INTERLEUKIN-12 MODULATES THE PROTECTIVE IMMUNE-RESPONSE IN SCID MICE INFECTED WITH HISTOPLASMA-CAPSULATUM

Infection with Histoplasma capsulatum results in a subclinical infecti on in immunocompetent hosts due to an effective cellular immune respon se, By contrast, immunodeficient individuals can have a severe dissemi nated and potentially fatal disease, In a previous study, it was demon strated that normal mice infected intravenously with H. capsalatum and treated with interleukin-12 (IL-12) at the time of infection were pro tected from a fatal outcome, In this study, we examined the immunomodu latory effects of IL-12 on disseminated histoplasmosis in immunodefici ent SCID mice. SCID mice infected with H. capsulatum and treated,vith IL-12 showed an increase in survival and a reduction in the colony cou nts of H. capsulatum in internal organs at 14 days after infection, Th e protective effect of IL-12 was abrogated if animals were also treate d with a neutralizing antibody to gamma interferon (IFN-gamma). IL-12 treatment also resulted in an increase in mRNA expression and protein production for IFN-gamma, tumor necrosis factor alpha (TNF-alpha), and nitric oxide from spleen cells, When IL-12 was combined with amphoter icin B (AmB) treatment, there was a significant increase in survival c ompared with either modality alone, Moreover, combined treatment resul ted in an increase in both IFN-gamma and TNF-alpha production, as well as in a substantial reduction in H, capsulatum burden at 35 and 90 da ys postinfection. This study demonstrates that IL-12 modulates the pro tective immune response to histoplasmosis in SCID mice and also sugges ts that IL-12 in combination with AmB may be useful as a treatment for H. capsulatum in immunodeficient hosts.