Endogenous interleukin-18 is involved in immunity to Leishmania donovani but its absence does not adversely influence the therapeutic activity of sodium stibogluconate

Abstract

Immunity to Leishmania donovani is associated with an interleukin (IL)-12 driven T helper 1 (Th1) response. In addition, the ability to respond to chemotherapy with sodium stibogluconate (SSG) requires a fully competent immune response and both Th1 and Th2 responses have been shown to positively influence the outcome of drug treatment. In the present study, the influence of IL-18, which can modulate both interferon (IFN)-gamma and IL-4 production, on the outcome of primary L. donovani infection and SSG therapy following infection was assessed using BALB/c IL-18-deficient and wild type mice. IL-18 deficiency was associated with an increased susceptibility to L. donovani infection, evident by day 40 post infection, resulting in higher parasite burdens in the spleen, liver, and bone marrow compared with wild type control animals. Infected IL-18-deficient mice had significantly lower splenocyte concanavalin A (ConA) induced IFN-gamma production as well as lower serum IL-12 and IFN-gamma levels, indicating a reduced Th1 response. However, drug treatment was equally effective in both mouse strains and restored serum IL-12 and IFN-gamma levels, and IFN-gamma production by ConA stimulated splenocytes of IL-18-deficient mice, to levels equivalent to similarly treated wild type mice.

Figure 1

The effect of SSG treatment on parasite spleen, liver, and bone marrow L. donovani parasite burdens of IL-18-deficient and wild type mice on day 40 post infection. Mice were infected with L. donovani strain 200016 and treated on days 14 and 15 postinfection with PBS (control) or SSG (III mg Sb^v/kg/day). Results from one of two independent experiments are shown. *P < 0·05 compared to wild type control, ^aP < 0·05 SSG-treated compared to corresponding control.

Figure 2

Parasite-specific IgG1 and IgG2a levels (a), serum IL-12 levels (b), and serum IFN-γ levels (c), and IFN-γ levels by in vitro stimulated splenocytes (d) on day 40 post infection for wild type and IL-18-deficient mice, infected with L. donovani strain 200016. Mice were treated on days 14 and 15 post infection with PBS (control) or SSG (III mg Sb^v/kg/day). Results from one of two independent experiments are shown. *P < 0·05, **P < 0·01 compared to wild type control, ^aP < 0·05 SSG-treated compared to corresponding control.