- Meeting abstract
- Open Access
T Cell Maturation in Inflammatory Synovitis
Arthritis Research & Therapyvolume 1, Article number: S25 (1999)
Functional maturation of T cells towards a Th1 or Th2 phenotype has important implications in the generation and perpetuation of autoimmune responses. Those factors that promote and sustain Th1 responses in rheumatoid arthritis (RA) are unclear. We are currently exploring the functional effects of the predominantly macrophage-derived cytokines, IL-12, IL-15 and IL-18, on synovial T cells. We have previously shown a role for IL-15 in synovial T cell chemokinesis and in TNFα production through promotion of cytokine-mediated T cell/macrophage cell contact. We have now extended these studies to include IL-12 and IL-18. IL-18 mRNA and protein may be detected by RT-PCR, ELISA, and immunohistochemistry in RA synovial membrane. The absolute levels present vary considerably between patients. In synergy with IL-12 and IL-15, IL-18 induces high levels of IFNγ, TNFα, and GM-CSF production. IL-18 mediates effects directly on synovial T cells and macrophages. IL-18 and IL-15 expression is itself enhanced by IL-1β/TNFα in vitro, suggesting the existence of feedback loops that provide reciprocal amplification of Th1 cells and monokine production within the synovial membrane. These data clearly indicate that synergistic combinations of T cell activatory cytokines can promote synovial inflammation. This has important implications for the choice of therapeutic targets designed to suppress Th1 cell activity in autoimmune lesions.
Wilkinson PC, Liew FY: Chemoattraction of human blood T lymphocytes by interleukin-15. J Exp Med. 1995, 181: 1255-1259. 10.1084/jem.181.3.1255.
Kotake S, Schumacher HR, Yarboro CH, et al: In vivo gene expression of type 1 and type 2 cytokines in synovial tissues from patients in early stages of rheumatoid, reactive, and undifferentiated arthritis. Proc Assoc Am Physicians . 1997, 109: 286-301.
McInnes IB, Leung BP, Sturrock RD, Field M, Liew FY: Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis. Nat Med . 1997, 3: 189-195. 10.1038/nm0297-189.
Thurkow EW, Van der Heijden IM, Breedveld FC, et al: Increased expression of IL-15 in the synovium of patients with rheumatoid arthritis compared with patients with Yersinia-induced arthritis and osteoarthritis. J Pathol. 1997, 181: 444-450. 10.1002/(SICI)1096-9896(199704)181:4<444::AID-PATH778>3.0.CO;2-O.
Oppenheimer-Marks N, Brezinschek RI, Mohamadzadeh M, Vita R, Lipsky PE: Interleukin 15 is produced by endothelial cells and increases the transendothelial migration of T cells in vitro and in the SCID mouse- human rheumatoid arthritis model in vivo. J Clin Invest. 1998, 101: 1261-1272.
Ruchatz H, Leung BP, Wei XQ, McInnes IB, Liew FY: Soluble IL-15 receptor alpha-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology. J Immunol. 1998, 160: 5654-5660.
Harada S, Yamamura M, Okamoto H, Morita Y, Kawashima M, Aita T, Makino H: Production of interleukin-7 and interleukin-15 by fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum. 1999, 42: 1508-1516. 10.1002/1529-0131(199907)42:7<1508::AID-ANR26>3.0.CO;2-L.