sm-8668 and Chronic-Disease

Paracoccidioidomycosis is characterized by depressed cellular but enhanced humoral immune responses, which suggests a Th2 type of response to infection. We investigated possible therapeutic roles for anti-IL-4, interferon-gamma (IFN-gamma) and/or SCH 42427 (SCH), a new triazole antifungal agent, and their effect on serum IgE levels in a murine model of chronic Paracoccidioides brasiliensis infection. BALB/c mice infected by the pulmonary route were studied with three programmes. The subacute model and one acute model experiment investigated cytokine secretion by lymph node cells (LNC), and in a second acute experiment mice were given anti-IL-4, IFN-gamma or nothing 24 h post infection, then killed at 4 weeks. In the chronic model, mice began treatment at 4 weeks post infection, receiving either SCH, IFN-gamma alone, SCH+IFN-gamma, or no treatment for 8 weeks. At 2-week intervals lung and spleen burdens of infection and serum polyclonal IgE levels were determined. In the subacute model (non-progressive infection), initially there was dual production of IL-4 and IFN-gamma by antigen-stimulated LNC. In the acute progressive infection model IL-4, but not IFN-gamma, was secreted. Anti-IL-4 treatment of the acute phase resulted in enhanced host resistance to infection, which correlated with decreased serum IgE. The chronic model, in which the in vivo efficacy of SCH against P. brasiliensis was shown, suggests possible synergy between immunomodulation and antimicrobial chemotherapy (IFN-gamma and SCH). Decreased organ burdens of infection in the chronic model after treatment with SCH, SCH plus IFN-gamma, or anti-IL-4 correlated with decreased serum IgE. These promising novel approaches to treatment of systemic fungal infections suggest a Th2 type of response to P. brasiliensis infection, which can be reversed with successful therapy.

Topics: Animals; Antibodies, Monoclonal; Antifungal Agents; Chronic Disease; Immunoglobulin E; Interferon-gamma; Interleukin-4; Mice; Mice, Inbred BALB C; Paracoccidioidomycosis; T-Lymphocytes, Helper-Inducer; Triazoles

Congenitally athymic (nu/nu) mice were inoculated sc with 10(5) conidia of Fonsecaea pedrosoi and treated orally from the 1st to the 16th week of infection with either a new triazole, SCH39304, or itraconazole at doses of 20 or 60 mg/kg/day. The volumes of the lesions were measured with calipers at 4 week intervals and compared statistically by the Wilcoxon test. At the end of the experiment, mice were killed and samples of the lesions were examined histopathologically and by electron microscopy. Treatment with itraconazole or SCH39304 significantly reduced lesion sizes as compared with controls. There were no differences between the 2 drugs at the dosages used. Histopathologically, lesions of mice treated with either drug had less inflammation with fewer fungi and more diffuse fibrosis than controls. Electron microscopy showed damage to the fungal cell walls in mice treated with itraconazole or SCH39304, characterized by gaps, fragmentation, and delamination. These studies confirm clinical observations that itraconazole is effective in chromoblastomycosis and suggest that SCH39304 should be considered for clinical evaluation.

Topics: Animals; Antifungal Agents; Chromoblastomycosis; Chronic Disease; Disease Models, Animal; Female; Itraconazole; Ketoconazole; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron; Mitosporic Fungi; Skin; Triazoles