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TNF Is Essential for the Cell-Mediated Protective Immunity Induced by the Radiation-Attenuated Schistosome Vaccine¹

Miyoko Street^2,*, Patricia S. Coulson^*, Clare Sadler^*, Lorna J. Warnock^*, Deborah McLaughlin^*, Horst Bluethmann and R. Alan Wilson^*

^* Department of Biology, University of York, York, United Kingdom; and Department Roche Genetics, Hoffmann-La Roche, Basel, Switzerland

C57BL/6 mice exposed to the radiation-attenuated schistosome vaccine exhibit high levels of protective immunity. The cell-mediated pulmonary effector mechanism involves IFN--producing CD4⁺ T cells in a focal response around challenge larvae. IFN- can promote production of TNF and can synergize with this cytokine in its actions on responder cells. We have examined whether TNF plays a role in lung phase immunity to schistosomes using mice with a disrupted gene for TNFRI (TNFRI^-/-). The most dramatic finding was that the schistosome vaccine elicited no protection whatsoever in these mice. However, this could not be attributed to a lack of responder cells, because more lymphocytes were lavaged from the airways of TNFRI^-/- than wild-type mice. Furthermore, CD4⁺ T cells were equally represented in airway populations from the two groups and produced IFN- upon Ag stimulation in vitro. In contrast, pulmonary macrophage function was defective in TNFRI^-/- mice, as indicated by a failure to up-regulate inducible NO synthase mRNA. Histopathological analysis revealed that focal infiltrates were of similar size and cell composition in the two groups but that more parasites were free of foci in the TNFRI^-/- mice. These animals had a greatly impaired IgG response to schistosomes, which may explain their lack of residual protection due to Ab in a situation where cell-mediated immunity is disabled. We suggest that the absence of protective immunity could result from a retarded build-up of leukocytes around migrating lung worms and/or a deficit in accessory cell function within a focus, both of which would permit parasite escape.

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