Combined therapy with adipose tissue-derived mesenchymal stromal cells and meglumine antimoniate controls lesion development and parasite load in murine cutaneous leishmaniasis caused by Leishmania amazonensis

Abstract

Background Leishmaniasis is a neglected disease caused by Leishmania spp. One of its characteristics is an imbalance of host immune responses to foster parasite survival. In this setting, mesenchymal stromal cells (MSCs) may be a viable therapeutic alternative, given their well-established immunomodulatory potential. In this study, we compared the effects of therapy with bone marrow (BM)- and adipose tissue (AD)-derived MSCs in leishmaniasis caused by Leishmania amazonensis in C57BL/6 mice. After determining the most effective MSC source, we then combined these cells with meglumine antimoniate (a pentavalent antimonial commonly used for the treatment of leishmaniasis) to treat the infected mice. Methods In vitro, co-culture of AD-MSCs and BM-MSCs with Leishmania amazonensis- infected macrophages was performed to understand the influence of both MSC sources in infected cells. In vivo, infected C57BL/6 mice were treated with phosphate-buffered saline (PBS), AD-MSCs and BM-MSCs, and then meglumine antimoniate was combined with MSCs from the most effective source. Results In vitro, co-culture of Leishmania amazonensis -infected macrophages with BM-MSCs, compared to AD-MSCs, led to a higher parasite load and lower production of nitric oxide. Fibroblasts grown in conditioned medium from co-cultures with AD-MSCs promoted faster wound healing. Despite a non-significant difference in the production of vascular endothelial growth factor, we observed higher production of tumor necrosis factor-α and interleukin (IL)-10 in the co-culture with AD-MSCs. In vivo, treatment of infected mice with BM-MSCs did not lead to disease control; however, the use of AD-MSCs was associated with partial control of lesion development, without significant differences in the parasite load. AD-MSCs combined with meglumine antimoniate reduced lesion size and parasite load when compared to PBS and AD-MSC groups. At the infection site, we detected a small production of IL-10, but we were unable to detect production of either IL-4 or interferon-γ, indicating resolution of infection without effect on the percentage of regulatory T cells. Conclusion Combination treatment of cutaneous leishmaniasis with AD-MSCs and meglumine antimoniate may be a viable alternative.

Stem cells therapy research for the treatment of parasitic infections

“…Attempted treatment with MSCs showed a significant regression in the cutaneous lesions produced by L. major [40] . Moreover, treatment with AD-MSCs combined with meglumine antimoniate reduced the cutaneous lesion size produced by L. amazonensis [41] . Additional combination of AD-MSCs with glucantime improved the cutaneous lesions' healing and decreased parasite burden caused by L. major [42] .…”

Nutritional Modulation of the Immune Response Mediated by Nucleotides in Canine Leishmaniosis

“…CanL management could benefit from novel therapies, which, besides being safe and efficacious, would not be used in humans hence reducing the potential risk of developing drug-resistant parasites that would be passed on to people [64]. These solutions might come from alternative therapies, which are currently either under investigation or already available but not yet widely used, such as cell therapy [99], autovaccine [73], artemisinin and derivatives [66,67,100], aminosidine [101], or some types of immunotherapy [95].…”