Combination Therapy with Paromomycin-Associated Stearylamine-Bearing Liposomes Cures Experimental Visceral Leishmaniasis through Th1-Biased Immunomodulation
Combination Therapy with Paromomycin-Associated Stearylamine-Bearing Liposomes Cures Experimental Visceral Leishmaniasis through Th1-Biased Immunomodulation
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DOI：
10.1128/aac.00524-10
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发表时间：
2011-04-01
影响因子：
4.9
通讯作者：
Ali, Nahid
中科院分区：
文献类型：
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作者：
Banerjee, Antara;De, Manjarika;Ali, Nahid
由寄生虫杜氏利什曼原虫引起的内脏利什曼病 (VL) 是一种潜在致命的疾病。现有的有限药物有毒，需要较长的治疗时间，而且价格昂贵。一种低成本的硫酸巴龙霉素 (PM) 肠外制剂最近被批准用于治疗 VL。 PM 单一疗法存在产生耐药性的风险。因此，需要努力开发PM与其他药物的联合治疗，以缩短治疗时间并延长药物的有效寿命。 PM 采用含有杀利什曼病的硬脂胺 (SA) 磷脂酰胆碱 (PC) 脂质体配制而成，用于低剂量治疗。确定了组合药物的体外和体内抗利什曼效应。使用酶联免疫吸附测定 (ELISA) 和流式细胞术测定 PC-SA-PM 的免疫调节作用。排除脾脏（其治疗效果是相加的），用 PC-SA 相关 PM 的单次低剂量治疗在 BALB/c 小鼠中实现了显着的治疗和预防协同活性。 PC-SA-PM 对 CD4(+) 和 CD8(+) T 细胞产生γ干扰素 (IFN-γ) 具有免疫调节作用，并将疾病相关白细胞介素 10 (IL-10) 和转化生长因子 β (TGF-β) 下调至几乎可以忽略不计的水平。这种联合化疗可能为治疗利什曼病提供一种有希望的替代方案，使宿主免疫反应从疾病促进模式转变为表明长期耐药的 Th1 偏向反应。
Visceral leishmaniasis (VL) caused by the parasite Leishmania donovani is a potentially fatal disease. Available limited drugs are toxic, require prolonged treatment duration, and are costly. A low-cost parenteral formulation of paromomycin sulfate (PM) has recently been approved for the treatment of VL. Monotherapy with PM runs the risk of development of resistance. Hence, efforts are needed to develop a combination therapy of PM with other drugs to shorten the duration of treatment and prolong the effective life of the drug. PM was formulated with leishmanicidal stearylamine (SA)-bearing phosphatidylcholine (PC) liposomes for low-dose therapy. In vitro and in vivo antileishmanial effects of the combination drug were determined. The immunomodulatory role of PC-SA-PM was determined using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Excluding the spleen, for which the therapeutic effect was additive, a remarkable synergistic activity toward cure and prophylaxis with a single-shot low-dose treatment with PC-SA-associated PM was achieved with BALB/c mice. PC-SA-PM showed an immunomodulatory effect on CD4(+) and CD8(+) T cells for gamma interferon (IFN-gamma) production and downregulated disease-associated interleukin-10 (IL-10) and transforming growth factor beta (TGF-beta) to almost negligible levels. Such combination chemotherapy may provide a promising alternative for the cure of leishmaniasis, with a plausible conversion of the host immune response from a disease-promoting pattern to a Th1-biased response indicative of long-term resistance.