Therapeutic inhibition of tumour necrosis factor alpha reduces oligoclonality in the selected T-cell receptor BV families in rheumatoid arthritis

Background

Treatment of rheumatoid arthritis (RA) with the recombinant p75 tumour necrosis factor (TNF) receptor fusion protein etanercept is clinically highly effective. Clonally expanded, autoreactive CD4⁺CD28 null T cells can be found in the peripheral blood of patients with RA, and have been shown to use distinct BV–BJ combinations in their T-cell receptor (TCR).

Objective

This study was undertaken to investigate the influence of anti-TNF-α treatment on expanded clonotypes in the peripheral CD4⁺ T-cell compartment.

Methods

We investigated the size of the CD4⁺CD28 null compartment and the TCR β-chain repertoire of expanded CD4⁺ clonotypes in 19 patients with RA, before the initiation of treatment with etanercept and after 2, 4 and 18 months of TNF-α blocking therapy by complementarity-determining region 3 (CDR3) length analysis (spectrotyping) in the BV6 and BV14 TCR families. This was done with primers specific for three arbitrarily chosen β-chain joining elements (BJ1S2, BJ2S3 and BJ2S7).

Results

TNF-α inhibition significantly reduced the total number of expanded clonotypes found in the TCR BV6 family after 4 months of treatment, and was even more pronounced after 18 months. In contrast, however, the number of detected BV14 clones was not affected. The percentage of CD4⁺CD28 null cells, which has been shown to correlate with expanded clonotypes using BV14–BJ1S2 and BV14–BJ2S3 combinations, but not with the number of BV6 clones, remained unchanged under therapy.

Conclusion

Therapeutic blockade of the proinflammatory cytokine TNF-α, which leads to a profound decrease of disease activity in treated patients, was also found to influence the size of expanded CD4⁺ clonotypes in the peripheral circulation in RA patients. This effect was dependent on the TCR BV-BJ combinations used in the clonotypes, however, and was restricted to the BV6 family in our study, while BV14 clonotypes were not affected.