Gene Targeting of Cytokines and the Mitogen-Activated Protein Kinase Pathways in Human Rheumatoid Synovium Using the Severe Combined Immunodeficiency Mouse Model

Abstract

Rheumatoid arthritis (RA) is the most common inflammatory joint disease, and frequently accompanied by extra-articular systemic manifestations. Hallmarks of RA are: (1) inflammation of the synovial tissue owing to infiltration of inflammatory cells (T cells, B cells, macrophages); (2) synovial hyperplasia, partly owing to an impaired balance of apoptosis and growth of synovial cells; and (3) pathological immune phenomena. These factors result subsequently in the progressive destruction of cartilage and bone (1,2). Because the etiology of the disease remains unknown, a causal therapy does not exist. The current treatment of patients focuses mainly on antagonizing the inflammatory reaction (nonsteroidal anti-inflammatory drugs; NSAIDs), and suppressing the upregulated immune response (immunosuppressive drugs, disease-modifying anti-rheumatic drugs; DMARDs) (3–5). However, there is no compelling evidence that any of these agents alter substantially the long-term progression and the outcome of RA, which results in disability and enhances the socioeconomic burden. During the past years, progress in molecular biology has led to a better understanding of the pathophysiology underlying RA and has offered new therapeutic options (6–9). Biologic agents (10,11) have been developed that act as antagonists of proinflammatory cytokines (e.g., interleukin-1 receptor antagonist [IL-1Ra]) (12), that are soluble receptors of IL-1 (sIL-1R) (13) and tumor necrosis factor-a (sTNFR) (14), or that have anti-inflammatory properties (e.g., IL-4, IL-10) (15,16).