PREVENTION OF MURINE COLLAGEN-INDUCED ARTHRITIS IN THE KNEE AND IPSILATERAL PAW BY LOCAL EXPRESSION OF HUMAN INTERLEUKIN-1 RECEPTOR ANTAGONIST PROTEIN IN THE KNEE

Objective. To determine the efficacy of local human interleukin-l rece ptor antagonist (HuIL-1Ra) gene therapy in murine collagen-induced art hritis (CLA). Methods. DBA/1 mice were immunized against bovine type I I collagen, Before the onset of arthritis, NIH/3T3 fibroblasts transfe cted 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, Sw elling of the knee joints was measured by external gamma counting of ( 99m)technetium accumulation in the joint. Paws and knee joints were di ssected and processed for histologic studies to evaluate inflammation and cartilage destruction. Results. The NIH/3T3 fibroblasts survived i n the joint cavity of DBA mice for at least 7 days. The transduced cel ls expressed immunoreactive and bioactive HuIL-1Ra in the knee joint, and produced sufficient amounts to block the effect of 1 ng of recombi nant murine IL-1 alpha on chondrocyte proteoglycan synthesis. The onse t of CIA was almost completely prevented in knee joints containing HuI L-1Ra-producing cells, whereas joints containing normal cells showed s evere inflammation and destruction of cartilage. Moreover, onset of CI A in the draining joints (ipsilateral paws) of the HuIL-1Ra gene-beari ng knees was also prevented. Conclusion. Local production of HuIL-1Ra in the knee was able to ameliorate the effects of IL-1 on cartilage an d could prevent the onset of CW 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.