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preparation with 7.5 Gy single-exposure TBl delivered at 26 R/min. In con-
trast, 8 of 13 patients receiving identically treated marrow after prepara-
tion with fractionated TBl (10.0-12.0 Gy) had primary or secondary graft
failure.
Similar results were observed in subsequent experiments with animals.
Soderling et al.
[71]
showed that conditioning regimens of 13.2 Gy TBI given
in 4 fractions and 7.5 Gy TBI given as a single exposure were sufficient to
prevent rejection of intact BALB/c marrow and spleen cells in C57BL/6
recipients, but these same regimens were not sufficient to prevent rejection
of T-cell-depleted grafts. Rejection of T-cell-depleted grafts could be over-
come by giving 13.2 Gy TBI in 4 fractions instead of 8 fractions, by condi-
tioning with a single 9 Gy TBI exposure instead of 7 Gy TBI, or by combining
7 Gy TBI with two 120 mg/kg doses of cyclophosphamide.
Further evidence suggesting an important role for donor lymphocytes in
preventing graft rejection came from experiments with the canine models
in which a marrow graft contains relatively few T cells. Infusions of donor
blood leukocytes prevented rejection of DLA-non-identical unrelated mar-
row grafts
[95]
. Irradiation of the donor blood leukocytes prevented this
beneficial effect, and the effect was diminished when recipients were given
cyclosporin
[109]
. Infusion of donor thoracic duct lymphocytes also pre-
vented rejection
[96]
, indicating that the benefit could not be attributed to
hematopoietic stem cells
[110]
.
102
Findings in human marrow transplantation that T-cell depletion increases
the risk of graft rejection were consistent with findings in animal models.
Findings that more intensive pretransplant conditioning can facilitate
engraftment of T-cell-depleted marrow were also similar in humans and in
animal models. It was speculated that donor cells might produce cytokines
that promote or facilitate donor hematopoiesis in allogeneic recipients or
that factors elaborated by T cells are directly or indirectly responsible for sus-
taining hematopoietic function such that graft failure after T-cell-depleted
HCT is caused by deficiency of one or more of these factors. However, donor
T cells actually suppress donor-derived hematopoiesis after HCT when the
conditioning regimen is sufficient to prevent rejection of grafts that do not
contain T cells
[111]
. Taken together, the clinical and experimental results
indicate that certain T cells facilitate durable engraftment not by promoting
donor hematopoietic function but by eliminating recipient cells that can
cause graft rejection.
Support for this hypothesis came from experiments showing that under
certain conditions, donor T cells were necessary to prevent marrow graft
rejection in mice
[112]
. In MHC-incompatible strain combinations where
donor marrow is rejected by T cells and not by NK cells in the recipient,
treatment of the recipient with at least 900 cGy TBI before transplantation
is generally sufficient to prevent rejection of T-cell-depleted donor mar-
row. With TBI exposures at 800 cGy or lower, however, T-cell-depleted grafts
are generally rejected, and recipients reconstitute hematopoiesis through
recovery of endogenous marrow cells surviving after TBI. The exact “tipping
point” of TBI exposure that crosses from rejection to engraftment of T-cell-
depleted marrow varies to some extent, depending on the sensitivity of the
recipient to TBI and the degree of donor MHC-mismatching.
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