Maini R N, Elliott M, Brennan F M, Williams R O, Feldmann M
Kennedy Institute of Rheumatology, London, U.K.
Clin Exp Rheumatol. 1994 Nov-Dec;12 Suppl 11:S63-6.
Our pre-clinical studies have demonstrated a pathogenic role for TNF alpha in RA. Firstly, TNF alpha and its receptors are upregulated and co-expressed in the synovium and cartilage-pannus junction of RA joints. Secondly, mononuclear cells from RA joints maintained in culture produce many cytokines with pro-inflammatory activity, including TNF alpha. Neutralizing TNF alpha antibodies in vitro reduces the production of these pro-inflammatory cytokines, including IL-1, IL-8, and GM-CSF. Thirdly, when injected into arthritic DBA/l mice with collagen-induced arthritis, monoclonal anti-TNF antibodies decrease inflammatory damage of joints. Clinical trials employing cA2, a monoclonal chimeric anti-TNF alpha antibody, in open-label and randomized placebo-controlled studies have demonstrated a dose-dependent efficacy with impressive improvement in disease activity and acute phase responses lasting several weeks. We conclude that TNF alpha is a critical mediator of inflammation in RA and is an important therapeutic target in this disease.
我们的临床前研究已证明肿瘤坏死因子α（TNFα）在类风湿性关节炎（RA）中具有致病作用。首先，TNFα及其受体在RA关节的滑膜和软骨-血管翳交界处上调并共同表达。其次，培养的RA关节单核细胞可产生多种具有促炎活性的细胞因子，包括TNFα。体外中和TNFα抗体可减少这些促炎细胞因子的产生，包括白细胞介素-1（IL-1）、白细胞介素-8（IL-8）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）。第三，将单克隆抗TNF抗体注射到患有胶原诱导性关节炎的DBA/l小鼠体内，可减少关节的炎性损伤。在开放标签和随机安慰剂对照研究中，使用单克隆嵌合抗TNFα抗体cA2的临床试验已证明其具有剂量依赖性疗效，可显著改善疾病活动度，并使急性期反应持续数周。我们得出结论，TNFα是RA炎症的关键介质，也是该疾病的重要治疗靶点。
