Emergence of oligoclonal T cell populations following therapeutic T cell depletion in rheumatoid arthritis

Arthritis Rheum. 1995 Sep;38(9):1242-51. doi: 10.1002/art.1780380912.


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.

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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antigens, CD / immunology
  • Antigens, Neoplasm*
  • Arthritis, Rheumatoid / pathology*
  • Arthritis, Rheumatoid / therapy*
  • CD4-Positive T-Lymphocytes / pathology
  • CD52 Antigen
  • Cell Line
  • Female
  • Flow Cytometry
  • Glycoproteins*
  • Humans
  • Lymphocyte Depletion*
  • Male
  • Middle Aged
  • Synovial Membrane / immunology
  • Synovial Membrane / pathology
  • Synovitis / immunology
  • Synovitis / pathology
  • T-Lymphocytes / pathology*


  • Antigens, CD
  • Antigens, Neoplasm
  • CD52 Antigen
  • CD52 protein, human
  • Glycoproteins