ANTITUMOR NECROSIS FACTOR AMELIORATES JOINT DISEASE IN MURINE COLLAGEN-INDUCED ARTHRITIS
ANTITUMOR NECROSIS FACTOR AMELIORATES JOINT DISEASE IN MURINE COLLAGEN-INDUCED ARTHRITIS
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DOI：
10.1073/pnas.89.20.9784
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发表时间：
1992-10-15
影响因子：
11.1
通讯作者：
MAINI, RN
中科院分区：
文献类型：
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作者：
WILLIAMS, RO;FELDMANN, M;MAINI, RN
有相当多的证据表明肿瘤坏死因子α（TNF-α）在类风湿性关节炎的发病机制。这一证据不仅基于TNF-α在关节炎关节中的普遍存在，伴随着TNF-α受体的上调，而且基于中和TNF-α在关节细胞培养物中的作用。因此，体外中和TNF-α导致抑制白细胞介素1的产生，白细胞介素1与TNF-α一样，被认为有助于关节炎症和侵蚀。为了确定这一概念在体内的有效性，已经研究了对患有胶原诱导的关节炎的小鼠施用TNF-中和抗体的效果。选择这种疾病模型是因为它与人类类风湿性关节炎具有许多免疫学和病理学相似性。TN 3 -19.12是一种抗鼠TNF-α/β的仓鼠IgG 1单克隆抗体，在关节炎发作前或临床疾病确立后经腹腔注射给小鼠。在疾病发作前给予抗TNF显著降低了爪肿胀和关节炎的组织学严重程度，而不降低关节炎的发生率或循环抗II型胶原IgG的水平。与人类疾病更相关的是抗体降低临床评分、爪肿胀和疾病的组织学严重程度的能力，即使在临床关节炎发作后注射。这些结果对人类关节炎的可能治疗模式具有启示。
There is considerable evidence implicating tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of rheumatoid arthritis. This evidence is based not only on the universal presence of TNF-alpha in arthritic joints accompanied by the upregulation of TNF-alpha receptors but also on the effects of neutralizing TNF-alpha in joint cell cultures. Thus, neutralization of TNF-alpha in vitro results in inhibition of the production of interleukin 1, which like TNF-alpha, is believed to contribute to joint inflammation and erosion. To determine the validity of this concept in vivo, the effect of administering TNF-neutralizing antibodies to mice with collagen-induced arthritis has been studied. This disease model was chosen because of its many immunological and pathological similarities to human rheumatoid arthritis. TN3-19.12, a hamster IgG1 monoclonal antibody to murine TNF-alpha/beta, was injected i.p. into mice either before the onset of arthritis or after the establishment of clinical disease. Anti-TNF administered prior to disease onset significantly reduced paw swelling and histological severity of arthritis without reducing the incidence of arthritis or the level of circulating anti-type II collagen IgG. More relevant to human disease was the capacity of the antibody to reduce the clinical score, paw swelling, and the histological severity of disease even when injected after the onset of clinical arthritis. These results have implications for possible modes of therapy of human arthritis.