Suppression of Immune Response and Protective Immunity to a Japanese Encephalitis Virus DNA Vaccine by Coadministration of an IL-12-Expressing Plasmid

Abstract

IL-12 plays a central role in both innate and acquired immunity and has been demonstrated to potentiate the protective immunity in several experimental vaccines. However, in this study, we show that IL-12 can be detrimental to the immune responses elicited by a plasmid DNA vaccine. Coadministration of the IL-12-expressing plasmid (pIL-12) significantly suppressed the protective immunity elicited by a plasmid DNA vaccine (pE) encoding the envelope protein of Japanese encephalitis virus. This suppressive effect was associated with marked reduction of specific T cell proliferation and Ab responses. A single dose of pIL-12 treatment with plasmid pE in initial priming resulted in significant immune suppression to subsequent pE booster immunization. The pIL-12-mediated immune suppression was dose dependent and evident only when the IL-12 gene was injected either before or coincident with the pE DNA vaccine. Finally, using IFN-γ gene-disrupted mice, we showed that the suppressive activity of the IL-12 plasmid was dependent upon endogenous production of IFN-γ. These results demonstrate that coexpression of the IL-12 gene can sometimes produce untoward effects to immune responses, and thus its application as a vaccine adjuvant should be carefully evaluated.

Subsets of Memory Cytotoxic T Lymphocytes Elicited by Vaccination Influence the Efficiency of Secondary Expansion In Vivo

“…The p18-specific CD8 ϩ response in mice receiving plasmid IL-12 on day 0 was diminished compared to that of mice receiving the gp120 DNA alone. These data are consistent with reports demonstrating the suppressive nature of plasmid IL-12 when given at high concentrations concurrently with antigen (5,8,15). While further dose titration studies demonstrated that 20 g of PMV-IL-12 administered concurrently with gp120 DNA could increase the early expansion phase of the p18-specific CTL response, this augmentation was transient, with CTL declining to levels comparable to those observed in mice immunized with gp120 alone as the response reached its plateau phase (data not shown).…”

Co-expression of Japanese encephalitis virus prM–E–NS1 antigen with granulocyte-macrophage colony-stimulating factor enhances humoral and anti-virus immunity after DNA vaccination

“…L929 cells, infected with JEV 16-18 h before the assay, were used as target cells, as described previously [27]. Then, the target cells were distributed into wells of a U-bottom 96-well plate (5 × 10 3 cells/well) in triplicate, followed by addition of the effector cells at various effector: target (E:T) ratios (50:1, 100:1 and 200:1).…”

Immune response to vaccines based upon the VapA protein of the horse pathogen, Rhodococcus equi, in a murine model

“…This decrease in the Th1 bias may also be due to Th1 immunosuppressive effects produced by IL-12. This phenomenon has been described by Chen and co-workers who demonstrated that the administration of an IL-12 expression plasmid as an adjuvant adversely affected T-cell responses to the vaccine under certain conditions (Chen et al, 2001). More recently, studies have shown that IL-12 is required for the expansion of Th1 cells rather than for the initiation of a Th1-type immune response (Trinchieri et al, 2003).…”