Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease

Steroid-refractory Crohn’s disease responds to therapy with the chimeric anti-tumor necrosis factor (TNF)-α antibody infliximab. Etanercept, a recombinant TNF receptor/immunoglobulin G fusion protein, is highly effective in rheumatoid arthritis but not in Crohn’s disease. Because both infliximab and etanercept are TNF-α-neutralizing drugs, we investigated the differences in TNF-α-neutralizing capacity and human lymphocyte binding and apoptosis-inducing capacity of both molecules. We used a nuclear factor κB reporter assay and a cytotoxicity bioassay to study TNF-α neutralization by infliximab and etanercept. Lymphocyte binding and apoptosis-inducing capacity was investigated using fluorescence-activated cell sorter analysis, annexin V staining, and cleaved caspase-3 immunoblotting using mixed lymphocyte reaction-stimulated peripheral blood lymphocytes (PBL) from healthy volunteers and lamina propria T cells from patients with Crohn’s disease. Both infliximab and etanercept neutralized TNF-α effectively. Infliximab bound to activated PBL and lamina propria T cells, whereas binding of etanercept was equal to a nonspecific control antibody. Infliximab but not etanercept induced peripheral and lamina propria lymphocyte apoptosis when compared with a control antibody. Infliximab activated caspase 3 in a time-dependent manner, whereas etanercept did not. Although both infliximab and etanercept showed powerful TNF-α neutralization, only infliximab was able to bind to PBL and lamina propria T cells and subsequently to induce apoptosis of activated lymphocytes. These data may provide a biological basis for the difference in efficacy of the 2 TNF-α-neutralizing drugs.