Suppression of collagen-induced arthritis through adenovirus-mediated transfer of a modified tumor necrosis factor
C H Le1, A G Nicolson, A Morales
1Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Objective:
To evaluate the efficacy of systemic and intraarticular adenoviral transfer of a modified tumor necrosis factor alpha receptor (TNF alphaR) gene and its expression in rat collagen-induced arthritis (CIA).
Methods:
Rats with CIA received injections of replication-deficient adenovirus containing either a TNF alpha inhibitor (TNFI) gene or a control beta-galactosidase (beta-gal) gene. The TNFI gene codes for a fusion protein consisting of the human 55-kd TNF alphaR and a mouse IgG heavy chain. Successful gene transfer was determined by serum TNF alphaR measurements and by histologic examination of injected joints with in situ blue staining.
Results:
Serum TNF alphaR levels were detectable for 8 days following systemic TNFI gene transfer. CIA severity was significantly suppressed by TNFI gene transfer, both prior to and following arthritis onset (P = 0.0001, by repeated-measures 2-factor analysis of variance). Direct synovial TNFI gene transfer was successful, but induced an inflammatory response without any net TNFI benefit.
Conclusion:
Systemic adenoviral-mediated transfer of the TNFI gene suppressed CIA during its transitory expression. Intraarticular gene transfer was limited by an adenoviral synovitis that was not overcome by delivery of the TNFI gene. TNFI is an excellent protein candidate for further therapeutic study.
