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who received donor buffy coat had rejection, compared to 7 of 22 patients
who received only marrow
[97]
. The use of buffy coat infusions to prevent
rejection, however, was associated with an increased risk of chronic GVHD.
This approach was abandoned when it was observed that rejection could
be overcome successfully without causing chronic GVHD by adding ATG to
cyclophosphamide in the conditioning regimen.
Results showing that large numbers of T-cell-depleted marrow cells could
overcome graft rejection caused by recipient T cells in mice led to studies
testing whether a similar approach could be used successfully in humans
with HLA-haploidentical donors
[98,99]
. Since the number of cells that can
be obtained from donors by marrow aspiration is limited, growth factor-
mobilized blood cells were used as a supplement to marrow cells. T cells were
depleted by soybean lectin agglutination and sheep erythrocyte rosetting.
Initial results showed that the addition of T-cell-depleted mobilized blood
cells to T-cell-depleted marrow cells yielded a 10- to 20-fold increase in the
numbers of mononuclear cells and T cells in the graft. Sustained engraft-
ment of donor cells was observed in 80% of the patients who received com-
bined marrow and mobilized blood cell grafts containing approximately 5
× 10
8
mononuclear cells and a median of 10.7 × 10
6
CD34
+
cells and 2 ×
10
5
CD3
+
cells per kg recipient body weight. Sustained engraftment was not
observed in any of the five patients who received T-cell-depleted marrow
from HLA-haploidentical donors without added mobilized blood cells after
the same pretransplant conditioning regimen
[99]
.
99
Umbilical cord blood has become more widely used as a source of stem
cells for HCT during the past decade, particularly when an HLA-matched
unrelated donor is not readily available or when transplantation cannot
be delayed until a donor is identified
[100]
. The number of cells in cord
blood products is limited, and hematopoietic reconstitution is delayed
when compared to results with marrow or mobilized blood cells. Graft-
ing with at least 2.5 × 10
7
total nucleated cells/kg recipient body weight is
ideally required for timely hematopoietic reconstitution after cord blood
transplantation. Historically, cord blood transplantation was used primar-
ily for children. To some extent, the problem of limited cell dose has been
overcome by the simultaneous use of two cord blood products, and cord
blood transplantation is now widely used both for children and adults. Chi-
merism testing has shown that cells of one cord blood donor disappear,
while those derived from the other donor persist. Other approaches are
being explored in efforts to overcome the limitations of low cell dose for
cord blood transplantation
[101]
.
Hematopoietic stem cell dose
The hematopoietic stem cells (HSC) that are essential for engraftment and
restoration of hematopoietic function after HCT comprise a small sub-
set within a marrow or growth factor-mobilized blood cell graft. In mice,
hematopoietic stem cells are enriched within a population of cells with low
expression of Thy-1, absent or low expression of lineage-specific markers,
and high expression of Sca-1. These cells represent approximately 1 in 2000
marrow cells. In humans, hematopoietic stem cells are enriched within
a population of cells with high expression of CD34 and low expression of
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