title: Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease.
abstract: OBJECTIVE
  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.
authors.affiliation: Laboratory for Experimental Internal Medicine, G2-133, Academic Medical Center, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands. j.vandenbrande@amc.uva.nl
authors.forename: Jan M H
authors.initials: JM
authors.lastname: Van den Brande
authors.forename: Henri
authors.initials: H
authors.lastname: Braat
authors.forename: Gijs R
authors.initials: GR
authors.lastname: van den Brink
authors.forename: Henri H
authors.initials: HH
authors.lastname: Versteeg
authors.forename: Christiaan A
authors.initials: CA
authors.lastname: Bauer
authors.forename: Inge
authors.initials: I
authors.lastname: Hoedemaeker
authors.forename: Catherine
authors.initials: C
authors.lastname: van Montfrans
authors.forename: Daan W
authors.initials: DW
authors.lastname: Hommes
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.forename: Sander J H
authors.initials: SJ
authors.lastname: van Deventer
mesh_terms: D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003167:Complement Activation; D003424:Crohn Disease / Q000188:drug therapy* / Q000276:immunology; D000068800:Etanercept; D053804:Granzymes; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000276:immunology*; D008213:Lymphocyte Activation; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000627:therapeutic use; D012697:Serine Endopeptidases / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000068800:Etanercept