BACKGROUND The 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. METHODS Here, 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. RESULTS Both 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. CONCLUSIONS Overall, 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.

中文翻译：

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利什曼原虫多诺万尼感染过程中辛基-β-D-半乳糖呋喃糖苷的体外和体内免疫调节特性。

背景技术鉴于许多缺点，例如高成本，毒性或新出现的耐药性，目前可用于治疗内脏利什曼病的化学武库受到限制。特别需要新的治疗策略来改善免疫抑制患者的管理和治疗效果。免疫调节药物与常规抗利什曼原虫病治疗的结合是一个新兴的概念，旨在将免疫偏倚从Th2应答逆转为Th1应答，以促进愈合并防止复发。方法在这里，在人单核细胞衍生的巨噬细胞（HM）和鼠模型中，在用利什曼原虫（Leishmania donovani）前鞭毛体攻击后，评估了辛基-β-D-半乳糖呋喃糖（Galf）的免疫刺激和利什曼杀虫特性。我们记录了HM和小鼠器官（肝脏，脾，骨髓），然后用游离（Galf）和脂质体（L-Galf）制剂治疗。结果两种治疗均显着降低了HM中的寄生虫增殖以及体内肝脏寄生虫的负担（Galf，P <0.05）。与体外结果一致，我们显示，经Galf和L-Galf处理的小鼠显示出增强的Th1免疫应答，尤其是在脾中，与之相比，促炎性细胞因子TNF-α，IL-1β和IL-12明显过量表达。控制组。髓过氧化物酶（MPO）诱导增加了五倍，这与肉芽肿中MPO阳性细胞的数量增加有关，这也证明了L-Galf治疗可促进肝细胞的募集。相比之下，各种细胞因子（例如IL-1β，IL-6，治疗结束时，IL-17A或IL-27显着降低。结论总体而言，这些结果表明Galf可以作为佐剂与目前的抗寄生虫药联合测试，以在免疫抑制小鼠模型中恢复针对感染的有效免疫应答。