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P061. Anti-TNF-induced regulatory macrophages – mechanisms of immunosuppression

A. Levin1, M. Wildenberg1, A.C. Vos2, D.W. Hommes3, G. van den Brink4

1AMC, Tytgat Institute, Amsterdam, Netherlands; 2Leiden University Medical Center, Gastroenterology-Hepatalogy, Leiden, Netherlands; 3UCLA, Division of Digestive Diseases, Los Angeles, United States; 4Academic Medical Center, Gastroenterology & Hepatology, Amsterdam, Netherlands

Background: Anti TNF‑α antibodies are effective at inducing and maintaining remission in Crohn's disease, although the exact mechanism by which they exert this function is not fully understood. We have previously shown that anti-TNF‑α antibodies induce a distinct population of macrophages with immune-regulatory and wound healing properties. How these macrophages exert these functions has remained unclear. The aim of this study was to elucidate which pathways are involved in the wound healing and regulatory functions of anti‑TNF induced regulatory macrophages.

Methods: PBMC were isolated from peripheral blood of healthy donors. Mixed lymphocyte reactions were established by co-culturing PBMC of two individual donors in a 1:1 ratio. Cultures were treated with infliximab and macrophages were isolated using CD14-microbeads. Inflammatory M1 type macrophages were generated by culturing of monocytes in the presence of IFN-gamma. Gene expression was determined by microarray followed by pathway analysis.

Results: As expected, infliximab-induced macrophages displayed upregulation of a number of genes associated with regulatory or wound healing macrophages including CD206 and CD163. Expression of known anti-inflammatory cytokines such as IL‑10 and TGF‑beta was not altered, indicating alterative mechanisms of immune-suppression. Interestingly, various lipid processing and signalling pathways were upregulated in infliximab induced regulatory macrophages, including cholesterol signalling through the lipid X and retinoic X receptors.

Conclusions: Infliximab-induced macrophages express a number of genes associated with M2 macrophages, but do not show a clear upregulation of anti-inflammatory cytokines. Instead, various lipid signalling pathways are activated, suggesting a role for these pathways in the immunosuppression exerted by anti‑TNF induced regulatory macrophages.