CYTOKINE MESSENGER-RNA IN THE CENTRAL-NERVOUS-SYSTEM OF SCID MICE INFECTED WITH TOXOPLASMA-GONDII - IMPORTANCE OF T-CELL-INDEPENDENT REGULATION OF RESISTANCE TO TOXOPLASMA-GONDII

Levels of cytokine mRNA were studied in the central nervous system (CN S) of SCID mice infected with Toxoplasma gondii. This infection led to 100% mortality by day 23 postinfection. Inflammation was observed in the lungs on day 7 and in the heart, liver, and kidneys on days 14 and 18 of infection. In the CNS, necrotic, acellular lesions that contain ed numerous parasites, accompanied by a localized astrocyte activation , were evident on day 14. Polymerase chain reaction-assisted amplifica tion of RNA revealed that, although transcripts for interleukin-1alpha (IL-1alpha) and IL-1beta were present in the brains of uninfected mic e, increased levels of these transcripts were detected on day 7 of inf ection. Transcripts for macrophage inflammatory protein 1 and transfor ming growth factor beta were also detected in brains of infected mice at this time point. On days 14 and 18, levels of these transcripts had increased and transcripts for IL-6, IL-10, gamma interferon (IFN-gamm a), tumor necrosis factor alpha (TNF-alpha), and granulocyte-macrophag e colony-stimulating factor (GM-CSF) were also detected. Transcripts f or IL-2 or IL-4 were not detected at any of the time points. Detection of locally produced cytokine transcripts may reflect involvement of t he cytokines in the immunopathogenesis of this infection or involvemen t in mediating antitoxoplasma activity. To assess the possible role of endogenous IFN-gamma, TNF-alpha, IL-10, IL-6, and GM-CSF, cytokine-ne utralizing monoclonal antibodies were administered to infected SCID mi ce. Neutralization of IFN-gamma or TNF-alpha led to earlier mortality than that in controls. In contrast, treatment with antibody to IL-10 a nd IL-6 increased survival time. Treatment with anti-GM-CSF did not al ter the time to death. These results indicate that TNF-alpha and IFN-g amma are both involved in T-cell-independent mechanisms of resistance to T. gondii in SCID mice and that IL-10 and IL-6 may downregulate the immune response to this pathogen.