Cholesterol Modification of p40-Specific Small Interfering RNA Enables Therapeutic Targeting of Dendritic Cells
Cholesterol Modification of p40-Specific Small Interfering RNA Enables Therapeutic Targeting of Dendritic Cells
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DOI：
10.4049/jimmunol.1402989
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发表时间：
2015-09-01
影响因子：
4.4
通讯作者：
Ghoreschi, Kamran
中科院分区：
文献类型：
--
作者：
Brueck, Juergen;Pascolo, Steve;Ghoreschi, Kamran
基于小干扰RNA(SiRNA)的治疗方法可以有针对性地纠正不同细胞群体中的分子缺陷。尽管树突状细胞(DC)在多个细胞群中有效，但它似乎抵抗siRNA的传递。利用荧光标记和放射性标记，我们发现胆固醇修饰能够在体外和体内使树突状细胞摄取siRNA。经胆固醇修饰的p40 siRNA选择性地抑制了p40转录，并抑制了TLR触发的DC产生p40。在CFA的多肽免疫过程中，胆固醇修饰的p40 siRNA产生p40缺陷的、产生IL-10的树突状细胞，阻止IL-17/Th17和干扰素-γ/Th1反应。只有胆固醇修饰的p40-siRNA建立了对实验性自身免疫性脑脊髓炎的保护性免疫，并抑制了中枢神经系统渗入的单个核细胞的干扰素-γ和IL-17的表达，而不诱导调节性T细胞。由于胆固醇修饰的siRNA可以在体内改变选定的DC功能，因此它对过敏、自身免疫或肿瘤疾病的靶向免疫治疗很有吸引力。
Small interfering RNA (siRNA)-based therapies allow targeted correction of molecular defects in distinct cell populations. Although efficient in multiple cell populations, dendritic cells (DCs) seem to resist siRNA delivery. Using fluorescence labeling and radiolabeling, we show that cholesterol modification enables siRNA uptake by DCs in vitro and in vivo. Delivery of cholesterol-modified p40 siRNA selectively abolished p40 transcription and suppressed TLR-triggered p40 production by DCs. During immunization with peptide in CFA, cholesterol-modified p40 siRNA generated p40-deficient, IL-10-producing DCs that prevented IL-17/Th17 and IFN-gamma/Th1 responses. Only cholesterol-modified p40-siRNA established protective immunity against experimental autoimmune encephalomyelitis and suppressed IFN-gamma and IL-17 expression by CNS-infiltrating mononuclear cells without inducing regulatory T cells. Because cholesterol-modified siRNA can thus modify selected DC functions in vivo, it is intriguing for targeted immune therapy of allergic, autoimmune, or neoplastic diseases.