Effective treatment of established murine collagen-induced arthritis by systemic administration of dendritic cells genetically modified to express IL-4
Effective treatment of established murine collagen-induced arthritis by systemic administration of dendritic cells genetically modified to express IL-4
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DOI：
10.4049/jimmunol.166.5.3499
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发表时间：
2001-03-01
影响因子：
4.4
通讯作者：
Robbins, PD
中科院分区：
文献类型：
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作者：
Kim, SH;Kim, S;Robbins, PD
树突状细胞 (DC) 是能够刺激或抑制免疫反应的 APC，具体取决于 MHC I 类和 II 类共刺激分子和细胞因子的表达水平。我们之前的研究表明，观察到的对侧效应（将携带某些免疫调节基因的载体注射到一个关节中，会抑制未经治疗的关节中的关节炎）是由 DC 的体内修饰介导的。因此，我们检查了转基因 DC 在静脉注射后抑制已建立的小鼠胶原诱导性关节炎 (CIA) 的能力。送货。重复注射重组蛋白或注射表达 IL-4 的腺病毒载体后，IL-4 已被证明可以部分减轻 CIA 的严重程度。在这里我们证明了 i.v.将感染有表达 IL-4 的腺病毒载体的未成熟 DC 注射到已建立 CW 的小鼠中，几乎完全抑制了疾病，治疗后长达 4 周没有复发。荧光标记的 DC 的结果表明，细胞在 6 小时后迅速迁移到肝脏和脾脏，并在 24 小时后迁移到淋巴结。在培养中，DC/IL-4 处理的小鼠的脾细胞在受到胶原蛋白刺激后产生的 IFN-γ 少于对照组。此外，DC/IL-4施用降低了针对II型胶原的特异性抗体的水平，特别是治疗后14天的IgG2 Th1同种型。这些结果证明了通过全身施用表达IL-4的DC来有效治疗已形成的小鼠关节炎的能力。
Dendritic cells (DC) are APCs that are able to stimulate or inhibit immune responses, depending on levels of expression of MHC class I and II costimulatory molecules and cytokines, Our previous studies have suggested that the observed contralateral effect, where injection of a vector carrying certain immunomodulatory genes into one joint resulted in inhibition of arthritis in untreated joints, is mediated by in vivo modification of DC. Therefore, we have examined the ability of genetically modified DC to suppress established murine collagen-induced arthritis (CIA) after i.v. delivery. IL-4 has been shown to partially reduce the severity of CIA after repeated injection of recombinant protein or by injection of an adenoviral vector expressing IL-4. Here we demonstrate that i.v. injection of immature DC, infected with an adenoviral vector expressing IL-4, into mice with established CW resulted in almost complete suppression of disease, with no recurrence for up to 4 wk posttreatment, Injection i.v. of fluorescently labeled DC demonstrated that the cells rapidly migrated to the liver and spleen after 6 h and to the lymph nodes by 24 h, In culture, spleen cells from DC/IL-4-treated mice produced less IFN-gamma after stimulation by collagen than did control groups. In addition, DC/IL-4 administration decreased the level of specific Abs against type II collagen, in particular the IgG2 Th1 isotype 14 days posttreatment, These results demonstrate the ability to treat effectively established murine arthritis by systemic administration of DC expressing IL-4.