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Complete Cure of Experimental Visceral Leishmaniasis with Amphotericin B in Stearylamine-Bearing Cationic Liposomes Involves Down-Regulation of IL-10 and Favorable T Cell Responses¹

Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata, India

Visceral leishmaniasis caused by Leishmania donovani is a life-threatening disease involving uncontrolled parasitization of liver, spleen, and bone marrow. Most available drugs are toxic. Moreover, relapse after seemingly successful therapy remains a chronic problem. In this study, we evaluated a new therapeutic approach based on combination of a low dose of amphotericin B (AmB) in association with suboptimum dose of stearylamine (SA)-bearing cationic liposomes, itself having leishmanicidal activity. We demonstrate that a single-shot therapy with this formulation caused clearance of parasites from liver and spleen below the level of detection in the selected piece of the organs of BALB/c mice. The combination was superior to free AmB and AmBisome for therapy, as well as for prevention of relapse and reinfection. Besides having better killing activity, AmB in SA liposomes, in contrast to AmBisome, maintained the immunomodulatory effect of free AmB on CD4⁺ and CD8⁺ T cells for IFN- production, at the same time reducing the toxic effects of the drug, reflected through decline in TNF-. In addition, IL-10 was down-regulated to almost negligible levels, most efficiently through therapy with SA-bearing cationic liposomes-AmB. This IL-10-deficient environment of IFN--secreting T cells probably up-regulated the enhanced IL-12 and NO production observed in splenic culture supernatants of these mice, correlating with prolonged disease suppression better than free AmB and AmBisome. The ability of the formulation to elicit protective immunity was reconfirmed in a prophylactic model. Our results emphasize the requirement of effective immune stimulation, additionally, by antileishmanials for persistent disease protection, demonstrated by this liposomal AmB formulation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported through grants from Indian Council of Medical Research, Government of India. A.B. was a Senior Research Fellow supported by Council of Scientific and Industrial Research, Government of India.

² Address correspondence and reprint requests to Dr. Nahid Ali, Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, 4, Raja Subodh Chandra Mullick Road, Kolkata 700032, India. E-mail address: nali{at}iicb.res.in

³ Abbreviations used in this paper: VL, visceral leishmaniasis; AmB, amphotericin B; DTH, delayed-type hypersensitivity; LAg, leishmanial Ag; LDU, Leishman-Donovan unit; PC-SA, stearylamine-bearing cationic liposome; PKC, protein kinase C; SA, stearylamine.