Repetitive injections of dendritic cells matured with tumor necrosis factor alpha induce antigen-specific protection of mice from autoimmunity.
Repetitive injections of dendritic cells matured with tumor necrosis factor alpha induce antigen-specific protection of mice from autoimmunity.
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DOI：
10.1084/jem.20011341
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发表时间：
2002-01-07
影响因子：
15.3
通讯作者：
Lutz, Manfred B
中科院分区：
文献类型：
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作者：
Menges, Mauritius;Rossner, Susanne;Voigtlander, Constanze;Schindler, Heike;Kukutsch, Nicole A;Bogdan, Christian;Erb, Klaus;Schuler, Gerold;Lutz, Manfred B
成熟的树突状细胞（DC）被认为诱导T细胞免疫，而未成熟的DC诱导T细胞耐受。在这里，我们描述了注射肿瘤坏死因子（TNF）-α成熟的DC（TNF/DC）诱导小鼠实验性自身免疫性脑脊髓炎（EAE）的抗原特异性保护。TNF-α诱导的成熟诱导了DC上高水平的主要组织相容性复合物II类和共刺激分子，但它们仍然是促炎细胞因子的弱生产者。一次注射这种用自身抗原肽脉冲的TNF/DC改善了EAE的疾病评分。这在未成熟DC或用脂多糖（LPS）加抗CD 40成熟的DC中不能观察到。连续三次注射来自野生型的肽脉冲的TNF/DC导致肽特异性主要产生白细胞介素（IL）-10的CD 4 + T细胞的诱导和对EAE的完全保护。在体内阻断IL-10只能部分恢复EAE的易感性，提示IL-10在EAE预防中具有重要但非唯一的作用。值得注意的是，保护是肽特异性的，因为用无关肽脉冲的TNF/DC不能预防EAE。总之，本研究描述了TNF-α刺激导致不完全成熟的DC（半成熟DC），其在体内诱导肽特异性IL-10产生T细胞并预防EAE。
Mature dendritic cells (DCs) are believed to induce T cell immunity, whereas immature DCs induce T cell tolerance. Here we describe that injections of DCs matured with tumor necrosis factor (TNF)-α (TNF/DCs) induce antigen-specific protection from experimental autoimmune encephalomyelitis (EAE) in mice. Maturation by TNF-α induced high levels of major histocompatibility complex class II and costimulatory molecules on DCs, but they remained weak producers of proinflammatory cytokines. One injection of such TNF/DCs pulsed with auto-antigenic peptide ameliorated the disease score of EAE. This could not be observed with immature DCs or DCs matured with lipopolysaccharide (LPS) plus anti-CD40. Three consecutive injections of peptide-pulsed TNF/DCs derived from wild-type led to the induction of peptide-specific predominantly interleukin (IL)-10–producing CD4+ T cells and complete protection from EAE. Blocking of IL-10 in vivo could only partially restore the susceptibility to EAE, suggesting an important but not exclusive role of IL-10 for EAE prevention. Notably, the protection was peptide specific, as TNF/DCs pulsed with unrelated peptide could not prevent EAE. In conclusion, this study describes that stimulation by TNF-α results in incompletely matured DCs (semi-mature DCs) which induce peptide-specific IL-10–producing T cells in vivo and prevent EAE.