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Blood, 15 May 2002, Vol. 99, No. 10, pp. 3668-3675
IMMUNOBIOLOGY
Changes in T-cell receptor VB repertoire in aplastic anemia:
effects of different immunosuppressive regimens
Hoon Kook,
Antonio M. Risitano,
Weihua Zeng,
Marcin Wlodarski,
Craig Lottemann,
Ryotaro Nakamura,
John Barrett,
Neal S. Young, and
Jaroslaw P. Maciejewski
From the Hematology Branch of the National Heart, Lung,
and Blood Institute, National Institutes of Health, Bethesda, MD.
We studied the degree and the pattern of skewing of the variable
region of  -chain (VB) T-cell receptor (TCR) repertoire in aplastic anemia (AA) at initial presentation and after
immunosuppression using a high-resolution analysis of the TCR VB
complementarity-determining region 3 (CDR3). Age-matched healthy
individuals and multitransfused patients with non-immune-mediated
hematologic diseases were used as controls. In newly diagnosed AA, the
average frequency of CDR3 size distribution deviation indicative of
oligoclonal T-cell proliferation was increased (44% ± 33% vs 9% ± 9%; P = .0001); AA patients with human leukocyte antigen
(HLA)-DR2 and those with expanded paroxysmal nocturnal hemoglobinuria
clones showed more skewed VB repertoires. Nonrandom oligoclonal
patterns were found for VB6, VB14-16, VB21, VB23, and VB24 subfamilies
in more than 50%, and for VB15, VB21, and VB24 in more than 70% of AA
patients with HLA-DR2. Patients received immunosuppression with
antithymocyte globulin (ATG)/cyclosporine (CsA) or cyclophosphamide
(CTX) with CsA in combination, and their VB repertoire was reanalyzed
after treatment. Whereas no significant change in the degree of VB
skewing in patients who had received ATG was seen, patients treated
with CTX showed a much higher extent of oligoclonality within all VB
families, consistent with a profound and long-lasting contraction of
the T-cell repertoire. VB analysis did not correlate with the
lymphocyte count prior to lymphocytotoxic therapy; however, after
therapy the degree of VB skewing was highly reflective of the decrease
in lymphocyte numbers, suggesting iatrogenic gaps in the VB repertoire
rather than the emergence of clonal dominance. Our data indicate that
multiple specific clones mediate the immune process in AA.
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