The roles of interleukin-4 (IL-4) and IL-13 in the regulation of immunity to Leishmania donovani infection are still poorly understood. Here we show that the increased parasite load observed in IL-4 ؊/؊ and IL-4 receptor ␣ ؊/؊ mice correlates with retarded granuloma maturation and antileishmanial activity and that the increased parasite load observed in IL-4 receptor ␣ ؊/؊ mice correlates with increased NOS2 expression and decreased serum gamma interferon levels. IL-4 and IL-13 appear to play little role in regulating collagen deposition in L. donovani-induced granulomas.
It is well established that a fully competent immune response is required for the successful drug treatment of visceral leishmaniasis. However, recent studies have cast some doubt as to which elements of the immune response synergize with chemotherapeutic treatment. The role of the Th2 response and IL‐4 in particular during visceral leishmaniasis awaits clarification. We, therefore, examined the effectiveness of sodium stibogluconate treatment on Leishmania donovani infection in BALB/c wild‐type and IL‐4–/– mice. Parasite burdens in L. donovani‐infected IL‐4+/+ and IL‐4–/–, as we have previously shown for B6/129 mice, were similar, despite an apparent type 1 antibody response in infected IL‐4–/– mice, demonstrated by increased levels of parasite‐specific IgG2a and decreased IgG1. Unexpectedly IL‐4–/– mice responded poorly to sodium stibogluconate treatment with increased parasite burdens in all tissues examined. Furthermore, drug therapy of IL‐4–/– but not IL‐4+/+ mice resulted in significant reductions in splenocyte IFN‐γ mRNA transcripts and in serum IFN‐γ levels. These results demonstrate that IL‐4 has an important role in effective anti‐leishmanial chemotherapy which seems to be related to modulation of IFN‐γ production.
Objectives: Previous studies have reported the ability of several phospholipid analogues to successfully inhibit the growth of Acanthamoeba species in vitro. This study tests further phospholipid analogues, either as free drug or in liposomal formulations, and unlike previous studies, examines their comparative toxicities to mammalian cells.
Methods:The relative cytotoxic activities of the phospholipid derivatives hexadecyl-PC, octadecyl-PC, elaidyl-PC, erucyl-PC and edelfosine, against Acanthamoeba castellanii, Acanthamoeba polyphaga and a rabbit corneal epithelial (RCE) cell line, was determined by the alamarBlue TM assay. Free and liposomal formulations were compared for hexadecyl-PC and elaidyl-PC.Results: Both hexadecyl-PC and octadecyl-PC (IC 50 values between 3.9 and 7.8 mM) demonstrated considerable activity against A. castellanii, as did elaidyl-PC (IC 50 values between 15.6 and 31.25 mM). Both hexadecyl-PC and elaidyl-PC also proved effective against A. polyphaga (IC 50 values between 15.6 and 31.25 and between 31.25 and 62.5 mM, respectively). In contrast, neither erucyl-PC nor edelfosine was inhibitory against either Acanthamoeba species. The growth of RCE cells was inhibited by octadecyl-PC, erucyl-PC and edelfosine (octadecyl-PC and erucyl-PC IC 50 values between 7.8 and 15.6 mM and edelfosine IC 50 values between 31.25 and 62.5 mM). Liposomal formulations of hexadecyl-PC and elaidyl-PC were less effective than free drug against both Acanthamoeba species.Conclusions: These results demonstrate that hexadecyl-PC has the highest therapeutic index and is the most promising for the treatment of acanthamoebiasis.
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