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, IL-12, and TNF-
Are Required to Maintain Reduced Liver Pathology in Mice Vaccinated with Schistosoma mansoni Eggs and IL-121
*
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
Biomedical Research Institute, Rockville, MD 20852
The development of hepatic fibrosis and portal hypertension is the
principal cause of morbidity and mortality in schistosomiasis mansoni.
Nevertheless, relatively little is known about the mechanisms that lead
to excessive collagen deposition during infection with
Schistosoma mansoni. In the murine model, infection
leads to significant egg-induced granuloma formation, tissue
eosinophilia, and hepatic fibrosis. The pathology has been linked to
dominant type 2 cytokine expression, and our recent studies showed that
sensitizing animals to egg Ags in combination with IL-12, before
infection, led to a highly significant reduction in egg-induced
immunopathology. In this study, we demonstrate that in contrast with
egg/IL-12-sensitized animals that showed marked decreases in pathology,
mice similarly sensitized but depleted of IFN-
, IL-12, or TNF-
at
the time of egg laying developed granulomas that were similar to the
non-IL-12-treated control group. Although all three
anti-cytokine-treated groups exhibited a dominant type 1 response
in lymph node cells restimulated ex vivo, the expression of type 2
cytokine mRNA was markedly restored at the site of granuloma formation,
which suggests that all three cytokines are required to maintain the
suppressed type 2 pattern. Moreover, egg/IL-12-sensitized mice depleted
of IFN- or IL-12 displayed a partial reduction in IFN-
production, suggesting that multiple type 1 cytokines were required to
maintain polarized type 1 responses to chronic type 2-inducing stimuli.
Together, these data reveal key roles for IFN-, IL-12, and TNF-
in the protective effects mediated by this IL-12-based vaccine to
prevent pathology.
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