VACCINATION ROUTES THAT FAIL TO ELICIT PROTECTIVE IMMUNITY AGAINST SCHISTOSOMA-MANSONI INDUCE THE PRODUCTION OF TGF-BETA, WHICH DOWN-REGULATES MACROPHAGE ANTIPARASITIC ACTIVITY

C57BL/6 mice immunized intradermally (i.d.) with bacillus Calmette Gue rin (BCG) plus killed skin-stage schistosomula are protected against s ubsequent infection with Schistosoma mansoni, whereas immunization by i.v. or i.m. routes is not protective. Moreover, previous immunization via the nonprotective i.v. route interfered with the ability to subse quently induce protection by i.d. vaccination, suggesting that inhibit ory responses are invoked. Given the evidence that activated macrophag es (M phi) play a role as effector cells in protection against schisto somiasis, we investigated the ability of spleen cells from protected a nd nonprotected immunized mice to produce M phi activating and deactiv ating cytokines. Exposure to supernatant fluids (SNs) from Ag stimulat ed spleen cells of i.d., but not i.v, or i.m., immunized mice activate d inflammatory M phi for in vitro killing of schistosome larvae, throu gh a mechanism dependent on both IFN gamma and TNF-alpha. No evidence was observed for the preferential induction of the M phi activating Th 1 cytokines IFN-gamma and IL-2 in i.d. immunized mice, nor did spleen cells from nonprotected animals produce higher levels of the Th2 assoc iated cytokines IL-4 and IL-10, which are known to prevent M phi activ ation. TCF-beta was, however, detected in SNs from unprotected mice. M oreover, the M phi inhibitory activity detected in these SNs was heat stable and neutralized by anti-TGF-beta Abs, suggesting that productio n of TCF-beta is at least partially responsible for the failure of i.m . and i.v. immunized mice to develop immunity to S. mansoni. Thus, the induction of down-regulatory cytokines may be an important factor lim iting the efficacy of certain vaccination protocols.