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either of which could cause primary graft failure. Recipients with antibod-
ies against donor cells, however, do not uniformly reject hematopoietic cell
grafts, indicating that the presence of anti-donor antibodies is not neces-
sarily sufficient to cause rejection.
NK cells
PRECLINICAL STUDIES
Cudkowitz and Bennett first showed that radioresistant cells in F1 mice
(which later became known as NK cells) could mediate resistance (termed
“hybrid resistance”) against parental homozygous allogeneic bone mar-
row cell grafts
[20]
. Subsequent work using SCID mice clearly showed that
a non-T-cell component, i.e. NK cells, could mediate hybrid resistance in
unsensitized recipients, but also mediate specific resistance against fully
MHC-mismatched progenitor cell grafts with rapid kinetics (2-3 days)
compared to T-cell-mediated resistance occurring within approximately
1 week
[23,63]
. Radioresistant cells with large granular lymphoid morphol-
ogy and NK activity were identified in DLA-mismatched canine recipients,
and removal of NK cells in non-human primates was also associated with
improved allogeneic engraftment
[22,24,64]
.
90
Despite demonstration of the importance of NK cells in resistance pathways,
a precise understanding of the interactions and effector pathways responsi-
ble for elimination of donor cells remains to be elucidated. NK effector activ-
ity is based on the relative balance of activating receptor signaling through
receptors coupled to transduction molecules that contain an immune-tyro-
sine activating motif (ITAM) (e.g. DAP12) and inhibitory receptor signaling
via killer inhibitory receptors containing immuno-tyrosine inhibitory motifs
(ITIM) that recruit phosphatases to block activation. Thus allogeneic stem
cells lacking some MHC-class I ligands may be directly susceptible to elimi-
nation by selective NK cell clones
[65]
. An
ex vivo
study co-cultured highly
enriched allogeneic and semi-allogeneic NK and HSC populations for sev-
eral hours to assess the consequence on subsequent HSC repopulation but
did not detect any reduction in the number of viable HSCs
[66]
.
The contribution of cytotoxic and cytokine pathways in NK-mediated resis-
tance in mice has not identified a single pathway responsible for removal
of donor cells
[31-36]
. Studies assessing NK-dependent resistance across
MHC disparities after lethal total body irradiation did not detect a diminu-
tion in the resistance against relatively low numbers of marrow cells (2 ×
10
6
) by recipients lacking perforin and FasL-Fas mediated killing individu-
ally or combined
[31]
. Similar results were reported in a different MHC dis-
parate combination after lethal conditioning and transplant of 300-6000
purified
c-Kit
+
Thy-1
lo
Lin
−/lo
Sca
+
HSC in which elimination of either perfo-
rin- or FasL-dependent cytotoxicity was ineffective in reducing resistance
to engraftment
[36]
. Granzyme B was also unnecessary for hematopoietic
allograft resistance in an NK- dependent hybrid resistance model following
transplantation of 6 × 10
6
marrow cells
[32]
. Other studies showed strain and
environmental differences. Resistance was stronger in 129 recipients than
in B6 recipients, and perforin was unnecessary for NK resistance under spe-
cific pathogen-free conditions but not under conventional housing
[33]
.
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