Infliximab downregulates interferon-gamma production in activated gut T-lymphocytes from patients with Crohn's disease.
The tumour necrosis factor-alpha (TNF-alpha) neutralizing antibody, Infliximab (Ifx), reduces disease activity in patients with active steroid-dependent or fistulizing Crohn's disease. The mechanisms underlying the effects of Ifx are not fully understood. This study aims to investigate if and how Ifx regulates the interferon-gamma (IFN-gamma) production in human intestinal T-cells. Colonic T cells were expanded from 25 patients with Crohn's disease and ten healthy controls in an in vitro system, using medium supplemented with interleukin-2 and interleukin-4 but without exogenous antigen. The effect of Ifx was investigated in these in situ activated T cell cultures regarding the IFN-gamma production, proliferation, transmembrane TNF-alpha expression, cytolysis and apoptosis. T cell cultures from patients with Crohn's disease produced significantly higher levels of IFN-gamma (<0.001) and TNF-alpha (P=0.04) than T cell cultures from healthy controls. The production of IFN-gamma was downregulated by Ifx in early T cell cultures (P=0.002). Ifx bound to transmembrane TNF-alpha of activated T cells without inducing complement-mediated cytolysis, apoptosis and without affecting proliferation. Besides its known TNF-alpha neutralizing property, Ifx downregulates INF-gamma production in colonic T cell cultures. Colonic T cells express transmembrane TNF-alpha that binds Ifx. The data suggest that Ifx reduces the level of at least two pro-inflammatory cytokines leading to lower disease activity.
Agnholt
J
J
Department of Medicine, Aarhus University Hospital, Aarhus C, Denmark. agnholt@dalnet.dk
Kaltoft
K
K
D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D003106:Colon / Q000166:cytology; D003424:Crohn Disease / Q000276:immunology* / Q000378:metabolism*; D015536:Down-Regulation; D004768:Enterotoxins / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000069285:Infliximab; D007371:Interferon-gamma / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011485:Protein Binding; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000911:Antibodies, Monoclonal; D004768:Enterotoxins; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; C026066:enterotoxin A, Staphylococcal; D007371:Interferon-gamma; D000069285:Infliximab