FAILURE OF P-STRAIN MICE TO RESPOND TO VACCINATION AGAINST SCHISTOSOMIASIS CORRELATES WITH IMPAIRED PRODUCTION OF IL-12 AND UP-REGULATION OF TH2 CYTOKINES THAT INHIBIT MACROPHAGE ACTIVATION

In contrast to most inbred strains, P mice fail to develop significant resistance to Schistosoma mansoni infection as a result of vaccinatio n with either radiation-attenuated cercariae or schistosome antigens p lus Bacillus Calmette Guerin, and this failure correlates with defects in macrophage larvicidal activity. Supernatant fluids from antigen-tr eated in vitro cultures of splenocytes from vaccinated P mice demonstr ate less macrophage stimulatory activity than do supernatants from cel ls of vaccine-responsive strains such as C57BL/6. This is not due eith er to diminished production of the macrophage-activating cytokine IFN- gamma by P mice, or to a lesser responsiveness of macrophages from P m ice to activation by IFN gamma. Rather, P splenocytes produce two-to t hreefold higher amounts of IL-4 and IL-10, cytokines which down-regula te the cytotoxic potential of IFN gamma-treated macrophages. Thus, the macrophage-activating potential of cytokine preparations from vaccina ted P mice can be completely recovered by in vitro treatment with anti bodies to IL-4 or IL-10. Moreover, lower levels of IL-12, a cytokine i nvolved in promoting development of Th1 responses, are produced by spl enocytes from P mice as compared to C57BL/6 counterparts. These studie s indicate that a genetic predisposition toward an impaired production of IL-12 and an increased production of down-regulatory Th2 cytokines correlate with low response to vaccination against S. mansoni.