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CD40 基因沉默可减缓实验性狼疮肾炎的进展，调节局部微环境和全身机制。

CD40 gene silencing reduces the progression of experimental lupus nephritis modulating local milieu and systemic mechanisms.

机构信息

Laboratory of Experimental Nephrology, IDIBELL.Hospital Universitari de Bellvitge, L'Hospitalet, Barcelona, Spain.

出版信息

PLoS One. 2013 Jun 14;8(6):e65068. doi: 10.1371/journal.pone.0065068. Print 2013.

DOI:10.1371/journal.pone.0065068
PMID:23799000
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3683035/
Abstract

Lupus nephritis (LN) is an autoimmune disorder in which co-stimulatory signals have been involved. Here we tested a cholesterol-conjugated-anti-CD40-siRNA in dendritic cells (DC) in vitro and in a model of LPS to check its potency and tissue distribution. Then, we report the effects of Chol-siRNA in an experimental model of mice with established lupus nephritis. Our in vitro studies in DC show a 100% intracellular delivery of Chol-siRNA, with a significant reduction in CD40 after LPS stimuli. In vivo in ICR mice, the CD40-mRNA suppressive effects of our Chol-siRNA on renal tissue were remarkably sustained over a 5 days after a single preliminary dose of Chol-siRNA. The intra-peritoneal administration of Chol-siRNA to NZB/WF1 mice resulted in a reduction of anti-DNA antibody titers, and histopathological renal scores as compared to untreated animals. The higher dose of Chol-siRNA prevented the progression of proteinuria as effectively as cyclophosphamide, whereas the lower dose was as effective as CTLA4. Chol-siRNA markedly reduced insterstitial CD3+ and plasma cell infiltrates as well as glomerular deposits of IgG and C3. Circulating soluble CD40 and activated splenic lymphocyte subsets were also strikingly reduced by Chol-siRNA. Our data show the potency of our compound for the therapeutic use of anti-CD40-siRNA in human LN and other autoimmune disorders.

摘要

狼疮性肾炎 (LN) 是一种自身免疫性疾病，其中共刺激信号已被涉及。在这里，我们在体外的树突状细胞 (DC) 中测试了胆固醇偶联的抗 CD40-siRNA，并在 LPS 模型中检查了其效力和组织分布。然后，我们报告了 Chol-siRNA 在已建立狼疮性肾炎的实验模型中小鼠中的作用。我们在 DC 中的体外研究表明，Chol-siRNA 具有 100%的细胞内递送率，并在 LPS 刺激后显著降低了 CD40。在 ICR 小鼠体内，我们的 Chol-siRNA 对肾脏组织中 CD40-mRNA 的抑制作用在单次预给药 Chol-siRNA 后 5 天内显著持续。将 Chol-siRNA 腹膜内给药给 NZB/WF1 小鼠，与未治疗的动物相比，降低了抗 DNA 抗体滴度和组织病理学肾脏评分。高剂量的 Chol-siRNA 可有效预防蛋白尿的进展，与环磷酰胺一样有效，而低剂量与 CTLA4 一样有效。Chol-siRNA 明显减少了间质 CD3+和浆细胞浸润以及肾小球 IgG 和 C3 的沉积。循环可溶性 CD40 和激活的脾淋巴细胞亚群也被 Chol-siRNA 明显减少。我们的数据表明，我们的化合物在人类 LN 和其他自身免疫性疾病中使用抗 CD40-siRNA 的治疗潜力。

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