Interleukin-12 regulation of host defenses against Coccidioides immitis.
We have previously reported on the alternate regulation of gamma interferon (IFN-gamma) and interleukin-4 (IL-4) in inbred mouse strains which differ in their susceptibility to Coccidioides immitis. The genetically resistant DBA/2 mice manifest a predominant T-helper 1 (Th1) response, with early production of IFN-gamma, whereas susceptible BALB/c mice show an early production of the Th2 cytokine IL-4. Since IL-12 is one cytokine that can act early during host defenses to promote the differentiation of cytokine production towards IFN-gamma and thus may promote expression of a protective immune response, we investigated the role of IL-12 in resistance to C. immitis. Administration of recombinant IL-12 to the susceptible mouse strain before and after systemic (intraperitoneal) challenge with C. immitis significantly ameliorated the course of the disease, as measured by a reduction in the fungal load in the lungs, liver, and spleen. Analysis of the cytokine mRNA in lungs from infected BALB/c mice revealed that the protective effect of recombinant IL-12 was accompanied by a shift from a Th2 to a Th1 response. The importance of IL-12 in resistance to this fungus was further established by showing that neutralization of endogenous IL-12 in the resistant DBA/2 mouse strain led to a significant increase in the fungal burden in pulmonary and extrapulmonary tissues. These results establish that IL-12 plays a pivotal role in the host defense against systemic challenge with C. immitis.
Magee
D M
DM
Department of Clinical Investigation, Texas Center for Infectious Diseases, San Antonio 78223, USA. mmagee@tcid.tdh.state.tx.us
Cox
R A
RA
D000818:Animals; D003045:Coccidioides / Q000276:immunology*; D003047:Coccidioidomycosis / Q000276:immunology* / Q000628:therapy; D005260:Female; D007167:Immunotherapy; D018664:Interleukin-12 / Q000502:physiology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D011994:Recombinant Proteins; D018664:Interleukin-12