2008-06-01
期刊：
影响因子：
5.1
通讯作者：
Amalfitano, A.
中科院分区：
文献类型：
--
作者：
Appledorn, D. M.;Kiang, A.;Amalfitano, A.
目前，可选择的人和非人Ad血清型载体被研究用于基因治疗和/或疫苗应用，以利用它们可能避免预先存在的对HAd5的免疫的能力。然而，对于可供选择的Ad血清型所产生的先天免疫反应的性质和范围的关注相对较少。在这项研究中，我们研究了静脉注射野生型Ad血清型HAd31、HAd3、HAd5、HAd37、SAd23和HAd41后的几种天然免疫反应，分别代表A-F组。值得注意的是，生物分布研究显示，血清型之间存在显著差异，在肝脏和肺中发现高水平的HAd3基因组，而在全身给药后在脾中发现HAd37基因组。与其他Adserotype的类似处理相比，HAd3和SAd23诱导了先天免疫反应的改变，表现为在几个组织中诱导更高水平的细胞基因转录，以及更高水平的细胞因子和趋化因子。我们还研究了补体相互作用是否在HAd3和SAd23诱导的反应中发挥作用。我们证实了补体依赖基因转录、血浆细胞因子/趋化因子反应以及注射HAd3和SAd23后发生的肝脏毒性。这项研究强调了提议将替代的Ad血清型用于基因治疗或疫苗应用的潜在好处和/或局限性。
Alternative human and non-human Ad serotype vectors are currently studied for gene therapy and/or vaccine applications to capitalize upon their likely ability to avoid pre-existing immunity to HAd5. However, relatively little attention has been given to the nature and scope of innate immune responses generated by alternative Ad serotypes. In this study, we characterized several innate immune responses after intravenous administration of wild-type Ad serotypes HAd31, HAd3, HAd5, HAd37, SAd23 and HAd41, representing groups A-F, respectively. Notably, biodistribution studies revealed significant differences between the serotypes, with high levels of HAd3 genomes found in the liver and lung, and HAd37 genomes found in the spleen after systemic administration. Relative to similar treatments with other Adserotypes, HAd3 and SAd23 induced altered innate immune responses, illustrated by induction of higher levels of cellular gene transcription in several tissues, and higher plasma levels of cytokines and chemokines. We also investigated whether complement interactions have a role in HAd3- and SAd23-induced responses. We confirmed complement dependent gene transcription, plasma cytokine/chemokine responses, and liver toxicities incurred after administration of HAd3 and SAd23. This study highlights the potential benefits and/or limitations to the proposed use of alternative Ad serotypes for gene therapy or vaccine applications.