Maarten Cozijnsen

17 Chapter 1 General introduction 1. Neutralisation of tmTNF and sTNF 2. Reverse signalling leading to reduced pro-inflammatory cytokine production or apoptosis 3. Complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity 4. Induction of immunosuppressive macrophages tmTNF + cell Reduced cytokines Apoptosis Mϕ Mϕind Mϕ Complement Apoptosis of tmTNF + cell tmTNF + cell Anti-TNF antibody FAB region FC region sTNF tmTNF tmTNF + cell Figure 2. Overview mechanisms of action anti-TNF antibodies Displaying four mechanisms of action of anti-TNF antibodies in treating CD. Via its binding fragment (FAB) region, anti-TNF antibodies can (1) neutralize both soluble (s)TNF and transmembrane (tm) TNF, and (2) elicit reverse signaling that can reduce pro-inflammatory cytokine production of the tmTNF + cell or induce apoptosis. Through its fragment crystallizable (FC) region, (3) complement and natural killer (NK) cells—among others—can bind to the antibodies and can elicit apoptosis through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Moreover, (4) macrophages (Mφ) can bind to the antibody-antigen complex which leads to the induction of immunosuppressive macrophages (Mφind), able to produce anti-inflammatory proteins, inhibit T-cell proliferation and promote wound healing. Relative effectiveness of anti-TNF treatment Both IFX and ADA are efficacious in treatment of pediatric CD and are considered equally effective – although a head-to-head comparison is lacking. 8 They can both be used to induce and maintain remission in pediatric CD patients. The available prospective trials demonstrate that more than 80% of therapy refractory patients respond to induction