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

Abstract

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(R), 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 PA.