Influence of therapy with chimeric monoclonal tumour necrosis factor-alpha antibodies on intracellular cytokine profiles of T lymphocytes and monocytes in rheumatoid arthritis patients.
BACKGROUND
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-alpha (TNFalpha) antibodies (cA2) proved to be very effective in improving clinical disease activity and reducing inflammatory parameters in RA.


OBJECTIVE
To investigate whether anti-TNFalpha 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 1beta (IL-1beta), IL-6, TNFalpha, IL-10 and IL-12 in monocytes and IL-2, IL-4 and interferon-gamma in T lymphocytes of 15 patients, before, after 24 h and after 6 months of therapy with monoclonal chimeric anti-TNFalpha 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-1beta, IL-6 and TNFalpha were significantly decreased 24 h after the first administration of anti-TNFalpha (for IL-1beta P < 0.01; for IL-6 P < 0.01; for TNF P < 0.003) and after 6 months of therapy (for IL-1beta P < 0.02; for IL-6 P < 0.03; for TNFalpha P < 0.001). For IL-12, basal levels were significantly decreased 24 h and 6 months after the start of therapy with anti-TNFalpha 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 T(H2)/T(H1) cytokine ratio in CD4+ T cells was significantly increased after 24 h and after 6 months of anti-TNFalpha therapy (P=0.003; P=0.0007).


CONCLUSIONS
Anti-TNFalpha therapy might down-regulate the monocytic capacity to produce pro-inflammatory cytokines and induces a shift to a more pronounced anti-inflammatory T(H2) cytokine production.
Schuerwegh
A J
AJ
Department of Immunology, Allergology and Rheumatology, University of Antwerp, Belgium.
Van Offel
J F
JF
Stevens
W J
WJ
Bridts
C H
CH
De Clerck
L S
LS
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000628:therapy*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D008070:Lipopolysaccharides; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha