Immune responses to the radiation-attenuated schistosome vaccine: what can we learn from knock-out mice?

The goal of an effective schistosomiasis vaccine has proved elusive but the protective immunity induced in mice by radiation-attenuated cercaria larvae provides an appropriate model from which such a vaccine might be developed. Using gene-disrupted mice, we have analysed the process of immune priming by attenuated larvae of Schistosoma mansoni and the nature of the pulmonary effector response directed against a challenge infection. Vaccination stimulates expansion of IFNgamma-producing T-helper cells in the skin-draining lymph nodes. IL-12 is crucial in determining the Thl direction of this initial response but the cells of origin and the parasite components which stimulate its production are unknown. In the effector response, focal aggregates comprising mainly mononuclear cells accumulate around challenge larvae in the lungs, a process orchestrated by IFNgamma. This cytokine up-regulates nitric oxide synthase activity but we were unable to implicate nitric oxide as a cytotoxic agent causing challenge parasite elimination. An alternative action for IFNgamma may be to up-regulate adhesion molecule expression, increasing the cohesiveness of effector foci the better to block parasite migration, but the adhesive interactions so far examined do not appear relevant. In contrast, TNF induction is essential to protection, and we are currently testing the hypothesis that it determines the speed of the effector response following arrival of challenge larvae in the lungs.