Endogenous IL-4 is necessary for effective drug therapy against visceral leishmaniasis

Abstract

It is well established that a fully competent immune response is required for the successful drug treatment of visceral leishmaniasis. However, recent studies have cast some doubt as to which elements of the immune response synergize with chemotherapeutic treatment. The role of the Th2 response and IL‐4 in particular during visceral leishmaniasis awaits clarification. We, therefore, examined the effectiveness of sodium stibogluconate treatment on Leishmania donovani infection in BALB/c wild‐type and IL‐4–/– mice. Parasite burdens in L. donovani‐infected IL‐4+/+ and IL‐4–/–, as we have previously shown for B6/129 mice, were similar, despite an apparent type 1 antibody response in infected IL‐4–/– mice, demonstrated by increased levels of parasite‐specific IgG2a and decreased IgG1. Unexpectedly IL‐4–/– mice responded poorly to sodium stibogluconate treatment with increased parasite burdens in all tissues examined. Furthermore, drug therapy of IL‐4–/– but not IL‐4+/+ mice resulted in significant reductions in splenocyte IFN‐γ mRNA transcripts and in serum IFN‐γ levels. These results demonstrate that IL‐4 has an important role in effective anti‐leishmanial chemotherapy which seems to be related to modulation of IFN‐γ production.

Cytokines and visceral leishmaniasis: a comparison of plasma cytokine profiles between the clinical forms of visceral leishmaniasis

“…However, its role in the induction of Th2 responses is has not been resolved. In vitro, when IL-4 is added after cell stimulation, the production of IFN-γ is reduced (Biedermann et al 2001), whereas the addition of IL-4 to cells before stimulation increases IFN-γ production (Alexander et al 2000, Biedermann et al 2001, Peruhype-Magalhães et al 2005. A synergism between IL-4 and IL-10 has been reported in the literature.…”

IL-4–producing B cells regulate T helper cell dichotomy in type 1- and type 2-controlled diseases

“…These discrepancies have been attributed to strain differences in the source of parasites, parasite dose, and the embryonic stem cells used to generate IL-4 knockout mice. Moreover, apart from a Th2-promoting role, IL-4 has also been reported to instruct DCs to secrete IL-12 for protective Th1 responses to L. major LV39 (25,52) and shown to instruct protective immunity and successful chemotherapy to L. donovani infection (53). Altogether, these reports and the work presented here highlight that IL-4 plays a dynamic, multifaceted role in the spectrum of human leishmaniasis, and these differing roles must be considered in targeting this cytokine in a treatment or vaccine.…”

Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

“…Oral miltefosine, recently shown to be effective in VL (70), has also more recently been shown to be compatible for use in combination therapy with Amphotericin B (71). Of note, it has been long recognized from studies in experimental VL that the efficacy of the antimonial drugs is exquisitely dependent upon host immune function, being modulated by a number of key T cell-derived cytokines (11,14,44). Although amphotericin B is less immune dependent in its mode of action in mice (11), clinical experience in the treatment of VL in HIV-infected patients, using this drug (72) as well as miltefosine (73), suggest that in humans, all antileishmanial drugs in current use probably have some degree of dependency on host immune effector mechanisms, particularly when measured in terms of the frequency of relapse.…”

“…Conventional chemotherapy for leishmaniasis involves the use of pentavalent antimonial drugs (sodium stibogluconate; Sb v ), and treatment of leishmaniasis with Sb v represents a paradigm for cytokine-dependent chemotherapy (11,44). IFN-γ and TNF have been shown in vitro, in experimental models, and (in the case of IFN-γ) in humans to synergize with antimonial drugs (45)(46)(47), and blockade of IL-10 is associated with improved chemotherapy (14).…”