Combination therapy of pentoxifylline and TNF alpha monoclonal antibody in dextran sulphate-induced mouse colitis: Alimentary Pharmacology & Therapeutics

Background: Tumour necrosis factor-alpha (TNF alpha) has been suspected of playing an important role in the pathogenesis of inflammatory bowel diseases, and has become a target for the treatment of these diseases. Open-label, placebo controlled studies have shown that engineered CDP571 and chimeric anti-TNF antibody (cA2) provide a significant benefit in Crohn's disease. Since these antibodies have to be used repeatedly to maintain remission in inflammatory bowel disease, there is a concern that their use may compromise host defence and produce toxic side-effects. Methods: We evaluated the combined use of mouse specific TNF alpha mab (25 mu g/mouse, Endogen) and pentoxifylline (PF, 100 mg/kg/day, p.o., TNF alpha release inhibitor) in the DSS (3% dextran sulphate solution) model of mouse colitis. Colitis was induced by the feeding of 3% DSS for three cycles. The study groups were: Group I: single injection of rat anti-mouse IgG, Group II: single injection of TNF alpha mab, Group III: daily PF for three cycles, Group IV: single injection of TNF alpha mab + PF for three cycles, Group V: TNF alpha. mab at the beginning of each cycle (three injections) and Group VI: TNF alpha mab (three injections) + daily PF for three cycles. Daily disease activity (DAI) was measured throughout the study, At the end of each cycle, colon tissue was processed for histology, myeloperoxidase (MPO) and plasma TNF alpha. Results: Mice treated with a single injection of TNF alpha. alone or TNF alpha: mab + PF showed significantly lower DAI, inflammation scores and ulcer index compared with the IgG treated group. Mice treated with TNF alpha mab + PF had no ulcers, Multiple injections of TNF alpha mab or TNF alpha mab + PF showed greater inhibition in DAI and cytokines in the first two cycles. However, in the third cycle, multiple injections of TNF alpha mab showed adverse proinflammatory effects, Conclusion: The simultaneous administration of pentoxifylline and TNF alpha mab may enhance therapeutic outcomes in inflammatory bowel disease and reduce the side-effects associated with the repeated use of TNF alpha mab.