Up regulation of the production of tumour necrosis factor alpha and interferon gamma by T cells in ankylosing spondylitis during treatment with etanercept.
BACKGROUND
Treatment of active ankylosing spondylitis (AS) with the recombinant, soluble tumour necrosis factor alpha (TNFalpha) receptor molecule etanercept has been shown to be clinically highly effective. The precise mechanism of action, however, is not known.


OBJECTIVE
To assess the change in the cytokine secreting ability of CD4+ and CD8+ T cells and macrophages during etanercept treatment.


METHODS
Peripheral blood mononuclear cells from 10 patients with AS treated with 25 mg etanercept and 10 patients with AS treated with placebo were investigated during treatment given twice weekly subcutaneously. Production of cytokines by T cells was investigated after in vitro stimulation by flow cytometry.


RESULTS
Twelve weeks of etanercept treatment induced a significant increase in the number of interferon gamma (IFNgamma) positive (14.2% (9.6-19.5%) before v 24.4% (13.4-36.4%) after) and TNFalpha positive CD4+ T cells (p=0.008 for both cytokines) and IFNgamma positive (37.5% (19.0-45.4%) before v 52.9% (33.2-60.0%) after) and TNFalpha positive CD8+ T cells (p=0.008 for both cytokines) upon phorbol myristate acetate/ionomycin stimulation, but not in the placebo group. Furthermore, etanercept treatment induced a significant increase in the number of IFNgamma positive CD8+ T cells (p=0.024 at 12 weeks) and a non-significant increase of TNFalpha positive CD8+ T cells after in vitro stimulation with the aggrecan derived peptides.


CONCLUSIONS
Neutralisation of peripheral TNFalpha does not induce a down regulation of the ability of T cells to produce TNFalpha but rather an up regulation, possibly due to a counterregulatory mechanism.
Zou
J
J
Rheumatology, Benjamin Franklin Klinikum, Deutsches RheumaForschungszentrum, Berlin, Germany.
Rudwaleit
M
M
Brandt
J
J
Thiel
A
A
Braun
J
J
Sieper
J
J
D018501:Antirheumatic Agents / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004311:Double-Blind Method; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis*; D008137:Longitudinal Studies; D008213:Lymphocyte Activation; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D013167:Spondylitis, Ankylosing / Q000188:drug therapy* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects
D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D000068800:Etanercept