101. Role of IFN-gamma in regulating T2 immunity and the development of alternatively activated macrophages during allergic bronchopulmonary mycosis.
- Author
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Arora S, Hernandez Y, Erb-Downward JR, McDonald RA, Toews GB, and Huffnagle GB
- Subjects
- Animals, Arginase biosynthesis, Cryptococcosis genetics, Cryptococcosis microbiology, Cryptococcosis pathology, Cryptococcus neoformans growth & development, Cryptococcus neoformans immunology, Female, Immunoglobulin E biosynthesis, Immunoglobulin E blood, Inflammation Mediators metabolism, Interferon-gamma deficiency, Interferon-gamma genetics, Interferon-gamma physiology, Lectins biosynthesis, Lung enzymology, Lung immunology, Lung pathology, Lung Diseases, Parasitic genetics, Lung Diseases, Parasitic microbiology, Lung Diseases, Parasitic pathology, Lymph Nodes immunology, Lymph Nodes metabolism, Lymph Nodes microbiology, Macrophage Activation genetics, Macrophages metabolism, Macrophages microbiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Nitric Oxide Synthase biosynthesis, Nitric Oxide Synthase Type II, Th2 Cells metabolism, beta-N-Acetylhexosaminidases biosynthesis, Cryptococcosis immunology, Lung Diseases, Parasitic immunology, Macrophage Activation immunology, Macrophages immunology, Th2 Cells immunology
- Abstract
Pulmonary Cryptococcus neoformans infection of C57BL/6 mice is an established model of a chronic pulmonary fungal infection accompanied by an "allergic" response (T2) to the infection, i.e., a model of an allergic bronchopulmonary mycosis. Our objective was to determine whether IFN-gamma plays a role in regulating the pulmonary T2 immune response in C. neoformans-infected C57BL/6 mice. Long-term pulmonary fungistasis was lost in IFN-gamma knockout (KO) mice, resulting in an increased pulmonary burden of fungi at wk 3. IFN-gamma was required for the early influx of leukocytes into the lungs but was not required later in the infection. By wk 3, eosinophil and macrophage numbers were elevated in the absence of IFN-gamma. The inducible NO synthase to arginase ratio was lower in the lungs of IFN-gamma KO mice and the macrophages had increased numbers of intracellular cryptococci and YM1 crystals, indicative of alternatively activated macrophages in these mice. There was evidence of pulmonary fibrosis in both wild-type and IFN-gamma KO mice by 5 wk postinfection. IFN-gamma production was not required for the development of T2 cytokine (IL-4, IL-5, IL-13) producing cells in the lungs and lung-associated lymph nodes or induction of an IgE response. At a number of time points, T2 cytokine production was enhanced in IFN-gamma KO mice. Thus, in the absence of IFN-gamma, C57BL/6 mice develop an augmented allergic response to C. neoformans, including enhanced generation of alternatively activated macrophages, which is accompanied by a switch from a chronic to a progressive pulmonary cryptococcal infection.
- Published
- 2005
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