INHIBITION OF SUPERANTIGEN-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION AND INFLAMMATORY ARTHRITIS IN MRL-LPR LPR MICE BY A TRANSCRIPTIONAL INHIBITOR OF TNF-ALPHA/

We have used fas-defective MRL-lpr/lpr mice to study the effects of th e staphylococcal enterotoxin superantigens on the development of autoi mmune, inflammatory joint disease In animals that are susceptible to t he development of rheumatoid arthritis-like disease. We show that syst ematic administration by a single i.p. injection of staphylococcal ent erotoxin B (SEB; 10 mu g/mouse) caused a mild, inflammatory arthritis +30 days postchallenge in the knee joints of young (<2-mo-old) MRL-lpr /lpr mice, but not aged-matched MRL +/+ mice, In aged (>8-mo-old) MRL- lpr/lpr mice, but not in aged MRL +/+ mice, SEB caused a severe, infla mmatory arthritis, as assessed histologically, and systemic autoimmune disease, including glomerulonephritis and autoantibody production. Fu rthermore, in aged MRL-lpr/lpr mice, SEB but not heat-denatured SEB ca used acute weight loss and elevated levels of serum proinflammatory cy tokines. Compared with highly purified peritoneal macrophages obtained from either aged MRL +/+, young MRL-lpr/lpr, or young MRL +/+, perito neal macrophages obtained from aged MRL-lpr/lpr mice constitutively ex pressed 2- to 10-fold greater levels of TNF-alpha, IL-1 beta, IL-6, an d IL-10, and produced elevated amounts of these cytokines when treated in vitro with SEB. SEB-challenged aged MRL-lpr/lpr mice treated with anti-TNF mAb (100 mu g/mouse; every other day), anti-V beta 8 TCR mAb (250 mu g/mouse; every other day), or orally with the novel TNF-alpha inhibitor MDL 201,449A (9-[(1R, 3R)-trans-cyclopentan-3-ol] adenine; 2 5 mg/kg/day) exhibited reduced inflammatory arthritis, autoantibody fo rmation, and serum TNF-alpha levels, but not IL-10 levels, after +30 d ays of treatment. These data suggest that SEB is an extremely potent m acrophage-activating factor in vitro and in vivo, enhancing several as pects of autoimmune disease in MRL-lpr/lpr mice, and that anti-TNF the rapies may have potential use in inflammatory arthritis.