Cyclophosphamide diminishes inflammation and prolongs transgene expression following delivery of adenoviral vectors to mouse liver and lung
Cyclophosphamide diminishes inflammation and prolongs transgene expression following delivery of adenoviral vectors to mouse liver and lung
复制标题
DOI：
10.1089/hum.1996.7.13-1555
复制
发表时间：
1996-08-20
影响因子：
4.2
通讯作者：
Wilson, JM
中科院分区：
文献类型：
--
作者：
Jooss, K;Yang, YP;Wilson, JM
对腺病毒介导的基因转移的免疫反应会导致瞬时重组基因表达、炎症和载体重新施用困难等问题。 CD4(+) T 细胞的激活是充分实现 CD8(+) T 细胞（即细胞毒性 T 细胞）和 B 细胞（即中和抗体）的效应功能所必需的，我们在这项研究中评估了短程高剂量环磷酰胺阻断小鼠免疫反应的有效性，该小鼠将载体注射到 C57BL/6 小鼠的肺和肝脏中。 带有针对肝脏的载体的环磷酰胺阻断了 CD4(+) 和 CD8(+) T 细胞的激活和动员，因此延长了转基因表达，减少了炎症，并且在较高剂量的环磷酰胺下，阻止了中和抗体的形成，并且成功地重新施用了载体。在肺中的类似研究证明了 T 和 B 细胞的有效阻断 与肝脏相比，在肝脏中稳定转基因表达比防止中和抗体更容易，环磷酰胺在所有剂量下都能防止肺中中和抗体的形成，而转基因表达的稳定只能在最高剂量下实现。这些实验开始定义环磷酰胺可用作基因治疗辅助剂的参数。
Immune responses to adenovirus-mediated gene transfer contribute to the problems of transient recombinant gene expression, inflammation, and difficulties with vector readministration. Activation of CD4(+) T cells is required for full realization of effector function of both CD8(+) T cells (i,e,, cytotoxic T cells) and B cells (i,e,, neutralizing antibody), We evaluate in this study the effectiveness of a short course of high-dose cyclophosphamide to block immune responses in mice administered vector into lung and liver of C57BL/6 mice, Administration of cyclophosphamide with vector directed to liver blocked activation and mobilization of both CD4(+) and CD8(+) T cells, As a result, transgene expression was prolonged, inflammation was reduced, and, at the higher doses of cyclophasphamide, formation of neutralizing antibody was prevented and the vector was successfully readministered, Similar studies in the lung demonstrated an effective blockade of T and B cell responses, In contrast to the liver, where it was easier to stabilize transgene expression than to prevent neutralizing antibody, cyclophosphamide prevented the formation of neutralizing antibodies at all doses in the lung, whereas stabilization of transgene expression was only achieved at the highest dose, These experiments begin to define the parameters by which cyclophosphamide could be used as an adjunct in gene therapy.