IL-12 prevents mortality in mice infected with Histoplasma capsulatum through induction of IFN-γ

P. Zhou, M. C. Sieve, J. Bennett, K. J. Kwon-Chung, R. P. Tewari, R. T. Gazzinelli, A. Sher, R. A. Seder

Research output: Contribution to journalArticle

Abstract

Histoplasma capsulatum is a pathogenic fungus found in discrete geographic locations throughout the world. The fungus invades the reticuloendothelial organs such as the spleen and liver of immunocompetent hosts where it is usually controlled. However, in individuals with immune deficiency, histoplasmosis is a severe and potentially fatal disease. Resistance to this infection is due primarily to a cellular immune response mediated by T cells and macrophages. Moreover, IFN-γ is critical in activating macrophages to kill the organism. Herein we study the regulation of cytokine induction in mice infected with H. capsulatum and the effects of IL-12 in the course of infection. Mice infected with H. capsulatum and treated with neutralizing Abs to IFN-γ, TNF-α, or IL-12 experienced accelerated mortality, indicating that endogenous production of these cytokines plays an important role in response to infection. In contrast, mice treated with IL-12 or a neutralizing Ab to IL-4 at the initiation of infection had substantially diminished mortality. Moreover, mice infected and treated with IL-12 show a two- to threefold increase in the amount of IFN-γ 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-γ was given at the same time, demonstrating that the role of IL-12 in protection was mediated by IFN-γ. Additionally, infected mice treated with IL-12 had a severalfold decrease in the colony counts of H. capsulatum in spleen cells after 5 days of infection as compared with control animals. Lastly, spleen cells from infected animals treated with IL-12 showed a striking decrease in their proliferative response to mitogen or H. capsulatum Ag. Responses could be restored by adding inhibitors of IFN-γ or of nitric oxide to the in vitro cultures. The above observations suggest that IL-12 may be useful in immunologic intervention against this opportunistic pathogen.

Original languageEnglish (US)
Pages (from-to)785-795
Number of pages11
JournalJournal of Immunology
Volume155
Issue number2
StatePublished - Jan 1 1995

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'IL-12 prevents mortality in mice infected with Histoplasma capsulatum through induction of IFN-γ'. Together they form a unique fingerprint.

  • Cite this

    Zhou, P., Sieve, M. C., Bennett, J., Kwon-Chung, K. J., Tewari, R. P., Gazzinelli, R. T., Sher, A., & Seder, R. A. (1995). IL-12 prevents mortality in mice infected with Histoplasma capsulatum through induction of IFN-γ. Journal of Immunology, 155(2), 785-795.