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Bennett's group examined the effect of transfecting hematopoietic stem
and progenitor cells with c-FLIP, an anti-apoptotic molecule that binds to
the Fas-associated death domain (FADD) and inhibits caspase 8 activa-
tion. These studies indicated that in the absence of perforin, engraftment
was increased, thereby supporting a role for cytotoxicity in NK-mediated
resistance against class I deficient donor cells
[34]
. Hamby et al. demon-
strated a role for perforin and a limited role for FasL-dependent killing by
Ly49D-expressing NK cells in a model of hybrid resistance using an MHC-
mismatched strain combination in the presence of anti-T-cell antibody and
costimulatory CD154 (CTLA4) blockade
[38]
. Notably, these transplants
were performed under non-myeloablative conditions using a busulfan-
based preparative regimen, perhaps illustrating a need for perforin-medi-
ated killing under less inflammatory conditions. Studies employing specific
cytokine receptor knock-out strains and anti-cytokine specific monoclonal
antibodies did not detect a significant contribution by INF-γ, TNF-α, TGF-β,
IL-4, IL-10 and IL-12 in hybrid resistance
[33,35,36,38]
.
Overall, the results from models differing in genetics, conditioning, the
nature of the graft and number of cells in the graft suggest that maximal
resistance to engraftment mediated by NK cells requires perforin-mediated
cytotoxicity. At low marrow cell doses, recipients could reject grafts in the
absence of perforin or Fas-mediated mechanisms. At slightly higher mar-
row cell doses, rejection of BALB/c grafts by B6 recipients depended on
perforin. Further studies showed that perforin-deficient 129:B6 recipients
housed under specific pathogen-free conditions could reject grafts in the
presence of Fas signaling but not in the absence of Fas signaling
[35]
. Evi-
dence suggests that additional effector mechanisms may contribute to NK-
dependent resistance when the conditioning regimen causes high levels of
“cytokine storm” and inflammatory activity.
91
Additional information suggests that non-NK and T-cell pathways contrib-
ute to marrow graft resistance. A recent study showed that HSC and pro-
genitor cells express CD47, an immunoglobulin-like surface protein that
interacts with SIRPα (signal regulatory protein alpha, i.e. CD172a) recep-
tors on macrophages to inhibit phagocytosis of healthy cells
[67]
. The level
of CD47 expression was inversely correlated with HSC uptake by macro-
phages, and CD47 levels were upregulated by inflammatory cytokines,
including some that are elicited by TBI. The possibility that interactions
between T cells, NK cells and macrophages might individually and interde-
pendently contribute to immune resistance remains to be explored.
CLINICAL STUDIES
Little, if any, direct evidence is available to demonstrate that recipient
NK cells cause rejection after HCT in humans. Indirect evidence that NK
cells can cause rejection in humans has come from analyses of donor and
recipient ligands that bind killer immunoglobulin-like receptors (KIRs)
[68]
.
HLA-C alleles can be divided into two groups according to their ability to
bind KIRs that inhibit NK-mediated killing. HLA-C alleles that have Asp at
position 80 (C1 KIR ligands) bind to KIR2DL2/3, whereas HLA-C alleles that
have Lys at position 80 (C2 KIR ligands) bind to KIR2DL1. Donor cells that
lack the appropriate HLA-C KIR ligand cannot inhibit killing by certain NK
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