Protective effect of neoglycoprotein-conjugated muramyl dipeptide against Leishmania donovani infection: the role of cytokines

Sarkar, K. ; Das, P. K. (1997) Protective effect of neoglycoprotein-conjugated muramyl dipeptide against Leishmania donovani infection: the role of cytokines Journal of Immunology, 158 (11). pp. 5357-5365. ISSN 0022-1767

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Official URL: http://www.jimmunol.org/cgi/content/abstract/158/1...

Abstract

Active targeting of muramyl dipeptide (MDP) to macrophages was studied by conjugation with the neoglycoprotein, mannosyl human serum albumin (mannose-HSA) using visceral leishmaniasis as the model macrophage disease. Conjugation did not decrease the affinity of the neoglycoprotein for macrophage mannose receptor. Mannose-HSA-MDP was 50 times more efficient than free MDP in inhibiting the growth of Leishmania donovani inside peritoneal macrophages. Moreover, in a 60- day murine model of visceral leishmaniasis, 95% of the spleen parasite burden was reduced by mannose-HSA-MDP at a dose of 0.5 mg/kg/day given for 4 days. Free MDP at a similar dose had very little effect. In vitro exposure of MDP caused enhanced generation of O2- by macrophages, whereas generation of nitric oxide (NO) was not induced. The elevated antileishmanial activity of MDP-treated macrophages in culture was abrogated by O2- scavengers. In contrast, considerably enhanced amounts of NO and O2- were generated from macrophages of mannose-HSA-MDP- treated animals, and their splenocytes secreted soluble factors providing all the signals required for the induction of NO biosynthesis. The increase in NO production was paralleled by a concomitant increase in antileishmanial activity, which was reversed by NO synthesis inhibitors. Splenocyte supernatants treated with anti-IFN- gamma or anti-TNF-alpha Abs suppressed inducible NO generation by macrophages. Moreover, i.v. administration of anti-IFN-gamma and anti- TNF-alpha along with mannose-HSA-MDP greatly reduced protection against L. donovani infection. Neoglycoprotein-conjugated MDP, therefore, activated mouse macrophages in vivo to kill L. donovani, and this may depend on the physiologic generation of NO induced by IFN-gamma and TNF- alpha.

Item Type:Article
Source:Copyright of this article belongs to American Association of Immunologists.
ID Code:30455
Deposited On:23 Dec 2010 13:31
Last Modified:31 May 2011 06:44

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