Endogenous interleukin 12 (IL-12) regulates granuloma formation induced by eggs of Schistosoma mansoni and exogenous IL-12 both inhibits and prophylactically immunizes against egg pathology.
Morbidity in humans infected with Schistosoma mansoni results primarily from the deposition of parasite eggs in portal areas where they induce a granulomatous response. In mice infected with this helminth granuloma formation is a CD4+ T helper (Th) cell-dependent process that is associated with a strong Th2 cytokine response which appears to evolve through a Th0 phase. In this report, we asked whether endogenously synthesized or exogenously induced interferon (IFN)gamma through its suppression of Th2 cell expansion exerts a regulatory role on egg pathology. Depletion of IFN-gamma or natural killer cells resulted in a marked enhancement of granuloma formation around intravenously injected eggs and was associated with increased Th2 and decreased Th1 and interleukin (IL)12 mRNA expression. Similar changes occurred when egg-injected mice were treated with neutralizing monoclonal antibodies specific for IL-12 indicating a role for this cytokine in the regulation of the granulomatous response. In contrast, treatment with exogenous rIL-12 profoundly inhibited primary granuloma formation while increasing IFN-gamma, IL-2, IL-10, and IL-12 pulmonary mRNA levels and suppressing IL-4, IL-5, IL-6, and IL-13 mRNA expression. Cytokine depletion studies indicated that the effects of IL-12 could be attributed primarily to increased IFN-gamma. Importantly, IL-12 also inhibited secondary granuloma formation in mice presensitized with eggs demonstrating a role for the cytokine in reversing established Th2-type responses. Moreover, mice sensitized with eggs in combination with IL-12 to precommit them toward a Th1 response developed only minimal granulomas upon subsequent egg challenge. The latter findings suggest that simultaneous vaccination with antigen plus IL-12 may provide a strategy for the prevention of schistosome egg pathology as well as other diseases stemming from Th2 cytokine production.
Wynn
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Immunology and Cell Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Eltoum
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Oswald
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Cheever
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Sher
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D000818:Animals; D001483:Base Sequence; D004247:DNA; D005260:Female; D006099:Granuloma / Q000276:immunology* / Q000469:parasitology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12; D007378:Interleukins / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D010063:Ovum / Q000276:immunology; D016133:Polymerase Chain Reaction; D012550:Schistosoma mansoni / Q000276:immunology* / Q000472:pathogenicity; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000517:prevention & control; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D007378:Interleukins; D018664:Interleukin-12; D007371:Interferon-gamma; D004247:DNA