Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 108

mice, recipients of alloreactive NK cells - but not recipients of 20-fold
greater numbers of non-alloreactive NK cells - exhibited virtually 100%
donor chimerism after 6.0 Gy TBI and 50% chimerism following 5.0 Gy
TBI conditioning [136] . The use of non-myeloablative-conditioning regi-
mens utilizing fludarabine and busulfan, melphalan or cyclophosphamide
yielded results that were comparable to those with TBI [134] .

Despite these findings, identifying potential NK reactivity via KIR map-
ping or generating functional NK populations may not predict successful
engraftment by such donor NK populations. Indeed, not all clinical studies
have found benefits of donor NK reactivity towards the host [137-139]. In
one report examining clinical allogeneic HCT, potential donor NK alloreac-
tivity was not associated with a decreased risk of graft failure, and it was sug-
gested that the potential benefits of NK alloreactivity might be diminished
when the graft contains T cells [137] . NK cells can mediate anti-tumor reac-
tivity after allogeneic HCT. Several factors are likely to affect the influence of
NK cells on engraftment, GVHD and GVL effects, including the composition
of the graft, post-transplant immunosuppression, the cytokine milieu and
the timing of donor NK cell infusions. Further studies will be necessary to
optimize the beneficial effects of conditioning regimens that employ donor
NK cells to prevent rejection or recurrent malignancy.

110

Facilitator cells

Facilitator cells encompass populations other than hematopoietic pro-
genitors, T cells and NK cells that support hematopoietic engraftment.
Promotion of engraftment by such cells could involve removing or block-
ing recipient T, NK or antibody-mediated immune resistance, eliminat-
ing recipient stem cells to increase the amount of available niche space
or providing signals that support differentiation and growth of infused
donor stem cell and progenitor cell populations. As discussed earlier, donor
T- and NK-cell populations function through either active mechanisms
involving recognition and destruction of recipient hematopoietic cell pop-
ulations or passive veto activity. The pathways used by facilitator popula-
tions are less well defined.

The presence of cells with facilitative activity in the donor marrow was sug-
gested by observations that equal numbers of infused HSC in unfraction-
ated marrow engrafted more efficiently than highly enriched progenitor
populations [102] . Subsequent studies identified several small subsets of
marrow cells with facilitating activity [102,140-142] . Two groups identi-
fied several CD8 + subsets comprising <2% of the donor marrow popula-
tion that promoted engraftment after transplantation of low numbers
(500-1000) of purified Lin − Sca-1 + HSC-enriched populations in lethally
irradiated, MHC-mismatched recipients [140,141] . Populations of both
CD8 + TCR − CD3 − CD11c + and CD8 + TCR + CD3 + cells promoted engraftment
in both MHC-mismatched and MHC-matched recipients [141] . Facilita-
tive activity was not affected by the absence of granzyme B expression. This
group also examined CD8 + TCR − CD3 + populations but could not identify
facilitative activity with the small numbers of cells that could be isolated.
In contrast, 30 000 CD8 + TCR − CD3 + ClassII dim Thy1 + marrow cells obtained
from B10.BR donors did facilitate engraftment of HSC-enriched donor cells