Immunochemotherapy for Leishmania donovani Infection in Golden Hamsters: Combinatorial Action of Poly ICLC Plus L-Arginine and Sodium Stibogluconate (Stibanate®)

Abstract

We demonstrate that golden hamsters infected with Leishmania donovani amastigotes develop the capacity to eliminate intracellular pathogens on treatment with low-dose standard antileishmanial sodium stibogluconate (Stibanate) in combination with polyinosinic-polycytidilic acid stabilized with polylysine and carboxymethycellulose (poly ICLC), a potent inducer of interferon (IFN) and immune enhancer, plus L-arginine. Data suggest that low doses of both Stibanate and poly ICLC plus L-arginine provide marginal inhibition against L. donovani infection in golden hamsters. When given in combination, however, a significant inhibition was achieved without toxicity, as all the animals survived up to 45 or 60 days. These results suggest that combination therapy using Stibanate and poly ICLC plus L-arginine may be very effective in reducing the dose of Stibanate and, hence, its dose-dependent toxicity in clinical situations.

Kinetoplastid Membrane Protein-11 DNA Vaccination Induces Complete Protection against Both Pentavalent Antimonial-Sensitive and -Resistant Strains of Leishmania donovani That Correlates with Inducible Nitric Oxide Synthase Activity and IL-4 Generation: Evidence for Mixed Th1- and Th2-Like Responses in Visceral Leishmaniasis

“…iNOS transcripts could not be readily detected from splenic macrophages of blank vector-immunized or infected hamsters. Previously iNOS activation and NO-mediated leishmanicidal activity was implicated in L. donovani-challenged golden hamsters treated with polyinosinic-polycytidylic acid and L-arginine that was inhibited by N-w-nitro-L-arginine, an inhibitor of iNOS (48). Our finding is commensurate with extremely elevated IFN-␥ and TNF-␣ transcripts produced from the splenocytes of the KMP-11 DNA vaccinated hamsters.…”

Clinical and Experimental Advances in Treatment of Visceral Leishmaniasis

“…In normal mice, IL-12-or IFN-␥-induced killing or control of visceral parasite replication can be achieved by treatment with (i) exogenous recombinant cytokine (112,117,179), (ii) cytokine gene transfer (1,180), and (iii) inducers of endogenous IFN-␥ (24,114,117). Similar experimental approaches in cutaneous L. major infection, worth testing in visceral disease models, include injecting (i) pertussis toxin to induce IL-12 (74), (ii) IL-18 to stimulate IFN-␥ secretion (137), and (iii) synthetic oligodeoxynucleotides containing nonmethylated CpG dinucleotides to preferentially promote Th1-cell responses (185,192).…”

“…However, when combined with Sb, experimental effects in visceral infection can also be induced by other cytokines (IL-12 [125]), cytokine inducers (24), and agents which appear to target the macrophage (70). Other drugs have also been successfully combined with IFN-␥ (89), and even though amphotericin B acts independently of host T-cell mechanisms (115), its visceral antileishmanial efficacy can readily be enhanced by cotreatment with IL-12 (H. Murray, unpublished observations).…”

To investigate the therapeutic potential of immunochemotherapy with cisplatin + 78 kDa + MPL‐A against Leishmania donovani in BALB/c mice

“…Immunochemotherapy has been used with various combinations of drugs and vaccines mostly in case of cutaneous leishmaniasis. Some of them are sodium stibogluconate with poly ICLC (Polyinosinic‐po lycytidilic acid) plus arginine , antimony with interferon–gamma , N ‐methyl meglumine antimoniate with recombinant Leish‐110f plus MPL‐SE vaccine , killed Leishmania promastigotes with antimonials and alum precipitated autoclaved Leishmania promastigote (ALUM/ALM) plus BCG with sodium stibogluconate .…”