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

Abstract

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.

A clioquinol-containing Pluronic® F127 polymeric micelle system is effective in the treatment of visceral leishmaniasis in a murine model

“…Here, the treatment of the infected mice using miltefosine also induced the activation of Th1-type immune cells, with high levels of antileishmanial IFN-c, IL-12 and GM-CSF cytokines being found in the cell supernatant of the stimulated cells. These findings are consistent with reports in the literature on the protective effect of miltefosine to treat Leishmania infection [38]. ICHQ/Mic-treated mice also presented a Th1-type immune response and, more importantly, they did not show adverse effects and/or inflammatory reactions after the administration of doses.…”

Glutamine supplementation improves the efficacy of miltefosine treatment for visceral leishmaniasis

“…Although our data demonstrate that glutamine supplementation per se is not a protective agent for parasite elimination, glutamine supplementation as an adjuvant to Miltefosine potentiated its anti-Leishmania activity. Given that miltefosine is not only capable of inducing direct parasite killing but also of modulating the host immunity by activating Th1 cytokines particularly represented by increased IFN-γ and interleukin 12 (IL-12) [44] and this activation is absolutely dependent on extracellular glutamine consumption [33], we hypothesized that the increased glutamine bioavailability will be crucial for the fitness of T cell response potentiating the development of a more effective anti-leishmania immune response.…”

Liposomal Formulation of ChimeraT, a Multiple T-Cell Epitope-Containing Recombinant Protein, Is a Candidate Vaccine for Human Visceral Leishmaniasis

“…Alternative therapeutic agents include miltefosine, which was originally developed as an anticancer drug [ 9 ]. Miltefosine is the first drug used orally for treating VL patients [ 10 , 11 ], but it can cause teratogenicity, and parasite resistance has also been reported [ 12 , 13 ], which also impacts on its clinical use. The development of a prophylactic human vaccine against VL is strongly considered as a non-toxic, safer, and low-cost alternative to control the spread of disease worldwide.…”