Activation of human dendritic cells by recombinant modified vaccinia virus Ankara vectors encoding survivin and IL-2 genes in vitro.
Modified vaccinia virus Ankara (MVA) has attracted significant attention as a safe, promising vector for immunotherapy. However, the precise effects of MVA infection on immune responses in humans remain largely unknown. We constructed recombinant MVA (rMVA) encoding both a human tumor-associated antigen (survivin) and the proinflammatory cytokine interleukin (IL)-2 and investigated their effects on human monocyte-derived dendritic cells (DCs). The results showed that infection with rMVA slightly impaired the upregulation of CD83 and reduced the production of IL-10 in DCs after lipopolysaccharide stimulation. However, rMVA-infected DCs were still able to express high levels of target genes and the costimulatory molecules CD80 and CD86 and to produce significant amounts of the proinflammatory cytokine tumor necrosis factor alpha. Moreover, rMVA-infected DCs exhibited a greater capacity than uninfected cells to stimulate T-cell proliferation and to reverse MVA-induced apoptosis in syngeneic T cells. Coculture of lymphocytes with rMVA-infected DCs significantly increased cytotoxic potential and interferon gamma production by cytotoxic T cells. These findings suggest that rMVA encoding survivin and IL-2 can effectively stimulate the activation of human DCs and overcome defects such as impairment of DC maturation and apoptosis of lymphocytes that are caused by vector alone. Thus, this study may provide a rational basis for further optimization of MVA vector.
Tao
Ran
R
State Key Laboratory of Biocontrol, Cancer Center, Sun Yat-Sen (Zhongshan) University , Guangzhou 510275, P.R. China.
Li
Lian
L
Huang
Wenlin
W
Zheng
Limin
L
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010957:Plasmids / Q000235:genetics; D000077022:Survivin; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics*
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D007376:Interleukin-2; D008869:Microtubule-Associated Proteins; D000077022:Survivin