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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.
Stem Cell Research & Therapy ( IF 7.5 ) Pub Date : 2020-08-31 , DOI: 10.1186/s13287-020-01889-z
Tadeu Diniz Ramos 1, 2 , Johnatas Dutra Silva 3 , Alessandra Marcia da Fonseca-Martins 1 , Juliana Elena da Silveira Pratti 1 , Luan Firmino-Cruz 1 , Diogo Maciel-Oliveira 1 , Julio Souza Dos-Santos 1 , João Ivo Nunes Tenorio 4 , Almair Ferreira de Araujo 4 , Célio Geraldo Freire-de-Lima 2 , Bruno Lourenço Diaz 4 , Fernanda Ferreira Cruz 3 , Patricia Rieken Macedo Rocco 3, 5 , Herbert Leonel de Matos Guedes 1, 6, 7
Affiliation  

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. 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. 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. Combination treatment of cutaneous leishmaniasis with AD-MSCs and meglumine antimoniate may be a viable alternative.

中文翻译:

脂肪组织来源的间充质基质细胞和葡甲胺锑酸盐的联合治疗可控制由亚马逊利什曼原虫引起的小鼠皮肤利什曼病的病变发展和寄生虫负荷。

利什曼病是由利什曼原虫引起的一种被忽视的疾病。其特征之一是宿主免疫反应失衡,无法促进寄生虫的生存。在这种情况下,鉴于间充质基质细胞已确立的免疫调节潜力,它们可能是可行的治疗选择。在这项研究中,我们比较了骨髓(BM)和脂肪组织(AD)来源的MSC在C57BL / 6小鼠中由亚马逊利什曼原虫引起的利什曼病的治疗效果。确定最有效的MSC来源后,我们将这些细胞与葡甲胺锑酸盐(通常用于治疗利什曼病的五价锑)合并,以治疗感染的小鼠。体外,进行AD-MSC和BM-MSC与亚马逊利什曼原虫感染的巨噬细胞的共培养,以了解两种MSC来源对感染细胞的影响。在体内,用磷酸盐缓冲盐水(PBS),AD-MSC和BM-MSC处理感染的C57BL / 6小鼠,然后将葡甲胺锑酸盐与最有效来源的MSC合并。在体外,与AD-MSC相比,亚马逊利什曼原虫感染的巨噬细胞与BM-MSC共同培养导致较高的寄生虫载量和一氧化氮的产生。在与AD-MSC共同培养的条件培养基中生长的成纤维细胞促进了伤口的更快愈合。尽管在血管内皮生长因子的产生方面无显着差异,但我们观察到与AD-MSC共同培养的肿瘤坏死因子-α和白介素(IL)-10的产生更高。体内,用BM-MSC治疗感染的小鼠没有导致疾病控制;然而,AD-MSCs的使用与病变发展的部分控制相关,而寄生虫负荷没有显着差异。与PBS和AD-MSC组相比,AD-MSC与葡糖胺锑酸盐的结合可减少病灶大小和寄生虫负荷。在感染部位,我们检测到少量的IL-10产生,但是我们无法检测到IL-4或干扰素-γ的产生,表明感染的消退对调节性T细胞的百分比没有影响。用AD-MSC和葡甲胺锑酸盐联合治疗皮肤利什曼病可能是一种可行的选择。寄生虫负荷无明显差异。与PBS和AD-MSC组相比,AD-MSC与葡糖胺锑酸盐的结合可减少病灶大小和寄生虫负荷。在感染部位,我们检测到少量的IL-10产生,但是我们无法检测到IL-4或干扰素-γ的产生,表明感染的消退对调节性T细胞的百分比没有影响。用AD-MSC和葡甲胺锑酸盐联合治疗皮肤利什曼病可能是一种可行的选择。寄生虫负荷无明显差异。与PBS和AD-MSC组相比,AD-MSC与葡糖胺锑酸盐的结合可减少病灶大小和寄生虫负荷。在感染部位,我们检测到少量的IL-10产生,但是我们无法检测到IL-4或干扰素-γ的产生,表明感染的消退对调节性T细胞的百分比没有影响。用AD-MSC和葡甲胺锑酸盐联合治疗皮肤利什曼病可能是一种可行的选择。表明感染的消退对调节性T细胞的百分比没有影响。用AD-MSC和葡甲胺锑酸盐联合治疗皮肤利什曼病可能是一种可行的选择。表明感染的消退对调节性T细胞的百分比没有影响。用AD-MSC和葡甲胺锑酸盐联合治疗皮肤利什曼病可能是一种可行的选择。
更新日期:2020-08-31
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