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

Michael C. Jendro, Tom Ganten, Eric Lawrence Matteson, Cornelia M. Weyand, Jörg J. Goronzy

Research output: Contribution to journalArticle

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Abstract

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) β 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 β-chain sequencing and by semiquantitative hybridization with oligonucleotides specific for the V-D-Jβ 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/μl 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 β- 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.

Original languageEnglish (US)
Pages (from-to)1242-1251
Number of pages10
JournalArthritis and Rheumatism
Volume38
Issue number9
DOIs
StatePublished - Sep 1995

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Rheumatoid Arthritis
T-Lymphocytes
Population
Therapeutics
T-Cell Antigen Receptor
Monoclonal Antibodies
Lymphopenia
CD4 Lymphocyte Count
Clone Cells
T-Cell Antigen Receptor Specificity
Synovial Membrane
Oligonucleotides
Homeostasis
Fluorescence

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Emergence of oligoclonal T cell populations following therapeutic T cell depletion in rheumatoid arthritis. / Jendro, Michael C.; Ganten, Tom; Matteson, Eric Lawrence; Weyand, Cornelia M.; Goronzy, Jörg J.

In: Arthritis and Rheumatism, Vol. 38, No. 9, 09.1995, p. 1242-1251.

Research output: Contribution to journalArticle

Jendro, Michael C. ; Ganten, Tom ; Matteson, Eric Lawrence ; Weyand, Cornelia M. ; Goronzy, Jörg J. / Emergence of oligoclonal T cell populations following therapeutic T cell depletion in rheumatoid arthritis. In: Arthritis and Rheumatism. 1995 ; Vol. 38, No. 9. pp. 1242-1251.
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abstract = "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) β 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 β-chain sequencing and by semiquantitative hybridization with oligonucleotides specific for the V-D-Jβ 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/μl 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 β- 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.",
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