Rheumatology Advance Access originally published online on February 28, 2003
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Rheumatology 2003; 42: 541-548
© 2003 British Society for Rheumatology
Influence of therapy with chimeric monoclonal tumour necrosis factor-
antibodies on intracellular cytokine profiles of T lymphocytes and monocytes in rheumatoid arthritis patients
Department of Immunology, Allergology and Rheumatology, University of Antwerp, Belgium
Introduction. It has been shown that T lymphocytes and monocytes/macrophages, producing pro-inflammatory cytokines, play a pivotal role in the pathophysiology of rheumatoid arthritis (RA). In recent placebo-controlled double-blind randomized studies, chimeric (human/mouse) tumour necrosis factor-
(TNF) antibodies (cA2) proved to be very effective in improving clinical disease activity and reducing inflammatory parameters in RA.
Objective. To investigate whether anti-TNF therapy influences the in vitro intracellular cytokine production in peripheral blood monocytes and T lymphocytes of RA patients after one single (24 h) and multiple intravenous infusions (6 months).
Methods. An intracellular flow cytometric technique was applied to measure interleukin 1ß (IL-1ß), IL-6, TNF, IL-10 and IL-12 in monocytes and IL-2, IL-4 and interferon-
in T lymphocytes of 15 patients, before, after 24 h and after 6 months of therapy with monoclonal chimeric anti-TNF antibodies (3 mg/kg, bimonthly i.v.). All patients were on stable therapy with methotrexate (15–20 mg/week i.m.). Cytokine content in monocytes was measured directly after blood sampling (basal levels), after 8 h of culture (spontaneous production) and after 8 h of stimulation with lipopolysaccharides (LPS-stimulated production).
Results. Basal levels and production (after 8 h) of IL-1ß, IL-6 and TNF were significantly decreased 24 h after the first administration of anti-TNF (for IL-1ß P < 0.01; for IL-6 P < 0.01; for TNF P < 0.003) and after 6 months of therapy (for IL-1ß P < 0.02; for IL-6 P < 0.03; for TNF P < 0.001). For IL-12, basal levels were significantly decreased 24 h and 6 months after the start of therapy with anti-TNF antibodies (P=0.0001; P=0.003, respectively). In contrast, IL-10 production increased significantly after 24 h and after 6 months (P=0.02; P=0.01). The TH2/TH1 cytokine ratio in CD4+ T cells was significantly increased after 24 h and after 6 months of anti-TNF therapy (P=0.003; P=0.0007).
Conclusion. Anti-TNF therapy might down-regulate the monocytic capacity to produce pro-inflammatory cytokines and induces a shift to a more pronounced anti-inflammatory TH2 cytokine production.
KEY WORDS: Tumour necrosis factor-, Anti-TNF therapy, RA, Cytokine.
Correspondence to: W. J. Stevens, University of Antwerp UIA, Department of Immunology, Allergology and Rheumatology, Universiteitsplein 1, B-2610 Antwerp, Belgium. E-mail: wim.stevens{at}ua.ac.be
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