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Molecular Cell Biology Laboratory, Indian Institute of Chemical Biology, Calcutta, India
The virulence of Leishmania donovani in mammals
depends at least in part on cysteine proteases because they play a key
role in CD4+ T cell differentiation. A 6-fold increase in
NO production was observed with 0.5 µM chicken cystatin, a natural
cysteine protease inhibitor, in IFN-
-activated macrophages. In a
45-day BALB/c mouse model of visceral leishmaniasis, complete
elimination of spleen parasite burden was achieved by cystatin in
synergistic activation with a suboptimal dose of IFN-. In contrast
to the case with promastigotes, cystatin and IFN- inhibited the
growth of amastigotes in macrophages. Although in vitro cystatin
treatment of macrophages did not induce any NO generation,
significantly enhanced amounts of NO were generated by macrophages of
cystatin-treated animals. Their splenocytes secreted soluble factors
required for the induction of NO biosynthesis, and the increased NO
production was paralleled by a concomitant increase in antileishmanial
activity. Moreover, splenocyte supernatants treated with
anti-IFN- or anti-TNF-
Abs suppressed inducible NO
generation, whereas i.v. administration of these anticytokine Abs along
with combined therapy reversed protection against infection. mRNA
expression and flow cytometric analysis of infected spleen cells
suggested that cystatin and IFN- treatment, in addition to greatly
reducing parasite numbers, resulted in reduced levels of IL-4 but
increased levels of IL-12 and inducible NO synthase. Not only was this
treatment curative when administered 15 days postinfection, but it also
imparted resistance to reinfection. These studies provide a promising
alternative for protection against leishmaniasis with a switch of
CD4+ differentiation from Th2 to Th1, indicative of
long-term resistance.
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