ABSTRACT
OX2 (CD200) is a broadly expressed membrane glycoprotein, shown here to be important for regulation of the macrophage lineage. In mice lacking CD200, macrophage lineage cells, including brain microglia, exhibited an activated phenotype and were more numerous. Upon facial nerve transection, damaged CD200-deficient neurons elicited an accelerated microglial response. Lack of CD200 resulted in a more rapid onset of experimental autoimmune encephalomyelitis (EAE). Outside the brain, disruption of CD200-CD200 receptor interaction precipitated susceptibility to collagen-induced arthritis (CIA) in mice normally resistant to this disease. Thus, in diverse tissues OX2 delivers an inhibitory signal for the macrophage lineage.
Subject(s)
Antigens, Surface/metabolism , Down-Regulation , Macrophages/physiology , Animals , Antigens, CD , Arthritis, Experimental/immunology , Arthritis, Experimental/pathology , Cell Lineage , Central Nervous System/immunology , Central Nervous System/pathology , Denervation , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Facial Nerve , Gene Targeting , Joints/immunology , Joints/pathology , Lymph Nodes/cytology , Macrophage Activation , Macrophages/cytology , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Microglia/physiology , Neurons/physiology , Rats , Receptors, Immunologic/metabolism , Spleen/cytologyABSTRACT
Because histoplasmosis is a life-threatening disease in AIDS and other compromised patients, we examined the efficacy of D0870 (Zeneca) in immunosuppressed mice against systemic histoplasmosis. Oral therapy with fluconazole given once daily (QD) was ineffective in prolonging survival, whereas itraconazole given once or twice daily (BID), fluconazole given BID or D0870 given QD or given every other day (QOD) were efficacious (P < 0.001). Burdens of Histoplasma capsulatum in the liver and spleen of survivors showed that D0870 given QD or QOD and itraconazole given BID caused dose-responsive reduction of infectious burden. Infection was cleared more readily from the liver than from the spleen. Overall, D0870 was > or = 20-fold more efficacious than fluconazole or itraconazole and itraconazole was > ten-fold better than fluconazole for the treatment of systemic histoplasmosis in the immunosuppressed model.
Subject(s)
Antifungal Agents/therapeutic use , Histoplasmosis/drug therapy , Immunosuppression Therapy , Triazoles/therapeutic use , Animals , Cortisone/analogs & derivatives , Cortisone/pharmacology , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Fluconazole/therapeutic use , Histoplasmosis/immunology , Immunosuppressive Agents/pharmacology , Itraconazole/therapeutic use , Mice , Mice, Inbred StrainsABSTRACT
The activity of the novel triazole SCH 51048 was tested against Coccidioides immitis. SCH 51048 inhibited C. immitis in vitro; MICs for 13 isolates ranged from < or = 0.39 to 0.78 micrograms/ml, and minimum fungicidal concentrations ranged from < or = 0.39 to 1.6 micrograms/ml. In vivo, no mice treated with SCH 51048 at 2 to 50 mg/kg of body weight or 100 mg of fluconazole or itraconazole per kg died of systemic coccidioidomycosis, whereas 60 to 100% of the control mice died. SCH 51048 given at 25 or 50 mg/kg was curative, whereas fluconazole or itraconazole given at 100 mg/kg was not curative. Pharmacokinetic studies showed peak levels in serum of > 14 micrograms/ml, with an estimated half-life of > 12 h. SCH 51048 was 5- to 50-fold or more superior to fluconazole or itraconazole.
