Siefert Alyssa L, Ehrlich Allison, Corral María Jesús, Goldsmith-Pestana Karen, McMahon-Pratt Diane, Fahmy Tarek M
Yale School of Engineering and Applied Science, USA.
Yale School of Public Health, USA.
Biomaterials. 2016 Nov;108:168-76. doi: 10.1016/j.biomaterials.2016.09.004. Epub 2016 Sep 6.
Leishmania (Viannia) panamensis (L. (V.) panamensis) is a species of protozoan parasites that causes New World leishmaniasis, which is characterized by a hyper-inflammatory response. Current treatment strategies, mainly chemotherapeutic, are suboptimal due to adverse effects, long treatment regimens, and increasing drug resistance. Recently, immunotherapeutic approaches have shown promise in preclinical studies of leishmaniasis. As NPs may enable broad cellular immunomodulation through internalization in phagocytic and antigen-presenting cells, we tested the therapeutic efficacy of biodegradable NPs encapsulating a pathogen-associated molecular pattern (PAMP), CpG-rich oligonucleotide (CpG; NP-CpG), in mice infected with L. (V.) panamensis. NP-CpG treatment reduced lesion size and parasite burden, while neither free CpG nor empty NP showed therapeutic effects. NP-encapsulation led to CpG persistence at the site of infection along with an unexpected preferential cellular uptake by myeloid derived suppressor cells (MDSCs; CD11b(+)Ly6G(+)Ly6C(-)) as well as CD19(+) dendritic cells. This corresponded with the suppression of the ongoing immune response measured by the reduction of pathogenic cytokines IL-10 and IL-13, as well as IL-17 and IFNγ, in comparison to other treatment groups. As chronic inflammation is generally associated with the accumulation of MDSCs, this study may enable the rational design of cost-effective, safe, and scalable delivery systems for the treatment of inflammation-mediated diseases.
巴拿马利什曼原虫（Leishmania (Viannia) panamensis，L. (V.) panamensis）是一种原生动物寄生虫，可引发新大陆利什曼病，其特征为过度炎症反应。目前的治疗策略主要是化疗，但由于存在不良反应、治疗方案冗长以及耐药性增加等问题，效果并不理想。最近，免疫治疗方法在利什曼病的临床前研究中显示出了前景。由于纳米颗粒（NPs）可通过被吞噬细胞和抗原呈递细胞内化来实现广泛的细胞免疫调节，我们测试了包裹病原体相关分子模式（PAMP）富含CpG的寡核苷酸（CpG；NP-CpG）的可生物降解纳米颗粒对感染巴拿马利什曼原虫小鼠的治疗效果。NP-CpG治疗可减小病变大小并减轻寄生虫负荷，而游离CpG和空纳米颗粒均未显示出治疗效果。纳米颗粒包封导致CpG在感染部位持续存在，同时意外地被髓源性抑制细胞（MDSCs；CD11b(+)Ly6G(+)Ly6C(-)）以及CD19(+)树突状细胞优先摄取。与其他治疗组相比，这与通过降低致病性细胞因子IL-10、IL-13以及IL-17和IFNγ来衡量的正在进行的免疫反应受到抑制相对应。由于慢性炎症通常与MDSCs的积累有关，这项研究可能有助于合理设计经济有效、安全且可扩展的递送系统，用于治疗炎症介导的疾病。
