Combination of Liposomal CpG Oligodeoxynucleotide 2006 and Miltefosine Induces Strong Cell-Mediated Immunity during Experimental Visceral Leishmaniasis

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

doi:10.1371/journal.pone.0094596

Cited by 42 publications

(48 citation statements)

References 55 publications

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“…These results differ from previous studies employing CpG delivered in liposomes [25], where a Th1 response was induced; however, multiple differences between this previous work, including the delivery system of dipalmitoylphosphatidylcholine and cholesterol, route of delivery (intraperitoneal versus cutaneous), and level of CpG (10 μg versus 93 ng) administered could account for the differential impact on the immune response.…”

Section: Resultscontrasting

confidence: 99%

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Immunomodulatory nanoparticles ameliorate disease in the Leishmania (Viannia) panamensis mouse model

et al. 2016

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Leishmania (Viannia) panamensis (L. (V.) panamensis) is a species of protozoan parasites that causes New World leishmaniasis, which is characterized by a hyper-inflammatory response. Current treatment strategies, mainly chemotherapeutic, are suboptimal due to adverse effects, long treatment regimens, and increasing drug resistance. Recently, immunotherapeutic approaches have shown promise in preclinical studies of leishmaniasis. As NPs may enable broad cellular immunomodulation through internalization in phagocytic and antigen-presenting cells, we tested the therapeutic efficacy of biodegradable NPs encapsulating a pathogen-associated molecular pattern (PAMP), CpG-rich oligonucleotide (CpG; NP-CpG), in mice infected with L. (V.) panamensis. NP-CpG treatment reduced lesion size and parasite burden, while neither free CpG nor empty NP showed therapeutic effects. NP-encapsulation led to CpG persistence at the site of infection along with an unexpected preferential cellular uptake by myeloid derived suppressor cells (MDSCs; CD11b+Ly6G+Ly6C−) as well as CD19+ dendritic cells. This corresponded with the suppression of the ongoing immune response measured by the reduction of pathogenic cytokines IL-10 and IL-13, as well as IL-17 and IFNγ, in comparison to other treatment groups. As chronic inflammation is generally associated with the accumulation of MDSCs, this study may enable the rational design of cost-effective, safe, and scalable delivery systems for the treatment of inflammation-mediated diseases.

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Section: Resultscontrasting

confidence: 99%

“…As such, either mechanism (or both) may improve efficacy of a small concentration of CpG [20, 21]. NPs have been explored in Leishmania models, including chitosan NP for delivery of the drug amphotericin B (AmpB) [22], as vaccine systems [23, 24], and treatment of visceral disease with liposomes [25]. …”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory nanoparticles ameliorate disease in the Leishmania (Viannia) panamensis mouse model

et al. 2016

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“…NO generation was quantified by measuring the accumulation of nitrite in culture supernatants by Griess reagent 45 .…”

Section: Methodsmentioning

confidence: 99%

Mahanine exerts in vitro and in vivo antileishmanial activity by modulation of redox homeostasis

Roy

Dutta

Satyavarapu

et al. 2017

Sci Rep

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Leishmania is an obligatory intracellular protozoan parasite responsible for the development of a spectrum of disease manifestation ranging from cutaneous to the more destructive visceral form 1 . Visceral leishmaniasis (VL) is a neglected tropical disease, mainly caused by the species L. donovani, which is prevalent in the Indian subcontinent with 40,000 cases registered each year and 147 million people under the risk 2 . Macrophages are the primary host for the parasite to survive and multiply in the mammalian system. Development of antileishmanial immunity depends on the Th1 type immune response generated by IL-12 secretion by antigen presenting cells (APCs) which in turn induce IFNγ secretion by T cells. This secreted IFNγ further induce macrophages for generation of nitric oxide (NO) and reactive oxygen species (ROS), which are the major antileishmanial defense molecules 3 . Uncoupling protein (UCP) is a mitochondrial membrane transporter which takes part in the regulation of mitochondrial ROS generation in macrophages 4 . Leishmania developed several strategies to dodge the host immune response to the establishment of successful infection in the hostile environment. This parasite induces the expression of negative regulatory protein UCP2 in macrophages as well as utilizes their own cascade of antioxidant enzymes like ascorbate peroxidase (APX), glutathione synthetase, tryparedoxin peroxidase for the suppression of ROS generation thereby neutralizing oxidative stress in host for their survival [5][6][7][8] . Due to unavailability of effective vaccines, treatment solely relies on chemotherapy. Although pentavalent antimonials were the mainstream therapy for past 70 years, a large percentage of patients are resistant to this drug. Currently, amphotericin B (conventional deoxycholate or liposomal formulations) has emerged as the first line of treatment. Miltefosine is the only oral drug. However, emerging resistance to miltefosine is particularly worrying. Alongside, most of these synthetic antileishmanial drugs are highly expensive and suffer from various side effects, long treatment regimen and acute toxicity, thus pose a real challenge for the management and elimination

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“…Thus, PAF receptor contributes to miltefosine-induced antileishmanial functions. The PAF receptor-dependent component of HPC perhaps accounts for the heightened inflammation observed in miltefosine-treated mice and patients (17,18). Altogether, involvement of PAF receptor in the miltefosine-induced elimination of intracellular parasites is a novel finding that stresses the dual role of miltefosine as a direct antiparasitic effector and as an immunomodulator that may expand its range of activities on intracellular pathogens.…”

mentioning

confidence: 96%

Platelet-Activating Factor Receptor Contributes to Antileishmanial Function of Miltefosine

Gangalum

Castro

Vieira

et al. 2015

The Journal of Immunology

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Miltefosine [hexadecylphosphocholine (HPC)] is the only orally bioavailable drug for the disease visceral leishmaniasis, which is caused by the protozoan parasite Leishmania donovani. Although miltefosine has direct leishmanicidal effects, evidence is mounting for its immune system–dependent effects. The mechanism of such indirect antileishmanial effects of miltefosine remains to be discovered. As platelet-activating factor and HPC share structural semblances and both induce killing of intracellular Leishmania, we surmised that platelet-activating factor (PAF) receptor had a significant role in the antileishmanial function of miltefosine. The proposition was supported by molecular dynamic simulation of HPC docking into PAF receptor and by comparison of its leishmanicidal function on PAF receptor–deficient macrophages and mice under HPC treatment. We observed that compared with wild-type macrophages, the PAF receptor–deficient macrophages showed 1) reduced binding of a fluorescent analog of HPC, 2) decreased TNF-α production, and 3) lower miltefosine-induced killing of L. donovani. Miltefosine exhibited significantly compromised leishmanicidal function in PAF receptor–deficient mice. An anti-PAF receptor Ab led to a significant decrease in miltefosine-induced intracellular Leishmania killing and IFN-γ production in a macrophage–T cell coculture system. These results indicate significant roles for PAF receptor in the leishmanicidal activity of HPC. The findings open new avenues for a more rational understanding of the mechanism of action of this drug as well as for improved therapeutic strategies.

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Combination of Liposomal CpG Oligodeoxynucleotide 2006 and Miltefosine Induces Strong Cell-Mediated Immunity during Experimental Visceral Leishmaniasis

Cited by 42 publications

References 55 publications

Immunomodulatory nanoparticles ameliorate disease in the Leishmania (Viannia) panamensis mouse model

Immunomodulatory nanoparticles ameliorate disease in the Leishmania (Viannia) panamensis mouse model

Mahanine exerts in vitro and in vivo antileishmanial activity by modulation of redox homeostasis

Platelet-Activating Factor Receptor Contributes to Antileishmanial Function of Miltefosine

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