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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-01-0155.
Submitted January 18, 2002
Accepted June 24, 2002
Loss of T lymphocyte clonal dominance in patients with myelodysplastic syndrome responsive to immunosuppression
James N Kochenderfer, Sumiko Kobayashi, Eric D Wieder, Chunliu Su, and Jeffrey J Molldrem*
Transplantation Immunology Section, Department of Blood and Marrow Transplantation, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
* Corresponding author; email: jmolldre{at}notes.mdacc.tmc.edu.
There is evidence that T lymphocyte-mediated inhibition of hematopoiesis in myelodysplastic syndrome (MDS) contributes to cytopenia in some patients and can be reversed by treatment with immunosuppression. We examined the T-cell repertoires of 12 MDS patients before and after ATG-based treatment by T-cell receptor-Vß (TCR-Vß) spectratype analysis. The average number of TCR-Vß families with skewed spectratypes, representative of clonal or oligoclonal T-cell populations, was 7.6 in pre-treatment MDS patients and 3.2 in healthy controls, p=0.02. Four patients that recovered effective hematopoiesis after treatment lost prominent, skewed peaks on their spectratypes, suggesting loss or diminution of over-represented clonal T-cell populations. In contrast, patients that did not recover effective hematopoiesis showed persistently skewed repertoires 3 to 6 months after treatment. In 3 patients with skewed repertoires, cDNA from the complementarity-determining region 3 (CDR3) of 4 TCR-Vß families was cloned and repetitively sequenced, confirming clonal T-cell dominance in each family. In one non-responder, 16 of 19 CDR3 sequences were identical; demonstrating that 9.3% of the total T-cell population was made up of a single clone. By 6 months after treatment, this clone persisted on both spectratype and DNA sequence complementarity and when analyzed by flow cytometry was shown to be CD8+/CD45RA+/HLA-DR-. T-cell clones were not anergic since they could be expanded 4-fold in vitro. Our results demonstrate that predominant clonal T-cells that appear to be antigen-driven persist in MDS patients unresponsive to immunosuppression, but predominant clones regress in responders to immunosuppression.
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