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Blood, Vol. 95 No. 1 (January 1), 2000:
pp. 352-359
Reconstitution of T-cell receptor repertoire diversity following
T-cell depleted allogeneic bone marrow transplantation is related to
hematopoietic chimerism
Catherine J. Wu,
Antoinette Chillemi,
Edwin P. Alyea,
Enrica Orsini,
Donna Neuberg,
Robert
J. Soiffer, and
Jerome Ritz
From the Center for Hematologic Oncology and Department of
Biostatistics, Dana-Farber Cancer Institute; Department of Medicine,
Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
CDR3 spectratyping was used to analyze the complexity of the T-cell
repertoire and to define the mechanisms and kinetics of the
reconstitution of T-cell immunity after allogeneic bone marrow transplantation (BMT). This method, which is based on polymerase chain
reaction amplification of all CDR3 regions using the T-cell receptor
(TCR) V genes, was used to examine serial samples of peripheral
blood lymphocytes from 11 adult patients with chronic myelogenous
leukemia (CML) who underwent T-cell-depleted allogeneic BMT. In
contrast to 10 normal donors who display highly diverse and polyclonal
spectratypes, patient samples before and early after BMT revealed
markedly skewed repertoires, consisting of absent, monoclonal, or
oligoclonal profiles for the majority of V subfamilies. To quantify
changes in TCR repertoire over time, we established an 8-point scoring
system for each V subfamily. The mean complexity score for patient
samples before transplant (130.8) was significantly lower than that for
normal donors (183; P = 0.0007). TCR repertoire complexity
was abnormal in all patients at 3 months after BMT (mean
score = 87). Normalization of repertoire began in 4 patients at 6 months after BMT, but the majority of patients continued to display
abnormal repertoires for up to 3 years after BMT. To determine whether
the reconstituted T-cell repertoire was derived from the donor or
recipient, unique microsatellite loci were examined to establish
chimeric status. At 3 months after BMT, 7 patients demonstrated mixed
chimerism; 4 had complete donor hematopoiesis (CDH). CDH strongly
correlated with likelihood of restoration of T-cell repertoire
complexity (P = 0.003). In contrast, patients who
demonstrated persistence of recipient hematopoiesis failed to
reconstitute a diverse TCR repertoire. These findings suggest that the
reconstitution of a normal T-cell repertoire from T-cell progenitors in
adults is influenced by interactions between recipient and donor
hematopoietic cells. (Blood. 2000;95: 352-359)
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