Natural killer cells in graftversus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 339

colleagues [89] reported that following T-cell-depleted HLA-matched HSCT,
NK cells expressing a nonself KIR were hyperresponsive and capable of pro-
ducing high levels of IFN-γ. These NK cells gradually became tolerized to self
in the recipient by day 100 post-HSCT. Bjorklund and colleagues [90] , how-
ever, found that NK cells expressing KIR for nonself remained tolerant in the
recipient. They studied both T-cell-replete and T-cell-depleted HLA-matched
HSCT. NK cells expressing a KIR recognizing self expressed higher levels of
CD107a compared with NK cells expressing a KIR that recognized nonself,
similar to findings reported by Foley and colleagues [85] . Post-transplant
immune suppression may partially explain the differences seen, as patients
receiving T-cell-depleted HSCT in the study by Bjorklund and colleagues [90]
received cyclosporin A, whereas patients in the study by Yu and colleagues
[89] received no immune suppression. Cyclosporin A has been shown to alter
NK cell differentiation and function [91] . Yu and colleagues also found that
NK cells expressing NKG2A were hyporesponsive post-HSCT, whereas NK
cells expressing NKG2A had the strongest expression of CD107a in the study
by Bjorklund and colleagues. These differences could be attributed to differ-
ent functional assays used in each study, in that Yu and colleagues mainly
studied IFN-γ production, whereas Bjorklund and colleagues used CD107a
as a marker of degranulation.

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In both these studies donor and recipient were HLA matched. Haas and
colleagues [92] investigated the role of NK cell education following both
KIR-ligand-matched and KIR-ligand-mismatched unmanipulated HSCT.
In accordance with Bjorklund and colleagues [90] , NK cells adhered to
the rules of education, that is, NK cells expressing a nonself KIR remained
hyporesponsive in the recipient and those expressing a self KIR were func-
tional. Similar to Bjorklund and colleagues [90] and Foley and colleagues
[85] , the subset of NK cells coexpressing a self KIR and NKG2A had the high-
est expression of CD107a, consistent with the hypothesis that expression of
more than one self-recognizing inhibitory receptor results in higher capac-
ity for degranulation [37] . Where there was a KIR-ligand mismatch, NK cell
responsiveness adhered to the HLA ligands present in the donor.

Two studies using murine models were the first to demonstrate that NK cells
could be re-educated in a new host [93,94] . Educated mature NK cells, when
adoptively transferred into an MHC class I-deficient mouse, become anergic
to receptor stimulation. In the reverse scenario, NK cells from an MHC class
I-deficient mouse gain effector functions when adoptively transferred into
an MHC class I-sufficient mouse [93] . How these findings may influence NK
cell functions in humans remains unclear. In the transplant setting, once
donor chimerism has been established, cells of hematopoietic origin are
donor derived, and the findings from Haas and colleagues [92] could imply
that these cells are involved in educating reconstituting NK cells. However,
adoptively transferred NK cells, which are discussed below, will encounter
hematopoietic cells of recipient origin and re-education may occur.

Adoptive NK cell therapy

The second method to deliver alloreactive NK cells to the patient involves
adoptive transfer of donor NK cells purified ex vivo and infused into the
recipient. These NK cells are presumed to be mature and fully functional