Université Paris-13 Sorbonne Paris Cité, EA4222, Paris, France.
Clin Exp Immunol. 2013 Apr;172(1):54-62. doi: 10.1111/cei.12040.
Active anti-tumour necrosis factor (TNF)-α immunization with the kinoid of TNF-α (TNF-K) induces polyclonal anti-TNF-α antibodies and ameliorates arthritis in human TNF-α (hTNF-α) transgenic mice (TTg). We compared the efficacy of TNF-K to that of infliximab (IFX) and of TNF-K and IFX co-administration, and evaluated whether the titres of anti-hTNF-α antibodies induced by immunization were a determinant of TNF-K efficacy. Forty-eight TTg mice received one of the following treatments: TNF-K immunization (TNF-K group); weekly IFX throughout the study duration (IFXw0-15); TNF-K plus weekly IFX for 4 weeks (TNF-K + IFX); and weekly IFX for 4 weeks (IFXw0-4); PBS. Animals were killed at week 16. Anti-hTNF-α antibody titres and clinical and histological scores were compared. All TNF-K immunized mice (TNF-K and TNF-K + IFX) produced anti-hTNF-α antibodies. Titres were higher in TNF-K versus TNF-K + IFX (P < 0·001) and correlated inversely with histological inflammation (R = -0·78; P = 0·0001) and destruction (R = -0·67; P = 0·001). TNF-K + IFX had higher histological inflammation and destruction versus TNF-K (P < 0·05). A receiver operating characteristic (ROC) analysis of anti-hTNF-α antibody titres identified the criterion cut-off value to discriminate most effectively between the TNF-K and TNF-K + IFX groups. Mice with high versus low titres had less histological inflammation and destruction (P < 0·05). In a model of TNF-α-dependent arthritis, protection from articular damage by TNF-K correlates with the titres of induced anti-hTNF-α antibodies. The co-administration of TNF-K and a short course of infliximab does not result in less articular damage versus solely TNF-K, due probably to lower anti-hTNF-α antibody production. These results are relevant for future development of active anti-TNF-α immunization in human disease.
使用 TNF-α 的 Kinoid（TNF-K）进行主动抗肿瘤坏死因子（TNF）-α免疫接种会诱导多克隆抗 TNF-α 抗体，并改善人 TNF-α（hTNF-α）转基因小鼠（TTg）的关节炎。我们比较了 TNF-K 与英夫利昔单抗（IFX）的疗效，以及 TNF-K 和 IFX 联合给药的疗效，并评估了免疫接种诱导的抗 hTNF-α 抗体滴度是否是 TNF-K 疗效的决定因素。48 只 TTG 小鼠接受以下治疗之一：TNF-K 免疫接种（TNF-K 组）；整个研究期间每周接受英夫利昔单抗（IFXw0-15）；TNF-K 加每周 IFX 治疗 4 周（TNF-K+IFX）；每周 IFX 治疗 4 周（IFXw0-4）；PBS。动物在第 16 周被处死。比较抗 hTNF-α 抗体滴度和临床及组织学评分。所有接受 TNF-K 免疫接种的小鼠（TNF-K 和 TNF-K+IFX）均产生抗 hTNF-α 抗体。TNF-K 组的滴度高于 TNF-K+IFX 组（P<0.001），与组织学炎症（R=-0.78；P=0.0001）和破坏（R=-0.67；P=0.001）呈负相关。与 TNF-K 相比，TNF-K+IFX 具有更高的组织学炎症和破坏（P<0.05）。抗 hTNF-α 抗体滴度的受试者工作特征（ROC）分析确定了区分 TNF-K 和 TNF-K+IFX 组的最佳临界值。高滴度与低滴度相比，组织学炎症和破坏更少（P<0.05）。在 TNF-α 依赖性关节炎模型中，TNF-K 对关节损伤的保护作用与诱导的抗 hTNF-α 抗体滴度相关。TNF-K 与短期英夫利昔单抗联合使用不会导致关节损伤少于仅 TNF-K，可能是由于产生的抗 hTNF-α 抗体较少。这些结果与未来在人类疾病中进行主动抗 TNF-α 免疫接种的发展有关。
