title: Naive human T-cells become non-responsive towards anti-TNFalpha (infliximab) treatment in vitro if co-stimulated through CD28.
abstract: Tumour necrosis factor alpha (TNFalpha) inhibitors are widely used successfully as immunomodulatory agents in various autoimmune diseases. They primarily target the direct pro-inflammatory effect of TNFalpha. They have also been found to be critical for T-cell viability and activation. In this study we evaluated the effect of infliximab treatment under different in vitro stimulatory conditions of naive human cord blood T-cells and adult peripheral blood mononuclear cells (PBMC). PBMC and negatively selected cord blood naive human T-cells were stimulated with alphaCD3 with or without alphaCD28 co-stimulation. The role of in vitro infliximab treatment was evaluated in relation to transforming growth factor-beta1 (TGF-beta1) under the above different stimulatory conditions. Anti-TNFalpha treatment with infliximab significantly suppressed proliferation of adult and cord blood T-cells (P < 0.013) during suboptimal stimulatory conditions. Infliximab prevented division of naive CD4+ and CD8+ T-cells and consequently also activation induced cell death, which was induced after three cell divisions. Interleukin (IL)-2 secretion was significantly decreased during infliximab treatment of suboptimally stimulated T-cells (P < 0.05) while TGF-beta1 levels were unchanged. Strikingly, the anti-proliferative effect of infliximab was overcome by the administration of anti-TGF-beta1 or by the addition of exogenous IL-2. Interestingly, CD28 mediated co-stimulation restored the proliferative response in a dose-responsive manner during infliximab treatment. Finally, exogenous TNFalpha administration during suboptimal stimulation reduced the inhibitory effect of TGF-beta1 upon proliferation (P < 0.03). These results demonstrate that anti-TNFalpha treatment is primarily working upon T cells under low stimulatory conditions and probably through TGF-beta1.
authors.affiliation: Department of Immunology, Landspitali-University Hospital, Reykjavik, Iceland.
authors.forename: B
authors.initials: B
authors.lastname: Gunnlaugsdottir
authors.forename: I
authors.initials: I
authors.lastname: Skaftadottir
authors.forename: B R
authors.initials: BR
authors.lastname: Ludviksson
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D018106:CD28 Antigens / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D006801:Humans; D007231:Infant, Newborn; D000069285:Infliximab; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab