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

Background & aims: Steroid-refractory Crohn's disease responds to therapy with the chimeric anti-tumor necrosis factor (TNF)-alpha 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-alpha-neutralizing drugs, we investigated the differences in TNF-alpha-neutralizing capacity and human lymphocyte binding and apoptosis-inducing capacity of both molecules.

Methods: We used a nuclear factor kappaB reporter assay and a cytotoxicity bioassay to study TNF-alpha 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.

Results: Both infliximab and etanercept neutralized TNF-alpha 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.

Conclusions: Although both infliximab and etanercept showed powerful TNF-alpha 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-alpha-neutralizing drugs.