Effect of anti-IL-4, interferon-gamma and an antifungal triazole (SCH 42427) in paracoccidioidomycosis: correlation of IgE levels with outcome

Abstract

SUMMARYParacoccidioidomycosis 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-y) 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-y 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-y alone, SCH + IFN-y, 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-y by antigen-stimulated LNC. In the acute progressive infection model IL-4, but not IFN-y, 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-y and SCH). Decreased organ burdens of infection in the chronic model after treatment with SCH, SCH plus IFN-y, 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.

Interferon‐γ as an Antifungal

“…This was consistent with a shift from a Th1 to a Th2 response with progressive disease [68]. In our model of paracoccidioidomycosis, in the nonprogressive setting, we saw dual production of IFN-g and IL-4 by antigenstimulated lymph node cells, and, in the chronic form of the disease, administering IFN-g with antifungal therapy produced a synergistic effect [69]. We found IFN-g to be a prominent part of the local immune response in brain in experimental cryptococcosis [70].…”

Lack of Galectin-3 Drives Response to Paracoccidioides brasiliensis toward a Th2-Biased Immunity

“…These two mentioned processes resulting from IL-4 overproduction can render mice more susceptible to intracellular pathogens. Indeed, IL-4 neutralization leads to protection against several fungi [31] – [33] , including P. brasiliensis [23] , [34] , [35] . In P. brasiliensis -infected C57BL/6 mice, IL-4 neutralization leads to less severe pulmonary disease, low production of Th2 cytokines, high TNF-α and IL-12 synthesis, and low IgG1 antibodies levels [23] .…”

Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases

“…Again, optimal therapy may be achieved by combining antifungal drug therapy (e.g., fluconazole, amphotericin B, itraconazole, or ketoconazole) with cytokine therapy. Since IL-12 acts partially through stimulation of IFN-␥, IFN-␥ should also be considered in the treatment of fungal diseases (171). Given the poor prognosis of fungal (particularly Aspergillus) endocarditis, hepatosplenic candidiasis, and disseminated mycoses in general, cytokine therapy in conjunction with antifungal drug therapy should be considered in these conditions.…”

“…Bloom has advocated the use of antibodies against type 2 cytokines for certain disease states (e.g., leishmaniasis) in which CMI is impaired (31). Anti-IL-4 may play a role in treating fungal (171) and parasitic infections and other conditions associated with increased IgE levels. Conversely, antibody against IL-12 or therapy with IL-4 itself (306) may be of value in some autoimmune conditions, such as MS, by decreasing the ratio of type 1 to type 2 cytokines (208).…”