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脂质体CpG寡脱氧核苷酸2006与米替福新联合使用可在实验性内脏利什曼病期间诱导强烈的细胞介导免疫。

Combination of liposomal CpG oligodeoxynucleotide 2006 and miltefosine induces strong cell-mediated immunity during experimental visceral leishmaniasis.

作者信息

Shivahare Rahul, Vishwakarma Preeti, Parmar Naveen, Yadav Pawan Kumar, Haq Wahajul, Srivastava Mrigank, Gupta Suman, Kar Susanta

机构信息

Division of Parasitology, CSIR-Central Drug Research Institute, Lucknow, India.

Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India.

出版信息

PLoS One. 2014 Apr 14;9(4):e94596. doi: 10.1371/journal.pone.0094596. eCollection 2014.

DOI:10.1371/journal.pone.0094596
PMID:24732039
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3986403/
Abstract

Immuno-modulators in combination with antileishmanial drug miltefosine is a better therapeutic approach for treatment of Visceral Leishmaniasis (VL) as it not only reduces the dose of miltefosine but also shortens the treatment regimen. However, immunological mechanisms behind the perceived benefits of this combination therapy have not been investigated in detail. In the present study, we hypothesized that potential use of drugs that target the host in addition to the parasite might represent an alternative strategy for combination therapy. We investigated immune responses generated in Leishmania donovani infected animals (hamsters and mice) treated with combination of CpG-ODN-2006 and miltefosine at short dose regimen. Infected animals were administered CpG-ODN-2006 (0.4 mg/kg, single dose), as free and liposomal form, either alone or in combination with miltefosine for 5 consecutive days and parasite clearance was evaluated at day 4 and 7 post treatment. Animals that received liposomal CpG-ODN-2006 (lipo-CpG-ODN-2006) and sub-curative miltefosine (5 mg/kg) showed the best inhibition of parasite multiplication (∼97%) which was associated with a biased Th1 immune response in. Moreover, compared to all the other treated groups, we observed increased mRNA expression levels of pro-inflammatory cytokines (IFN-γ, TNF-α and IL-12) and significantly suppressed levels of Th2 cytokines (IL-10 and TGF-β) on day 4 post treatment in animals that underwent combination therapy with lipo-CpG-ODN-2006 and sub-curative miltefosine. Additionally, same therapy also induced heightened iNOS mRNA levels and NO generation, increased IgG2 antibody level and strong T-cell response in these hamsters compared with all the other treated groups. Collectively, our results suggest that combination of lipo-CpG-ODN-2006 and sub-curative miltefosine generates protective T-cell response in an animal model of visceral leishmaniasis which is characterized by strong Th1 biased immune response thereby underlining our hypothesis that combination therapy, at short dose regimen can be used as a novel way of treating visceral leishmaniasis.

摘要

免疫调节剂与抗利什曼原虫药物米替福新联合使用，是治疗内脏利什曼病（VL）的一种更好的治疗方法，因为它不仅可以降低米替福新的剂量，还能缩短治疗疗程。然而，这种联合疗法显著疗效背后的免疫机制尚未得到详细研究。在本研究中，我们假设除了靶向寄生虫外，靶向宿主的药物的潜在用途可能代表联合疗法的一种替代策略。我们研究了用短剂量方案的CpG-ODN-2006和米替福新联合治疗的杜氏利什曼原虫感染动物（仓鼠和小鼠）产生的免疫反应。感染动物分别单独或与米替福新联合连续5天给予游离形式和脂质体形式的CpG-ODN-2006（0.4mg/kg，单剂量），并在治疗后第4天和第7天评估寄生虫清除情况。接受脂质体CpG-ODN-2006（lipo-CpG-ODN-2006）和亚治疗剂量米替福新（5mg/kg）的动物对寄生虫增殖的抑制作用最佳（约97%），这与偏向Th1的免疫反应有关。此外，与所有其他治疗组相比，我们观察到在接受lipo-CpG-ODN-2006和亚治疗剂量米替福新联合治疗的动物中，治疗后第4天促炎细胞因子（IFN-γ、TNF-α和IL-12）的mRNA表达水平升高，Th2细胞因子（IL-10和TGF-β）水平显著降低。此外，与所有其他治疗组相比，相同的疗法还诱导了这些仓鼠中iNOS mRNA水平升高和NO生成增加、IgG2抗体水平升高以及强烈的T细胞反应。总体而言，我们的结果表明，lipo-CpG-ODN-2006和亚治疗剂量米替福新的联合使用在内脏利什曼病动物模型中产生了保护性T细胞反应，其特征是强烈的Th1偏向免疫反应，从而强调了我们的假设，即短剂量方案的联合疗法可作为治疗内脏利什曼病的一种新方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f19/3986403/2de562870837/pone.0094596.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f19/3986403/a2e3eb43274a/pone.0094596.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f19/3986403/fb2d3e3b67c0/pone.0094596.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f19/3986403/179a360ed12e/pone.0094596.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f19/3986403/2de562870837/pone.0094596.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f19/3986403/a2e3eb43274a/pone.0094596.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f19/3986403/fb2d3e3b67c0/pone.0094596.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f19/3986403/179a360ed12e/pone.0094596.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f19/3986403/2de562870837/pone.0094596.g004.jpg

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本文引用的文献

[1]
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[2]
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Treatment of Leishmania donovani-infected hamsters with miltefosine: analysis of cytokine mRNA expression by real-time PCR, lymphoproliferation, nitrite production and antibody responses.

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