Comparison of HPV DNA vaccines employing intracellular targeting strategies
Comparison of HPV DNA vaccines employing intracellular targeting strategies
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DOI：
10.1038/sj.gt.3302252
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发表时间：
2004-06-01
期刊：
影响因子：
5.1
通讯作者：
Wu, TC
中科院分区：
文献类型：
--
作者：
Kim, JW;Hung, CF;Wu, TC
基因枪皮内接种可有效地将DNA疫苗递送至皮肤的树突状细胞（DCs）中，导致抗原特异性T细胞在体内的激活和引发。在DNA疫苗的背景下，我们以前使用基因枪方法来测试几种细胞内靶向策略，这些策略能够将模型抗原（如人乳头瘤病毒16型（HPV-16）E7）路由到所需的亚细胞区室，以增强抗原加工和呈递给T细胞。这些策略包括使用溶酶体相关膜蛋白（LAMP-1）、结核分枝杆菌热休克蛋白70（HSP 70）、钙网蛋白（CRT）和铜绿假单胞菌外毒素A（ETA）的易位结构域（dII）的分选信号。用编码E7抗原的DNA疫苗与这些分子中的任何一种连接，都导致E7特异性CD 8（+）T细胞免疫应答的显著增强和对表达E7的肿瘤TC-1的强抗肿瘤作用。然而，我们有兴趣为我们未来的临床试验确定最有效的DNA疫苗。因此，我们进行了一系列实验，以直接比较各种DNA疫苗的效力。在我们测试的DNA疫苗中，我们发现用pcDNA 3-CRT/E7疫苗接种产生了最高数量的E7特异性CD 8（+）T细胞，并对小鼠中表达E7的肿瘤产生了有效的长期保护和治疗效果。有趣的是，我们观察到，pcDNA 3-CRT/E7也能够保护E7表达肿瘤与下调的MHC I类表达，一个共同的特点，与大多数HPV相关的宫颈癌。我们的数据表明，连接CRT到E7（CRT/E7）的DNA疫苗可能是一个合适的候选人，用于控制HPV感染和HPV相关病变的人体试验。
Intradermal vaccination via gene gun efficiently delivers DNA vaccines into dendritic cells (DCs) of the skin, resulting in the activation and priming of antigen-specific T cells in vivo. In the context of DNA vaccines, we previously used the gene gun approach to test several intracellular targeting strategies that are able to route a model antigen, such as the human papillomavirus type-16 (HPV-16) E7, to desired subcellular compartments in order to enhance antigen processing and presentation to T cells. These strategies include the use of the sorting signal of lysosome-associated membrane protein (LAMP-1), Mycobacterium tuberculosis heat-shock protein 70 (HSP70), calreticulin (CRT) and the translocation domain (dII) of Pseudomonas aeruginosa exotoxin A (ETA). Vaccination with DNA vaccines encoding E7 antigen linked to any of these molecules all led to a significant enhancement of E7-specific CD8(+) T-cell immune responses and strong antitumor effects against an E7-expressing tumor, TC-1. However, we were interested in identifying the most potent DNA vaccine for our future clinical trials. Thus, we performed a series of experiments to directly compare the potency of the various DNA vaccines. Among the DNA vaccines we tested, we found that vaccination with pcDNA3-CRT/E7 generated the highest number of E7-specific CD8(+) T cells and potent long-term protection and treatment effects against E7-expressing tumors in mice. Interestingly, we observed that pcDNA3-CRT/E7 is also capable of protecting against an E7-expressing tumor with downregulated MHC class I expression, a common feature associated with most HPV-associated cervical cancers. Our data suggest that the DNA vaccine linking CRT to E7 (CRT/E7) may be a suitable candidate for human trials for the control of HPV infections and HPV-associated lesions.