EFFECT OF ANTI-IL-4, INTERFERON-GAMMA AND AN ANTIFUNGAL TRIAZOLE (SCH-42427) IN PARACOCCIDIOIDOMYCOSIS - CORRELATION OF IGE LEVELS WITH OUTCOME

Paracoccidioidomycosis is characterized by depressed cellular but enha nced humoral immune responses, which suggests a Th2 type of response t o infection. We investigated possible therapeutic roles for anti-IL-4, interferon-gamma (IFN-gamma) and/or SCH 42427 (SCH), a new triazole a ntifungal agent, and their effect on serum IgE levels in a murine mode l of chronic Paracoccidioides brasiliensis infection. BALB/c mice infe cted by the pulmonary route were studied with three programmes. The su bacute model and one acute model experiment investigated cytokine secr etion 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 wee ks post infection, receiving either SCH, IFN-gamma alone, SCH + IFN-ga mma, 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 t he acute progressive infection model IL-4, but not IFN-gamma, was secr eted. Anti-IL-4 treatment of the acute phase resulted in enhanced host resistance to infection, which correlated with decreased serum IgE. T he chronic model, in which the in vivo efficacy of SCH against P. bras iliensis was shown, suggests possible synergy between immunomodulation and antimicrobial chemotherapy (IFN-gamma and SCH). Decreased organ b urdens of infection in the chronic model after treatment with SCH, SCH plus IFN-gamma, or anti-IL-4 correlated with decreased serum IgE. The se promising novel approaches to treatment of systemic fungal infectio ns suggest a Th2 type of response to P. brasiliensis infection, which can be reversed with successful therapy.