Protection from direct cerebral cryptococcus infection by interferon-gamma-dependent activation of microglial cells.
The brain represents a significant barrier for protective immune responses in both infectious disease and cancer. We have recently demonstrated that immunotherapy with anti-CD40 and IL-2 can protect mice against disseminated Cryptococcus infection. We now applied this immunotherapy using a direct cerebral cryptococcosis model to study direct effects in the brain. Administration of anti-CD40 and IL-2 significantly prolonged the survival time of mice infected intracerebrally with Cryptococcus neoformans. The protection was correlated with activation of microglial cells indicated by the up-regulation of MHC II expression on brain CD45(low)CD11b(+) cells. CD4(+) T cells were not required for either the microglial cell activation or anticryptococcal efficacy induced by this immunotherapy. Experiments with IFN-gamma knockout mice and IFN-gammaR knockout mice demonstrated that IFN-gamma was critical for both microglial cell activation and the anticryptococcal efficacy induced by anti-CD40/IL-2. Interestingly, while peripheral IFN-gamma production and microglial cell activation were observed early after treatment, negligible IFN-gamma was detected locally in the brain. These studies indicate that immunotherapy using anti-CD40 and IL-2 can augment host immunity directly in the brain against C. neoformans infection and that IFN-gamma is essential for this effect.
Zhou
Qing
Q
Division of Blood and Marrow Transplantation, Cancer Center and Department of Pediatrics, MMC 109, University of Minnesota, Minneapolis, MN 55455, USA.
Gault
Ruth A
RA
Kozel
Thomas R
TR
Murphy
William J
WJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001921:Brain / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000276:immunology; D007167:Immunotherapy; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D007376:Interleukin-2 / Q000627:therapeutic use*; D016919:Meningitis, Cryptococcal / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D000096743:Interferon gamma Receptor
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007371:Interferon-gamma; D007376:Interleukin-2; D012333:RNA, Messenger; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor