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models it was predicted that alloreactive NK cells can prevent GVHD by
eliminating recipient antigen-presenting cells (APCs), which can initiate
GVHD and enhance engraftment by killing residual recipient T cells fol-
lowing preparative regiments. In a follow-up study published in 2007
[61]
,
lower rate of relapse, event-free survival, and remission were still signifi-
cantly associated with NK cell alloreactivity.
On the basis of these findings several retrospective analyses were conducted
with conflicting results. Giebel and colleagues
[62]
demonstrated a benefi-
cial effect of KIR ligand mismatching studying 130 unrelated donor trans-
plants, of which 20 had predicted NK cell alloreactivity. Event-free survival
was markedly increased (87% vs 46%,
p
= 0.006). As in the Perugia study,
NK cell alloreactivity was beneficial predominately for myeloid malignan-
cies, yet not all studies using a similar platform agree. In a different setting
of 175 unrelated mismatched transplants, there was no beneficial effect of
KIR ligand incompatibility
[63]
. In perhaps one of the largest retrospective
analyses of KIR ligand mismatching, a study that examined over 1500 unre-
lated transplants found no beneficial effect and reported that KIR ligand
incompatibility was associated with increased GVHD, treatment-related
mortality, and shorter leukemia-free survival compared with HLA-matched
transplants
[64]
. Improved survival was observed following HLA-matched
sibling transplant in myeloid patients in which the recipient lacked a KIR
ligand
[65]
, and lower relapse following unrelated HSCT was also associated
when the recipient lacked a KIR ligand.
339
There are several factors that may explain the disparities between the Peru-
gia findings and subsequent retrospective analyses and studies. In the
Perugia study, donor allografts were extensively T-cell depleted using a com-
bination of CD34
+
selection, soybean agglutination, and E-rosetting. It was
predicted that extensive T-cell depletion was necessary for the expansion
of alloreactive donor NK cells
in vivo,
as T cells present in the graft would
compete with NK cells for cytokines and initiate GVHD before NK cells were
able to eliminate residual host APCs. Two studies that examined NK cell
alloreactivity in T-cell-replete HSCT found no beneficial effect of KIR ligand
mismatching
[66,67]
. Differing pretransplant conditioning regimes and
post-transplant GVHD prophylaxis may also play roles in the efficacy of NK
cell alloreactivity. KIR ligand mismatching has also been studied following
umbilical cord blood (UCB) HSCT. Willemze and colleagues
[68]
reported
on the outcomes of 218 single-unit UCB transplants in AML and ALL
patients. Donor-recipient pairs with KIR ligand incompatibilities showed
improved leukemia-free survival and decreased relapse for patients with
AML. Patients with ALL also showed a trend toward better outcomes when
there was predicted KIR ligand incompatibility. In contrast, Brunstein and
colleagues
[69]
reported a negative effect of KIR ligand incompatibilities in
a cohort of 257 UCB HSCT recipients. Following myeloablative condition-
ing regimens, KIR ligand incompatibilities had no effect on the occurrence
of acute GVHD, relapse, or survival; however, following reduced-intensity
conditioning, a higher incidence of acute GVHD and lower overall survival
were seen. There were no differences in relapse.
Although these retrospective analyses used the KIR ligand incompatibility
model to predict NK alloreactivity, unlike the Perugia study, the ability of the
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