Tumor Necrosis Factor Receptor gene therapy affects cellular immune response in collagen-induced arthritis in mice

Paramita Mukherjee ¹, Shang-You Yang ¹, Bin Wu ¹, Zheng Song ¹, Linda K Myers ², Paul D Robbins ³ and Paul H Wooley ^1*

¹ Wayne State University, United States
² University of Tennessee, United States
³ University of Pittsburgh, United States

^* To whom correspondence should be addressed. E-mail: ad8754{at}wayne.edu.

Accepted 3 April 2005

Abstract

Objectives: Collagen induced arthritis (CIA) is an animal model of rheumatoid arthritis (RA) amenable to immunotherapy directed against tumor necrosis factor alpha (TNF). We evaluated whether local TNF receptor (TNF-R) gene therapy in DBA/1 mice exerts an influence beyond anti-inflammatory effects. Two parameters of CIA pathogenesis were investigated, namely immunity to collagen II (CII) 245-270 peptide (the major immunodominant epitope within bovine CII) and the preferential activation of T cell Vb8.2 variable region receptors in arthritic DBA/1 mice.

Methods: DBA/1 mice received single peri- articular injections of media or retroviral vectors containing LacZ or human TNF-R into affected arthritic paws at disease onset. Disease severity was monitored, immune responses towards the immunodominant bovine CII(245-270) and sub-dominant CII(334-360) peptide epitopes was assessed by ELISA, and T cell Vb usage was analyzed by real time PCR for the, LacZ-transduced , TNF-R and viral- free media treated control animals. The therapeutic influence of TNF-R gene transduction was compared with other groups at different time points following therapy.

Results: Reduced disease severity was observed 15- 35 days post therapy, with a concomitant increase in immunity towards the sub-dominant CII 334-360 peptide epitope rather than the immunodominant CII 245-270 peptide in TNF-R treated animals. Early in disease, TNF- R treated animals demonstrated a reduction of bias towards the otherwise predominant Vb8.2 T cell subset.

Conclusions: These finding indicate that TNF-R gene therapy influences the cellular immunity in CIA, leading to overall disease amelioration, thus suggesting that TNF inhibition may have therapeutic potential beyond the control of inflammation in RA.

Keywords: Experimental models, TNF receptor, cellular immunity, collagen-induced arthritis, gene therapy

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