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 disease. To directly examine the contribution of CD4 T cells in synovitis, T cells 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-1beta (loss of 70%), TNF-alpha (loss of 86%), and IL-15 (loss of 84%) mRNA. 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 from the tissue upon T cell depletion. Adoptive transfer of autologous tissue-derived T cell lines and T cell clones into synovium-SCID mouse chimeras augmented the production of IFN-gamma as well as TNF-alpha in the synovial infiltrates. Administration of IFN-gamma in small doses to anti-CD2-treated chimeras restored the survival and the functional activity of CD68(+) synovial cells. In vitro studies confirmed the critical role of synovial T cells and IFN-gamma in the survival of synovial CD68(+) cells. These data demonstrate that the production of proinflammatory cytokines and of tissue-degrading enzymes in rheumatoid synovitis is T cell dependent and that CD4 T cells are primary regulatory cells in this disease.
Klimiuk
P A
PA
Division of Rheumatology, Mayo Clinic and Foundation, Rochester, Minnesota, 55905, USA.
Yang
H
H
Goronzy
J J
JJ
Weyand
C M
CM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000502:physiology; D015214:Antigens, Differentiation, Myelomonocytic / Q000502:physiology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D017364:Collagenases / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000494:pharmacology / Q000502:physiology; D007375:Interleukin-1 / Q000096:biosynthesis; D019409:Interleukin-15 / Q000096:biosynthesis; D008264:Macrophages / Q000502:physiology; D020781:Matrix Metalloproteinase 1; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D011994:Recombinant Proteins; D013585:Synovitis / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000097382:CD68 Molecule
D000906:Antibodies; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017364:Collagenases; D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D007375:Interleukin-1; D019409:Interleukin-15; D020781:Matrix Metalloproteinase 1; D019278:Matrix Metalloproteinase 3; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule