AbstractObjective. To determine the efficacy of local human interleukin‐1 receptor antagonist (HuIL‐1Ra) gene therapy in murine collagen‐induced arthritis (CIA).Methods. DBA/1 mice were immunized against bovine type II collagen. Before the onset of arthritis, NIH/3T3 fibroblasts transfected with pMFG‐IRAP were transplanted into the knee cavity. Normal NIH/3T3 cells served as controls. Paws were evaluated macroscopically for redness, swelling, and deformities during the course of arthritis. Swelling of the knee joints was measured by external gamma counting of 99mtechnetium accumulation in the joint. Paws and knee joints were dissected and processed for histologic studies to evaluate inflammation and cartilage destruction.Results. The NIH/3T3 fibroblasts survived in the joint cavity of DBA mice for at least 7 days. The transduced cells expressed immunoreactive and bioactive HuIL‐1Ra in the knee joint, and produced sufficient amounts to block the effect of 1 ng of recombinant murine IL‐1α on chondrocyte proteoglycan synthesis. The onset of CIA was almost completely prevented in knee joints containing HuIL‐1Ra‐producing cells, whereas joints containing normal cells showed severe inflammation and destruction of cartilage. Moreover, onset of CIA in the draining joints (ipsilateral paws) of the HuIL‐1Ra gene‐bearing knees was also prevented.Conclusion. Local production of HuIL‐1Ra in the knee was able to ameliorate the effects of IL‐1 on cartilage and could prevent the onset of CIA not only in that knee, but also in the “draining” paw. This indicates the feasibility of gene transfer as a therapeutic approach to modulating arthritis.