Recombinant IL–12 prevents formation of blocking IgA antibodies to recombinant adenovirus and allows repeated gene therapy to mouse lung-猫眼课题宝

重组 IL-12 可防止形成针对重组腺病毒的阻断性 IgA 抗体，并允许对小鼠肺进行重复基因治疗

DOI：

10.1038/nm0995-890

发表时间：

1995

期刊：

Nature Medicine

影响因子：

82.9

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

Yiping Yang;G. Trinchieri;James M. Wilson

在基因治疗中使用重组腺病毒的热情已经被对病毒和病毒感染的细胞产生的有问题的免疫反应所缓和。对输入病毒蛋白质的体液免疫应答产生中和抗体，所述中和抗体阻碍多次有效施用治疗的尝试。先前在囊性纤维化（CF）基因治疗小鼠模型中的研究表明，伊加亚型的腺病毒抗体的形成（一个依赖于TH 2亚群的T辅助细胞的过程）有助于在第二次给予病毒后发生的基因转移阻断。我们在这份报告中表明，干扰素-γ（IFN-γ）（或白细胞介素-12，激活TH-1细胞分泌IFN-γ）与重组腺病毒共同给药到C57 BL/6小鼠气道减少TH-2细胞的激活和中和抗体的形成，允许重组病毒的有效再给药。这表明CF的基因治疗策略，其中在基因治疗时施用短效免疫调节剂可能足以克服体液免疫的问题。

Enthusiasm for the use of recombinant adenoviruses in gene therapy has been tempered by the problematic immune responses that develop to the virus and virus–infected cells. Humoral immune responses to the input viral proteins generate neutralizing antibodies that thwart attempts to effectively administer the therapy more than once. Previous studies in murine models of gene therapy for cystic fibrosis (CF) have shown that the formation of adenoviral antibodies of the IgA subtype, a process that is dependent on T helper cells of the TH2 subset, contributes to a block in gene transfer that occurs following a second administration of virus. We show in this report that coadministration of interferon–γ (IFN–γ) (or interleukin–12, which activates TH1 cells to secrete IFN–γ) with the recombinant adenovirus into the airway of C57BL/6 mice diminishes the activation of TH2 cells and formation of neutralizing antibody, allowing for efficient readministration of recombinant virus. This suggests a strategy for gene therapy of CF in which administration of a short–acting immune modulator at the time of gene therapy may be sufficient to overcome the problems of humoral immunity.