Antitumor necrosis factor therapy in rat chronic granulomatous colitis: Critical dose-timing effects on outcome

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