Interleukin-12 modulates the protective immune response in SCID mice infected with Histoplasma capsulatum

Infect Immun. 1997 Mar;65(3):936-42. doi: 10.1128/IAI.65.3.936-942.1997.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphotericin B / pharmacology
  • Animals
  • Cytokines / biosynthesis
  • Female
  • Histoplasmosis / immunology*
  • Histoplasmosis / microbiology
  • Interferon-gamma / biosynthesis
  • Interleukin-12 / pharmacology*
  • Mice
  • Mice, SCID
  • RNA, Messenger / analysis
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Cytokines
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Amphotericin B
  • Interferon-gamma