Soluble Human P55 And P75 Tumor Necrosis Factor Receptors Reverse Spontaneous Arthritis In Transgenic Mice Expressing Transmembrane Tumor Necrosis Factor Alpha

Objective. The roles of the transmembrane and secreted forms of tumor necrosis factor alpha (TNF alpha) in rheumatoid arthritis (RA) remain unclear. Agents used to inhibit TNF alpha have shown varying efficacy in RA patients, suggesting that anti-TNF alpha agents possess dissimilar mechanisms of action, including the ability to neutralize transmembrane (tmTNF alpha) and secreted TNF alpha. In this study, TNF alpha-knockout (TNF alpha-KO) mice that were genetically altered to express elevated levels of tmTNFa were constructed to further understand the roles of the 17-kd secreted, trimeric, and 26-kd transmembrane forms of TNF alpha.Methods. A speed-congenic mating scheme was used to generate 3 unique strains of mice: 1) transgenic tmTgA86 mice overexpressing 26-kd tmTNF alpha and also secreting 17-kd trimeric TNFa (tmTNF alpha-transgenic), 2) TNF alpha(-/-) mice (TNF alpha-KO), and 3) transgenic mice overexpressing tmTNF alpha backcrossed to TNF alpha-KO mice (tmTNF alpha-transgenic/TNF alpha-KO). Mice were treated with phosphate buffered saline (as vehicle control), dexamethasone (as positive control), or modified recombinant human soluble TNF receptor (sTNFR) p55 or p75, and were assessed clinically and histopathologically for signs of inflammation and development of arthritis.Results. The tmTNFa-transgenic/TNF alpha-KO mice were born with crinkled tails and spinal deformities similar to those in ankylosing spondylitis. By 2-4 weeks, these mice developed symmetric inflammatory arthritis, characterized by tissue swelling, pannus formation, and bone deformities. The tmTNF alpha-transgenic mice also developed spontaneous-onset arthritis, but at a slower rate (100% incidence by 10-12 weeks). Clinical and histologic progression of arthritis in the tmTNF alpha-transgenic/TNF alpha-KO mice was reduced by treatment with dexamethasone or with the p55 or p75 sTNFR (69% and 63% reduction in total histologic score, respectively).Conclusion. These data show that arthritis is sufficiently initiated and maintained in tmTNF alpha-transgenic/TNF alpha-KO mice, and that it can be neutralized by recombinant human p55 or p75 sTNFR, resulting in amelioration of the biologic and subsequent histologic destructive effects of tmTNF alpha.