DEVELOPMENT OF TH1 AND TH2 POPULATIONS AND THE NATURE OF IMMUNE-RESPONSES TO HEPATITIS-B VIRUS-DNA VACCINES CAN BE MODULATED BY CODELIVERY OF VARIOUS CYTOKINE GENES

y In this study, we provide direct evidence that the magnitude and nat ure of the immune response to a DNA vaccine can be differentially regu lated by codelivery of various mouse cytokine genes, Mice immunized wi th a hepatitis B virus (HBV) DNA vaccine and the IL-12 or IFN-gamma ge ne exhibited a significant enhancement of Th1 cells and increased prod uction of anti-HBV surface IgG2a rib, as well as a marked inhibition o f Th2 cells and decreased production of IgG1 Ab. In contrast, coinject ion of the IL-4 gene significantly enhanced the development of specifi c Th1 cells and increased production of IgG1 Ab, whereas Th1 different iation and IgG2a production were suppressed, Coinjection of the IL-2 o r the granulocyte-macrophage-CSF gene enhanced the development of Th1 cells, while the development of Th2 cells was not affected, and the pr oduction of IgG1 and IgG2a Ab were both increased, The CTL activity in duced by HBV DNA vaccination was most significantly enhanced by codeli very of the IL-12 or IFN-gamma gene, followed by the IL-2 or granulocy te-macrophage-CSF gene, whereas modeling of the IL-4 gene suppressed t he activity. When challenged with HBV surface Ag (HBsAg)-expressing sy ngeneic tumors, significant reduction of tumor growth was observed in mice that were coadministered the IL-12 gene but not the IL-4 gene, Ta ken together, these results demonstrate that application of a cytokine gene in a DNA vaccine formulation can influence the differentiation o f Th cells as well as the nature of an immune response and may thus pr ovide a strategy to improve its prophylactic and therapeutic efficacy.