Plasmid DNA encoding transforming growth factor-β1 suppresses chronic disease in a streptococcal cell wall-induced arthritis model

Abstract

Transforming growth factor β is a potent immunomodulator with both pro- and antiinflammatory activities. Based on its immunosuppressive actions, exogenous TGF-β has been shown to inhibit autoimmune and chronic inflammatory diseases. To further explore the potential therapeutic role of TGF-β, we administered a plasmid DNA encoding human TGF-β1 intramuscularly to rats with streptococcal cell wall-induced arthritis. A single dose of 300 μg plasmid DNA encoding TGF-β1, but not vector DNA, administered at the peak of the acute phase profoundly suppressed the subsequent evolution of chronic erosive disease typified by disabling joint swelling and deformity (articular index = 8.17±0.17 vs. 1.25±0.76, n = 6, day 26, P < 0.01). Moreover, delivery of the TGF-β1 DNA even as the chronic phase commenced virtually eliminated subsequent inflammation and arthritis. Both radiologic and histopathologic as well as molecular evidence supported the marked inhibitory effect of TGF-β1 DNA on synovial pathology, with decreases in the inflammatory cell infiltration, pannus formation, cartilage and bone destruction, and the expression of proinflammatory cytokines that characterize this model. Increases in TGF-β1 protein were detected in the circulation of TGF-β1 DNA-treated animals, consistent with the observed therapeutic effects being TGF-β1 dependent. These observations provide the first evidence that gene transfer of plasmid DNA encoding TGF-β1 provides a mechanism to deliver this potent cytokine that effectively suppresses ongoing inflammatory pathology in arthritis.