Administration of HPV DNA vaccine via electroporation elicits the strongest CD8+ T cell immune responses compared to intramuscular injection and intradermal gene gun delivery.
Administration of HPV DNA vaccine via electroporation elicits the strongest CD8+ T cell immune responses compared to intramuscular injection and intradermal gene gun delivery.
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DOI：
10.1016/j.vaccine.2009.07.005
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发表时间：
2009-09-04
期刊：
影响因子：
5.5
通讯作者：
Pai SI
中科院分区：
文献类型：
--
作者：
Best SR;Peng S;Juang CM;Hung CF;Hannaman D;Saunders JR;Wu TC;Pai SI
DNA疫苗是诱导抗原特异性免疫的一种有吸引力的方法。肿瘤抗原通过其与免疫刺激分子如钙网蛋白（CRT）的连接的细胞内靶向可以通过MHC I类途径改善抗原加工和呈递，并增加细胞毒性CD 8 + T细胞的产生。然而，即使有这些增强，这种免疫策略的功效也取决于DNA施用的有效途径和方法的鉴定。电穿孔和基因枪介导的颗粒递送是DNA疫苗递送的主要方法，其可以在实验模型中产生保护和治疗水平的免疫应答。在这项研究中，我们进行了一个头对头的比较三种接种方法-常规肌肉注射，电穿孔介导的肌肉内递送，表皮基因枪介导的颗粒递送-在产生抗原特异性细胞毒性CD 8 + T细胞反应的能力，以及抗肿瘤免疫反应的HPV-16 E7表达肿瘤细胞系使用pNGVL 4a-CRT/E7（排毒）DNA疫苗。通过电穿孔的疫苗接种产生了最高数量的E7特异性细胞毒性CD 8 + T细胞，这与生长肿瘤治疗的改善结果相关。此外，我们证明，电穿孔的结果在显着更高水平的循环蛋白相比，基因枪或肌肉注射疫苗，这可能会增强钙网蛋白的作用，作为一个局部肿瘤抗血管生成剂。我们的结论是，电穿孔是一种很有前途的方法交付HPV DNA疫苗，并应考虑在人体临床试验的DNA疫苗交付。
DNA vaccines are an attractive approach to eliciting antigen-specific immunity. Intracellular targeting of tumor antigens through its linkage to immunostimulatory molecules such as calreticulin (CRT) can improve antigen processing and presentation through the MHC Class I pathway and increase cytotoxic CD8+ T cell production. However, even with these enhancements, the efficacy of such immunotherapeutic strategies is dependent on the identification of an effective route and method of DNA administration. Electroporation and gene gun-mediated particle delivery are leading methods of DNA vaccine delivery that can generate protective and therapeutic levels of immune responses in experimental models. In this study, we perform a head-to-head comparison of three methods of vaccination – conventional intramuscular injection, electroporation mediated intramuscular delivery, and epidermal gene gun-mediated particle delivery - in the ability to generate antigen specific cytotoxic CD8+ T cell responses as well as anti-tumor immune responses against an HPV-16 E7 expressing tumor cell line using the pNGVL4a-CRT/E7(detox) DNA vaccine. Vaccination via electroporation generated the highest number of E7-specific cytotoxic CD8+ T cells, which correlated to improved outcomes in the treatment of growing tumors. In addition, we demonstrate that electroporation results in significantly higher levels of circulating protein compared to gene gun or intramuscular vaccination, which likely enhances calreticulin’s role as a local tumor anti-angiogenesis agent. We conclude that electroporation is a promising method for delivery of HPV DNA vaccines and should be considered for DNA vaccine delivery in human clinical trials.
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