Experimental histoplasmosis in mice treated with anti-murine interferon-gamma antibody and in interferon-gamma gene knockout mice

Histoplasma capsulatum is an important fungal pathogen in immunocompromised hosts, including AIDS patients. Experimental evidence suggests interferon- gamma (IFN) plays a role in host defense against H, capsulatum. In these st udies we sought to demonstrate the importance of IFN in innate resistance t o systemic histoplasmosis. The possible exacerbation of infection in BALB/c mice was assessed by administering 200 mu g of hamster anti-IFN antibody p rior to infection with H. capsulatum (2 X 10(6) yeasts, i,v.) and by compar ing the severity of infection between BALB/c IFN gene knockout mice (GKO) a nd congenic control animals. In two separate studies, we found that anti-IF N treatment caused a dramatic loss of resistance to lethal infection and re sulted in earlier mortality of IFN-depleted animals compared with normal Ig G or no treatment (P < 0.001). GKO mice were significantly (P < 0.001) more susceptible to lethal infection than were control animals, and histologica l studies corroborated this, These studies clearly demonstrate that IFN is a vital part of the host's innate resistance to systemic infection with H, capsulatum and provide an additional rationale for studying IFN as an immun omodulatory therapeutic for the treatment of this disease. (C) 2000 Edition s scientifiques et medicales Elsevier SAS.