Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA.
Mol Ther. 2010 Mar;18(3):609-16. doi: 10.1038/mt.2009.279. Epub 2009 Dec 1.
Innate immune responses are a major barrier to safe systemic gene therapy with adenovirus (Ad) vectors. We show that intravenous (IV) injection of rats with Ad5 vectors causes a novel rapid shock reaction that involves hypotension, hemoconcentration, tissue edema, and vasocongestion, with notable pathology in the pancreas and the gastrointestinal system. We show for the first time that this reaction is dependent on platelet-activating factor (PAF), a lipid signaling molecule that is a known shock inducer. Ad upregulated PAF within 5 minutes in vivo, and antagonists of the PAF receptor were able to prevent Ad-induced shock. Ad upregulated PAF via the reticuloendothelial system (RES), because splenectomy or depletion of phagocytes blocked the ability of Ad to induce both PAF and shock. Rats were considerably more sensitive to Ad-induced shock than were mice, but PAF mediated shock in both species. Other Ad-induced innate immune responses such as cytokine induction and thrombocytopenia were not mediated by PAF. In summary, systemic IV injection of Ad stimulates the RES to upregulate PAF within a matter of minutes, which results in shock. The identification of this novel pathway suggests strategies to improve the safety of systemic gene therapy with Ad vectors.
先天免疫反应是腺病毒 (Ad) 载体进行安全全身基因治疗的主要障碍。我们表明，静脉内 (IV) 注射大鼠 Ad5 载体引起一种新的快速休克反应，涉及低血压、血液浓缩、组织水肿和血管充血，胰腺和胃肠道有明显的病变。我们首次表明，这种反应依赖于血小板激活因子 (PAF)，一种已知的休克诱导剂的脂质信号分子。Ad 在体内 5 分钟内上调 PAF，PAF 受体拮抗剂能够预防 Ad 诱导的休克。Ad 通过网状内皮系统 (RES) 上调 PAF，因为脾切除术或吞噬细胞耗竭阻断了 Ad 诱导 PAF 和休克的能力。大鼠对 Ad 诱导的休克比小鼠敏感得多，但 PAF 在两种物种中都介导休克。其他 Ad 诱导的先天免疫反应，如细胞因子诱导和血小板减少，不受 PAF 介导。总之，全身 IV 注射 Ad 可在数分钟内刺激 RES 上调 PAF，从而导致休克。这种新途径的鉴定提示了改善 Ad 载体全身基因治疗安全性的策略。
