Macrophages as a therapeutic target in inflammatory bowel disease: Lessons learned from anti-TNF therapy

This thesis explores the need for Fc-FcγR interaction by anti-TNF antibodies to achieve therapeutic response in inflammatory bowel disease (IBD). Multiple anti-TNF agents have been evaluated for IBD, including IgG1 antibodies infliximab and adalimumab, pegylated Fab’ fragment certolizumab, IgG4 anti-TNF CDP571, soluble TNF receptor I onercept and TNF receptor II-Fc fusion protein etanercept. While these TNF blocking strategies established their value in several immune mediated diseases, only IgG1 monoclonal antibodies demonstrated induction of complete endoscopic remission in IBD. This suggests that additional features besides TNF neutralization are necessary for therapeutic efficacy and these clinical observations initiated a closer evaluation of the effector mechanism of anti-TNF by multiple groups. This thesis focusses on Fc-FcγR interaction and investigates macrophages as effector cells.
In conclusion, this thesis shows evidence that the effector mechanism of anti-TNF requires FcγR cross-linking on macrophages to establish repolarization of an inflammatory macrophage towards a regulatory phenotype. The importance of macrophages in IBD etiology and therapeutics, defines shifting inflammatory macrophages towards a regulatory state as a goal for future therapeutic strategies.