Use of antimony in the treatment of leishmaniasis: current status and future directions

Abstract

In the recent past the standard treatment of kala-azar involved the use of pentavalent antimonials Sb(V). Because of progressive rise in treatment failure to Sb(V) was limited its use in the treatment program in the Indian subcontinent. Until now the mechanism of action of Sb(V) is not very clear. Recent studies indicated that both parasite and hosts contribute to the antimony efflux mechanism. Interestingly, antimonials show strong immunostimulatory abilities as evident from the upregulation of transplantation antigens and enhanced T cell stimulating ability of normal antigen presenting cells when treated with Sb(V) in vitro. Recently, it has been shown that some of the peroxovanadium compounds have Sb(V)-resistance modifying ability in experimental infection with Sb(V) resistant Leishmania donovani isolates in murine model. Thus, vanadium compounds may be used in combination with Sb(V) in the treatment of Sb(V) resistance cases of kala-azar.

Figure 1

Proposed structural formula for 364 Da and 365 Da ions identified by ESI (−)-MS in aqueous solutions of meglumine antimoniate and stibogluconate, respectively. Adapted from [25].

Figure 2

SAG increases MHC class I mediated antigen presentation and upregulates expression of MHC class I. MΦs isolated from BALB/c and C57BL/6 mice, cultured in presence or absence of SAG for 24 h. (a) To study the antigen presenting function, peritoneal MΦs from BALB/c and C57BL/6 mice either kept untreated or treated with SAG for 24 h, were used as antigen presenting cells to drive the T-cell hybridoma in presence of appropriate peptide and IL-2 secretion was tested on IL-2-dependent cell line (HT-2). The growth of HT-2 was studied using ³H-Thymidine incorporation. The studies showed that class I but not class II restricted presentation was significantly (P < .001) enhanced upon SAG treatment both in normal and infected MΦ. (b) To study the expression of MHC I molecules, untreated (filled histogram) and SAG-treated (open histogram) MΦs from BALB/c mice were stained with FITC labeled anti-D^d (BD Pharmingen) according to manufacturer's instruction and either analyzed on flow cytometer or examined under a confocal laser scanning microscope. The studies showed that class I expression was significantly (P < .001) enhanced upon SAG treatment. Antigen presentation assay was performed at least thrice and the results are presented as mean ± SD. For flow cytometry and confocal microscopy, representative data of 3 similar experiments is presented here.

Figure 3

SAG directly stimulates proliferation of T cells. 10⁵ lymphocytes, from normal BALB/c mice (a) and 5 × 10⁴ IL-2-dependent CD8⁺ cytotoxic T cell line (CTLL-2) were plated in each well and were kept either untreated or treated in vitro with various concentrations of SAG. Proliferation of each type of cells was monitored by ³H thymidine incorporation. Each experiment was performed at least thrice and results are presented as mean ± SD.

Figure 4

Structures and formulae of the PV compounds [218].