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

Transforming growth factor beta is a potent immunomodulator with both pro-and antiinflammatory activities. Based on its immunosuppressive actions, exogenous TGF-beta has been shown to inhibit autoimmune and chronic inflammatory diseases. To further explore the potential therapeutic role of TGF-beta, we administered a plasmid DNA encoding human TGF-beta 1 intramuscularly to rats with streptococcal cell wall-induced arthritis. A single dose of 300 mu g plasmid DNA encoding TGF-beta 1, 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-beta 1 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-beta 1 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-beta 1 protein were detected in the circulation of TGF-beta 1 DNA-treated animals, consistent with the observed therapeutic effects being TGF-beta 1 dependent. These observations provide the first evidence that gene transfer of plasmid DNA encoding TGF-beta 1 provides a mechanism to deliver this potent cytokine that effectively suppresses ongoing inflammatory pathology in arthritis.