Dendritic cells matured with TNF can be further activated in vitro and after subcutaneous injection in vivo which converts their tolerogenicity into immunogenicity
Dendritic cells matured with TNF can be further activated in vitro and after subcutaneous injection in vivo which converts their tolerogenicity into immunogenicity
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DOI：
10.1097/01.cji.0000210081.60178.b4
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发表时间：
2006-07-01
影响因子：
3.9
通讯作者：
Lutz, Manfred B.
中科院分区：
文献类型：
--
作者：
Voigylaender, Constanze;Roessner, Susanne;Lutz, Manfred B.
树突状细胞 (DC) 成熟可以通过不同类型的刺激发生。之前，我们描述了用肿瘤坏死因子（TNF）上调表面MHC和共刺激分子但缺乏细胞因子释放的小鼠DC成熟，因此将其称为半成熟DC。在实验性自身免疫性脑脊髓炎 (EAE) 模型中静脉 (IV) 注射后，这些 TNF/DC 诱导耐受。在这里，我们证明 TNF/DC 不是终末分化的，但仍然可以对微生物刺激脂多糖做出反应。皮下注射 TNF/DC 会诱导非极化 T(H)1/T(H)2 反应，并且在实验性自身免疫性脑脊髓炎模型中没有保护作用。尽管 TNF/DC 位于引流淋巴结，但它们的细胞内细胞因子染色仍呈阴性。然而，非迁移的内源性 DC 开始以旁观者的方式产生白细胞介素 (IL)-12p40、TNF 和少量 IL-6、IL-10 和 MCP-1。总之，在炎症刺激物 TNF 的作用下成熟的 DC 仍然对体外和体内的进一步信号做出反应。这些信号可以由病原体或皮下注射途径提供，这可以将它们从耐受性DC转变为免疫原性DC。这些发现对于选择合适的人 DC 注射途径进行肿瘤免疫治疗非常重要。
Dendritic cell (DC) maturation can occur by different types of stimuli. Previously, we described that murine DC matured with tumor necrosis factor (TNF) up-regulate surface MHC and costimulatory molecules but lack cytokine release, and therefore termed them semi-mature DC. These TNF/DC-induced tolerance after intravenous (IV) injection in a model of experimental autoimmune encephalomyelitis (EAE). Here, we show that TNF/DC are not terminally differentiated but can still respond to the microbial stimulus lipopolysaccharide. Subcutaneously injected TNF/DC induce an unpolarized T(H)1/T(H)2 response and are not protective in the experimental autoimmune encephalomyelitis model. Although TNF/DC home to the draining lymph node, they remain negative for intracellular cytokine stainings. However, the nonmigrating, endogenous DC started to produce interleukin (IL)-12p40, TNF and little IL-6, IL-10, and MCP-1 in a bystander fashion. Together, DC matured with the inflammatory stimulus TNF remains responsive to further signals in vitro and in vivo. These signals can be provided by pathogens or the subcutaneous injection route, which can convert them from tolerogenic to immunogenic DC. These findings are important for selecting the appropriate injection route of human DC for tumor immunotherapy.