Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins

J Clin Invest. 2003 Jul;112(1):109-17. doi: 10.1172/JCI17293.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Apoptosis*
  • Biolistics
  • CD11c Antigen / analysis
  • CD8-Positive T-Lymphocytes / immunology
  • Caspase 3
  • Caspases / genetics
  • DNA / administration & dosage*
  • Dendritic Cells / physiology
  • Female
  • Lysosome-Associated Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Oncogene Proteins, Viral / immunology
  • Papillomavirus E7 Proteins
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Vaccination
  • Vaccines, DNA / immunology*
  • bcl-X Protein

Substances

  • Antigens, CD
  • Bcl2l1 protein, mouse
  • CD11c Antigen
  • Lysosome-Associated Membrane Glycoproteins
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Vaccines, DNA
  • bcl-X Protein
  • oncogene protein E7, Human papillomavirus type 16
  • DNA
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases