Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis.

Abstract

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.

Deactivation of vascular endothelium by monoclonal anti–tumor necrosis factor α antibody in rheumatoid arthritis

“…The pivotal role of TNFa in the pathogenesis of RA suggested that this cytokine was a potential therapeutic target, and this concept was validated in our laboratory in the murine model of collagen-induced arthritis, the development of which can be inhibited by treatment with anti-TNFa after disease onset (9). In addition, recent studies have demonstrated that anti-TNFa treatment of rats with active arthritis markedly improved clinical scores and was paralleled by inhibition of leukocyte accumulation in the joints (10).…”

CD200‐FC, a novel antiarthritic biologic agent that targets proinflammatory cytokine expression in the joints of mice with collagen‐induced arthritis

“…A semiquantitative scoring system, giving a maximum possible score of 12 per mouse, was used (9). The thickness of the hind paws was monitored using calipers.…”

“…Tissue sections were prepared and stained with hematoxylin and eosin. Histopathologic changes were assessed using a semiquantitative scoring system for each paw (0-3 scale, where 0 ϭ normal, 1 ϭ minimal synovial inflammation, with cartilage and bone erosions limited to discrete foci, 2 ϭ synovial inflammation and moderate erosion, with normal joint architecture intact, and 3 ϭ severe inflammation and severe erosion, with joint architecture disrupted), as described previously (9).…”

Evaluation of therapeutic targets in animal models of arthritis: How does it relate to rheumatoid arthritis?

“…The role of TNF␣ and the effect of blocking its activity were investigated in various animal models. A hamster antibody specific for murine TNF was capable of reducing clinical manifestations and histologic scores in a mouse CIA model, also after disease onset (76). Spontaneously developed arthritis in human TNF-transgenic mice was blocked by treatment with a human TNF␣-specific antibody (69).…”