Grafting of fibroblasts isolated from the synovial membrane of rheumatoid arthritis (RA) patients induces chronic arthritis in SCID mice - A novel model for studying the arthritogenic role of RA fibroblasts in vivo

The objective of this study was to verify whether isolated rheumatoid arthr itis (RA) synovial fibroblasts induce chronic arthritis in SCID mice, in an alogy to whole tissue pieces. Fibroblasts were isolated from the synovial m embrane of four RA patients (or controls) by out-growth and repeated-passag e culture. Following flow-cytometry characterization, 2x10(6) cells were tr ansferred into the left knee joint of SCID mice. The development of arthrit is was assessed by joint swelling and histological changes. Human and murin e cytokines were measured in vitro in co-cultures (or Transwell(TM) systems ) of human and murine cells. Purified RA synovial fibroblasts, but not heal thy synovial or skin fibroblasts, induced hu/mu arthritis within 6 weeks. I n-vitro secretion of murine and human interleukin(IL)-6, as well as murine tumour necrosis factor (TNF)-alpha, indicated cross-activation between muri ne macrophages and human RA fibroblasts. Soluble-factor mechanisms proved m ore effective than cell-contact mechanisms. Purified RA fibroblasts can, al one, induce hu/mu SCID arthritis. The cytokine profile suggests that xenoge neic interaction between human fibroblasts and murine macrophages may deter mine the sequence of events leading to hu/mu arthritis. (C) 2000 Academic P ress.