Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution

Daniel C. Douek, Robert A. Vescio, Michael R. Betts, Jason M. Brenchley, Brenna J. Hill, Lan Zhang, James R. Berenson, Robert H. Collins, Richard A. Koup

Research output: Contribution to journalArticle

433 Citations (Scopus)

Abstract

Background. The potential benefits of haematopoietic stem-cell transplantation are tempered by the depletion of T-cells accompanying this procedure. We used a new technique which quantifies the excisional DNA products of T-cell-receptor (TCR) gene rearrangement to measure thymic output directly in patients with multiple myeloma, and thus assessed the contribution of the thymus to immune recovery after transplantation. Methods. We studied 40 patients, 34-66 years of age, who had been randomly assigned myeloablative chemotherapy and autologous peripheral-blood haematopoietic stem-cell transplantation with unmanipulated grafts or grafts enriched for CD34 stem cells. CD4 and CD8 T-cell counts were measured, thymic output was estimated serially until 2 years after transplantation, and percentages of naive T-cells were measured. Findings. The production of substantial numbers of new naive T cells by the thymus could be detected by 100 days post-transplant; there was a significant inverse relation between age and recovery of new T cells. In the CD34-unselected group, numbers of TCR-rearrangement excision circles returned to baseline after 2 years, whereas in the CD34-selected group, numbers at 2 years were significantly higher than both baseline numbers (p = 0.004), and 2-year numbers in the unselected group (p = 0.046). Increased thymic output correlated with, and was predictive of, increased naive T-cell numbers and broader T-cell-receptor repertoires. Interpretation. Our results provide evidence that the adult thymus contributes more substantially to immune reconstitution after haematopoietic stem-cell transplantation than was previously thought, and therefore could be a target for therapeutic intervention.

Original languageEnglish (US)
Pages (from-to)1875-1881
Number of pages7
JournalLancet
Volume355
Issue number9218
StatePublished - May 27 2000

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Hematopoietic Stem Cell Transplantation
T-Lymphocytes
Thymus Gland
T-Cell Antigen Receptor
Transplants
Cell Count
Transplantation
T-Lymphocyte Gene Rearrangement
T-Cell Receptor Genes
Peripheral Blood Stem Cell Transplantation
Multiple Myeloma
Stem Cells
Drug Therapy
DNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Douek, D. C., Vescio, R. A., Betts, M. R., Brenchley, J. M., Hill, B. J., Zhang, L., ... Koup, R. A. (2000). Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet, 355(9218), 1875-1881.

Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. / Douek, Daniel C.; Vescio, Robert A.; Betts, Michael R.; Brenchley, Jason M.; Hill, Brenna J.; Zhang, Lan; Berenson, James R.; Collins, Robert H.; Koup, Richard A.

In: Lancet, Vol. 355, No. 9218, 27.05.2000, p. 1875-1881.

Research output: Contribution to journalArticle

Douek, DC, Vescio, RA, Betts, MR, Brenchley, JM, Hill, BJ, Zhang, L, Berenson, JR, Collins, RH & Koup, RA 2000, 'Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution', Lancet, vol. 355, no. 9218, pp. 1875-1881.
Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L et al. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet. 2000 May 27;355(9218):1875-1881.
Douek, Daniel C. ; Vescio, Robert A. ; Betts, Michael R. ; Brenchley, Jason M. ; Hill, Brenna J. ; Zhang, Lan ; Berenson, James R. ; Collins, Robert H. ; Koup, Richard A. / Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. In: Lancet. 2000 ; Vol. 355, No. 9218. pp. 1875-1881.
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AU - Vescio, Robert A.

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AU - Hill, Brenna J.

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N2 - Background. The potential benefits of haematopoietic stem-cell transplantation are tempered by the depletion of T-cells accompanying this procedure. We used a new technique which quantifies the excisional DNA products of T-cell-receptor (TCR) gene rearrangement to measure thymic output directly in patients with multiple myeloma, and thus assessed the contribution of the thymus to immune recovery after transplantation. Methods. We studied 40 patients, 34-66 years of age, who had been randomly assigned myeloablative chemotherapy and autologous peripheral-blood haematopoietic stem-cell transplantation with unmanipulated grafts or grafts enriched for CD34 stem cells. CD4 and CD8 T-cell counts were measured, thymic output was estimated serially until 2 years after transplantation, and percentages of naive T-cells were measured. Findings. The production of substantial numbers of new naive T cells by the thymus could be detected by 100 days post-transplant; there was a significant inverse relation between age and recovery of new T cells. In the CD34-unselected group, numbers of TCR-rearrangement excision circles returned to baseline after 2 years, whereas in the CD34-selected group, numbers at 2 years were significantly higher than both baseline numbers (p = 0.004), and 2-year numbers in the unselected group (p = 0.046). Increased thymic output correlated with, and was predictive of, increased naive T-cell numbers and broader T-cell-receptor repertoires. Interpretation. Our results provide evidence that the adult thymus contributes more substantially to immune reconstitution after haematopoietic stem-cell transplantation than was previously thought, and therefore could be a target for therapeutic intervention.

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