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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.
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