Therapeutic Regulation of T Cells in Rheumatoid Arthritis

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Abstract
TCR repertoire studies in RA have yielded conflicting data. These studies were initiated on the premise that clonal expression of T cells at the site of inflammation could serve as a target for immune therapies designed on the basis of the option to inactivate or eliminate the presumed pathogenic T cells. These analyses have demonstrated the existence of a highly diverse overall TCR repertoire on the basis of extensive usage of TCR V genes both in synovial fluid and tissue. However, clusters of RA patients can be recognized who share increased usage frequencies of defined TCR V genes among synovial fluid or synovial tissue lymphocytes. Subsequent analysis of the CDR3 regions among diverse overall TCR repertoires have revealed the presence of conserved amino acid sequences in the CDR3 regions of the variable portions of TCRs in T lymphocytes derived from the site of inflammation. These findings suggest that a selective, antigen-driven expansion of T lymphocytes is occurring in the inflamed joints. Parallel to the TCR-repertoire studies, we investigated whether vaccines prepared from synovial T cells could modulate T-cell reactivity. The studies were based on previous work on TCV in animals, revealing that attenuated non-specific T-cell lines could serve as a vaccine. The results obtained in 13 RA patients showed no clear indication for a cellular or humoral immune response. Our experience with TCV in RA patients showed that this technique is feasible and safe. We found some evidence for a modulated T-cell reactivity both in vivo and in vitro. These results show at least some immunomodulatory effect af T-cell vaccination, although the antigen specificity of the effect of this intervention remains to be shown. Because of the convincing studies in animals and MS patients, further studies in RA should focus on the effect of vaccination using vaccines prepared from disease-inducing cells. In this respect, determination of the CDR3 regions of synovial T cells could lead to the identification of those T cells that are relevant for the disease.