Targeting of Autoantigens to DEC205+ Dendritic Cells In Vivo Suppresses Experimental Allergic Encephalomyelitis in Mice
Targeting of Autoantigens to DEC205+ Dendritic Cells In Vivo Suppresses Experimental Allergic Encephalomyelitis in Mice
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DOI：
10.4049/jimmunol.1202592
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发表时间：
2013-09
期刊：
影响因子：
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通讯作者：
S. Ring;Michael Maas;D. Nettelbeck;A. Enk;K. Mahnke
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作者：
S. Ring;Michael Maas;D. Nettelbeck;A. Enk;K. Mahnke
树突状和上皮细胞受体的分子量。DEC 205由树突状细胞（DC）表达，并促进Ag呈递。在将与DEC 205特异性Ab偶联的Ag注射到小鼠中后，未活化的DC发生Ag呈递，这导致诱导调节性T细胞（T细胞）。为了测试该系统在实验性变态反应性脑脊髓炎（EAE）中的耐受诱导，我们创建了对DEC 205特异性的单链片段变量（scFv），并将scFv融合到自身Ag髓鞘少突胶质细胞糖蛋白（MOG; scFv DEC：MOG）。抗β-半乳糖苷酶scFv：MOG融合蛋白（scFv GL 117：MOG）用作同种型对照。用纯化的scFv DEC：MOG体外染色DC后，与DC的结合和与MHC II类的共定位是明显的，而同种型对照没有结合。接下来，我们将scFvDEC：MOG注射到小鼠体内，观察到脾脏中高度活化、产生IL-10的CD 4 + CD 25 + Foxp 3 + Tregs（占CD 4的17%）数量增加，与同种型对照和未注射的小鼠（占CD 4的12%）相比。此外，从注射scFv DEC：MOG的动物分离的DC产生显著增加的TGF-β水平。最重要的是，当在注射scFv DEC：MOG的小鼠中诱导EAE时，90%的小鼠被保护免于EAE，而同种型对照（scFv GL 117：MOG）中的所有小鼠经历EAE的发展。当将scFv DEC：MOG应用于已经经历EAE症状的小鼠时，在90%的动物中疾病的消除是明显的，而对照组中的所有动物都经历了严重EAE的发展。因此，这些数据表明MOG在体内靶向“稳态”DC可以提供通过DC/Treg驱动机制预防和治疗EAE的工具。
The dendritic and epithelial cell receptor with a m.w. of 205 kDa (DEC205) is expressed by dendritic cells (DCs) and facilitates Ag presentation. After injection of Ags coupled to Abs specific for DEC205 into mice, Ag presentation occurs by nonactivated DCs, which leads to induction of regulatory T cells (Tregs). To test this system for tolerance induction in experimental allergic encephalomyelitis (EAE), we created single-chain fragment variables (scFv) specific for DEC205 and fused the scFv to the self-Ag myelin oligodendrocyte glycoprotein (MOG; scFv DEC:MOG). An anti–β-galactosidase scFv:MOG fusion protein (scFv GL117:MOG) served as isotype control. After staining of DCs in vitro with purified scFv DEC:MOG, binding to DCs and colocalization with MHC class II was apparent, whereas isotype controls did not bind. We next injected scFv DEC:MOG into mice and observed elevated numbers of highly activated, IL-10–producing CD4+CD25+Foxp3+ Tregs (17% of CD4) in spleens, as compared with isotype controls and uninjected mice (12% of CD4). Furthermore, DCs isolated from scFv DEC:MOG-injected animals produced significantly increased levels of TGF-β. Most importantly, when EAE was induced in scFv DEC:MOG-injected mice, 90% of the mice were protected from EAE, whereas all mice in the isotype controls (scFv GL117:MOG) experienced development of EAE. When applying scFv DEC:MOG to mice that had already experienced EAE symptoms, abrogation of the disease in 90% of the animals was apparent, whereas all animals in the control groups experienced development of severe EAE. Thus, these data indicate that targeting of MOG to “steady-state” DCs in vivo may provide a tool to prevent and to treat EAE by a DC/Treg-driven mechanism.