Dendritic cells infected with a vaccinia virus interleukin-2 vector secrete high levels of IL-2 and can become efficient antigen presenting cells that secrete high levels of the immunostimulatory cytokine IL-12.
Dendritic cell (DC) therapies using DC presenting tumor antigen/s can induce CD8(+) CTL that mediate tumor eradication, nonetheless many patients remain unresponsive. Thus, cytokine gene vectors applied to DC may amplify these responses. Herein, we examined the responses that monocyte-derived DC (at different maturational stages) make when infected with a vaccinia virus-interleukin-2 (VV-IL-2) vector in vitro. VV-IL-2-infected DC secreted significant levels of bioactive IL-2 and maintained their antigen presentation function. However, we show that DC are exquisitely sensitive to their local antigenic microenvironment, and that responses generated by one antigen can be altered by another. VV-IL-2 infection of immature DC led to DC activation (upregulation of CD80, CD86 and class II surface molecules) when the virus was propagated through xenogeneic, but not syngeneic, mammalian cells; these DC secreted IL-10 and tumor necrosis factor-alpha (TNF-alpha), but not IL-12. In contrast, after VV-IL-2 infection (regardless of their mammalian cellular context), IFNgamma/LPS-matured DC inevitably downregulated their antigen presenting machinery. In conclusion, immunostimulatory DC can be generated by VV-IL-2, but this depends upon (i) infecting immature DC only, (ii) the mammalian cells through which the virus is prepared and (iii) individual donors; hence donors must be screened to assess their specific responses.
Mukherjee
Sutapa
S
Department of Medicine, University of Western Australia, Perth, Australia.
Upham
John W
JW
Ramshaw
Ian
I
Bundell
Christine
C
van Bruggen
Ivonne
I
Robinson
Bruce W S
BW
Nelson
Delia J
DJ
D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000951:Antigens, Neoplasm; D000954:Antigens, Surface / Q000378:metabolism; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D015536:Down-Regulation; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism*; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D009000:Monocytes; D013601:T-Lymphocytes; D014162:Transfection; D015854:Up-Regulation; D014616:Vaccinia virus / Q000235:genetics
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D007376:Interleukin-2; D018664:Interleukin-12