CONSTITUTIVE INTRAARTICULAR EXPRESSION OF HUMAN IL-1-BETA FOLLOWING GENE-TRANSFER TO RABBIT SYNOVIUM PRODUCES ALL MAJOR PATHOLOGIES OF HUMAN RHEUMATOID-ARTHRITIS

To investigate the pathophysiologic effects of chronically elevated in tra-articular levels of IL-1 beta, we used an ex vivo gene transfer me thod to deliver and express human IL-1 beta (hIL-1 beta) in the knee j oints of rabbits, Expression of hIL-1 beta resulted in a severe, highl y aggressive form of arthritis analogous to chronic rheumatoid arthrit is in humans, Intra-articular manifestations included intense inflamma tion, leukocytosis, synovial hypertrophy and hyperplasia, and highly a ggressive pannus formation with erosion of the articular cartilage and periarticular bone, Systemic effects were also observed, including di arrhea, fever, weight loss, and an increased erythrocyte sedimentation rate, In addition, the hIL-1 beta was found to induce elevated levels of both rabbit IL-1 beta and TNF-alpha in synovial fluid, Following t he loss of hIL-1 beta transgene expression between 14 and 28 days post -transplantation, many of these changes began to normalize, These resu lts suggest that chronically elevated intra-articular levels of IL-1 b eta alone are sufficient to produce virtually all the pathologies foun d in rheumatoid arthritis, and furthermore, demonstrate that gene tran sfer can be used to investigate the roles of specific gene products in the pathogenesis of arthritis.