title: A comparative study into the mechanisms of action of anti-tumor necrosis factor alpha, anti-CD4, and combined anti-tumor necrosis factor alpha/anti-CD4 treatment in early collagen-induced arthritis.
abstract: OBJECTIVE
  Anti-tumor necrosis factor alpha (anti-TNFalpha) therapy is very effective in rheumatoid arthritis (RA), whereas depleting anti-CD4 therapy is relatively ineffective. To explain the differences in efficacy between these 2 therapies, we used an animal model of RA to compare their effects on different aspects of the disease process.
  
  
  METHODS
  Mice with collagen-induced arthritis were treated with depleting anti-CD4 monoclonal antibodies (mAb), anti-TNFalpha mAb, or phosphate buffered saline. Another group was given a combination of anti-TNFalpha plus anti-CD4. The treatments were compared for their ability to down-regulate the expression of proinflammatory cytokines and adhesion molecules, reduce the cellularity of the joint, and inhibit Th1 activity.
  
  
  RESULTS
  Anti-TNFalpha significantly reduced the numbers of cells expressing TNFalpha, interleukin-1beta (IL-1beta), very late activation antigen 4 (VLA-4), vascular cell adhesion molecule 1 (VCAM-1), and numbers of CD4+ T cells and macrophages in the joint. Anti-CD4 treatment led to a small reduction in the expression of TNFalpha, IL-1beta, VLA-4, and VCAM-1, but this did not reach statistical significance. Depleting anti-CD4 was also surprisingly ineffective in eliminating CD4+ T cells from the joint. Anti-TNFalpha therapy was also more effective than anti-CD4 in reducing Thl activity, as assessed by the production of interferon-gamma in lymph node cell cultures. There was a synergistic relationship between anti-TNFalpha and anti-CD4 in the reduction of histologic score and inhibition of TNFalpha/IL-1beta expression in the joints.
  
  
  CONCLUSIONS
  The efficacy of the 3 treatments correlated with their ability to modulate the expression of inflammatory cytokines and adhesion molecules in the joint, reduce the cellularity of the joint, and inhibit Th1 activity. This kind of analysis may prove useful in the testing of novel therapies for RA.
authors.affiliation: Kennedy Institute of Rheumatology, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Marinova-Mutafchieva
authors.forename: R O
authors.initials: RO
authors.lastname: Williams
authors.forename: C
authors.initials: C
authors.lastname: Mauri
authors.forename: L J
authors.initials: LJ
authors.lastname: Mason
authors.forename: M J
authors.initials: MJ
authors.lastname: Walmsley
authors.forename: P C
authors.initials: PC
authors.lastname: Taylor
authors.forename: M
authors.initials: M
authors.lastname: Feldmann
authors.forename: R N
authors.initials: RN
authors.lastname: Maini
mesh_terms: D000818:Animals; D000906:Antibodies / Q000502:physiology* / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology*; D003094:Collagen / Q000276:immunology; D004359:Drug Therapy, Combination; D007150:Immunohistochemistry; D007264:Inguinal Canal; D039041:Integrin alpha4beta1; D016023:Integrins / Q000096:biosynthesis; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D007596:Joints / Q000737:chemistry; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D000906:Antibodies; D015704:CD4 Antigens; D039041:Integrin alpha4beta1; D016023:Integrins; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D007371:Interferon-gamma; D003094:Collagen