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Center for the Study of Host Resistance, Montreal General Hospital Research Institute and McGill University, Montreal, Quebec, Canada
In this study, we investigated the role of endogenous IL-12 in
protective immunity against blood-stage P. chabaudi AS
malaria using IL-12 p40 gene knockout (KO) and wild-type (WT) C57BL/6
mice. Following infection, KO mice developed significantly higher
levels of primary parasitemia than WT mice and were unable to rapidly
resolve primary infection and control challenge infection. Infected KO
mice had severely impaired IFN-
production in vivo and in vitro by
NK cells and splenocytes compared with WT mice. Production of TNF-
and IL-4 was not compromised in infected KO mice. KO mice produced
significantly lower levels of Th1-dependent IgG2a and IgG3 but a higher
level of Th2-dependent IgG1 than WT mice during primary and challenge
infections. Treatment of KO mice with murine rIL-12 during the early
stage of primary infection corrected the altered IgG2a, IgG3, and IgG1
responses and restored the ability to rapidly resolve primary and
control challenge infections. Transfer of immune serum from WT mice to
P. chabaudi AS-infected susceptible A/J mice completely
protected the recipients, whereas immune serum from KO mice did not, as
evidenced by high levels of parasitemia and 100% mortality in
recipient mice. Furthermore, depletion of IgG2a from WT immune serum
significantly reduced the protective effect of the serum while IgG1
depletion had no significant effect. Taken together, these results
demonstrate the protective role of a Th1-immune response during both
acute and chronic phases of blood-stage malaria and extend the
immunoregulatory role of IL-12 to Ab-mediated immunity against
Plasmodium parasites.
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