In vivo neutralization of TNF-alpha promotes humoral autoimmunity by preventing the induction of CTL.
In vivo neutralization of TNF-alpha promotes humoral autoimmunity by preventing the induction of CTL.
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DOI：
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发表时间：
2001
影响因子：
4.4
通讯作者：
C. Via;A. Shustov;V. Rus;T. Lang;P. Nguyen;F. Finkelman
中科院分区：
文献类型：
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作者：
C. Via;A. Shustov;V. Rus;T. Lang;P. Nguyen;F. Finkelman
类风湿性关节炎或克罗恩病患者TNF-α的中和与体液自身免疫的发生有关。为了确定TNF-α中和作用对细胞介导和体液介导的反应的影响，我们使用亲本进入F（1）模型，对经历急性移植物抗宿主病（GVHD）的小鼠施用抗TNF-α mAb。体内TNF-α的中和作用阻断了急性GVHD的淋巴细胞减少特征，并诱导狼疮样慢性GVHD表型（淋巴细胞增殖和自身抗体产生）。这些作用是由于完全抑制可检测的抗宿主CTL活性，并且在亲代细胞转移后的前4天需要存在抗TNF-α mAb，表明TNF-α在诱导CTL中起关键作用。此外，TNF-α的体内阻断优先抑制IFN-γ的产生并阻断Fas的IFN-γ依赖性上调;然而，细胞因子如IL-10、IL-6或IL-4不受抑制。这些结果表明，治疗性TNF-α阻断可通过选择性抑制通常抑制自身反应性B细胞的CTL应答的诱导来促进体液自身免疫。
Neutralization of TNF-alpha in humans with rheumatoid arthritis or Crohn's disease has been associated with the development of humoral autoimmunity. To determine the effect of TNF-alpha neutralization on cell-mediated and humoral-mediated responses, we administered anti-TNF-alpha mAb to mice undergoing acute graft-vs-host disease (GVHD) using the parent-into-F(1) model. In vivo neutralization of TNF-alpha blocked the lymphocytopenic features characteristic of acute GVHD and induced a lupus-like chronic GVHD phenotype (lymphoproliferation and autoantibody production). These effects resulted from complete inhibition of detectable antihost CTL activity and required the presence of anti-TNF-alpha mAb for the first 4 days after parental cell transfer, indicating that TNF-alpha plays a critical role in the induction of CTL. Moreover, an in vivo blockade of TNF-alpha preferentially inhibited the production of IFN-gamma and blocked IFN-gamma-dependent up-regulation of Fas; however, cytokines such as IL-10, IL-6, or IL-4 were not inhibited. These results suggest that a therapeutic TNF-alpha blockade may promote humoral autoimmunity by selectively inhibiting the induction of a CTL response that would normally suppress autoreactive B cells.