EXTENDED REPORT

TNF receptor gene therapy results in suppression of IgG2a anticollagen antibody in collagen induced arthritis

P Mukherjee¹, B Wu², L Mayton², S-H Kim³, P D Robbins³, P H Wooley^1,2

¹ Department of Immunology and Microbiology, Wayne State University School of Medicine Detroit, MI 48201, USA
² Department of Orthopaedic Surgery, Wayne State University School of Medicine Detroit, MI 48201, USA
³ Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

Correspondence to:
Correspondence to:
Professor P H Wooley, Department of Orthopedic Surgery, Wayne State University, 1 South, Hutzel Hospital, 4707 St Antoine Blvd, Detroit, MI 48201, USA;
pwooley{at}wayne.edu

Background: Therapeutic strategies to block tumour necrosis factor (TNF) activity in experimental autoimmune arthritis models and rheumatoid arthritis (RA) have proved highly successful, and provide sustained beneficial effects.

Objective: To examine whether TNF inhibition has immunological activity beyond the reduction of inflammation in collagen induced arthritis (CIA), an established experimental model of RA.

Methods: Arthritic DBA/1 mice received single periarticular injections of retroviral constructs encoding human TNF receptor (TNF-R) into the affected arthritic paw, at the onset of arthritis. Severity of arthritis, antibodies to collagen type II (CII), and extent of pathological joint damage of arthritic paws were compared between TNF-R and media treated (control) animals 3, 7, 14, 21, and 49 days after disease onset.

Results: Severity of CIA was significantly decreased in TNF-R treated animals compared with controls, 14–34 days after disease onset. Joint destruction was reduced in TNF-R injected joints and in the uninjected contralateral and ipsilateral paws of TNF-R treated animals. Seven days after disease onset, TNF-R treated mice had lower levels of inflammatory Th1 driven IgG2a antibodies to CII (p<0.05) than controls. This altered the anticollagen IgG2a:IgG1 ratio towards Th2 driven IgG1.

Conclusions: Local TNF-R gene therapy in CIA appears to have systemic effects on the anti-CII antibodies. The overall influence of TNF-R gene therapy is that it inhibits the progression of CIA mainly by suppressing the inflammatory Th1 response rather than by stimulating a Th2 response. Therefore, periarticular TNF-R gene therapy may have excellent therapeutic potential in RA.

Keywords: experimental models; rheumatoid arthritis, tumour necrosis factor receptor; gene therapy

Abbreviations: CIA, collagen induced arthritis; CII, collagen type II; DMEM, Dulbecco’s modified Eagle’s medium; ELISA, enzyme linked immunosorbent assay; GM-CSF, granulocyte macrophage-colony stimulating factor; IL, interleukin; PBS, phosphate buffered saline; RA, rheumatoid arthritis; SEM, standard error of mean; sTNF-RI, soluble tumour necrosis factor receptor I; TNF, tumour necrosis factor ; TNF-R, tumour necrosis factor receptor

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Butz, D. E., Li, G., Huebner, S. M., Cook, M. E. (2007). A mechanistic approach to understanding conjugated linoleic acid's role in inflammation using murine models of rheumatoid arthritis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293: R669-R676 [Abstract] [Full Text]  
• Adriaansen, J., Vervoordeldonk, M. J. B. M., Tak, P. P. (2006). Gene therapy as a therapeutic approach for the treatment of rheumatoid arthritis: innovative vectors and therapeutic genes. Rheumatology (Oxford) 45: 656-668 [Abstract] [Full Text]  
• Mukherjee, P, Yang, S-Y, Wu, B, Song, Z, Myers, L K, Robbins, P D, Wooley, P H (2005). Tumour necrosis factor receptor gene therapy affects cellular immune responses in collagen induced arthritis in mice. Ann Rheum Dis 64: 1550-1556 [Abstract] [Full Text]