The data show that cytokines can be successfully inserted into the genome of human RA synovial fibroblasts using a retroviral vector delivery system, and that the SCID mouse model of human RA is a valuable tool for examining the effects of gene transfer. In addition, inhibition of more than one cytokine pathway may be required to inhibit both synovial- and chondrocyte-mediated cartilage destruction in RA.
Rheumatoid arthritis (RA) is characterized by progressive destruction of synovial cartilage. In vitro, degradation of cartilage is stimulated by IL-1, a proinflammatory cytokine, which is released from RA synovial fibroblasts (RA-SF). To determine whether gene therapy using the gene encoding the naturally occurring inhibitor of IL-1, IL-1 receptor antagonist (IL-1Ra) is feasible, IL-1 Ra-transduced RA-SF were coimplanted with normal human cartilage in SCID mice. The IL-1 Ra-transduced RA-SF continued to secrete IL-1Ra over a 60-day period. Cartilage that was coimplanted with RA-SF transduced with a marker gene exhibited progressive, chondrocyte-mediated cartilage degradation, whereas no such degradation was observed in cartilage that was coimplanted with RA-SF transduced with IL-1 Ra. Thus, gene therapy using a retrovirus-based gene delivery system appears to be a feasible approach to effectively modifying the local synovial environment.
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