Successful Therapy of Lethal Murine Visceral Leishmaniasis with Cystatin Involves Up-Regulation of Nitric Oxide and a Favorable T Cell Response1
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Successful Therapy of Lethal Murine Visceral Leishmaniasis
with Cystatin Involves Up-Regulation of Nitric Oxide and a
Favorable T Cell Response1
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| Creator |
Das, Lopamudra
Dutta, Neeta Bandyopadhyay, Santu Das, Pijush K |
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| Subject |
Cell Biology & Physiology
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| Description |
The virulence of Leishmania donovani in mammals depends at least in part on cysteine proteases because they play a key role in
CD41 T cell differentiation. A 6-fold increase in NO production was observed with 0.5 mM chicken cystatin, a natural cysteine
protease inhibitor, in IFN-g-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-g. In contrast
to the case with promastigotes, cystatin and IFN-ginhibited 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-g or anti-TNF-a 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-g 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 CD41 differentiation from Th2 to Th1, indicative of long-term
resistance. The Journal of Immunology, 2001, 166: 4020–4028.
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| Date |
2001
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| Type |
Article
PeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/894/1/JOURNAL_OF_IMMUNOLOGY%2C_166(_6)%2C__4020%2D4028%2C2001[49].pdf
Das, Lopamudra and Dutta, Neeta and Bandyopadhyay, Santu and Das, Pijush K (2001) Successful Therapy of Lethal Murine Visceral Leishmaniasis with Cystatin Involves Up-Regulation of Nitric Oxide and a Favorable T Cell Response1. The Journal of Immunology, 166 (6). pp. 4020-4028. |
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| Relation |
http://dx.doi.org/
http://www.eprints.iicb.res.in/894/ |
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