Schulze-Koops H, Lipsky P E, Kavanaugh A F, Davis L S
University of Texas, Southwestern Medical Center, Harold C. Simmons Arthritis Research Center, Department of Internal Medicine, Dallas 75235-8884, USA.
Clin Exp Immunol. 1996 Nov;106(2):190-6. doi: 10.1046/j.1365-2249.1996.d01-828.x.
There is persistent excessive production of a number of pro-inflammatory cytokines in patients with rheumatoid arthritis (RA). A number of experimental therapies have been found to be effective in the treatment of RA, although the effects of these therapies on cytokine production have not been evaluated. One such experimental therapy involves administration of a MoAb to intercellular adhesion molecule-1 (ICAM-1) that has been shown to be clinically beneficial in approximately 60% of the patients, with some patients responding for up to 11 months. The current studies were carried out to determine whether the success of this therapy was associated with changes in mRNA levels for pro-inflammatory and other monocyte-derived cytokines in peripheral blood mononuclear cells (PBMC). Cytokine mRNA levels were assessed in freshly isolated unstimulated PBMC by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) after minimal in vitro manipulation of the cells. Anti-ICAM-1 MoAb administration was followed by an increase in IL-1 beta, IL-8, and tumour-necrosis factor-alpha (TNF-alpha) mRNA detected at 2 or 24 h after the initial infusion in the clinical responders, but no persistent change in these cytokine mRNA levels were observed that correlated with clinical benefit. By contrast, IL-6 mRNA levels declined immediately after the first MoAb infusion and reached pretreatment values variably after the 5 day treatment course. IL-6 mRNA levels remained significantly reduced in patients responding to therapy 1 months after treatment. Fluctuations in monocyte numbers within the PBMC after treatment did not account for the observed changes in cytokine mRNA levels. The results suggest that a decline in IL-6 mRNA levels is a pharmacological action of the MoAb to ICAM-1. Moreover, persistently diminished IL-6 mRNA levels induced by anti-ICAM-1 MoAb might be associated with the long-term benefit of this therapy. In addition, monitoring the activation status of monocytes in circulating PBMC may be useful in predicting response to therapy and warrants further investigation in a larger study population.
类风湿关节炎（RA）患者体内持续过量产生多种促炎细胞因子。已发现多种实验性疗法对RA治疗有效，尽管这些疗法对细胞因子产生的影响尚未得到评估。其中一种实验性疗法是给予抗细胞间黏附分子-1（ICAM-1）单克隆抗体（MoAb），该疗法已被证明对约60%的患者具有临床益处，部分患者的反应持续长达11个月。进行当前研究以确定该疗法的成功是否与外周血单核细胞（PBMC）中促炎和其他单核细胞衍生细胞因子的mRNA水平变化有关。在对细胞进行最少体外操作后，通过半定量逆转录-聚合酶链反应（RT-PCR）在新鲜分离的未刺激PBMC中评估细胞因子mRNA水平。在临床反应者中，首次输注后2或24小时检测到给予抗ICAM-1 MoAb后IL-1β、IL-8和肿瘤坏死因子-α（TNF-α）mRNA增加，但未观察到这些细胞因子mRNA水平与临床益处相关的持续变化。相比之下，首次输注MoAb后IL-6 mRNA水平立即下降，并在5天治疗疗程后不同程度地恢复到治疗前值。治疗1个月后，对治疗有反应的患者中IL-6 mRNA水平仍显著降低。治疗后PBMC中单核细胞数量的波动并不能解释观察到的细胞因子mRNA水平变化。结果表明，IL-6 mRNA水平下降是抗ICAM-1 MoAb的药理作用。此外，抗ICAM-1 MoAb诱导的IL-6 mRNA水平持续降低可能与该疗法的长期益处有关。此外，监测循环PBMC中单核细胞的活化状态可能有助于预测治疗反应，值得在更大的研究人群中进一步研究。
