Gene therapy of destructive arthritis in SCID mice

Background and objective

Synovial membrane fibroblasts in rheumatoid arthritis induce the destruction of cartilage and bone. We have isolated a fibroblast cell line which induces a rapid destruction of articular cartilage following intraarticular instillation in SCID mice and in vitro. Both approaches can be modulated by gene transfer.

Methods

As a cytokine with functions directed to inflammatory and immune cells as well as fibroblasts, interleukin-11 was selected to modulate invasive behaviour of fibroblasts. For transduction, a retroviral vector system, particle-mediated transfer (gene gun), and a lentiviral vector based on simian immunodeficiency virus were investigated. Cells (500,000) were injected directly into the knee joinst of mice with severe combined immunodeficiency (SCID). Mice were monitored for joint swelling, serological parameters and by radiological methods. In vitro, cells were coincubated with cartilage for 1 week. Finally, the histology of cartilage destruction and signs of apoptosis were studied.

Results

The efficacy of gene transfer was <10% for retroviral transfer or gene gun but >85% for lentiviral transfer. Therefore, animal testing and in vitro assays were performed with lentiviral-transfected cells in comparison with nontransfected invasive fibroblasts and control cells. Cartilage destruction within 10 days was induced by instillation of non-transfected cells. Morphology revealed invasion of fibroblast-like cells into the articular cartilage. Transfection with interleukin-11 did not act on swelling but slightly reduced cartilage invasion. In vitro, this effect was caused by reduction of apoptosis in chondrocytes.

Conclusion

Induction of cartilage destruction by intraarticular application of fibroblast like cells into SCID mice can be modulated by gene transfer. Lentiviral vectors systems offer a novel approach for highly efficient transduction of these cells. This model provides the opportunity to check novel therapeutic strategies for reduction of cartilage erosion.