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The Role of Recombinant Murine IL-12 and IFN- in the Pathogenesis of a Murine Systemic Candida albicans Infection

Department of Preclinical Research and Development, Genetics Institute, Inc., Andover, MA 01810

Studies on murine candidiasis suggest that resistance to disease is linked to a Th1 response and production of IFN-, while failure to elicit protection is associated with a Th2 response and production of IL-4 and IL-10. Experimental infection of C57BL/6 mice, IL-12 treatment of these mice, or both infection and IL-12 treatment resulted in a characteristic Th1 cytokine mRNA profile as measured by quantitative competitive PCR. Specifically, little or no IL-4 transcripts were detected, while IFN- message was elevated, particularly with IL-12 treatment. Despite its role in driving increased IFN- expression and production, IL-12 treatment, paradoxically, promoted disease progression in our model. Therefore, we examined the effect of IFN- neutralization on IL-12-induced susceptibility to infection. None of the systemically infected mice receiving IL-12 alone survived, while IL-12- and anti-IFN--treated mice had a 70% survival rate, similar to that after infection alone. These results suggested that IFN- induced by IL-12 treatment contributed to lethality. However, in separate studies, IFN- knockout mice were more susceptible to infection than their wild-type counterparts, suggesting that IFN- is required for resistance. Nonetheless, infected IFN- knockout mice treated with recombinant murine IL-12 exhibited enhanced resistance, suggesting that the toxicities observed with IL-12 are directly attributable to IFN- and that an optimal immune response to Candida infections necessitates a finely tuned balance of IFN- production. Thus, we propose that although IFN- can drive resistance, the overproduction of IFN- during candidiasis, mediated by IL-12 administration, leads to enhanced susceptibility.

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