Transient Pretreatment With Glucocorticoid Ablates Innate Toxicity of Systemically Delivered Adenoviral Vectors Without Reducing Efficacy
Transient Pretreatment With Glucocorticoid Ablates Innate Toxicity of Systemically Delivered Adenoviral Vectors Without Reducing Efficacy
复制标题
DOI：
10.1038/mt.2008.297
复制
发表时间：
2009-04-01
影响因子：
12.4
通讯作者：
Amalfitano, Andrea
中科院分区：
文献类型：
--
作者：
Seregin, Sergey S.;Appledorn, Daniel M.;Amalfitano, Andrea
超过 300 项人体临床试验利用重组腺病毒 (rAds) 作为基因转移载体，证实 rAds 仍然具有很高的临床意义。 rAds 的一个主要弱点是它们在高剂量、全身给药后迅速触发先天性促炎性免疫反应的倾向。在这项研究中，我们研究了抗炎糖皮质激素的先发制人治疗对 Ad 载体触发的炎症免疫反应可能产生的影响。我们发现，使用地塞米松 (DEX) 进行简单的预处理方案可以显着减少大多数 Ad 诱导的先天免疫反应。 DEX 以剂量依赖性方式阻止 rAd 诱导全身细胞因子/趋化因子释放，较高剂量可阻止 rAd 诱导急性血小板减少症、内皮细胞活化、促炎基因诱导和白细胞浸润转导器官。短暂糖皮质激素预处理还显着降低了 rAd 诱导的适应性免疫反应，包括减少 Ad 中和抗体 (NAb) 的诱导。重要的是，DEX 的使用不会降低 rAd 介导的基因转导或 rAd 衍生的转基因表达的功效。我们的结果表明，简单、先发制人和短暂的糖皮质激素预处理是减少 rAd 相关急性毒性的可行方法，目前这种毒性限制了 Ad 载体在全身临床应用中的使用。
More than 300 human clinical trials utilize recombinant adenoviruses (rAds) as a gene transfer vector, confirming that rAds continue to be of high clinical interest. A primary weakness of rAds is their known propensity to trigger an innate, proinflammatory immune response rapidly after high-dose, systemic administration. In this study, we investigated what affects that pre-emptive treatment with anti-inflammatory glucocorticoids might have upon Ad vector-triggered inflammatory immune responses. We found that a simple pretreatment regimen with Dexamethasone (DEX) can significantly reduce most Ad-induced innate immune responses. DEX prevented rAd induction of systemic cytokine/chemokine releases in a dose-dependent fashion, with higher dosages preventing rAd induction of acute thrombocytopenia, endothelial cell activation, proinflammatory gene induction, and leukocyte infiltration into transduced organs. Transient glucocorticoid pretreatment also significantly reduced rAd-induced adaptive immune responses, including a decreased induction of Ad-neutralizing antibodies (NAbs). Importantly, use of DEX did not reduce the efficacy of rAd-mediated gene transduction nor rAd-derived transgene expression. Our results demonstrate that a simple, pre-emptive and transient glucocorticoid pretreatment is a viable approach to reduce rAd-associated acute toxicities that currently limit the use of Ad vectors in systemic clinical applications.