Elevated expression of Th1 cytokines and nitric oxide synthase in the lungs of vaccinated mice after challenge infection with Schistosoma mansoni.
C57BL/6 mice were vaccinated with irradiated cercariae of Schistosoma mansoni, and, at various times after challenge infection, total lung mRNA was isolated to assess the induction of several cytokines that previously had been shown in in vitro studies to be involved in the activation of macrophages and/or endothelial cells for nitric oxide (NO) production and killing of schistosomula. Vaccinated mice demonstrated a highly significant increase in IFN-gamma mRNA upon subsequent infection when compared with infected nonvaccinated controls. A similar, although less dramatic, increase in two other macrophage-activating cytokines, TNF-alpha and IL-2, also was observed. In contrast, although the Th2 cytokines IL-4, IL-5, IL-10, and IL-13 were elevated in challenged vaccinated animals, only IL-10 and IL-13 showed increases that were significant with respect to the mRNA levels observed in challenged controls. Neutralization of IFN-gamma reduced immunity in vaccinated animals and resulted in decreased IFN-gamma, IL-2, IL-10, TNF-alpha, and IL-12 p40 but markedly increased IL-4, IL-5, and IL-13 mRNA expression and serum IgE levels. Pulmonary NO synthase expression was elevated in immunized mice at a time at which immune elimination of schistosomula is believed to occur. Moreover, suppression of NO synthase activity with the inhibitor aminoguanidine reduced immunity, as measured by a 32 to 33% increase in worm burden. Together, these data support previous in vitro studies that suggest a role for NO in schistosomulum killing. Furthermore, the observation that the down-regulatory cytokines IL-4, IL-10, and IL-13 are induced together with IFN-gamma may provide an explanation for the failure of this vaccine to provide complete protection.
Wynn
T A
TA
Immunology and Cell Biology Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.
Oswald
I P
IP
Eltoum
I A
IA
Caspar
P
P
Lowenstein
C J
CJ
Lewis
F A
FA
James
S L
SL
Sher
A
A
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D005260:Female; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase; D012550:Schistosoma mansoni / Q000276:immunology; D012555:Schistosomiasis mansoni / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014612:Vaccines / Q000276:immunology*
D000947:Antigens, Helminth; D016207:Cytokines; D014612:Vaccines; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases