THE ROLE OF RECOMBINANT MURINE IL-12 AND IFN-GAMMA IN THE PATHOGENESIS OF A MURINE SYSTEMIC CANDIDA-ALBICANS INFECTION

Studies on murine candidiasis suggest that resistance to disease is li nked to a Th1 response and production of IFN-gamma, while failure to e licit protection is associated with a Th2 response and production of I L-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 ch aracteristic Th1 cytokine mRNA profile as measured by quantitative com petitive PCR. Specifically, little or no IL-4 transcripts were detecte d, while IFN-gamma message was elevated, particularly with IL-12 treat ment. Despite its role in driving increased IFN-gamma expression and p roduction, IL-12 treatment, paradoxically, promoted disease progressio n in our model. Therefore, we examined the effect of IFN-gamma neutral ization on IL-12-induced susceptibility to infection. None of the syst emically infected mice receiving IL-12 alone survived, while IL-12- an d anti-IFN-gamma-treated mice had a 70% survival rate, similar to that after infection alone. These results suggested that IFN-gamma induced by IL-12 treatment contributed to lethality. However, in separate stu dies, IFN-gamma knockout mice were more susceptible to infection than their wild-type counterparts, suggesting that IFN-gamma is required fo r resistance. Nonetheless, infected IFN-gamma knockout mice treated wi th recombinant murine IL-12 exhibited enhanced resistance, suggesting that the toxicities observed with IL-12 are directly attributable to I FN-gamma and that an optimal immune response to Candida infections nec essitates a finely tuned balance of IFN-gamma production. Thus, we pro pose that although IFN-gamma can drive resistance, the overproduction of IFN-gamma during candidiasis, mediated by IL-12 administration, lea ds to enhanced susceptibility.