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.
Highlights
Host immune responses are pivotal for the successful treatment of the leishmaniases, a spectrum of infections caused by Leishmania parasites
Patients suffering from progressive visceral leishmaniasis (VL) showed a consistent lack of Th1 cytokine production [10], whereas expression of Th2 markers was detected in post-kala-azar dermal (PKDL) lesional tissues [10, 11]
Our objective was to systematically review how miltefosine affects markers of the host Th1 response associated with its immunomodulatory effect in the treatment of leishmaniasis in vitro, Antimicrobial Agents and Chemotherapy aac.asm.org 2
Summary
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. Our findings suggest that miltefosine-induced activation of Th1 cytokines, represented by increased gamma interferon (IFN-␥) and interleukin 12 (IL-12), is essential to prevail over the Leishmania-driven Th2 response. Heterogeneity among parasite species results in different clinical manifestations, with visceral leishmaniasis (VL) being the most severe and potentially lethal form of Leishmania infection. The Th1 versus Th2 dichotomy is typically less clear in human infection, the importance of the Th1/Th2 balance in obtaining control over the Leishmania infection has been observed in clinical studies. In localized CL lesions, the balance between Th1 and Th2 cytokines appears more complex, since even the healing lesions were shown to contain persisting levels of circulating Th2 cytokines [16]
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