A DNA vaccine co-expressing antigen and an anti-apoptotic molecule further enhances the antigen-specific CD8+ T-cell immune response |
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Authors: | Tae Woo Kim Chien-Fu Hung Meizi Zheng David A K Boyd Liangmei He Sara I Pai " target="_blank">T C Wu |
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Institution: | (1) Department of Pathology, The Johns Hopkins University School of Medicine, Ross 512H, 720 Rutland Avenue, 21205 Baltimore, Md, USA;(2) Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, Md., USA;(3) Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, Md., USA;(4) Department of Otolaryngology - Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Md., USA;(5) Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, Md., USA |
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Abstract: | We have shown that DNA encoding the anti-apoptotic protein Bcl-xL enhances E7-specific CD8+ T-cell responses and DNA encoding pro-apoptotic protein caspase-3 suppresses E7-specific CD8+ T-cell responses when co-administered intradermally via gene gun with DNA encoding human papillomavirus type 16 (HPV-16) E7 linked to the sorting signal of the lysosome-associated membrane protein type 1 (LAMP-1). E7 and LAMP-1 are linked to form the chimeric Sig/E7/LAMP-1 (SEL). Because co-administration does not ensure delivery of both constructs to a single cell, we used pVITRO, a mammalian expression vector with double promoters, to ensure expression of both molecules in the same cell. We vaccinated C57BL/6 mice with pVITRO-SEL-Bcl-xL, pVITRO-SEL-mtBcl-xL, pVITRO-SEL, or pVITRO-SEL-caspase-3 intradermally via gene gun and intramuscularly via injection. We demonstrated that vaccination with pVITRO achieved similar results to a co-administration strategy: that Bcl-xL enhanced the E7-specific CTL response and caspase-3 suppressed the E7-specific CTL response. In addition, we found intradermal vaccination elicited significantly higher numbers of E7-specific CD8+ T cells compared to intramuscular vaccination. Thus, intradermal vaccination with a pVITRO vector combining an anti-apoptotic strategy (Bcl-xL) and an intracellular targeting strategy (SEL) further enhances the E7-specific CD8+ T-cell response and guarantees co-expression of both encoded molecules in transfected cells.T.W.K. and C.-F.H. contributed equally to this work. |
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Keywords: | DNA vaccines Bcl-xL Caspase-3 Human papillomavirus Anti-apoptosis Immunotherapy pVITRO |
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