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Combination therapy of pentoxifylline and TNFalpha monoclonal antibody in dextran sulphate-induced mouse colitis
S Murthy1, H S Cooper, H Yoshitake
1Division of Gastroenterology and Hepatology, MCP Hahnemann University, Philadelphia, PA, USA. murthys@auhs.edu
Background:
Tumour necrosis factor-alpha (TNFalpha) 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 TNFalpha mab (25 microg/mouse, Endogen) and pentoxifylline (PF, 100 mg/kg/day, p.o., TNFalpha 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 TNFalpha mab, Group III: daily PF for three cycles, Group IV: single injection of TNFalpha mab + PF for three cycles, Group V: TNFalpha mab at the beginning of each cycle (three injections) and Group VI: TNFalpha 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 TNFalpha.
Results:
Mice treated with a single injection of TNFalpha alone or TNFalpha mab + PF showed significantly lower DAI, inflammation scores and ulcer index compared with the IgG treated group. Mice treated with TNFalpha mab + PF had no ulcers. Multiple injections of TNFalpha mab or TNFalpha mab + PF showed greater inhibition in DAI and cytokines in the first two cycles. However, in the third cycle, multiple injections of TNFalpha mab showed adverse proinflammatory effects.
Conclusion:
The simultaneous administration of pentoxifylline and TNFalpha mab may enhance therapeutic outcomes in inflammatory bowel disease and reduce the side-effects associated with the repeated use of TNFalpha mab.
Insights
Combining pentoxifylline with anti-Tumour Necrosis Factor-alpha (TNFalpha) monoclonal antibody (mab) improved outcomes in a mouse model of colitis. This combination therapy may reduce side effects from repeated anti-TNFalpha mab use in inflammatory bowel disease treatment.
Area of Science:
- Gastroenterology
- Immunology
- Pharmacology
Background:
- Tumour necrosis factor-alpha (TNFalpha) is implicated in inflammatory bowel diseases (IBD).
- Engineered anti-TNFalpha antibodies show benefit in Crohn's disease but raise concerns about host defense and toxicity with repeated use.
Purpose of the Study:
- To evaluate the combined efficacy of a mouse-specific TNFalpha monoclonal antibody (mab) and pentoxifylline (PF) in a dextran sulphate sodium (DSS) induced mouse model of colitis.
- To assess the impact of single and multiple administrations of TNFalpha mab, with or without PF, on disease activity and inflammatory markers.
Main Methods:
- Colitis was induced in mice using 3% DSS over three cycles.
- Experimental groups received varying treatments: control IgG, TNFalpha mab alone, PF alone, TNFalpha mab + PF, multiple TNFalpha mab injections, or multiple TNFalpha mab + PF injections.
- Disease activity (DAI), colon histology, myeloperoxidase (MPO), and plasma TNFalpha levels were assessed.
Main Results:
- Single administration of TNFalpha mab, with or without PF, significantly reduced disease activity, inflammation, and ulcer index compared to controls.
- The combination of TNFalpha mab + PF resulted in no ulcers.
- While multiple injections initially showed improved inhibition, repeated TNFalpha mab administration alone led to adverse proinflammatory effects in the third cycle.
Conclusions:
- Simultaneous administration of pentoxifylline and TNFalpha mab may enhance therapeutic outcomes in inflammatory bowel disease.
- This combined approach shows potential for reducing side-effects associated with repeated anti-TNFalpha mab therapy.