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Implant delivering hydroxychloroquine attenuates vaginal T lymphocyte activation and inflammation
Journal of Controlled Release ( IF 10.8 ) Pub Date : 2018-03-13 , DOI: 10.1016/j.jconrel.2018.03.010
Yufei Chen , Yannick L. Traore , Sidi Yang , Julie Lajoie , Keith R. Fowke , Daniel W. Rickey , Emmanuel A. Ho

Evidence suggests that women who are naturally resistant to HIV infection exhibit low baseline immune activation at the female genital tract (FGT). This “immune quiescent” state is associated with lower expression of T-cell activation markers, reduced levels of gene transcription and pro-inflammatory cytokine or chemokine production involved in HIV infection while maintaining an intact immune response against pathogens. Therefore, if this unique immune quiescent state can be pharmacologically induced locally, it will provide an excellent women-oriented strategy against HIV infection To our knowledge, this is the first research article evaluating in vivo, an innovative trackable implant that can provide controlled delivery of hydroxychloroquine (HCQ) to successfully attenuate vaginal T lymphocyte activation and inflammation in a rabbit model as a potential strategy to induce an “immune quiescent” state within the FGT for the prevention of HIV infection. This biocompatible implant can deliver HCQ above therapeutic concentrations in a controlled manner, reduce submucosal immune cell recruitment, improve mucosal epithelium integrity, decrease protein and gene expression of T-cell activation markers, and attenuate the induction of key pro-inflammatory mediators. Our results suggest that microbicides designed to maintain a low level of immune activation at the FGT may offer a promising new strategy for reducing HIV infection.



中文翻译:

植入物释放羟氯喹可减轻阴道T淋巴细胞的活化和炎症

有证据表明,对艾滋病毒感染具有自然抵抗力的女性在女性生殖道(FGT)的基线免疫激活较低。这种“免疫静止”状态与HIV感染中涉及的T细胞活化标记物的表达降低,基因转录水平降低以及促炎性细胞因子或趋化因子的产生有关,同时又保持了针对病原体的完整免疫应答。因此,如果可以在药理学上局部诱导这种独特的免疫静止状态,它将提供一种针对女性的极佳策略来抵抗HIV感染。据我们所知,这是第一篇在体内进行评估的研究文章,一种创新的可追踪植入物,可以提供羟氯喹(HCQ)的受控递送,以成功减轻兔子模型中阴道T淋巴细胞的活化和炎症反应,作为在FGT中诱导“免疫静止”状态以预防HIV感染的潜在策略。这种生物相容性植入物可以受控方式递送高于治疗浓度的HCQ,减少粘膜下免疫细胞募集,改善粘膜上皮完整性,降低T细胞活化标记物的蛋白质和基因表达,并减弱关键促炎性介质的诱导。我们的结果表明,旨在在FGT上维持较低水平的免疫活化的杀微生物剂可能为减少HIV感染提供了一种有希望的新策略。

更新日期:2018-03-13
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