Enhancement of DNA vaccine potency against herpes simplex virus 1 by co-administration of an interleukin-18 expression plasmid as a genetic adjuvant

Abstract

In this study, the immune-modulatory and vaccine effects of using an interleukin (IL)-18 expression plasmid as a genetic adjuvant to enhance DNA vaccine-induced immune responses were investigated in a mouse herpes simplex virus 1 (HSV-1) challenge model. BALB/c mice were immunized by three intramuscular inoculations of HSV-1 glycoprotein D (gD) DNA vaccine alone or in combination with a plasmid expressing mature IL-18 peptide. Both the serum IgG2a/IgG1 ratio and T helper 1-type (Th1) cytokines [IL-2 and interferon (IFN)-ª] were increased significantly by the co-injection of the IL-18 plasmid compared with the injection of gD DNA alone. However, the production of IL-10 was inhibited by IL-18 plasmid co-injection. Furthermore, IL-18 plasmid coinjection efficiently enhanced antigen-specific lymphocyte proliferation and the delayed-type hypersensitivity response. When mice were challenged with HSV-1 at the cornea, co-injection of IL-18 plasmid with gD DNA vaccine showed significantly better protection, manifested as lower corneal lesion scores and faster recovery. These experiments indicate that co-injection of an IL-18 plasmid with gD DNA vaccine efficiently induces Th1-dominant immune responses and improves the protective effect against HSV-1 infection. INTRODUCTIONNucleic acid immunization is an important vaccination strategy that has many characters desirable for an ideal vaccine, including induction of broad immune responses (humoral and cellular), long-lasting immunity and simple and cheap production. This technique is being explored as a vaccination strategy against a variety of infectious diseases, autoimmune diseases and cancers. The first generation of DNA-immunization experiments have shown that delivery of DNA constructs encoding a specific immunogen into the host could elicit effective immune responses in vivo in a safe and well-tolerated manner in various model systems. However, more efficacious and specific immune responses against the target pathogen are required in order to enhance its clinical utility. One strategy is the use of molecular adjuvants. Molecular or genetic adjuvants are different from the traditional adjuvants in that they consist of gene-expression constructs encoding immunologically important molecules, such as cytokines, chemokines and co-stimulatory molecules (Iwasaki et al., 1997;Kim et al., 1997Kim et al., , 2000Sin et al., 1999). Previous reports have shown that co-administration of genetic adjuvant constructs with immunogen constructs can modulate antigen-specific immune responses (Kim et al., , 1999a.Interleukin (IL)-18, first designed as an interferon (IFN)-ª-inducing factor, is a recently identified cytokine of the T helper 1 (Th1) type. It has been known to induce IFN-ª production by both CD4 þ T cells and natural killer (NK) cells (Okamura et al., 1995;Ushio et al., 1996) and to stimulate naive T cells to promote the development of Th1 cells (Kohno et al., 1997). Since IFN-ª is one of the most important cytokines that contributes to host defence, a cytokine capable of up-...

IL-18 Bridges Innate and Adaptive Immunity through IFN-γ and the CD134 Pathway

“…As an adjuvant, IL-18 has been incorporated into DNA vaccines to improve antitumor and antiviral responses (35,39,54,55). DCs and fibroblasts transfected with IL-18 become effective tumor vaccines (36,38).…”

“…Likewise, studies demonstrate enhanced memory T cell responses after signaling through the IL-18R (30). Ultimately, IL-18 mediates protection against Salmonella and Shigella (31,32), viral infections such as HIV and HSV (33)(34)(35), and in various tumor models (36 -39). These responses are largely T cell dependent, but a unifying mechanism linking IL-18, the innate, and adaptive immune systems is undefined.…”

Suppressive Effects of Chronic Stress on Influenza Virus Protection after Vaccination with Plasmid DNA-Encoded Nucleoprotein

“…These vaccines do not have the disadvantages of killed and inactivated vaccines [27], and due to their ability to induce both humoral and cellular immunity [28] have been investigated for many different diseases, such as HIV, HSV-1, hepatitis B or rabies [29,30,31,32,33]. Due to antigenic changes in the influenza virus, a DNA vaccine containing a conserved viral gene might induce active responses against a broad range of influenza viruses.…”

Human Dendritic Cells Engineered to Secrete Interleukin-18 Activate MAGE-A3-Specific Cytotoxic T Lymphocytesin vitro

“…In 1995 IL-18 was identified as a potent IFNγ-inducing factor (IGIF), IFN-γ being required for CTL activation, and was more recently termed interleukin-18 or interleukin-1 family 4 (Sims et al, 2001;Yu et al, 2008;Zhu et al, 2003). Like IL-1 and IFN-α, IL-18 is a proinflammatory cytokine which plays an important role in immune and inflammatory reactions.…”