The in vivo effects of tumour necrosis factor blockade on the early cell mediated immune events and syndrome expression in rat adjuvant arthritis
The in vivo effects of tumour necrosis factor blockade on the early cell mediated immune events and syndrome expression in rat adjuvant arthritis
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DOI：
10.1046/j.1365-2249.2002.01742.x
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发表时间：
2002-03-01
影响因子：
4.6
通讯作者：
Walker, JS
中科院分区：
文献类型：
--
作者：
Bush, KA;Kirkham, BW;Walker, JS
抗肿瘤坏死因子治疗类风湿性关节炎(RA)有效，但其作用机制尚不完全清楚。T细胞驱动的机制被认为在类风湿关节炎中起着重要作用，而肿瘤坏死因子阻断对这些机制的影响尚不清楚。佐剂性关节炎(AA)是一种T细胞依赖的炎性关节炎模型。本研究旨在探讨阻断肿瘤坏死因子对体内T细胞因子表达的影响，探讨肿瘤坏死因子在早期关节炎腹股沟淋巴结中的作用。雄性DA大鼠可诱发AA。大鼠在诱导后第0、2、4天分别给予3 mg/kg或10 mg/kg的聚乙二醇sTNF-RI，或在诱导关节炎的当天给予10 mg/kg的抗肿瘤坏死因子抗体。对照组大鼠接受生理盐水或正常绵羊血清。每隔3~4d评估一次足底体积。分别于诱导后0、6、13、21d处死大鼠。切除踝关节进行定量放射学检查和组织学检查。取滑膜和ILN进行细胞培养，半定量RT-PCR法检测细胞因子的mRNA表达。用生物测定法和酶联免疫吸附试验检测肿瘤坏死因子和干扰素-γ蛋白的产生。在再生障碍性关节炎早期，阻断肿瘤坏死因子不能抑制大鼠ILN中T细胞细胞因子的mRNA表达，提示T细胞活性持续存在。尽管培养前ILN细胞的mRNA表达增加，但经PEGsTNF-RI处理的大鼠ILN细胞在培养过程中产生的TNF蛋白减少。与抑制疾病的抗肿瘤坏死因子抗体相比，早期应用聚乙二醇sTNF-RI并不能减弱再生障碍性贫血。与抗肿瘤坏死因子抗体相比，聚乙二醇单抗的半衰期较短，或抗聚乙二醇单抗的发展可能解释了这些结果。
Anti-TNF therapy is effective in rheumatoid arthritis (RA); however, its mechanisms of action are incompletely understood. T cell-driven mechanisms are thought to play an important role in RA and the effects of TNF blockade on these mechanisms are unclear. Adjuvant arthritis (AA) is a T cell dependent model of inflammatory arthritis. The aims of this study were to investigate the effects of TNF blockade on in vivo T cell cytokine expression and to clarify the role of TNF in the inguinal lymph nodes (ILN) in early arthritis. AA was induced in male DA rats. Rats received either 3 mg/kg or 10 mg/kg PEG sTNF-RI at days 0, 2 and 4 postinduction or 10 mg/kg anti-TNF antibody on day of arthritis induction. Control rats received either saline or normal sheep serum. Paw volume was assessed every 3-4 days. Rats were sacrificed on days 0, 6, 13 and 21 postinduction. Ankles were removed for quantitative radiology and histology. Synovium and ILN were removed for cell culture and to determine mRNA expression of cytokines using semiquantitative RT-PCR. TNF and IFN-gamma protein production was measured using a bioassay and an ELISA. TNF blockade did not suppress mRNA expression of T cell cytokines in the ILN of rats in the early phase of AA, suggesting ongoing T cell activity. TNF protein production by ILN cells in culture was reduced in PEG sTNF-RI treated rats, although mRNA expression was increased in the ILN prior to culture. Early administration of PEG sTNF-RI did not attenuate AA, in contrast to an anti-TNF antibody, which suppressed disease. A shorter half-life for the PEG sTNF-RI compared with the anti-TNF antibody or the development of anti-PEG sTNF-RI antibodies may account for these results.