Roles of gamma interferon and interleukin-4 in genetically determined resistance to Coccidioides immitis

The profiles of gamma interferon (IFN-gamma) and interleukin-4 (IL-4) production were evaluated during the course of coccidioidomycosis in two inbred mouse strains which differ in their susceptibility to Coccidioides immitis. Cytokine responses, measured at the molecular and protein levels, showed increased levels of IFN-gamma in lung extracts from mice of the resistant DBA/2 strain after a pulmonary challenge, whereas the susceptible BALB/c strain manifested a predominant IL-4 response. The importance of these cytokines in host defense against C. immitis was established by treating the mice with recombinant cytokines or neutralizing anticytokine monoclonal antibodies. Treatment of the susceptible BALB/c mice with recombinant murine IFN-gamma significantly protected mice against systemic challenge, and in the reciprocal experiment, the administration of an anti-IFN-gamma monoclonal antibody to the resistant DBA/2 mice significantly decreased their capacity to control disease. Although the treatment of DBA/2 mice with recombinant IL-4 did not alter the disease, neutralization of endogenous IL-4 in infected BALB/c mice by administration of a neutralizing anti-IL-4 antibody led to a significant reduction in the fungal load in their tissues. These results, taken together, establish that IFN-gamma plays a pivotal role in resistance to C. immitis, whereas IL-4 down-regulates protective immunity against C. immitis.