Suppression of collagen-induced arthritis through adenovirus-mediated transfer of a modified tumor necrosis factor alpha receptor gene.
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.


CONCLUSIONS
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.
Le
C H
CH
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Nicolson
A G
AG
Morales
A
A
Sewell
K L
KL
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003094:Collagen / Q000009:adverse effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D007719:Knee Joint / Q000473:pathology / Q000821:virology; D009363:Neoplasm Proteins / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D047889:Receptors, Tumor Necrosis Factor, Type II; D013583:Synovial Membrane / Q000473:pathology; D053319:Tumor Necrosis Factor Decoy Receptors; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
D009363:Neoplasm Proteins; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D053319:Tumor Necrosis Factor Decoy Receptors; D003094:Collagen; D001616:beta-Galactosidase