Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 107

Donor NK cells

Pre-clinical mouse models first demonstrated the capacity of donor NK
cells to support hematopoietic engraftment during allogeneic marrow cell
transplantation [131,132] . Adoptive transfer of either donor type B6D2 or
recipient-type B6 lymphokine-activated BM or spleen cells with LAK activ-
ity inhibited the resistance of irradiated B6 mice to both B6D2 marrow
and third party-unrelated C3H marrow as measured by day 7 splenic CFU
[131] . The loss of activity by pre-depleting the LAK cells with asialo-GM1
and NK1.1, but not Lyt-2 expressing cells, or by irradiating the LAK marrow-
derived population, supports the conclusion that the effect was mediated
by NK cells. In addition to inhibiting allogeneic resistance, adoptively trans-
ferred recipient-type LAK cells blocked GVHD and permitted long-term
engraftment of allogeneic marrow [131] . With respect to the donor capac-
ity to enhance engraftment, veto activity against host alloreactive CTLs has
been proposed and activated NK cells are known to be efficient mediators of
veto activity [133] . A veto effect by recipient LAK cells could diminish GVHD
but cannot explain their ability to promote engraftment via inhibition of
recipient anti-donor immune resistance. Recent findings have suggested
that donor APCs may be critical for the induction of rejection by recipient T
cells. If so, it is possible that recipient LAK cells prevent rejection by elimi-
nating donor APCs before recipient T cells can be activated [134] .

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Subsequent studies utilized purified donor NK cells activated ex vivo by
rIL-2 and transferred in vivo with IL-2 to promote marrow engraftment
in lethally irradiated MHC-mismatched recipients [132] . These NK cells
induced earlier hematopoietic engraftment and increased the level of
donor chimerism, possibly resulting from some weakening of host resis-
tance [132] . Additional studies corroborated the ability of adherent lym-
phokine activated killer cells (ALAK) of donor (H2 d ) but not recipient (H2 b )
origin to suppress H2 b anti-H2 d responses ex vivo through mechanisms
that did not involve TGF-β but required perforin for optimal suppression
[135] . The inability of syngeneic H2 b or “3 rd ” party H2 k ALAK to suppress
H2 b anti-H2 d responses is consistent with veto-like activity in these cul-
tures. Donor ALAK promoted engraftment as assessed by chimerism tests
at 2 months after transplantation with ~5:1 ratios of ALAK and marrow cells
in sublethally irradiated (8.0-8.5 Gy) B6 recipients, under conditions where
engraftment was not observed in controls that did not receive ALAK cells
[135] . Although the mechanistic pathways that prevent rejection have not
been identified, the ability of donor ALAK populations to suppress specific
recipient anti-donor reactive T cells ex vivo is consistent with the possibility
that they could be used to prevent rejection in the absence of non-specific
global immune suppression.

Donor NK populations with specific anti-host alloreactivity can actively
target and deplete recipient cells that mediate immune resistance against
the graft. F1 H2 d/b NK cells expressing H2 d -speciic Ly49A/G2 receptors
killed B6 cells in vitro , and infusion of these cells into sublethally irradi-
ated B6 recipients prevented rejection of marrow from MHC-mismatched
H2 d/b donors [136] , whereas F1 NK cells that did not express these receptors
could not mediate these effects. When the alloreactive donor NK cells were
co-transplanted with donor marrow cells into non-lethal TBI-conditioned