SYSTEMIC ANTITUMOR NECROSIS FACTOR ANTIBODY TREATMENT EXACERBATES ENDOTOXIN-INDUCED UVEITIS IN THE RAT

Tumor necrosis factor is released in the circulation and aqueous humor during endotoxin-induced uveitis, and induces acute uveitis when inje cted intraocularly in rats. To elucidate the role of tumor necrosis fa ctor in the development of endotoxin-induced uveitis we analysed the e ffect of neutralizing anti-tumor necrosis factor antibodies and of pen toxifylline, a drug that inhibits tumor necrosis factor synthesis. Lew is rats were treated with: (a) a single intracardial injection of poly clonal rabbit anti-murine tumor necrosis factor antiserum prior to foo t pad injection of 200 mu g lipopolysaccharide; (b) an intraperitoneal injection of 10 mg pentoxifylline 1 hr before, at the time of, and 3 hr after foot pad injection of lipopolysaccharide; or (c) an intravitr eal injection of 20 to 500 mu g pentoxifylline together with 1 mu g li popolysaccharide. The ocular inflammation was examined by slit-lamp an d evaluated for the presence of hyperemia, flare, miosis, infiltrating cells or hypopyon. Levels of tumor necrosis factor in serum and aqueo us samples were determined using a bioassay. Systemic treatment with e ither anti-tumor necrosis factor antibodies or pentoxifylline resulted in a significant inhibition, 90 and 70% respectively, of serum tumor necrosis factor activity at 3 to 4 hr after lipopolysaccharide injecti on. Systemic pentoxifylline treatment had no influence on the severity of uveitis. Anti-tumor necrosis factor antibody treatment, in contras t, caused an exacerbation of endotoxin-induced uveitis at t = 20 hr; m ean uveitis score 3.9 vs. 1.4 in controls; P < 0.01. Intraocular admin istration of pentoxifylline together with lipopolysaccharide also had an aggravating effect on uveitis, that was associated with increased l evels of intraocular tumor necrosis factor. The results show that inhi bition of serum tumor necrosis factor activity does not block the deve lopment of endotoxin-induced uveitis. In fact, anti-tumor necrosis fac tor antibody treatment exacerbates the intraocular inflammation. These findings suggest that tumor necrosis factor may have other than proin flammatory properties in this uveitis model. (C) 1995 Academic Press L imited