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,
Departments of
*
Internal Medicine and
Microbiology, University of Iowa, and
Veterans Affairs Medical Center, Iowa City, IA 52242
IFN-
is critical for the cure of leishmaniasis in humans and
mice. BALB/c mice are genetically susceptible to infection with the
visceralizing species of Leishmania, L.
chagasi. We have evidence that a soluble factor(s) inhibits
IFN- production by cultured liver granuloma cells from BALB/c mice
during L. chagasi infection. In contrast, liver granulomas
from C3H.HeJ mice, which are genetically resistant to L.
chagasi infection, produce abundant IFN-. According to ELISAs
and neutralization studies, there was not evidence that the Th2-type
cytokines IL-10 or IL-4 contributed to IFN- suppression. However,
both Ab neutralization and immunohistochemistry showed that
granuloma-derived TGF-ß was, at least in part, responsible for
inhibiting IFN- release by CD4+ cells in BALB/c liver
granuloma cultures. Consistently, TGF-ß levels were high in liver
granulomas from susceptible BALB/c mice but low in resistant C3H mice
or in BALB/c mice that were immunized against L. chagasi
disease. Administration of recombinant adenovirus expressing TGF-ß
(AdV-TGFß) but not IL-10 (AdV-IL10) caused genetically resistant C3H
mice to become significantly more susceptible to L. chagasi
infection. In contrast, either AdV-TGFß or AdV-IL10 could abrogate
the protective immune response achieved by immunization of BALB/c mice.
We conclude that locally secreted TGF-ß inhibits Th1-associated cure
of murine visceral leishmaniasis caused by L. chagasi,
independently of Th2-type cytokines.
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