Immunity to Schistosoma mansoni in mice vaccinated with irradiated cercariae: cytokine interactions in the pulmonary protective response.

In C57BL/6 strain mice vaccinated with attenuated cercariae of Schistosoma mansoni, the major site of immune elimination of challenge parasites is the lungs. We have monitored pulmonary events after both vaccination and challenge by bronchoalveolar lavage, and examined the profile of cytokines released by recovered cells upon stimulation with larval antigens in vitro. From 14 days post-vaccination, lavage samples contain infiltrating lymphocytes which produce abundant interferon-gamma (IFN-gamma) and interleukin-3 (IL-3). We suggest that the lymphocytes recruited to the lungs are effector/memory cells of the Th1 subset. Challenge of vaccinated mice results in a second influx of IFN-gamma- and IL-3-secreting cells into the airways, earlier than after vaccination alone, or in appropriate controls. Ablation studies reveal that CD4+ T cells are the source of the IFN-gamma. The timing of cytokine production after both vaccination and challenge coincides with phases of macrophage activation already recorded, and with the presence of parasites in the lungs. Administration of monoclonal antibody directed against IFN-gamma, over the period of challenge elimination, almost completely abrogates protection in vaccinated mice, but does not affect the ratio of Th1:Th2 cells in the lungs. Immunity in this model is not, however, affected by inhibition of nitric oxide production, or neutralization of TNF. We suggest that the effector mechanism may operate by blocking parasite migration, and that loss of protection following neutralization of IFN-gamma may be attributed to changes in composition, density and cohesiveness of pulmonary foci.