ABSTRACT
Perhaps the most crucial cytokine necessary for survival of mice from rechallenge is TNF-a. In both the systemic and the pulmonary model, neutralization of TNF-a leads to fatal histoplasmosis [30,31]. In the systemic model, the influence ofTNF-a is not observed in immunocompetent mice, but only if this cytokine is neutralized in IFN-'Y knockout mice [31]. The effect of mAb to TNF-a in pulmonary histoplasmosis is manifest in otherwise immunocompetent mice. Unlike primary infection, neutralization of TNF-a does not alter nitric oxide levels [30], thus supporting previous evidence that nitric oxide is not involved in secondary infection [26]. In the pulmonary model, neutralization of TNF-a is associated with increases in the levels of IL-4 and IL-IO in lungs of mice. The bioactivity of these two cytokines contributes to the
downregulation of immunity. Administration of the combination of anti-IL-4 plus anti-IL-W mAb, but not either alone, restores the protective immune response [30]. The mechanism by which the elevated levels of IL-4 and IL-IO promote exacerbation is not known.
