AI Article Synopsis
- Regulatory macrophages are crucial for tissue repair, and combining anti-TNF antibodies with thiopurines has shown improved outcomes, but thiopurines have significant side effects.
- Researchers tested 1,600 drug compounds alongside anti-TNF to find safer alternatives for enhancing the induction of regulatory macrophages, using mixed lymphocyte reactions.
- The study identified albendazole as a promising compound that enhances regulatory macrophage induction and improves clinical symptoms in a colitis model, suggesting it could be a safe and effective alternative for combination therapy with anti-TNF in inflammatory bowel disease (IBD).
Article Abstract
Background And Aims: Regulatory macrophages play a critical role in tissue repair, and we have previously shown that anti-tumour necrosis factor [TNF] antibodies induce these macrophages in vitro and in vivo in IBD patients. The induction of regulatory macrophages can be potentiated using the combination of anti-TNF and thiopurines, consistent with the enhanced efficacy of this combination therapy described in clinical trials. As thiopurines are unfortunately associated with significant side effects, we here aimed to identify alternatives for combination therapy with anti-TNF, using the macrophage induction model as a screening tool.
Methods: Mixed lymphocyte reactions were treated with anti-TNF and a library of 1600 drug compounds. Induction of CD14+CD206+ macrophages was analysed by flow cytometry. Positive hits were validated in vitro and in the T cell transfer model of colitis.
Results: Among the 98 compounds potentiating the induction of regulatory macrophages by anti-TNF were six benzimidazoles, including albendazole. Albendazole treatment in the presence of anti-TNF resulted in alterations in the tubulin skeleton and signalling though AMPK, which was required for the enhanced induction. Combination therapy also increased expression levels of the immunoregulatory cytokine IL-10. In vivo, albendazole plus anti-TNF combination therapy was superior to monotherapy in a model of colitis, in terms of both induction of regulatory macrophages and improvement of clinical symptoms.
Conclusions: Albendazole enhances the induction of regulatory macrophages by anti-TNF and potentiates clinical efficacy in murine colitis. Given its favourable safety profile, these data indicate that the repurposing of albendazole may be a novel option for anti-TNF combination therapy in IBD.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881671 | PMC |
| http://dx.doi.org/10.1093/ecco-jcc/jjx104 | DOI Listing |
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