Paradoxical effects of adenovirus-mediated blockade of TNF activity in murine collagen-induced arthritis

Collagen-induced arthritis (CIA) is an experimental model of arthritis wide ly used to dissect the pathogenesis of human rheumatoid arthritis and to id entify potential therapeutic targets. Among these, TNF-alpha has been recog nized to play an important role. Here we investigate the feasibility and th erapeutic efficacy of prolonged blockade of TNF-alpha activity through the adenovirus-mediated gene delivery of a dimeric chimeric human p55 TNFR-IgG fusion protein and compare it to protein therapy In established CIA. A sing le i.v, administration of the replication-deficient adenovirus yielded micr ogram serum levels of the chimeric fusion protein and ameliorated CIA for 1 0 days, Subsequently, benefit was lost and a rebound to greater inflammator y activity was observed despite the continual presence of bioactive TNFR fu sion protein. A similar trend was also observed in mice injected directly w ith comparable amounts of a human TNFR-IgG fusion protein, whereas the admi nistration of a control adenovirus-encoding beta-galactosidase or of a cont rol human IgG1 protein did not significantly affect the disease course. The mechanisms of the rebound of CIA were investigated, and augmented Ab respo nse to collagen type II and TNFR were identified as potential causes. Our r esults confirm the feasibility of adenovirus-mediated gene delivery of cyto kine inhibitors in animal models of autoimmune diseases for investigational purposes and highlight the importance of prolonged studies. Further invest igations are needed to optimize ways of exploiting the potential of adenovi ral gene therapy in RA.