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/microliters 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 clonotypes. 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.


CONCLUSIONS
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.
Jendro
M C
MC
Mayo Clinic, Rochester, Minnesota 55905, USA.
Ganten
T
T
Matteson
E L
EL
Weyand
C M
CM
Goronzy
J J
JJ
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology; D000951:Antigens, Neoplasm; D001172:Arthritis, Rheumatoid / Q000473:pathology* / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D000074301:CD52 Antigen; D002460:Cell Line; D005260:Female; D005434:Flow Cytometry; D006023:Glycoproteins; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology; D013585:Synovitis / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology*
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D006023:Glycoproteins