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Blood, 1 March 2001, Vol. 97, No. 5, pp. 1458-1466

TRANSPLANTATION

Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation

Kenneth Weinberg, Bruce R. Blazar, John E. Wagner, Edward Agura, Brenna J. Hill, Monika Smogorzewska, Richard A. Koup, Michael R. Betts, Robert H. Collins, and Daniel C. Douek

From the Division of Research Immunology/Bone Marrow Transplantation, Childrens Hospital Los Angeles, CA; Division of Bone Marrow Transplantation, Department of Pediatrics, Cancer Center, University of Minnesota, Minneapolis, MN; Department of Internal Medicine, University of Texas Southwestern Medical Center, and the Sammons Cancer Center, Baylor University Medical Center, Dallas TX.

Hematopoietic stem cell transplantation (HSCT) is followed by profound immunodeficiency. Thymic function is necessary for de novo generation of T cells after HSCT. Circulating CD45RA+ naive T-cell levels are predictive of antigen-specific T-cell responses in the absence of graft-versus-host disease (GVHD). These T cells may not represent recent thymic emigrants, since naive T cells may maintain this phenotype if not antigen-activated. To accurately measure thymic output after HSCT and determine the factors that influence thymic function, T-cell receptor excision circles (TRECs) were examined in CD4+ and CD8+ cells from a cross-section of patients following HSCT. TREC levels rose weeks after HSCT and could be detected in patients 6 years after HSCT. TREC levels correlated with the frequency of phenotypically naive T cells, indicating that such cells were not expanded progeny of naive T cells present in the donor graft. Chronic GVHD was the most important factor that predicted low TREC levels even years after HSCT. Patients with a history of resolved GVHD had decreased numbers of TREC, compared with those with no GVHD. Because few adults had no history of GVHD, it was not possible to determine whether age alone inversely correlated with TREC levels. Recipients of cord blood grafts had no evidence of decreased TREC induced by immunosuppressive prophylaxis drugs. Compared with unrelated donor grafts, recipients of matched sibling grafts had higher TREC levels. Collectively, these data suggest that thymopoiesis is inhibited by GVHD. Larger studies will be needed to determine the independent contributions of age and preparative regimen to post-transplant thymopoietic capacity.

© 2001 by The American Society of Hematology.
 

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Hematology, January 1, 2002; 2002(1): 422 - 444.
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J. Storek, A. Joseph, G. Espino, M. A. Dawson, D. C. Douek, K. M. Sullivan, M. E. D. Flowers, P. Martin, G. Mathioudakis, R. A. Nash, et al.
Immunity of patients surviving 20 to 30 years after allogeneic or syngeneic bone marrow transplantation
Blood, December 15, 2001; 98(13): 3505 - 3512.
[Abstract] [Full Text] [PDF]


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D. C. Douek, M. R. Betts, B. J. Hill, S. J. Little, R. Lempicki, J. A. Metcalf, J. Casazza, C. Yoder, J. W. Adelsberger, R. A. Stevens, et al.
Evidence for Increased T Cell Turnover and Decreased Thymic Output in HIV Infection
J. Immunol., December 1, 2001; 167(11): 6663 - 6668.
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B. Chung, L. Barbara-Burnham, L. Barsky, and K. Weinberg
Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation
Blood, September 1, 2001; 98(5): 1601 - 1606.
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E. P. Hochberg, A. C. Chillemi, C. J. Wu, D. Neuberg, C. Canning, K. Hartman, E. P. Alyea, R. J. Soiffer, S. A. Kalams, and J. Ritz
Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults
Blood, August 15, 2001; 98(4): 1116 - 1121.
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