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

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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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.