Vol. 287, Issue 3, 854-859, December 1998

Antitumor Necrosis Factor Therapy in Rat Chronic Granulomatous Colitis: Critical Dose-Timing Effects on Outcome¹

Sebastián Videla, Ana García-Lafuente, María Antolín, Jaime Vilaseca, Francisco Guarner, Ernesto Crespo, Guadalupe González, Antonio Salas and Juan R. Malagelada

Digestive System Research Unit (S.V., A.G.-L., M.A., J.V., F.G., J.R.M.) and Department of Microbiology (E.C.), Hospital General Vall d'Hebron, Department of Pathology (G.G., A.S.), Barcelona, Spain

Inhibition of tumor necrosis fact (TNF) is of potential benefit in the treatment of chronic inflammatory conditions. However, TNF plays an important role in host defenses against infection, and blocking TNF production may also have adverse effects. We tested the efficacy and safety of anti-TNF therapy in experimental colitis induced by trinitrobenzenesulfonic acid. We cultured colonic wall specimens for bacterial growth and measured native TNF protein synthesis in colonic tissue at days 0, 1, 4, 10 and 18 after induction of colitis. Anti-TNF therapy (monoclonal g1 immunoglobulin, 15 mg/kg i.p., every third day) was started on either day 4 or day 10 after induction of colitis. On day 18, we measured the release of inflammatory mediators and scored colonic lesions. In acute lesions, several species of the common flora were grown, including Streptococcus, Staphylococcus, Bacteroides, clostridia and enterobacteria. In chronic lesions, only enterobacteria, clostridia and lactobacilli were isolated. TNF production by inflamed colonic tissue was increased in both acute and chronic lesions. Anti-TNF therapy induced a significant decrease in the release of inflammatory mediators and histopathological remission when treatment started on day 10. However, anti-TNF therapy increased eicosanoid release and lesion scores when treatment started on day 4. In conclusion, acute colonic lesions showed polymicrobial infection. Anti-TNF therapy induced remission of chronic intestinal inflammation, but early treatment did not prove effective.