EA4222, Physiopatologie et Biothérapies de la Polyarthrite Rhumatoïde, Sorbonne Paris Cité-Université Paris 13, 93000 Bobigny, France.
J Immunol. 2011 Apr 1;186(7):3899-910. doi: 10.4049/jimmunol.1003372. Epub 2011 Feb 23.
CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) are involved in several autoimmune diseases, including rheumatoid arthritis. TNF-α blockers induce therapeutic benefits in rheumatoid arthritis via a variety of mechanisms. We aimed to characterize the impact on Treg of TNF-α overexpression in vivo and of TNF-α inhibiting treatments. We used human TNF-α transgenic mice as a model of strictly TNF-α-dependent arthritis. Our study showed that initial Treg frequency was lower in TNF-α transgenic mice than in wild-type mice. However, the course of arthritis was marked by elevation of Treg frequency and a dramatic increase in expression of TNFR2. Antagonizing TNF-α with either the anti-human TNF-α Ab (infliximab) or active immunotherapy (TNF-kinoid) increased the Treg frequency and upregulated CTLA-4, leading to enhancement of suppressor activity. Moreover, both anti-TNF-α strategies promoted the differentiation of a CD62L(-) Treg population. In conclusion, in an in vivo model of TNF-α-driven arthritis, Treg frequency increased with inflammation but failed to control the inflammatory process. Both passive and active TNF-α-inhibiting strategies restored the suppressor activity of Treg and induced the differentiation of a CD62L(-) Treg population.
CD4(+)CD25(+)Foxp3(+)调节性 T 细胞 (Treg) 参与多种自身免疫性疾病，包括类风湿关节炎。TNF-α 阻滞剂通过多种机制在类风湿关节炎中诱导治疗益处。我们旨在描述 TNF-α 过表达对体内 Treg 的影响以及 TNF-α 抑制治疗的影响。我们使用人 TNF-α 转基因小鼠作为严格依赖 TNF-α 的关节炎模型。我们的研究表明，TNF-α 转基因小鼠中的初始 Treg 频率低于野生型小鼠。然而，关节炎的过程伴随着 Treg 频率的升高和 TNFR2 的表达显著增加。用抗人 TNF-α Ab（英夫利昔单抗）或主动免疫疗法（TNF-kinoid）拮抗 TNF-α 增加了 Treg 的频率并上调 CTLA-4，从而增强了抑制活性。此外，两种抗 TNF-α 策略都促进了 CD62L(-) Treg 群体的分化。总之，在 TNF-α 驱动的关节炎的体内模型中，Treg 频率随着炎症而增加，但未能控制炎症过程。被动和主动 TNF-α 抑制策略均恢复了 Treg 的抑制活性，并诱导了 CD62L(-) Treg 群体的分化。
