Dynamic T cell receptor clonotype changes in synovial tissue of patients with early rheumatoid arthritis: effects of treatment with cyclosporin A (Neoral)

OBJECTIVE: To study T cell receptor (TCR) repertoire changes in synovial membrane
over a 16 week period in patients with early rheumatoid arthritis (RA); and to
study the influence of cyclosporin A (CSA) on TCR repertoire in a subgroup of
these patients. METHODS: Synovial tissue biopsies and paired blood samples were
obtained from 12 patients with early RA at 2 time points. Seven patients were
treated with CSA (Neoral-Sandimmun, 3 mg/kg/day) and 5 patients with placebo for
16 weeks. TCR V gene repertoires were analyzed by semiquantitative PCR-ELISA.
CDR3 spectratyping and sequence analysis was used to compare TCR clonotype
distributions. RESULTS: TCR-specific mRNA was detected in all synovial tissue
biopsies at the first sampling, but in only 8/12 biopsies 16 weeks later (4/7 CSA
group, 4/5 placebo group). Overrepresented TCR BV genes were found in biopsies of
10/12 patients at the first time point, and in 7/12 patients after 16 weeks (3/7
CSA, 4/5 placebo). CDR3 sequence analysis revealed dynamic repertoire changes
with only a few persisting clonotypes in the synovial tissue of placebo controls.
Persisting T cell clonotypes were more frequently found in the synovial tissue of
CSA treated patients compared to the placebo group. CONCLUSION: These data
suggest a dynamic process of T cell recruitment in the joints of RA patients.
This process, possibly due to activation and subsequent infiltration of new T
cell clones, apparently is influenced by CSA treatment. Synovial tissue T cells
were no longer detected after 16 weeks' CSA treatment in 3 patients. In the other
CSA treated patients, new T cell clones infiltrated, while other clones were
persistently represented in the joints. These data may have important
consequences for the design of T cell targeted therapies for RA.