Combination therapy of pentoxifylline and TNFα monoclonal antibody in dextran sulphate‐induced mouse colitis

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Abstract
Background: Tumour necrosis factor-alpha (TNFα) 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 TNFα mab (25 μg/mouse, Endogen) and pentoxifylline (PF, 100 mg/kg/day, p.o., TNFα 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 TNFα mab, Group III: daily PF for three cycles, Group IV: single injection of TNFα mab + PF for three cycles, Group V: TNFα mab at the beginning of each cycle (three injections) and Group VI: TNFα 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 TNFα. Results: Mice treated with a single injection of TNFα alone or TNFα mab + PF showed significantly lower DAI, inflammation scores and ulcer index compared with the IgG treated group. Mice treated with TNFα mab + PF had no ulcers. Multiple injections of TNFα mab or TNFα mab + PF showed greater inhibition in DAI and cytokines in the first two cycles. However, in the third cycle, multiple injections of TNFα mab showed adverse proinflammatory effects. Conclusion: The simultaneous administration of pentoxifylline and TNFα mab may enhance therapeutic outcomes in inflammatory bowel disease and reduce the side-effects associated with the repeated use of TNFα mab.