Production of cytokines and metalloproteinases in rheumatoid synovitis is T cell dependent

In rheumatoid arthritis, T lymphocytes have been proposed to play a pivotal role in the disease process, but they have also been considered to simply represent an epiphenomenon in a primarily synoviocyte/macrophage-driven dis ease. To directly examine the contribution of CD4 T cells in synovitis, T c ells were either depleted from or adoptively transferred into NOD-SCID mice engrafted with rheumatoid synovial tissue. Injection of anti-CD2 antibody resulted in the elimination of 80-90% of tissue-infiltrating T cells in the synovial grafts and was followed by a marked decline in the production of IL-1 beta (loss of 70%), TNF-alpha (loss of 86%), and IL-15 (loss of 84%) m RNA. Also, transcription of MMP-1 and MMP-2 was reduced by 72% in anti-CD2- treated chimeras. Immunohistochemistry demonstrated that the cytokines and proteases derived mostly from CD68(+) synovial cells, which disappeared fro m the tissue upon T cell depletion. Adoptive transfer of autologous tissue- derived T cell lines and T cell clones into synovium-SCID mouse chimeras au gmented the production of IFN-gamma as well as TNF-alpha in the synovial in filtrates. Administration of IFN-gamma in small doses to anti-CD2-treated c himeras restored the survival and the functional activity of CD68(+) synovi al cells. In vitro studies confirmed the critical role of synovial T cells and IFN-gamma in the survival of synovial CD68(+) cells. These data demonst rate that the production of proinflammatory cytokines and of tissue-degradi ng enzymes in rheumatoid synovitis is T cell dependent and that CD4 T cells are primary regulatory cells in this disease. (C) 1999 Academic Press.