Suzuki Motohiko, Yokota Makoto, Matsumoto Tamami, Ozaki Shinya
Int Arch Allergy Immunol. 2018;177(2):87-96. doi: 10.1159/000489862. Epub 2018 Jul 12.
We previously reported that siRNA-induced CD40-silenced dendritic cells (DCs) inhibit allergic responses and symptoms. However, more potent therapies are needed. To our knowledge, synergic effects of gene silencing in DCs by ≥2 siRNAs have not been reported to control allergic diseases. Therefore, we investigated the synergistic effects of the silencing of CD40 and CD86 in DCs on allergic responses.
Mice were treated with CD40/CD86-silenced DCs, which were transfected with CD40/CD86 siRNAs and pulsed with ovalbumin (OVA) antigen. The effects of these DCs on allergic symptoms and allergic responses were estimated.
The administration of CD40/CD86-silenced OVA-pulsed DCs significantly inhibited the number of sneezes and nasal rubbing movements, the number of eosinophils in the nasal mucosa, and the level of OVA-specific IgE when compared with those for CD40- or CD86-silenced OVA-pulsed DCs alone (p < 0.01). These inhibitory effects were detected before sensitization as well as after the establishment of allergic rhinitis. CD40/CD86-silenced OVA-pulsed DCs did not inhibit KLH-induced allergies. Foxp3 gene expression was significantly upregulated in CD40-silenced DCs compared to in CD86-silenced DCs (p < 0.01). IL-4 production by T cells was suppressed more substantially when using CD86-silenced DCs than with CD40-silenced DCs (p < 0.01).
These results indicate, for the first time, that siRNA-induced CD40/CD86-silenced antigen-specific DCs have greater inhibitory effects against allergic responses than those of CD40- or CD86-silenced antigen-specific DCs alone. This study also suggests that the synergic effects of gene silencing in DCs by ≥2 siRNAs are useful for the control of allergic diseases. Thus, owing to the synergistic effects, CD40 and CD86 silencing has the potential to substantially improve the treatment of allergic diseases.
我们之前报道过，小干扰RNA（siRNA）诱导的CD40沉默树突状细胞（DCs）可抑制过敏反应和症状。然而，仍需要更有效的治疗方法。据我们所知，尚未有关于≥2种siRNA在DCs中进行基因沉默以控制过敏性疾病的协同效应的报道。因此，我们研究了DCs中CD40和CD86沉默对过敏反应的协同效应。
用CD40/CD86沉默的DCs处理小鼠，这些DCs用CD40/CD86 siRNAs转染并用卵清蛋白（OVA）抗原脉冲处理。评估这些DCs对过敏症状和过敏反应的影响。
与单独使用CD40或CD86沉默的OVA脉冲DCs相比，给予CD40/CD86沉默的OVA脉冲DCs可显著抑制喷嚏次数和鼻摩擦动作次数、鼻黏膜中嗜酸性粒细胞数量以及OVA特异性IgE水平（p < 0.01）。在致敏前以及变应性鼻炎建立后均检测到这些抑制作用。CD40/CD86沉默的OVA脉冲DCs不抑制钥孔戚血蓝蛋白（KLH）诱导的过敏反应。与CD86沉默的DCs相比，CD40沉默的DCs中Foxp3基因表达显著上调（p < 0.01）。与CD40沉默的DCs相比，使用CD86沉默的DCs时T细胞产生的白细胞介素-4（IL-4）受到的抑制更显著（p < 0.01）。
这些结果首次表明，siRNA诱导的CD40/CD86沉默的抗原特异性DCs对过敏反应的抑制作用比单独的CD40或CD86沉默的抗原特异性DCs更强。本研究还表明，≥2种siRNA在DCs中进行基因沉默的协同效应有助于控制过敏性疾病。因此，由于协同效应，CD40和CD86沉默有可能显著改善过敏性疾病的治疗。
