Augmentation of antileishmanial efficacy of miltefosine in combination with tuftsin against experimental visceral leishmaniasis

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

doi:10.1007/s00436-012-2868-z

Cited by 15 publications

(32 citation statements)

References 23 publications

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“…As indicated by in vitro studies, IFN-γ activates macrophages, and miltefosine was shown to enhance the expression of IFN-γ in macrophages of BALB/c mice infected with L. donovani (42–44) Moreover, miltefosine was even able to upregulate IFN-γ levels in T-cell-deficient mice (46). In addition, control groups of mice and hamsters which were not treated with miltefosine demonstrated increased or unchanged parasite levels in comparison to those treated with subcurative and curative doses of miltefosine (50).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Various animal studies (Table 3) focused on the effects of miltefosine on IFN-γ production in both murine and hamster models of VL (42–49). Following miltefosine administration, all studies reported substantially increased IFN-γ levels in macrophages of Leishmania -infected animals in contrast to control groups (42–49). Several studies also showed that increases in IFN-γ levels were proportional to the dose of miltefosine administered and were accompanied by suppression of Th2-associated cytokine levels, together inducing the killing of parasites (43, 45, 50).…”

Section: Resultsmentioning

confidence: 99%

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Systematic Review of Host-Mediated Activity of Miltefosine in Leishmaniasis through Immunomodulation

Palić

Bhairosing

Beijnen

et al. 2019

Antimicrob Agents Chemother

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Host immune responses are pivotal for the successful treatment of the leishmaniases, a spectrum of infections caused by Leishmania parasites. Previous studies speculated that augmenting cytokines associated with a type 1 T-helper cell (Th1) response is necessary to combat severe forms of leishmaniasis, and it has been hypothesized that the antileishmanial drug miltefosine is capable of immunomodulation and induction of Th1 cytokines. A better understanding of the immunomodulatory effects of miltefosine is central to providing a rationale regarding synergistic mechanisms of activity to combine miltefosine optimally with other conventional and future antileishmanials that are currently under development. Therefore, a systematic literature search was performed to evaluate to what extent and how miltefosine influences the host Th1 response. Miltefosine’s effects observed in both a preclinical and a clinical context associated with immunomodulation in the treatment of leishmaniasis are evaluated in this review. A total of 27 studies were included in the analysis. Based on the current evidence, miltefosine is not only capable of inducing direct parasite killing but also of modulating the host immunity. Our findings suggest that miltefosine-induced activation of Th1 cytokines, particularly represented by increased gamma interferon (IFN-γ) and interleukin 12 (IL-12), is essential to prevail over the Leishmania-driven Th2 response. Differences in miltefosine-induced host-mediated effects between in vitro, ex vivo, animal model, and human studies are further discussed. All things considered, an effective treatment with miltefosine is acquired by enhanced functional Th1 cytokine responses and may further be enhanced in combination with immunostimulatory agents.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Systematic Review of Host-Mediated Activity of Miltefosine in Leishmaniasis through Immunomodulation

Palić

Bhairosing

Beijnen

et al. 2019

Antimicrob Agents Chemother

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“…Chemotherapy of leishmaniasis is often compromised due to suppression of immune function during the course of infection. Therefore, efficiency of any chemotherapy of leishmaniasis is dependent on the generation of effective cell‐mediated immune response suitable for disease resolution . Because of this close association between chemotherapy and cell‐mediated immunity, treatment for L. donovani infection has been thought to be more amenable to combined therapy, that is, immunochemotherapy .…”

Section: Introductionmentioning

confidence: 99%

To investigate the therapeutic potential of immunochemotherapy with cisplatin + 78 kDa + MPL‐A against Leishmania donovani in BALB/c mice

Joshi

Kaur

2013

Parasite Immunology

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Leishmaniasis has recently garnered attention as one of the diseases 'most neglected' by drug research and development, as the current therapeutic modalities available for the patients are ridden with unacceptable toxicity due to high dosage of the drug, prolonged treatment schedules, resistance and prohibitive costs. A successful chemotherapy requires a restoration of immune response; therefore, we combined Leishmania-specific 78 kDa antigen (with or without adjuvant MPL-A) along with a novel drug cisplatin in infected BALB/c mice and did its comparative analysis with chemotherapy and immunotherapy alone. Animals that were treated with immunochemotherapy showed maximum curative potential as demonstrated by a marked reduction in parasite load. Delayed-type hypersensitivity response to leishmanial antigens has been widely used to assess the level of host protection to the disease. An increased delayed-type hypersensitivity (DTH) response was observed in animals given immunotherapy or chemotherapy or immunochemotherapy; however, maximum DTH response was observed in animals treated with cisplatin + 78 kDa + MPL-A. These animals were also found to exhibit higher IgG2a levels greater cytokine (IFN-γ and IL-2) concentrations suggesting the generation of a strong Th1 type of immune response which is responsible for resolution of the disease.

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“…Tuftsin has also been used as a malaria and influenza A vaccine adjuvant [69–71], as a prophylactic in malaria animal models improving infection control [72], and as an immune-stimulating molecule along with antifungal agents in the treatment of opportunistic fungal infections [73]. In addition, combined anti-leishmanial drug treatment with tuftsin increases Leishmania parasite phagocytosis by macrophages [74], and when used as adjuvant treatment it helps to control sepsis in a murine model [75]. …”

Section: Introductionmentioning

confidence: 99%

Plasmodium falciparum malaria and invasive bacterial co-infection in young African children: the dysfunctional spleen hypothesis

Gómez-Pérez

Bruggen

Grobusch

et al. 2014

Malar J

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Children with recent or acute malaria episodes are at increased risk of invasive bacterial infections (IBI). However, the exact nature of the malaria-IBI association is still unclear. Young children have an age-related spleen immunologic immaturity, mainly due to the still ongoing development of the marginal zone (MZ) B cell subset. By mounting a rapid antibody response against encapsulated bacteria, these cells are critical for the defence against highly pathogenic microorganisms that do not elicit classical T cell-dependent responses. There is increasing evidence that the anatomy of the spleen becomes disorganized during malaria infection, with complete dissolution of the MZ and apoptosis of MZ B cells. Correspondingly, a reduction in the frequency of the peripheral equivalent of the MZ B cells has been found in malaria endemic areas. A remarkable similarity exists in IBI susceptibility between African children with malaria and hyposplenic or splenectomized patients. However, studies specifically assessing the immune function of the spleen in controlling bacterial infections in young children with malaria are scarce.Here, it is hypothesized that Plasmodium falciparum malaria infection constitutes a detrimental factor in the still immature spleen function of young children, resulting in a factually hyposplenic state during malaria episodes, putting children with malaria at a high risk to develop life-threatening bacterial infections. Studies to confirm or reject this hypothesis are greatly needed, as well as the development of affordable and feasible tools to assess the immune spleen function against encapsulated bacteria in children with malaria.

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Augmentation of antileishmanial efficacy of miltefosine in combination with tuftsin against experimental visceral leishmaniasis

Cited by 15 publications

References 23 publications

Systematic Review of Host-Mediated Activity of Miltefosine in Leishmaniasis through Immunomodulation

Systematic Review of Host-Mediated Activity of Miltefosine in Leishmaniasis through Immunomodulation

To investigate the therapeutic potential of immunochemotherapy with cisplatin + 78 kDa + MPL‐A against Leishmania donovani in BALB/c mice

Plasmodium falciparum malaria and invasive bacterial co-infection in young African children: the dysfunctional spleen hypothesis

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