CpG Oligodeoxynucleotide 2006 and Miltefosine, a Potential Combination for Treatment of Experimental Visceral Leishmaniasis

Gupta, Suman; Sane, Shraddha A.; Shakya, Nishi; Vishwakarma, Preeti; Haq, W.

doi:10.1128/aac.00137-11

Cited by 21 publications

(18 citation statements)

References 20 publications

(25 reference statements)

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“…Numerous reports have suggested use of CpG-ODN as an immunomodulator to boost host immunity based on its recognition by a variety of immune cells in various pathophysiological conditions [18], [19]. In leishmaniasis too we have earlier demonstrated that co-administration of lipo-CpG-ODN-2006 with sub-curative miltefosine increases the efficacy at short dose and time [23]. In the present study, we have shown that lipo-CpG-ODN-2006 in combination with sub-curative dose of miltefosine enhanced host immunological responses that helped in reducing parasite load.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…4). As CD40, IL-12, and TLRs modulate each other in initiation of cellular activation leading to parasite clearance (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40), we next attempted to explore the involvement of TLRs in astrakurkurone-mediated immunomodulation (Fig. 4).…”

Section: Astrakurkurone-induced Nitric Oxide Caused the Inhibition Ofmentioning

confidence: 99%

Successful Therapy of Murine Visceral Leishmaniasis with Astrakurkurone, a Triterpene Isolated from the Mushroom Astraeus hygrometricus, Involves the Induction of Protective Cell-Mediated Immunity and TLR9

Mallick

Dutta

Chaudhuri

et al. 2016

Antimicrob Agents Chemother

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eIn our previous report, we showed that astrakurkurone, a triterpene isolated from the Indian mushroom Astraeus hygrometricus (Pers.) Morgan, induced reactive oxygen species, leading to apoptosis in Leishmania donovani promastigotes, and also was effective in inhibiting intracellular amastigotes at the 50% inhibitory concentration of 2.5 g/ml. The aim of the present study is to characterize the associated immunomodulatory potentials and cellular activation provided by astrakurkurone, leading to effective antileishmanial activity in vitro and in vivo. Astrakurkurone-mediated antileishmanial activity was evaluated by real-time PCR and flow cytometry. The involvement of Toll-like receptor 9 (TLR9) was studied by in vitro assay in the presence of a TLR9 agonist and antagonist and by in silico modeling of a three-dimensional structure of the ectodomain of TLR9 and its interaction with astrakurkurone. Astrakurkurone caused a significant increase in TLR9 expression of L. donovani-infected macrophages along with the activation of proinflammatory responses. The involvement of TLR9 in astrakurkurone-mediated amastigote killing has been evidenced from the fact that a TLR9 agonist (CpG, ODN 1826) in combination with astrakurkurone enhanced the amastigote killing, while a TLR9 antagonist (bafilomycin A1) alone or in combination with astrakurkurone curbed the amastigote killing, which could be further justified by in silico evidence of docking between mouse TLR9 and astrakurkurone. Astrakurkurone was found to reduce the parasite burden in vivo by inducing protective cytokines, gamma interferon and interleukin 17. Moreover, astrakurkurone was nontoxic toward peripheral blood mononuclear cells of immunocompromised patients with visceral leishmaniasis. Astrakurkurone, a nontoxic antileishmanial, enhances the immune efficiency of host cells, leading to parasite clearance in vitro and in vivo.

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“…Recent insights into the host immune responses led to identification of immunomodulators which enhance the efficacy of antileishmanial drugs (Gupta et al, 2011; Seifert et al, 2015). The evidence that antitumor drugs may also display antileishmanial activity has also stimulated the screening of these compounds in vitro and in clinical trials (Fuertes et al, 2008; Sanderson et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Treatment of Leishmania (Leishmania) Amazonensis-Infected Mice with a Combination of a Palladacycle Complex and Heat-Killed Propionibacterium acnes Triggers Protective Cellular Immune Responses

et al. 2017

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Palladacycle complex DPPE 1.2 was previously reported to inhibit the in vitro and in vivo infection by Leishmania (Leishmania) amazonensis. The aim of the present study was to compare the effect of DPPE 1.2, in association with heat-killed Propionibacterium acnes, on L. (L.) amazonensis infection in two mouse strains, BALB/c and C57BL/6, and to evaluate the immune responses of the treated animals. Foot lesions of L. (L.) amazonensis-infected mice were injected with DPPE 1.2 alone, or associated with P. acnes as an adjuvant. Analysis of T-cell populations in the treated mice and in untreated controls was performed by FACS. Detection of IFN-γ-secreting lymphocytes was carried out by an ELISPOT assay and active TGF-β was measured by means of a double-sandwich ELISA test. The treatment with DPPE 1.2 resulted in a significant reduction of foot lesion sizes and parasite burdens in both mouse strains, and the lowest parasite burden was found in mice treated with DPPE 1.2 plus P. acnes. Mice treated with DPPE 1.2 alone displayed a significant increase of TCD4+ and TCD8+ lymphocytes and IFN-γ secretion which were significantly higher in animals treated with DPPE 1.2 plus P. acnes. A significant reduction of active TGF-β was observed in mice treated with DPPE 1.2 alone or associated with P. acnes. Moreover, DPPE 1.2 associated to P. acnes was non-toxic to treated animals. The destruction of L. (L.) amazonensis by DPPE 1.2 was followed by host inflammatory responses which were exacerbated when the palladacycle complex was associated with P. acnes.

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CpG Oligodeoxynucleotide 2006 and Miltefosine, a Potential Combination for Treatment of Experimental Visceral Leishmaniasis

Cited by 21 publications

References 20 publications

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

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

Successful Therapy of Murine Visceral Leishmaniasis with Astrakurkurone, a Triterpene Isolated from the Mushroom Astraeus hygrometricus, Involves the Induction of Protective Cell-Mediated Immunity and TLR9

Treatment of Leishmania (Leishmania) Amazonensis-Infected Mice with a Combination of a Palladacycle Complex and Heat-Killed Propionibacterium acnes Triggers Protective Cellular Immune Responses

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