Article Text
Abstract
Background: Collagen induced arthritis (CIA) is an animal model of rheumatoid arthritis (RA) amenable to immunotherapy directed against tumour necrosis factor α (TNFα).
Objective: To evaluate whether local TNF receptor (TNF-R) gene therapy in DBA/1 mice exerts an influence beyond anti-inflammatory effects. Two measures 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 Vβ8.2 variable region receptors in arthritic DBA/1 mice.
Methods: DBA/1 mice received single periarticular 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 subdominant CII 334–360 peptide epitopes were assessed by ELISA, and T cell Vβ usage was analysed by real time polymerase chain reaction 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 times after treatment.
Results: Reduced disease severity was seen 15–35 days after treatment, with a concomitant increase in immunity towards the subdominant CII 334–360 peptide epitope rather than the immunodominant CII 245–270 peptide in TNF-R treated animals. Early in the disease, TNF-R treated animals demonstrated a reduction of bias towards the otherwise predominant Vβ8.2 T cell subset.
Conclusions: TNF-R gene therapy influences 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.
- CIA, collagen induced arthritis
- CII, collagen type II
- DMEM, Dulbecco’s modified Eagle’s medium
- ELISA, enzyme linked immunosorbent assay
- INFγ, interferon γ
- MHC, major histocompatibility complex
- PCR, polymerase chain reaction
- RA, rheumatoid arthritis
- TCR, T cell receptor
- TNFα, tumour necrosis factor α
- TNF-R, TNF receptor
- Vβ, variable region β
- collagen induced arthritis
- gene therapy
- T cell receptors
- cellular immunity
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- CIA, collagen induced arthritis
- CII, collagen type II
- DMEM, Dulbecco’s modified Eagle’s medium
- ELISA, enzyme linked immunosorbent assay
- INFγ, interferon γ
- MHC, major histocompatibility complex
- PCR, polymerase chain reaction
- RA, rheumatoid arthritis
- TCR, T cell receptor
- TNFα, tumour necrosis factor α
- TNF-R, TNF receptor
- Vβ, variable region β