EMERGENCE OF OLIGOCLONAL T-CELL POPULATIONS FOLLOWING THERAPEUTIC T-CELL DEPLETION IN RHEUMATOID-ARTHRITIS

Objective, To examine the compartment of CD4+ T cells in patients with rheumatoid arthritis (RA) who have developed persistent lymphopenia following antibody-mediated T cell depletion and to investigate why T cell depletion is of limited therapeutic efficacy. Methods, Circulating T lymphocytes from 10 patients with seropositive RA treated with the monoclonal antibody (MAb) CAMPATH-1H were longitudinally monitored by fluorescence-activated cell sorter analysis with MAb. To assess the molecular diversity of repopulating T cells, random samples of T cell clones from the peripheral blood of 3 patients were analyzed by sequencing the T cell receptor (TCR) beta chains. At the time of recurring disease, the synovial tissue was examined by immunohistochemistry, and the repertoires of peripheral and synovial tissue T cells were compared by TCR beta-chain sequencing and by semiquantitative hybridization with oligonucleotides specific for the V-D-J beta junctional region of selected clones. Results, The reconstitution of the peripheral T cell compartment was very slow, A mean CD4+ T cell count of 105/mu l was reached 34 weeks following MAb treatment, After treatment, the percentage of CD4+ T cells with the CD45RO+ phenotype was significantly increased (P = 0.001), indicating the expansion of antigen-primed memory T cells, TCR beta-chain sequences revealed a marked restriction in the diversity of repopulating T cells with the emergence of dominant clonetypes, Despite the low counts of peripheral CD4+ T cells, the synovial tissue was infiltrated by CD4+ T cells to a similar extent as that in RA patients not treated with MAb, Selected clonotypes that had emerged in the peripheral blood compartment dominated the repertoire of tissue-infiltrating T cells in the synovium. Conclusion, In patients with RA, T cell depletion induces a long-term imbalance in T cell homeostasis. Clonal proliferation of CD4+ T cells severely restricts the diversity of available T cell specificities and results in the emergence of dominant clonotypes, which accumulate in the synovial tissue despite peripheral lymphopenia.