Infra-pinna anti-tumor vaccination with self-replicating infectious RNA or with DNA encoding a model tumor antigen and a cytokine
Infra-pinna anti-tumor vaccination with self-replicating infectious RNA or with DNA encoding a model tumor antigen and a cytokine
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DOI：
10.1038/sj.gt.3301220
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发表时间：
2000-07-01
期刊：
影响因子：
5.1
通讯作者：
von Hoegen, P
中科院分区：
文献类型：
--
作者：
Schirrmacher, V;Förg, P;von Hoegen, P
为了优化用于保护性抗肿瘤免疫的多核苷酸疫苗接种，我们使用了自我复制的RNA疫苗，其中塞姆利基森林病毒复制酶驱动编码β-半乳糖苷酶的lacZ基因的RNA表达作为模型肿瘤相关抗原（TAA）。将其与复制酶缺陷型对照RNA和lacZ DNA质粒在体外和体内的基因表达进行比较，并将其用于使用小鼠耳廓作为最佳免疫部位的疫苗接种，在体外，观察到自我复制RNA的最高表达。在耳廓接种非复制DNA质粒或自我复制RNA后的基因表达是相似的，持续2-3周。用RNA比用DNA获得更高的抗体应答。对lacZ DNA或RNA的β-Gal肽特异性CTL记忆应答持续超过6周，而由lacZ转染的肿瘤细胞诱导的相应应答仅持续2周。为了用自我复制的RNA实现针对lacZ肿瘤细胞的保护性应答，与DNA相比，低约100倍剂量的多核苷酸是足够的。保护性抗肿瘤免疫的程度不仅取决于用于疫苗接种的基因剂量，而且还取决于用于攻击的lacZ转染的肿瘤系的攻击性。与作为疫苗的lacZ转染的肿瘤细胞相比，多核苷酸疫苗接种也证明了交叉保护的优越性。将lacZ DNA与IL-2 DNA或IL-12 RNA共接种可显著增强小鼠的抗肿瘤保护性免疫力。IL-2 DNA而非IL-12 RNA也增强了CTL应答，而IL-12 RNA而非IL-2 DNA降低了抗体应答。这些结果证明了耳廓内lacZ TAA多核苷酸疫苗接种后有效的保护性抗肿瘤免疫，并显示了通过共同施用细胞因子多核苷酸的额外免疫调节作用。
To optimize polynucleotide vaccinations for protective anti-tumor immunity we used a self-replicating RNA vaccine in which Semliki Forest virus replicase drives RNA expression of the lacZ gene coding for beta-galactosidase as model tumor-associated antigen (TAA). This was compared with replicase-deficient control RNA and with lacZ DNA plasmids with respect to gene expression in vitro and in vivo and for vaccination using the mouse ear pinna as an optimal immunization site, in vitro, the highest expression was observed with self-replicating RNA. Gene expression following pinna inoculation of either non-replicating DNA plasmids or self-replicating RNA was similar, lasting for 2-3 weeks. Higher antibody responses were obtained with RNA than with DNA. beta-Gal peptide specific CTL memory responses to lacZ DNA or RNA lasted for more than 6 weeks while respective responses induced by lacZ-transfected tumor cells lasted for only 2 weeks. To achieve a protective response against lacZ tumor cells with self-replicating RNA about a 100-fold lower dose of polynucleotide was sufficient in comparison to DNA. The extent of protective antitumor immunity not only depended on the gene dose used for vaccination, but also on the aggressiveness of the lacZ-transfected tumor line used for challenge. In comparison to lacZ-transfected tumor cells as vaccines, polynucleotide vaccination also demonstrated superiority with regard to cross-protection. Protective antitumor immunity could be strongly increased upon co-inoculation of lacZ DNA with IL-2 DNA or IL-12 RNA. IL-2 DNA, but not IL-12 RNA, also augmented the CTL response while IL-12 RNA, but not IL-2 DNA, reduced the antibody response. These results demonstrate efficient protective antitumor immunity after intrapinna lacZ TAA polynucleotide Vaccination and show additional immunomodulatory effects by co-administration of cytokine polynucleotides.