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cells in the recipient, and in the absence of such inhibition, these recipient
NK cells can cause rejection. Hence, donor cells that are homozygous for C1
or C2 KIR ligands cannot inhibit NK cells in C1/C2 heterozygous recipients.
Likewise, C2-homozygous donor cells cannot inhibit NK cells in C1 homo-
zygous recipients, and C1-homozygous donor cells cannot inhibit NK cells
in C2-homozygous recipients.
An elegant study of 1790 unrelated Japanese donor-recipient pairs showed
no statistically significant association of HLA-C mismatching with the risk
of secondary graft failure
[68]
.The cumulative incidence of graft failure at 1
year after HCT, however, was 5.7% among the 106 HLA-C-mismatched pairs
with KIR2DL combinations that could not inhibit recipient NK cells, com-
pared to 1.8% among 447 HLA-C-mismatched pairs with KIR2DL combina-
tions that could inhibit recipient NK cells (
p
= 0.019). The hazard ratio was
4.39 (95% confidence interval, 1.38 - 13.96,
p
= 0.012). Taken together, these
results suggested that the association of HLA-C mismatching with graft fail-
ure resulted not from activation of alloreactive T cells in the recipient, but
from lack of an inhibitory effect on recipient NK cells.
These results conflicted with those of earlier studies suggesting that HLA-C
mismatching could cause rejection through activation of recipient T cells
[69]
. The discrepancy between the two reports could be explained by dif-
ferences in the definition of graft rejection. The earlier study included both
primary and secondary graft failure, whereas the Japanese study included
only secondary graft failure. Results of the Japanese study were unexpected
in two additional respects. First, nearly 90% of the recipients were given
cyclophosphamide as part of the conditioning regimen, although the report
did not indicate specifically whether the small number of recipients with
rejection had been treated with cyclophosphamide. As discussed above,
NK-mediated graft rejection in mice can be overcome by treatment of the
recipient with cyclophosphamide. Second, NK-mediated mechanisms of
rejection would be expected to cause primary graft failure, rather than sec-
ondary graft failure.
92
Impact of pretransplant conditioning on effector
mechanisms of rejection
Preclinical studies
Increasing the intensity of conditioning before transplantation reduces
the recipient's immune capacity and can enable engraftment of MHC-
mismatched marrow in experimental animal models. TBI has both myelo-
suppressive and immunosuppressive activity and has been the most
extensively used agent for pre-clinical studies. Single TBI exposures as high
as 9.0 Gy did not overcome resistance against MHC-mismatched unre-
lated donors in canines
[70]
. In unsensitized mice, engraftment is generally
observed after exposures that are considered lethal to individual strains,
for example ≥7.5 Gy in BALB/c recipients and ≥8.5 Gy in B6 recipients. The
transplant of high numbers of bone marrow cells (typically greater than
3-5 × 10
6
) overrides the more limited capacity of NK-dependent resistance.
Transplant of 2.5 × 10
7
marrow cells following a single 9.0 Gy TBI exposure
produced engraftment in 100% of B6 recipients after transplantation of
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