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Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins
Tae Woo Kim, … , Sharad Kumar, T.-C. Wu
Tae Woo Kim, … , Sharad Kumar, T.-C. Wu
Published July 1, 2003
Citation Information: J Clin Invest. 2003;112(1):109-117. https://doi.org/10.1172/JCI17293.
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Article Vaccines

Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins

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Abstract

Intradermal vaccination by gene gun efficiently delivers DNA vaccines into DCs of the skin, resulting in the activation and priming of antigen-specific T cells in vivo. DCs, however, have a limited life span, hindering their long-term ability to prime antigen-specific T cells. We reason that a strategy that prolongs the survival of DNA-transduced DCs will enhance priming of antigen-specific T cells and DNA vaccine potency. Here we show that codelivery of DNA encoding inhibitors of apoptosis (BCL-xL, BCL-2, XIAP, dominant negative caspase-9, or dominant negative caspase-8) with DNA encoding model antigens prolongs the survival of transduced DCs. More importantly, vaccinated mice exhibited significant enhancement in antigen-specific CD8+ T cell immune responses, resulting in a potent antitumor effect against antigen-expressing tumors. Among these antiapoptotic factors, BCL-xL demonstrated the greatest enhancement in antigen-specific immune responses and antitumor effects. Thus, coadministration of DNA vaccines with DNA encoding antiapoptotic proteins represents an innovative approach to enhance DNA vaccine potency.

Authors

Tae Woo Kim, Chien-Fu Hung, Morris Ling, Jeremy Juang, Liangmei He, J. Marie Hardwick, Sharad Kumar, T.-C. Wu

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Figure 1

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E7-specific CD8+ T cell immune responses and antitumor effect generated ...
E7-specific CD8+ T cell immune responses and antitumor effect generated by vaccination with E7 DNA mixed with DNA encoding antiapoptotic or proapoptotic proteins. The pcDNA3 (no insert) mixed with pSG5-BCL-xL was used as a negative control. (a) Representative figure of the flow-cytometry data. The data presented in this figure are from one representative experiment of three performed. (b) Bar graph depicting the number of antigen-specific IFN-γ–secreting CD8+ T cell precursors per 3 × 105 splenocytes (mean ± SD). (c) In vivo tumor-prevention experiment. Mice were immunized with pcDNA3-E7 mixed with pSG5 encoding BCL-xL, caspase-3, or no insert. The pcDNA3 (no insert) mixed with pSG5-BCL-xL was used as a negative control. One week after the last vaccination, mice were subcutaneously challenged with 5 × 104 TC-1 cells per mouse in the right leg. (d) In vivo Ab-depletion experiments to determine the contribution of various lymphocyte subsets on the tumor protection generated by the coadministration of pcDNA3-E7 and pSG5-BCL-xL DNA vaccine. CD4, CD8, and NK1.1 depletions were initiated 1 week before tumor challenge. (e) In vivo tumor-treatment experiment. Mice received 104 TC-1 tumor challenge and were immunized 3 days later with pcDNA3-E7 mixed with pSG5 encoding BCL-xL, caspase-3, or no insert. In vivo tumor protection, Ab depletion, and tumor-treatment experiments were performed three times. Casp, caspace.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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