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Journal of Virology, August 2003, p. 8272-8279, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8272-8279.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Exogenous Interleukin-12 Protects against Lethal Infection with Coxsackievirus B4

Department of Biomedical Sciences, School of Public Health, State University of New York at Albany, Albany, New York 12237,¹ Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York 12208,² Wadsworth Center, New York State Department of Health, Albany, New York 12201³

Received 28 February 2003/ Accepted 6 May 2003

Infections with the group B coxsackieviruses either can be asymptomatic or can lead to debilitating chronic diseases. To elucidate the mechanism by which these viruses cause chronic disease, we developed a mouse model of chronic pancreatitis by using a virulent variant of coxsackievirus B4, CVB4-V. Infection with CVB4-V results in an early, severe pancreatitis, which can lead to mortality or progress to chronic pancreatitis. Chronic pancreatitis, in this model, is due to immunopathological mechanisms. We investigated whether interleukin-12 (IL-12) could modulate the outcome of CVB4-V infection. Eighty-five percent of the infected mice treated with 500 ng of IL-12 survived, whereas all untreated mice succumbed. To understand the mechanism underlying the beneficial effect of IL-12, we investigated the role of gamma interferon (IFN-). Three lines of evidence suggest that the protective effect of IL-12 is due to IFN-. First, administration of IL-12 increased the production of endogenous IFN- in CVB4-V-infected mice. Both NK and NKT cells were identified as the source of IFN-. Second, IFN- knockout mice treated with IL-12 succumbed to infection with CVB4-V. Third, wild-type mice treated with IFN- survived infection with CVB4-V. Due to the antiviral effects of IFN-, we examined whether IL-12 treatment affected viral replication. Administration of IL-12 did not decrease viral replication in the pancreas, but it did prevent extensive tissue damage and the subsequent development of chronic pancreatitis. The data suggest that IL-12 treatment during CVB4-V infection is able to suppress the immunopathological mechanisms that lead to chronic disease.

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