Biology Reference
In-Depth Information
can contain a wide variety of other cell types that can profoundly influ-
ence outcomes either by promoting engraftment or by helping to overcome
resistance mediated by various recipient cell populations that can impede
engraftment or cause rejection. Under certain circumstances, an absence
of these cells in the graft can increase the risk of graft failure. The follow-
ing sections summarize preclinical and clinical information regarding the
identity of the various cell populations and the mechanisms they use to
affect engraftment after allogeneic HCT.
Nucleated cell dose
Experimental studies showed an inverse correlation between the number
of marrow cells used for HCT and the amount of immunosuppressive treat-
ment needed to prevent rejection. For example, when 40 × 10
7
marrow cells
were used for HCT in MHC-incompatible rats, a single 60 mg/kg dose of
cyclophosphamide together with a 35 mg/kg dose of busulfan was sufficient
to prevent rejection, whereas a threefold higher dose of cyclophosphamide
was needed to prevent rejection with 1.0 × 10
7
marrow cells
[69]
.
Transfusion-induced sensitization also has an effect on the relationship
between the number of donor cells and the risk of rejection. In an MHC-
mismatched strain combination where rejection is caused by T cells and
not by NK cells, T-cell-depleted grafts containing 3 × 10
6
marrow cells were
sufficient to establish engraftment in most naïve recipients prepared with
8 Gy TBI and dimethylmyleran but not in recipients sensitized with 1 × 10
6
irradiated donor cells 1 week before TBI
[92]
. Resistance induced by sensiti-
zation with 1 × 10
6
or 5 × 10
6
irradiated donor cells was overcome by increas-
ing the marrow cell dose to 20 × 10
6
cells. Grafts containing 20 × 10
6
cells,
however, did not overcome resistance induced by sensitization with 15 × 10
6
irradiated donor cells.
98
Studies with the same strain combination also showed that grafts contain-
ing large numbers of marrow cells could overcome rejection in sublethally
irradiated recipients
[93]
. At the minimum lethal TBI exposure (8.5 Gy), 95%
of the cells in the recipient blood were derived from the donor at 1 month
after transplantation with 10 × 10
6
T-cell-depleted marrow cells. After 6.5 Gy
TBI, however, the number of donor marrow cells needed to reach this level
of engraftment was at least four- to fivefold higher. These results indicated
that extremely high numbers of T-cell-depleted donor marrow cells could
overcome graft rejection caused by recipient T cells that survive the pre-
transplant conditioning regimen.
Studies in the mid-1970s showed that a marrow cell dose <3 × 10
8
cells/kg
recipient body weight was associated with an increased risk of rejection
in aplastic anemia patients with HLA-identical sibling donors. Infusion of
buffy coat cells isolated from the blood on days 1-4 after HCT was used in
an attempt to decrease the risk of rejection. This approach was prompted
by two observations: circulating stem cells had been shown to exist in sev-
eral species, and lymphocytes had been shown to enhance allogeneic mar-
row engraftment in mice and dogs
[94-96]
. The clinical studies showed that
the addition of buffy coat infusions after marrow transplantation reduced
the risk of rejection, thereby increasing survival in aplastic anemia patients
who had received transfusions. In the original study, only 6 of 43 patients
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