title: Evaluation of TNF-alpha and IL-1 blockade in collagen-induced arthritis and comparison with combined anti-TNF-alpha/anti-CD4 therapy.
abstract: We have evaluated the effects of anti-TNF-alpha, anti-IL-1, and combined anti-TNF-alpha/anti-CD4 therapy in collagen-induced arthritis. Blockade of TNF-alpha or IL-1 before disease onset delayed, but did not prevent, the induction of arthritis. When treatment was initiated after onset of arthritis, anti-TNF-alpha, anti-IL-1beta, and anti-IL-1R (which blocks IL-1alpha and IL-1beta) were all found to be effective in reducing the severity of arthritis, with anti-IL-1R and anti-IL-1beta showing greater efficacy than anti-TNF-alpha. Anti-IL-1beta was equally as effective as anti-IL-1R, indicating that IL-1beta plays a more prominent role than IL-1alpha in collagen-induced arthritis. An additive effect was observed between anti-TNF-alpha and anti-IL-1R in the prevention of joint erosion and in normalization of the levels of serum amyloid P. Combined anti-TNF-alpha/anti-CD4 therapy also caused normalization of serum amyloid P levels. The therapeutic effect of anti-TNF-alpha plus anti-CD4 was comparable to that of anti-TNF-alpha plus anti-IL-1R, suggesting that combined anti-TNF-alpha/anti-CD4 therapy prevents both TNF-alpha- and IL-1-mediated pathology. Anti-TNF-alpha treatment reduced IL-1beta expression in the joint and, conversely, anti-IL-1beta treatment reduced TNF-alpha expression. Combined anti-TNF-alpha/anti-CD4 treatment almost completely blocked the expression of IL-1beta, thereby confirming the ability of this form of combination therapy to prevent IL-1ss-mediated pathology.
authors: Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, London, United Kingdom. richard.o.williams@ic.ac.uk
authors: R O
authors: RO
authors: Williams
authors: L
authors: L
authors: Marinova-Mutafchieva
authors: M
authors: M
authors: Feldmann
authors: R N
authors: RN
authors: Maini
mesh_terms: D000210:Acute-Phase Reaction / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D015704:CD4 Antigens / Q000276:immunology*; D002417:Cattle; D003094:Collagen / Q000276:immunology*; D006224:Cricetinae; D004306:Dose-Response Relationship, Immunologic; D004359:Drug Therapy, Combination; D007115:Immunization Schedule; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D051381:Rats; D017472:Receptors, Interleukin-1 / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D015704:CD4 Antigens; D007074:Immunoglobulin G; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen