Effects of cytokines upon the immune response of swine to Aujeszky's disease virusS. Martina, P.F. Russella, P.M. Jaquaa, S. Grimma, D. Lowerya, D. Stromb and F.A. Zuckermannc
a Pharmacia & Upjohn Animal Health, 7923-190-353, 7000 Portage Rd, Kalamazoo, MI 49001, USA
b CSIRO, Division of Animal Health, Corner Flemington Road and Park Drive, Victoria 3052, Australia
c Department of Veterinary Pathobiology, University of Illinois, Urbana, Illinois, 61802, USA
Abstract - Aujeszky's disease is caused by suid herpesvirus 1 (SHV-1) a member of the alphaherpesvirinae. This large and complex virus has been the subject of many studies designed to identify successful vaccine formulations and many varied and efficacious vaccines have been described in the literature. SHV-1 infection can manifest as a broad range of clinical signs ranging from depression to death, and in many instances both the general health and immune status of the animal upon challenge determine the outcome. Interestingly, challenge with virulent SHV-1 can have significant effects upon the growth performance of pigs, apparent as a significant reduction in the accretion of body mass or even cachexia and emaciation. The change in weight seven days after challenge ( G7) has been shown to be a quantitative indicator of the magnitude of protection induced by vaccination. Several investigators have used the G7 weight change to define a spectrum of vaccine ability to protect swine from infection. Many of the studies have detailed that modified live virus vaccines (MLV) offer the best protection, with some of the most successful ones preventing animals from showing any decrease in the rate of gain during the first seven days of infection. In contrast, many of the killed virus vaccines and sub-unit vaccines (live vectored or inactivated), while engendering a protective immune response, fail to prevent the G7 day weight loss as effectively as some MLV. This model of weight loss due to infection offers a unique model that is able to quantitatively differentiate the performance of vaccines and their delivery vehicles (live vectors, adjuvants, etc). We have recently started to use this model to investigate the role of cytokine therapy upon the types of immune response generated during vaccination. Primarily using RT-PCR strategies we have obtained cDNAs encoding the open reading frames of several porcine cytokines. Experiments using genetic immunization approaches had identified this technology as a viable delivery system for functional cDNAs. Consequently, we decided to investigate this strategy for both vaccination and co-administration of a cytokine cDNA. The model system we are using utilizes an immunization vector that expresses the envelope glycoprotein gC of SHV-1. In addition several genetic immunization vectors have been constructed to express the porcine cytokine cDNAs for IL-1b, IL-2, IL-4, IL-5, IL-6, IFN- or GM-CSF. Some of these vectors express the cytokine alone, while others express them in a fusion with a truncated version of gC. All of these construct are currently being evaluated in vaccination trials of swine, using both in vitro analysis of immune responsiveness and challenge trials to determine the effects of these cytokines upon the porcine immune system. Groups of SHV-1 free piglets were immunized with purified plasmids encoding the cDNA for gC and/or a cDNA for a porcine cytokine. The developing SHV-1 specific immune response was monitored by in vitro assays measuring humoral response (ELISA and serum neutralization assays) and cell mediated immunity (IFN- ELISPOT and lymphoproliferation assays). Four to six weeks after vaccination the animals were weighed and challenged intranasally with virulent SHV-1. Surviving animals were weighed again seven days later. All animals vaccinated with plasmids encoding the gC protein developed a specific immune response against SHV-1 as measured with the in vitro assays. The magnitude of these responses were not as great as those induced by commercial vaccines (killed or MLV) and consequently the degree of protection against G7 weight changes was not as great. Co-administration of cytokines intended to bias the immune response towards a TH-1 (increase in IFN- -secreting antigen-specific cells) or TH-2 (decrease in IFN- -secreting antigen-specific cells) did not have the expected effect. While several studies have shown that IFN- can have small enhancing effects upon the IFN- secreting antigen specific response, the inhibitory effect of IL-10 co-administration was not seen. Surprisingly, despite the inhibitory effect of porcine IL-10 on in vitro mitogen stimulated IFN- secreting cells (unpublished data), co-administration of the plasmid encoding IL-10 had enhancing effects upon the induction the IFN- secreting SHV-1 specific cell response in vivo. A precise interpretation of this effect after challenge was further complicated by the modulating effect of the cytokine plasmids alone upon the G7 weight change. These unexpected effects of cytokine co-administration are being further evaluated using both genetic immunization and recombinant SHV-1 vectors. In conclusion, the data collected to date has demonstrated that cytokines delivered with genetic immunization can have an effect upon the developing immune response, and that the characteristic TH-1 and TH-2 biases described in other species may not function similarly in swine.
Corresponding author: S. Martin Tel.: (1) 616 833 3365;
© INRA, EDP Sciences 2000