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

Jan M.H. Van den Brande*, Henri Braat, Gijs R. Van den Brink, Henri H. Versteeg, Christiaan A. Bauer, Inge Hoedemaeker, Catherine Van Montfrans, Daan W. Hommes, Maikel P. Peppelenbosch, Sander J.H. Van Deventer

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

695 Citations (Scopus)

Abstract

Background & Aims: 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. Methods: We used a nuclear factor KB 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)1774-1785
Number of pages12
JournalGastroenterology
Volume124
Issue number7
DOIs
Publication statusPublished - 1 Jul 2003
Externally publishedYes

Bibliographical note

Funding Information:
Supported by an unrestricted educational grant from Johnson & Johnson (to J.M.H.V.), an unrestricted educational grant from Numico Research b.v. (to H.B.), the Amsterdam Medical Center Research b.v. (to G.R.V. and H.H.V.), the Meelmeijer Foundation (to C.V.), the Dutch Heart Foundation (99.188 to I.H.), and the Dutch Cancer Foundation (99.30 to M.P.P.).

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