IL-4, IgE, and interferon-gamma production in pulmonary blastomycosis: comparison in mice untreated, immunized, or treated with an antifungal (SCH 39304)

Abstract

The purpose of this study was to determine if there is a correlation between production of certain lymphokines in progressive blastomycosis in untreated mice, resistance to infection in immunized mice, and cure in antifungal triazole (SCH 39304)-treated mice. Infection was measured by colony-forming units of Blastomyces dermatitidis in lungs. Serum level of IgE was used as a marker for in vivo IL-4 activity. Serum IgE levels rose in untreated mice from 6 micrograms/ml at 3 weeks to 24 micrograms/ml by the fourth week as their infection progressed. This corresponded to a peak in vitro production of IL-4 (147 pg/ml) by antigen-stimulated spleen cells at Week 4. By contrast, there was an inverse relationship between serum IgE- and antigen-stimulated production of IFN-gamma in vitro, e.g., 80 U/ml at the third week and 4 U/ml at Week 4. In mice undergoing cure with SCH 39304, serum IgE decreased from 12 micrograms/ml at the third week to 2 micrograms/ml at Week 4. This correlated with a drop in IL-4 and an increase in IFN-gamma production in in vitro assays. As cure proceeded over the next 4 weeks, IgE and IFN-gamma measurements were near background levels. In immunized mice a low-grade chronic blastomycosis emerged after 3 weeks of infection. Chronic infection was associated with inverse cycles of elevated IgE in serum and IFN-gamma production as assayed in vitro. IL-4 production cycled directly with increased IgE levels in serum. Although spleen cells from untreated mice produced IFN-gamma and IL-4 when stimulated with antigen, they did not mount significant proliferative responses. By contrast, spleen cells and lymph node cells from immunized and SCH 39304-treated mice made good proliferative responses to antigen and this correlated with resistance and clearing of the infection, respectively. These data indicate that in pulmonary blastomycosis, serum IgE levels correlate directly with IL-4 and inversely with IFN-gamma production. Clearing of the infection by the antifungal agent SCH 39304 reduces lymphokine production to background levels but sensitizes lymphocytes for proliferative responses to antigen.