Benzimidazoles Promote Anti-TNF Mediated Induction of Regulatory Macrophages and Enhance Therapeutic Efficacy in a Murine Model

Background and Aims: Regulatory macrophagesplay 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 macrophagescan be potentiated using the combination of anti-TNF and thiopurines, consistent with the enhanced efficacy of this combination therapydescribed in clinical trials. As thiopurines are unfortunately associated with significant side effects, we here aimed to identify alternatives for combination therapywith anti-TNF, using the macrophage induction model as a screening tool. Methods: Mixed lymphocyte reactionswere 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 macrophagesby anti-TNF were six benzimidazoles, including albendazole. Albendazoletreatment 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 therapyalso increased expression levels of the immunoregulatory cytokine IL-10. In vivo, albendazoleplus anti-TNF combination therapywas superior to monotherapy in a model of colitis, in terms of both induction of regulatory macrophagesand improvement of clinical symptoms. Conclusions: Albendazoleenhances the induction of regulatory macrophagesby anti-TNF and potentiates clinical efficacy in murine colitis. Given its favourable safety profile, these data indicate that the repurposingof albendazolemay be a novel option for anti-TNF combination therapyin IBD