Severe inflammatory arthritis and lymphadenopathy in the absence of TNF

It has been postulated that TNF has a pivotal role in a cytokine cascade th at results in joint inflammation and destruction in rheumatoid arthritis (R A). To evaluate this, we examined the response of TNF-deficient (Tnf(-/-)) mice in two models of RA. Collagen-induced arthritis (CIA) was induced by i njection of chick type II collagen (CII) in CFA. Tnf(-/-) mice had some red uction in the clinical parameters of CIA and, on histology, significantly m ore normal joints. However, severe disease was evident in 54% of arthritic Tnf(-/-) joints. Tnf(-/-) mice had impaired Ig class switching, but preserv ed T cell proliferative responses to CII and enhanced IFN-gamma production. Interestingly, CII-immunized Tnf(-/-) mice developed lymphadenopathy and s plenomegaly associated with increased memory CD4(+) T cells and activated l ymph node B cells. Acute inflammatory arthritis was also reduced in Tnf(-/- ) mice, although again some mice exhibited severe disease. We conclude that TNF is important but not essential for inflammatory arthritis; in each mod el, severe arthritis could proceed even in the complete absence of TNF. The se results call into doubt the concept that TNF is obligatory for chronic a utoimmune and acute inflammatory arthritis and provide a rationale for furt her studies into TNF-independent cytokine pathways in arthritis.