title: Interleukin-12 modulates the protective immune response in SCID mice infected with Histoplasma capsulatum.
abstract: Infection with Histoplasma capsulatum results in a subclinical infection in immunocompetent hosts due to an effective cellular immune response. By contrast, immunodeficient individuals can have a severe disseminated and potentially fatal disease. In a previous study, it was demonstrated that normal mice infected intravenously with H. capsulatum and treated with interleukin-12 (IL-12) at the time of infection were protected from a fatal outcome. In this study, we examined the immunomodulatory effects of IL-12 on disseminated histoplasmosis in immunodeficient SCID mice. SCID mice infected with H. capsulatum and treated with IL-12 showed an increase in survival and a reduction in the colony counts of H. capsulatum in internal organs at 14 days after infection. The protective effect of IL-12 was abrogated if animals were also treated 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 amphotericin B (AmB) treatment, there was a significant increase in survival compared with either modality alone. Moreover, combined treatment resulted 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 days postinfection. This study demonstrates that IL-12 modulates the protective immune response to histoplasmosis in SCID mice and also suggests that IL-12 in combination with AmB may be useful as a treatment for H. capsulatum in immunodeficient hosts.
authors.affiliation: Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: P
authors.initials: P
authors.lastname: Zhou
authors.forename: M C
authors.initials: MC
authors.lastname: Sieve
authors.forename: R P
authors.initials: RP
authors.lastname: Tewari
authors.forename: R A
authors.initials: RA
authors.lastname: Seder
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006660:Histoplasmosis / Q000276:immunology* / Q000382:microbiology; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D000666:Amphotericin B; D007371:Interferon-gamma