Fava R A, Gates C, Townes A S
Department of Veterans Affairs Medical Center, White River Jct., VT.
Clin Exp Immunol. 1993 Nov;94(2):261-6. doi: 10.1111/j.1365-2249.1993.tb03441.x.
Studies have implicated tumour necrosis factor-alpha (TNF-alpha) in type-II collagen (CII)-induced arthritis (CIA), a well established animal model of human rheumatoid arthritis. Precisely how TNF is involved in CIA is not yet clear. In this study the effects of TNF on CIA were examined, independent of its potential effects on the immune response, by performing peri-articular injection of TNF in combination with passive immunization of rats. A sub-arthritic dose (5 mg) of affinity-purified anti-CII IgG, which alone was insufficient to induce spontaneous clinical arthritis, was used throughout the study. Obvious clinical arthritis that persisted for several days was rapidly induced by injections of 100 ng TNF into hindpaws of rats that were passively immunized shortly before the TNF injection. Injections of TNF in non-immunized control rats did not induce clinical arthritis, nor did buffer-only injections in passively immunized controls. The clinical arthritic response was a local phenomenon, limited only to the TNF-injected hindpaws. No swelling was observed in the opposite, buffer-injected hindpaws, indicating the effects of TNF were not systemic. Depletion of peripheral blood phagocytes with anti-rat neutrophil antiserum before passive immunization completely abolished the ability of TNF to induce clinical arthritis, identifying phagocytic cells as the essential target cells in evoking this arthritic response. A role for complement activation was also demonstrated in this model through the use of a soluble recombinant version of CD35, the cell surface complement receptor type-1 (sCR1, BRL55730), which significantly reduced TNF-induced arthritis in phagocyte-replete rats.
研究表明，肿瘤坏死因子-α（TNF-α）与II型胶原（CII）诱导的关节炎（CIA）有关，CIA是一种成熟的人类类风湿性关节炎动物模型。目前尚不清楚TNF在CIA中的确切作用机制。在本研究中，通过对大鼠进行关节周围注射TNF并结合被动免疫，研究了TNF对CIA的影响，排除了其对免疫反应的潜在影响。在整个研究中，使用了亚关节炎剂量（5mg）的亲和纯化抗CII IgG，其单独使用不足以诱导自发性临床关节炎。在TNF注射前不久进行被动免疫的大鼠后爪注射100ng TNF，可迅速诱发持续数天的明显临床关节炎。在未免疫的对照大鼠中注射TNF不会诱发临床关节炎，在被动免疫的对照大鼠中仅注射缓冲液也不会诱发临床关节炎。临床关节炎反应是一种局部现象，仅局限于注射TNF的后爪。在对侧注射缓冲液的后爪未观察到肿胀，表明TNF的作用不是全身性的。在被动免疫前用抗大鼠中性粒细胞抗血清耗尽外周血吞噬细胞，完全消除了TNF诱导临床关节炎的能力，确定吞噬细胞是引发这种关节炎反应的关键靶细胞。通过使用可溶性重组形式的CD35（细胞表面补体受体1型，sCR1，BRL55730），在该模型中也证明了补体激活的作用，sCR1可显著减轻吞噬细胞充足的大鼠中TNF诱导的关节炎。
