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CD34
+
cells
[104]
. Since the number of CD34
+
cells from the donor is lim-
ited, experiments were carried out to determine whether
in vitro
culture
could be used to increase the number of cells that can inhibit cytotoxic
responses against HSC-specific alloantigens
[105]
. Culture of CD34
+
CD33
−
cells in medium containing Flt3-ligand, kit-ligand and thrombopoietin for
7-12 days produced a 7- to 20-fold increase in the number of maturing cells
that expressed CD34
+
CD33
+
and CD34
-
CD33
+
phenotypes and had approxi-
mately fourfold increased inhibitory activity per cell. Thus, the
in vitro
cul-
ture produced an estimated 28- to 80-fold increase in overall inhibitory
activity compared to the original population.
The mechanism by which human CD34
+
cells inhibit the development of
cytotoxic responses against HSC-specific alloantigens appears to involve
induction of apoptosis in the cytotoxic precursors
[106]
. Thus, the inhibi-
tory activity of CD34
+
cells in mixed lymphocyte cultures could be blocked
by adding a caspase inhibitor to the culture medium. The inhibitory activity
of CD34
+
cells was also blocked by adding a neutralizing antibody against
TNF-α in the culture medium but not by adding an antibody that blocks
binding between FasL and Fas.
101
The use of CD34-positively selected cells has replaced older methods that
relied on soybean lectin agglutination and erythrocyte rosetting to deplete T
cells from marrow and mobilized blood cell grafts. This method provided a
median of 12 × 10
6
CD34
+
cells and a median of 1 × 10
4
CD3
+
T cells for HCT.
After HCT with HLA-haploidentical donors, 95% of the recipients had sus-
tained engraftment
[99]
. The extent to which high numbers of CD34-posi-
tively selected cells helped to prevent rejection cannot be determined from
these results, because the conditioning regimen used for these patients dif-
fered from the regimen used for patients who received grafts depleted by
soybean lectin agglutination and sheep erythrocyte rosetting
[98]
.
Donor T cells
ACTIVE RECOGNITION
Early studies showed that depletion of T cells from donor marrow was asso-
ciated with an increased risk of graft rejection. In one study, 11 patients with
chronic myelogenous leukemia in chronic phase or acute myeloid leuke-
mia in first remission received 12.0 Gy of fractionated TBI and HLA-iden-
tical marrow containing approximately 1 × 10
6
T cells
[107]
. Six recipients
developed irreversible graft failure between days 21 and 244 after transplant
ation, one developed graft failure that reversed spontaneously, and one had
mixed chimerism in hematopoietic and lymphoid cells. Among 41 patients
with advanced hematologic malignancies who received 15.75 Gy of frac-
tionated TBI and T-cell-depleted marrow, 7 had graft failure, and nearly all
recipients had mixed chimerism in hematopoietic cells.
The significant inverse association of graft failure with TBI suggested a
major role for host factors as the cause of graft failure after T-cell-depleted
HCT. Data from other centers confirmed the influence of the pretransplant
radiation regimen on the risk of graft failure after transplantation of T-cell-
depleted marrow. Patterson et al.
[108]
observed only 1 rejection among 37
patients receiving HLA-identical T-cell-depleted allogeneic marrow after
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