Systematic review of host-mediated activity of miltefosine in leishmaniasis through immunomodulation

Palic, S. and Bhairosing, P. and Beijnen, J. H. and Dorlo, T. P. C.

Antimicrobial Agents and Chemotherapy (2019) 63: e02507–18

DOI: https://doi.org/10.1128/AAC.02507-18

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-P) 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.

Citation

Palic, S., Bhairosing, P., Beijnen, J. H., & Dorlo, T. P. C. (2019). Systematic review of host-mediated activity of miltefosine in leishmaniasis through immunomodulation. Antimicrobial Agents and Chemotherapy, 63(7), e02507–18. https://doi.org/https://doi.org/10.1128/AAC.02507-18 cytokines, immunotherapy, animal models, systematic reviews, in vitro, infections, parasites, parasitoses, protozoal infections, laboratory animals, leishmaniasis, disease models, protozoal diseases, Animal and in vitro Models for Pharmaceuticals [VV450], Animal Models of Human Diseases [VV400], Pesticides and Drugs, cell lines, interferon-gamma, parasitic diseases, parasitic infestations, parasitosis, Protozoan, Helminth and Arthropod Parasites of Humans [VV220], Control [HH405], Leishmania, leishmaniosis, interleukin 12, cell cultures, miltefosine, Th1 lymphocytes, Th1 mediated response

Keywords

• cytokines
• immunotherapy
• animal models
• systematic reviews
• in vitro
• infections
• parasites
• parasitoses
• protozoal infections
• laboratory animals
• leishmaniasis
• disease models
• protozoal diseases
• Animal and in vitro Models for Pharmaceuticals [VV450]
• Animal Models of Human Diseases [VV400]
• Pesticides and Drugs
• cell lines
• interferon-gamma
• parasitic diseases
• parasitic infestations
• parasitosis
• Protozoan
• Helminth and Arthropod Parasites of Humans [VV220]
• Control [HH405]
• Leishmania
• leishmaniosis
• interleukin 12
• cell cultures
• miltefosine
• Th1 lymphocytes
• Th1 mediated response