Abstract
BackgroundLeishmaniasis remains a significant cause of morbidity and mortality in the tropics. Available therapies are problematic due to toxicity, treatment duration and emerging drug resistance. Mouse models of leishmaniasis have demonstrated that disease outcome depends critically on the balance between effector and regulatory CD4+ T cell responses, something mirrored in descriptive studies of human disease. Recombinant IL-2/diphtheria toxin fusion protein (rIL-2/DTx), a drug that is FDA-approved for the treatment of cutaneous T cell lymphoma, has been reported to deplete regulatory CD4+ T cells.Methodology/Principal FindingsWe investigated the potential efficacy of rIL-2/DTx as adjunctive therapy for experimental infection with Leishmania major. Treatment with rIL-2/DTx suppressed lesional regulatory T cell numbers and was associated with significantly increased antigen-specific IFN-γ production, enhanced lesion resolution and decreased parasite burden. Combined administration of rIL-2/DTx and sodium stibogluconate had additive biological and therapeutic effects, allowing for reduced duration or dose of sodium stibogluconate therapy.Conclusions/SignificanceThese data suggest that pharmacological suppression of immune counterregulation using a commercially available drug originally developed for cancer therapy may have practical therapeutic utility in leishmaniasis. Rational reinvestigation of the efficacy of drugs approved for other indications in experimental models of neglected tropical diseases has promise in providing new candidates to the drug discovery pipeline.
Highlights
Protozoa of the genus Leishmania cause a wide spectrum of human disease [1]
Kala azar has emerged as a significant problem in the setting of HIV/ AIDS, visceral leishmaniasis being the second most common opportunistic tissue protozoal disease in people infected with HIV [3]
Leishmaniasis is an infectious disease that causes a large burden of morbidity and mortality in the tropics
Summary
At the severe end of the spectrum, visceral leishmaniasis (kala azar), due to disseminated parasitism of macrophages and dendritic cells, causes an annual mortality of approximately 50,000, largely in India and Sudan [2]. Available therapies for kala azar, including pentavalent antimonials, some (but not all [4]) amphotericin B preparations, miltefosine and paromomycin, are problematic due to emerging drug resistance, toxicity, need for lengthy treatment and/or the development of post-kala azar dermal lesions [5,6,7,8,9]. Available therapies are problematic due to toxicity, treatment duration and emerging drug resistance. Mouse models of leishmaniasis have demonstrated that disease outcome depends critically on the balance between effector and regulatory CD4+ T cell responses, something mirrored in descriptive studies of human disease. Recombinant IL-2/diphtheria toxin fusion protein (rIL-2/DTx), a drug that is FDA-approved for the treatment of cutaneous T cell lymphoma, has been reported to deplete regulatory CD4+ T cells
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