Antigen-induced arthritis (AIA) in mice occurs after immunization and a subsequent intra-articular injection with methylated bovine serum albumin (mBSA). The role of T lymphocytes in the adoptive transfer of susceptibility to AIA into SCID mice was investigated. Pooled spleen and lymph node cells from immunized syngeneic or allogeneic donor mice, isolated either before or after the induction of arthritis, could transfer the capacity both to develop arthritis and to produce antibodies to mBSA, collagen type II and cartilage proteoglycans into SCID mice. The intra-articular injection of mBSA in responder animals, immediately after the cell transfer, resulted in a chronic arthritis in the induced joint. The histologic examination revealed synovial hyperplasia, mononuclear infiltration of the synovial membrane, exudation of polymorphonuclear leucocytes into the joint space, and chondrocyte death. The depletion of CD4+ T cells before transfer prevented the manifestation of arthritis in SCID mice, with a concomitant decrease in antibody levels to mBSA, collagen type II and cartilage proteoglycans. In contrast, removal of CD8+ T cells did not significantly affect the transfer of arthritis into SCID mice. The results demonstrate an essential role of CD4+ T cells in the pathogenesis of AIA, whereas CD8+ T cells do not seem to be required for the induction and perpetuation of this disease.

The effects of the T-cell-directed immunosuppressant cyclosporin A (CsA) on the development of antigen-induced arthritis (AIA) in rats as well as on cytokine levels in synovial fluid and serum were determined. The treatment with CsA effectively inhibited the chronic phase of arthritis as demonstrated by decreased joint swelling and reduced histological arthritic score. In animals with AIA the level of IL-6 in the synovial fluid and serum is increased, showing good correlation with the severity of the disease. The CsA treatment reduced IL-6 levels to normal. IL-1, IL-2 and TNF-alpha do not seem to be directly involved in the pathogenic mechanisms of chronic arthritis.

Adhesion molecules play important roles in immune reactions and inflammatory processes and may constitute attractive targets for immunomodulatory approaches. In this study, blocking mAbs against a series of adhesion molecules were tested for their therapeutic effect on developing arthritis in a mouse model. MAbs were given for a period of 4 weeks at the time of exspected incidence of visible disease symptoms, i.e. 4 weeks after priming with collagen type II. A significant reduction of incidence down to values of 13% and 29% of the controls was obtained with mAbs against CD44 and alpha 4-integrin, respectively, during an observation time of 13 weeks. MAbs against CD4 and LFA-1 resulted only in weaker, non-significant effects or a delay in the incidence. MAbs against other molecules including L-selectin, ICAM-1 or VCAM-1 were not effective. The development of antibodies against collagen type II, collagen type I, proteoglycans and the immunogen, bovine collagen type II was affected by mAb treatment to a different extent. In this case, the anti CD4 mAb was the most effective, followed by the anti alpha 4-antibodies in most cases, whereas anti CD44 showed less clear effects on the development of humoral responses. In a skin delayed type hypersensitivity model analyzed for comparison, mAbs against LFA-1/ICAM-1 and alpha 4-integrin showed the largest effects on ear swelling. These data show that mAbs against several adhesion molecules are able to block selectively distinct aspects of immune reactions, and that CD44 and alpha 4-integrins could be promising targets for an immunotherapy of rheumatoid arthritis with receptor-interfering agents.

In periarticular bone of AIA rats, OPG treatment reduced the loss of bone volume and decreased the bone turnover, thus preventing periarticular bone destruction. OPG treatment had no influence on inflammatory process or on cartilage destruction.

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