Schistosoma mansoni: protective immunity in IL-4-deficient mice

Vaccination of mice with radiation-attenuated Schistosoma mansoni larvae (cercariae) either once or multiple times produces similar levels of resistance to subsequent infection, but by different immunological mechanisms. In singly immunized mice, protection is CD4+ cell mediated and IFN-gamma dependent. Resistance in multiply immunized mice is humorally mediated (especially the IgG1 isotype), suggesting a key role of Th2-associated cytokine responses. Since IL-4 has been shown to regulate Th2 development, animals in which the IL-4 gene has been knocked out by homologous recombination (IL-4 -/-) or wild-type mice (IL-4 +/+) were immunized three times with attenuated cercariae and challenged with normal cercariae. In three separate experiments the percentage of reduction of adult worms in immunized compared to unimmunized IL-4 +/+ animals (68 to 82%) was equivalent to IL-4 -/- (52 to 66%), although protection tended to be lower in each experiment. Serum levels of adult worm (SWAP)-specific IgG2a and IgG2b were 10- and 2-fold higher in IL-4 -/- mice while IgA levels were equivalent between the two groups. Serum levels of SWAP-specific IgG1 were slightly lower in IL-4 -/- mice (P = 0.07) compared to wild-type animals and inversely correlated with worm burdens (r = -0.65, P = 0.02), suggesting that the slightly diminished IgG1 accounts for the tendency toward lower worm burdens in IL-4 -/- animals. No relationships between worm numbers and the other isotypes were observed. SWAP-induced IL-5 production by splenocytes from IL-4 -/- animals were 6-fold lower, although present, compared to IL-4 +/+ mice while Ag-induced IFN-gamma production was increased by over 4-fold. These results demonstrate that IL-4 is not essential for development of protective immunity in mice multiply vaccinated with irradiated cercariae and that compensatory or alternative pathways exist to generate a Th2-associated response. The limitations of mice with targeted gene deletions in delineating the role of specific cytokines in regulating the immune response to complex infections like schistosomiasis are emphasized.