IL-12 PREVENTS MORTALITY IN MICE INFECTED WITH HISTOPLASMA-CAPSULATUMTHROUGH INDUCTION OF IFN-GAMMA

Histoplasma capsulatum is a pathogenic fungus found in discrete geogra phic locations throughout the world. The fungus invades the reticuloen dothelial organs such as the spleen and liver of immunocompetent hosts where it is usually controlled. However, in individuals with immune d eficiency, histoplasmosis is a severe and potentially fatal disease. R esistance to this infection is due primarily to a cellular immune resp onse mediated by T cells and macrophages. Moreover, IFN-gamma is criti cal in activating macrophages to kill the organism. Herein we study th e regulation of cytokine induction in mice infected with H. capsulatum and the effects of IL-12 in the course of infection. Mice infected wi th H. capsulatum and treated with neutralizing Abs to IFN-gamma, TNF-a lpha, or IL-12 experienced accelerated mortality, indicating that endo genous production of these cytokines plays an important role in respon se to infection. In contrast, mice treated with IL-12 or a neutralizin g Ab to IL-4 at the initiation of infection had substantially diminish ed mortality. Moreover, mice infected and treated with IL-12 show a tw o- to threefold increase in the amount of IFN-gamma following in vitro stimulation with specific H. capsulatum Ag compared with the control infected mice. The protective effect of IL-12 could be abrogated if a neutralizing Ab to IFN-gamma was given at the same time, demonstrating that the role of IL-12 in protection was mediated by IFN-gamma. Addit ionally, infected mice treated with IL-12 had a severalfold decrease i n the colony counts of H. capsulatum in spleen cells after 5 days of i nfection as compared with control animals. Lastly, spleen cells from i nfected animals treated with IL-12 showed a striking decrease in their proliferative response to mitogen or H. capsulatum Ag. Responses coul d be restored by adding inhibitors of IFN-gamma or of nitric oxide to the in vitro cultures. The above observations suggest that IL-12 may b e useful in immunologic intervention against this opportunistic pathog en.