ROLE OF TUMOR-NECROSIS-FACTOR AND GAMMA-INTERFERON IN ACQUIRED-RESISTANCE TO CRYPTOCOCCUS-NEOFORMANS IN THE CENTRAL-NERVOUS-SYSTEM OF MICE

Although naive C.B-17 and BALB/cBy mice die of meningoencephalitis wit hin 5 weeks of intravenous infection with an opportunistic strain of C ryptococcus neoformans, immunized mice express an acquired, CD4(+) T-c ell-dependent immunity and sun ive an intravenous infection. Infusion of lymphocytes from immune mice into severe combined immunodeficiency (SCID) mice renders these mice more resistant to cryptococcal brain in fection than uninfused controls. We have investigated the role of gamm a interferon (IFN-gamma) and tumor necrosis factor (TNF) in acquired r esistance to C. neoformans. Neutralization of either IFN-gamma or TNF impaired resistance of immune BALB/cBy or C.B-17 mice to cryptococci. At 10 days postinfection, there were approximately 10 times as many ye ast cells in the brains of mice treated with either anticytokine antib ody as in the brains of mice treated with control antibody. Simultaneo us neutralization of IFN-gamma and TNF further exacerbated infection. Neutralization of IFN-gamma or TNF also impaired resistance in immune lymphocyte-infused SCID mice, resulting in significantly higher yeast burdens in brains of cytokine-neutralized mice than in brains of contr ols. Concurrent neutralization of IFN-gamma and TNF rendered SCID reci pients of immune cells equivalent to uninfused SCID mice with respect both to brain yeast burdens at 10 days and to survival. Anti-TNF treat ment alone also curtailed survival. Histological examination of the br ains of cytokine-neutralized mice repealed deficiencies in ability to focus inflammatory cells at brain lesions. These data demonstrate that both IFN-gamma and TNF are important mediators of acquired resistance to cryptococcal meningoencephalitis.