Constitutive Intra-Articular Expression of Human IL-1β Following Gene Transfer to Rabbit Synovium Produces All Major Pathologies of Human Rheumatoid Arthritis

To investigate the pathophysiologic effects of chronically elevated intra-articular levels of IL-1β, we used an ex vivo gene transfer method to deliver and express human IL-1β (hIL-1β) in the knee joints of rabbits. Expression of hlL-1β resulted in a severe, highly aggressive form of arthritis analogous to chronic rheumatoid arthritis in humans. Intra-articular manifestations included intense inflammation, leukocytosis, synovial hypertrophy and hyperplasia, and highly aggressive pannus formation with erosion of the articular cartilage and periarticular bone. Systemic effects were also observed, including diarrhea, fever, weight loss, and an increased erythrocyte sedimentation rate. In addition, the hIL-1β was found to induce elevated levels of both rabbit IL-1β and TNF-α in synovial fluid. Following the loss of hIL-1β transgene expression between 14 and 28 days post-transplantation, many of these changes began to normalize. These results suggest that chronically elevated intra-articular levels of IL-1β alone are sufficient to produce virtually all the pathologies found in rheumatoid arthritis, and furthermore, demonstrate that gene transfer can be used to investigate the roles of specific gene products in the pathogenesis of arthritis.