Chemokine Gene Adjuvants Can Modulate Immune Responses Induced by DNA Vaccines

Abstract

Nucleic acid immunization has been shown to induce both antigen-specific cellular and humoral immune responses in vivo. Moreover, immune responses induced by DNA immunization can be enhanced by the use of molecular adjuvants. For example, coadministration of costimulatory molecules (CD80 and CD86), proinflammatory cytokines (interleukin-1α [IL-1α], tumor necrosis factor-α [TNF-α, and TNF-β), Th1 cytokines (interleukin-2[IL-2], IL-12, IL-15, and IL-18), Th2 cytokines (IL-4, IL-5, and IL-10), and granulocytesmacrophage colony-stimulating factor (GM-CSF) with DNA vaccine constructs leads to modulation of the magnitude and direction (humoral or cellular) of the immune responses. To further engineer the immune response in vivo, we compared the induction and regulation of immune responses from the codelivery of chemokine (IL-8, interferon-γ-inducible protein-10 [γIP-10], macrophage inhibitory protein-1α [MIP-1α], and RANTES) genes with codelivery of cytokine genes. We found that as in cytokine gene codelivery, coimmunization with chemokine genes along with DNA immunogen constructs can modulate the direction and magnitude of induced immune responses. We observed that coimmunization with IL-8, γIP-10, and MIP-1α genes increased the antibody response. We also found that coinjection with IL-8, γIP-10, and RANTES resulted in a dramatic enhancement of T helper (Th) proliferation response. Furthermore, among all coinjection combinations, we found that RANTES coinjection caused a high level of cytotoxic lymphocyte (CTL) enhancement. This enhancement of CTL responses observed from the coinjection with RANTES was CD8⁺ T cell dependent. Together with earlier reports on the utility of coimmunizing immunologically important molecules with DNA immunogens, we demonstrate the potential of this strategy as an important tool for the development of more rationally designed vaccines.