Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins.
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.
Kim
Tae Woo
TW
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Hung
Chien-Fu
CF
Ling
Morris
M
Juang
Jeremy
J
He
Liangmei
L
Hardwick
J Marie
JM
Kumar
Sharad
S
Wu
T-C
TC
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D017209:Apoptosis; D019470:Biolistics; D039521:CD11c Antigen / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D053148:Caspase 3; D020169:Caspases / Q000235:genetics; D004247:DNA / Q000008:administration & dosage*; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D051907:Lysosomal Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*; D051020:bcl-X Protein
D015703:Antigens, CD; C494812:Bcl2l1 protein, mouse; D039521:CD11c Antigen; D051907:Lysosomal Membrane Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019444:Vaccines, DNA; D051020:bcl-X Protein; C059731:oncogene protein E7, Human papillomavirus type 16; D004247:DNA; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases