ABSTRACT
A. Production and Regulation of Cytokine Elaboration It is hypothesized that the primary mechanism for the action of CD4+ T-cells in protective immunity against the endemic fungi is through the elaboration of cytokines, with IFN-'Y being the most important cytokine associated with protection. As mentioned earlier, during the discussion of the regulation of induction of Th1 mediated immunity, there is a cross-regulating cascade that leads to the high level of IFN-'Y that characterizes protective primary immunity. The emphasis on IFN-'Y has resulted from experiments in which this cytokine was used as an immunotherapeutic agent or alternatively depleted via specific antibody or by gene disruption. In our model of C. immitis infection, the role of IFN-'Y has been examined in genetically susceptible and resistant mouse strains [61]. It was initially noted that resistant mice produce IFN-'Y earlier in the course of disease and at higher levels late in disease than do genetically susceptible mice. It was further noted that disease control was significantly reduced when IFN-'Y production was abrogated in vivo by treating resistant mice with specific antibody; conversely, disease control was enhanced by immunotherapy with recombinant IFN-'Y in susceptible mice. The importance ofIFN-'Y has also been shown in models of H. capsulatum [62] and P. brasiliensis [63] infection. IL-12 was another key cytokine defined as protective for the most of the endemic fungi [64-66]. This was most elegantly defined in the H. capsulatum model in which it was shown that the primary action ofIL-12 was actually mediated through IFN-'Y production [64]. Notwithstanding the importance of IFN·'Y, tumor necrosis factor alpha (TNF-a) (67,68) and granulocyte-macrophage colony-stimulating factor (GM-CSF) [69] were other cytokines important in the expression of protection against H. capsulatum.
