Modulation of immune responses to DNA vaccines by codelivery of cytokine genes

DNA vaccines containing genes for antigenic portions of viruses have recently been developed as a novel vaccination technology. Direct injection of plasmid DNA in vivo results in prolonged expression of viral proteins and may, thus, mimic the action of attenuated vaccines. An important advantage of this vaccination method is that in vivo-synthesized viral proteins can enter both major histocompatibility complex (MHC) class I and class II antigen-processing pathways to activate specific immunization. In many animal models for infectious diseases, DNA vaccines induced a broad range of immune responses, including antibody, CD8+ cytotoxic T lymphocytes (CTL) and CD4+ helper T (Th) lymphocyte responses, and protective immunity against challenge with the pathogen. The magnitude and nature of these immune responses to DNA vaccines can be further manipulated by codelivery of cytokine genes. Summarizing the many studies reported to date, we can draw conclusions regarding the adjuvant effects of these cytokine genes on DNA vaccines. Coadministration of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-2 genes induces higher antibody titers and T-cell proliferation responses than other cytokine genes tested to date. In contrast, the CTL activity is only modestly increased by the GM-CSF and IL-2 genes. The IL-12 gene polarizes the immune responses to DNA vaccines toward Th1 cell development and stimulates the strongest CTL activity. In contrast, co-injection of the IL-4 gene promotes the development of Th2 cells and increases production of antibodies, but suppresses CTL activity. Thus, the immune responses to DNA vaccines can be engineered by co-injection of an appropriate cytokine gene to favor the formation of either CTL or neutralization antibodies and, therefore, provide the best protection against a particular pathogen.