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首页> 外文期刊>Gene therapy >Intravenous administration of an E1/E3-deleted adenoviral vector induces tolerance to factor IX in C57BL/6 mice.
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Intravenous administration of an E1/E3-deleted adenoviral vector induces tolerance to factor IX in C57BL/6 mice.

机译：静脉内施用缺失E1 / E3的腺病毒载体可诱导C57BL / 6小鼠对IX因子的耐受性。

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Inbred immunocompetent C57BL/6 mice have been a favored strain to study transgene expression of human blood coagulation factor IX (hF.IX) from viral vectors because systemic expression of the secreted protein is not limited by antibody responses following intravenous (i.v.) injection of vector. For example, i.v. injection of an adenoviral (Ad) vector results in sustained expression of hF.IX in normal or hemophilic C57BL/6 mice, while anti-hF.IX antibodies rapidly emerge in other strains (Gene Therapy 4: 473; Blood 91: 784). To investigate these observations further, we injected naive C57BL/6 mice and C57BL/6 mice with pre-existing anti-hF.IX with Ad-hF.IX vector via peripheral vein. All mice expressed hF.IX antigen without detectable anti-hF.IX, even when challenged with hF.IX in different immunogenic settings at later time points. Moreover, in mice with pre-existing immunity, anti-hF.IX titers diminished to undetectable levels after i.v. administration of Ad-hF.IX. Lymphocytes from mice that had received Ad-hF.IX i.v. failed to proliferate when stimulated with hF.IX in vitro after the animals had been repeatedly challenged with hF.IX protein formulated in complete Freund's adjuvant. Thus, absence of anti-hF.IX in C57BL/6 mice after i.v. injection of Ad vector is not due to ignorance to the foreign transgene product. Similar experiments in other strains showed that immune tolerance to hF.IX does not correlate with the strain haplotype or expression of IL-10 cytokine. Given the well-documented immunogenicity of the first-generation adenoviral vector, data from C57BL/6 mice may therefore grossly underestimate immunological consequences in certain gene therapy protocols.
机译：自交免疫能力强的C57BL / 6小鼠已成为研究病毒载体中人凝血因子IX（hF.IX）转基因表达的首选菌株，因为在静脉内（iv）注射载体后，分泌蛋白的系统表达不受抗体反应的限制。例如，i.v。注射腺病毒（Ad）载体可导致hF.IX在正常或血友病C57BL / 6小鼠中持续表达，而抗hF.IX抗体在其他品系中迅速出现（基因疗法4：473;血液91：784）。为了进一步研究这些观察结果，我们通过外周静脉注射了天然的C57BL / 6小鼠和C57BL / 6小鼠，其中已有抗hF.IX和Ad-hF.IX载体。所有小鼠都表达了hF.IX抗原而没有可检测到的抗hF.IX，即使在以后的不同时间用不同的免疫原性环境中的hF.IX进行了攻击。此外，在具有预先存在的免疫力的小鼠中，静脉注射后抗-hF.IX效价降低至不可检测的水平。 Ad-hF.IX的管理。来自接受Ad-hF.IX i.v.的小鼠的淋巴细胞。在用弗氏完全佐剂配制的hF.IX蛋白反复攻击动物后，在体外用hF.IX刺激无法增殖。因此，静脉内注射后C57BL / 6小鼠中不存在抗hF.IX。注射Ad载体不是由于对外来转基因产物的了解不足。在其他菌株中进行的类似实验表明，对hF.IX的免疫耐受与菌株单倍型或IL-10细胞因子的表达无关。考虑到第一代腺病毒载体的充分证明的免疫原性，因此来自C57BL / 6小鼠的数据可能会严重低估某些基因治疗方案中的免疫学后果。

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