Immunological stimulation for the treatment of leishmaniasis: a modality worthy of serious consideration

Musa, Ahmed; Noazin, Sassan; Khalil, E. A. G.; Modabber, Farrokh

doi:10.1016/j.trstmh.2009.07.026

Cited by 45 publications

(36 citation statements)

References 6 publications

(6 reference statements)

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“…Infection inocula and parasite burdens at the end of treatment were similar in this study and the tolerability study (19). Combined treatment approaches are an increasingly attractive treatment option for VL and aim to increase efficacy and to reduce treatment durations and the risk of the emergence of drug resistance (9,20,21). An alternative approach to combination treatment or coadministration of small-molecule drugs is coadministration of drugs and immunotherapies targeted to stimulate the immune system.…”

supporting

confidence: 62%

Sequential Chemoimmunotherapy of Experimental Visceral Leishmaniasis Using a Single Low Dose of Liposomal Amphotericin B and a Novel DNA Vaccine Candidate

Seifert

Juhls

Salguero

et al. 2015

Antimicrob Agents Chemother

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dCombination therapies for leishmaniasis, including drugs and immunomodulators, are one approach to shorten treatment courses and to improve the treatment of complex manifestations of the disease. We evaluated a novel T-cell-epitope-enriched DNA vaccine candidate (LEISHDNAVAX) as host-directed immunotherapy in combination with a standard antileishmanial drug in experimental visceral leishmaniasis. Here we show that the DNA vaccine candidate can boost the efficacy of a single suboptimal dose of liposomal amphotericin B in C57BL/6 mice. The leishmaniases are neglected tropical diseases (NTDs) caused by protozoan parasites of the genus Leishmania. Visceral leishmaniasis (VL) is caused by Leishmania donovani and Leishmania infantum and presents as systemic disease with parasitic invasion, primarily of the mononuclear phagocytic system (1). Symptomatic VL is fatal if left untreated. Estimates suggest that there are between 200,000 to 400,000 cases and 20,000 to 40,000 deaths per year worldwide (2). Current drug therapies are unsatisfactory due to toxicity, long treatment courses, challenging routes of administration, and geographical differences in clinical responses to treatment (3, 4). Other disease manifestations include post-kala-azar dermal leishmaniasis (PKDL), which is a complication of VL that presents as a skin condition weeks to months after drug treatment (5), and cutaneous leishmaniasis (CL), which is characterized by skin lesions of variable severity (6). We recently reported on the development of a DNA vaccine candidate for leishmaniasis, based on minimalistic immunogenically defined gene expression vectors modified to foster Th1-type immune responses (MIDGE-Th1 vectors). The vaccine candidate, referred to as LEISHDNAVAX, is an equimass mixture of five independent MIDGE-Th1 vectors encoding different leishmanial antigens (KMP11, TSA, CPA, CPB, and P74) (7). Here we investigated whether LEISHDNAVAX can serve as an adjunct to antileishmanial drug treatment. We selected liposomal amphotericin B as the drug, based on recent developments in the treatment of VL. Single-dose liposomal amphotericin B was shown to be effective and safe in a phase III trial in India (8), is now a recommended first-line treatment for VL in South Asia (4), and also forms part of short-course multidrug therapies, which have recently undergone evaluations in phase III trials (9). Single doses of 10 mg/kg (in monotherapy) or 5 mg/kg (in combined therapy) of liposomal amphotericin B proved to be optimal for patients (8, 9). In this study, a suboptimal dose of liposomal amphotericin B was chosen, to enable demonstration of beneficial treatment effects of combined treatment regimens. From a clinical perspective, delivering reduced doses of this treatment would also result in reduced treatment costs.The cotherapeutic potential of LEISHDNAVAX was evaluated in female C57BL/6J mice (Charles River, United Kingdom) (7 to 8 weeks of age at the start of experiments and maintained under specific-pathogen-free conditions) that had been infected wi...

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supporting

confidence: 62%

Sequential Chemoimmunotherapy of Experimental Visceral Leishmaniasis Using a Single Low Dose of Liposomal Amphotericin B and a Novel DNA Vaccine Candidate

Seifert

Juhls

Salguero

et al. 2015

Antimicrob Agents Chemother

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“…Leish111f, formulated in monophosphoryl lipid A with a squalene oil emulsion [112], was used to treat refractory ML with promising results [113]. Immunotherapy associated with antimonials could be an alternative for the treatment of leishmaniasis, including HIV-Leishmania coinfection, PKDL and chronic refractory tegumentary leishmaniasis [114]. Furthermore, drug toxicity and the emergence of resistance could be dramatically reduced if the present long-term monotherapy was supplemented with immunotherapy.…”

Section: Immunotherapy/immunomodulationmentioning

confidence: 99%

Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis

Goto¹,

Lindoso

2010

Expert Review of Anti-infective Therapy

384

398

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“…It is usually associated with a depression of Th1 cells and preferential expansion of Th2 cells. Keeping the current status of leishmaniasis treatment in mind, use of low dose or a short course of an effective drug in combination with an immunomodulator has been a successful approach for effective treatment of leishmaniasis (Musa et al 2010). Several studies have already been reported emphasizing the benefits of a combination of antileishmanial drugs with immunostimulants.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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Current drugs for the treatment of visceral leishmaniasis are inadequate, and their efficacies are also compromised due to suppression of immune function during the course of infection. Miltefosine is the only promising orally active antileishmanial drug, but due to its long half-life, there is risk of development of resistance. To overcome these problems, efforts are needed to develop combination therapy of miltefosine with effective immunostimulating agents where a decrease of parasitic burden and simultaneous enhancement of adaptive immunity can be achieved. In the present study, we have explored the antileishmanial efficacy of a subcurative dose of miltefosine in combination with free as well as liposomal palmitoyl tuftsin (p-tuftsin) using a Leishmania donovani/BALB/c mouse model. When miltefosine (2.5 mg/kg for 5 days) was given with free p-tuftsin, the inhibitory effect was significantly increased from 49.6% to 66% (P < 0.01), which was further enhanced up to 81% (P < 0.001) when given after liposomal encapsulation of p-tuftsin. Significant enhancement in parasitic inhibition (93%, P < 0.01) was witnessed when animals were co-administered with liposomal p-tuftsin + 5 mg/kg × 5 days dose of miltefosine (72.1%). Enhancement in the production of Th1 cytokines (IL-12, TNF-α, and IFN-γ), reactive oxygen, and nitrogen metabolites was witnessed in the combination group. A remarkable increase in phagocytosis index was also observed indicating overall immunological enhancement to antileishmanial activity of miltefosine by p-tuftsin.

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Immunological stimulation for the treatment of leishmaniasis: a modality worthy of serious consideration

Cited by 45 publications

References 6 publications

Sequential Chemoimmunotherapy of Experimental Visceral Leishmaniasis Using a Single Low Dose of Liposomal Amphotericin B and a Novel DNA Vaccine Candidate

Sequential Chemoimmunotherapy of Experimental Visceral Leishmaniasis Using a Single Low Dose of Liposomal Amphotericin B and a Novel DNA Vaccine Candidate

Current diagnosis and treatment of cutaneous and mucocutaneous leishmaniasis

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

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