In vitro and in vivo immunomodulatory properties of octyl-β-d-galactofuranoside during Leishmania donovani infection

Abstract

BackgroundThe chemotherapeutic arsenal available to treat visceral leishmaniasis is currently limited, in view of many drawbacks such as high cost, toxicity or emerging resistance. New therapeutic strategies are particularly needed to improve the management and the outcome in immunosuppressed patients. The combination of an immunomodulatory drug to a conventional anti-Leishmania treatment is an emerging concept to reverse the immune bias from Th2 to Th1 response to boost healing and prevent relapses.MethodsHere, immunostimulating and leishmanicidal properties of octyl-β-d-galactofuranose (Galf) were assessed in human monocyte-derived macrophages (HM) and in a murine model, after challenge with Leishmania donovani promastigotes. We recorded parasite loads and expression of various cytokines and immune effectors in HM and mouse organs (liver, spleen, bone marrow), following treatment with free (Galf) and liposomal (L-Galf) formulations.ResultsBoth treatments significantly reduced parasite proliferation in HM, as well as liver parasite burden in vivo (Galf, P < 0.05). Consistent with in vitro results, we showed that Galf- and L-Galf-treated mice displayed an enhanced Th1 immune response, particularly in the spleen where pro-inflammatory cytokines TNF-α, IL-1β and IL-12 were significantly overexpressed compared to control group. The hepatic recruitment of myeloid cells was also favored by L-Galf treatment as evidenced by the five-fold increase of myeloperoxidase (MPO) induction, which was associated with a higher number of MPO-positive cells within granulomas. By contrast, the systemic level of various cytokines such as IL-1β, IL-6, IL-17A or IL-27 was drastically reduced at the end of treatment.ConclusionsOverall, these results suggest that Galf could be tested as an adjuvant in combination with current anti-parasitic drugs, to restore an efficient immune response against infection in a model of immunosuppressed mice.

Modulación del inflamasoma por Leishmania

“…está aumentando actualmente. Aunque la inmunoestimulación podría ser una estrategia prometedora para mejorar la eficacia y/o reducir la ingesta de fármacos leishmanicidas, debe adaptarse al entorno clínico, ya que el beneficio esperado puede variar según el entorno cutáneo o visceral de la enfermedad (52).…”

“…Por otro lado, a nivel sistémico estas citocinas se redujeron drásticamente al final del tratamiento (52).…”

Immunotherapy and immunochemotherapy in combating visceral leishmaniasis

“…Interestingly, IL-12 DNA played a crucial role in regulating the humoral-mediated responses toward the IgG2a isotype signifying its use as a viable vaccine adjuvant against VL ( 93 ). Immunostimulatory compounds such as Octyl-β-D-galactofuranose (Galf) clear intracellular parasites in Leishmania -infected human monocyte-derived macrophages and murine models with augmented IL-12 expression ( 74 ).…”