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

Abstract

Background and AimsRegulatory 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.MethodsMixed 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.ResultsAmong 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.ConclusionsAlbendazole 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.

Anti-TNF therapy in IBD exerts its therapeutic effect through macrophage IL-10 signalling

“…We have previously shown that the T-cell transfer colitis model responds to anti-TNFmAb therapy in a dose-dependent fashion 23. In this titration experiment, intestinal IL-10 levels were increased in animals treated with the effective dosage of anti-TNF (figure 3A).…”

“…Similarly, in a recent experiment with a small molecule kinase inhibitor, we observed almost complete mucosal healing without any effect on IL-10 expression in the same model (ME Wildenberg, personal communication 2019). In contrast, when we performed an unbiased drug screen for drugs that enhanced the anti-TNF-induced CD206+ regulatory macrophage polarisation, we identified albendazole as a drug that potentiates the effect of anti-TNF in vitro and in vivo 23. We found that albendazole specifically synergised with anti-TNF in upregulating IL-10 expression.…”

“…Il10 KO animals were treated with anti-mouse TNF, anti-mouse IL-12/23-p40 or isotype control mAbs, 300 µg, two times per week intraperitoneally from 8 to 14 weeks of age. The anti-TNF dose titration was described previously 23. The effective dosage of 100 µg anti-TNF twice a week intraperitoneally was used for all further experiments from 3 weeks after the T-cell transfer, when animals began to exhibit clinical signs of colitis, until the end of the experiments.…”

The Anti-virulence Efficacy of 4-(1,3-Dimethyl-2,3-Dihydro-1H-Benzimidazol-2-yl)Phenol Against Methicillin-Resistant Staphylococcus aureus

“…Nevertheless, the effects of benzimidazole derivatives to host immunity are noted in the literature. Wildenberg et al reported that six benzimidazole derivatives induced regulatory macrophages (Wildenberg et al, 2017). Rickard et al reported that the benzimidazole diamide GSK 669 inhibits NOD2, an intracellular pattern recognition receptor involved in the induction of pro-inflammatory cytokines (Rickard et al, 2013).…”

Prevention and Curation of DSS-induced IBD in Mice With Bacillus Subtilis Fermented Milk via Inhibition of the Inflammatory Responses and Regulation of the Intestinal Flora

“…It has been reported that TNF was over-expressed in the intestinal mucosa and could lead apoptosis of the intestinal epithelial cells (IECs) in IBD. [44][45][46] However, anti-in ammatory cytokine IL-10 exerted essential functions to maintain tissue homeostasis during infection and in ammation through restriction of excessive in ammatory responses and promotion of tissue repairing mechanisms. 47,48 IL-10 could secreted by both immune cells and IECs.…”