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Pediatr Blood Cancer 2007;49:615–623
REVIEW
Human Natural Killer Cells in Health and Disease
Evan Shereck,
MD,
1
Prakash Satwani,
1
MD,
Erin Morris,
Natural killer (NK) cells are an essential component of the innate
immune system and play a critical role in tumor immune
surveillance. NK cells express their own repertoire of receptors
(NKRs) that bind to major histocompatibility class I or class I-like
molecules. The balance of signals from stimulation or inhibition of
NKRs determines the ability of NK cells to lyse specific targets. In
haploidentical stem cell transplantation with purified stem cells,
NK cell alloreactivity (killer immunoglobulin-like receptor [KIR]
mismatch) has been demonstrated to reduce the risk of relapse in
Key words:
and Mitchell S. Cairo,
MD
1,2,3
*
acute myeloid leukemia. There is a need for adequately powered
prospective randomized studies to determine the usefulness of NK
cells as adoptive immunotherapy, optimal NK cell doses and timing
of administration. Further studies are required to determine optimal
selection of donors and recipients, both on NKR matching/
mismatching, undergoing haploidentical and unrelated hematopoetic stem cell transplantation. Pediatr Blood Cancer 2007;49:
615–623. ß 2007 Wiley-Liss, Inc.
natural killer cell immunology; function; review
INTRODUCTION
Human natural killer (NK) cells are an essential component of
the innate immune system. They have the ability to lyse target cells
and to secrete immunoregulatory cytokines [1]. NK cells comprise
approximately 10% of all peripheral blood lymphocytes and are
characterized by lack of expression of CD3 but have the expression
of CD56 [2] and morphology of large granular lymphocytes [3]. NK
cells were initially demonstrated by Cudkowicz and Bennett [4,5]
by their observation that lethally irradiated mice could mediate
rejection of allogeneic or parental strain bone marrow (BM)
allografts and later by their ability to mediate spontaneous tumor
cytotoxicity in vitro in a major histocompatibility complex (MHC)unrestricted manner [6,7]. NK cells reside in cord blood, peripheral
blood, BM, and the spleen where they can protect the host against
infectious organisms and malignant transformation [2,6,7]. NK
cells are different from other lymphocytes because they do not
require specific antigen recognition to lyse tumor cells [1,2,6].
NK Phenotype
Mature NK cells are characterized by CD56 expression and the
absence of CD3 [8]. NK cells can be classified based on the surface
density of CD56 expressed into CD56bright (high density) and
CD56dim (low density). Approximately 90% of NK cells are
CD56dim, which in the resting state are the more cytotoxic of the two
subsets and have high expression of CD16 (Fcg receptor III) and the
remaining 10% are CD56bright CD16dim[9]. The CD56dim cells,
which in the resting state are the more cytotoxic of the two subsets,
have high expression of CD16 which is the Fcg receptor III
(FcgRIII), whereas, the CD56bright NK cells are CD16dim. CD16 is
responsible for binding to antibody-coated targets and initiating
antibody-dependent cellular cytotoxicity (ADCC) [10].
Regulation of NK Cell Development
NK cells are derived from CD34þ hematopoietic stem or
progenitor cells and undergo maturation primarily in BM (Fig. 1)
[11,12]. Interleukin (IL)-15 appears to be the crucial factor for the
development of human and murine NK cells [13–15]. Human NK
cell development occurs in two phases. In the early phase, an NK
progenitor cell (CD34þLin) responds to early acting growth
ß 2007 Wiley-Liss, Inc.
DOI 10.1002/pbc.21158
1
RN,
factors (e.g., Flt-3 ligand or kit ligand) and develops into an NK-cell
precursor intermediate with the basic phenotype CD34þ IL-15Rþ
(Fig. 1). IL-15 then induces the development of mature NK cells
that are CD56bright which lyse tumor target cells and produce
immunoregulatory cytokines and chemokines upon stimulation
[16]. CD56dim cells are either derived from CD56bright cells in the
periphery or might be under the control of other cytokines (e.g.,
IL-21) [17]. However, with its higher intrinsic cytotoxicity, more
abundant expression of CD16, and absence of a proliferative
response, the CD56dim NK cell appears to be more terminally
differentiated than the CD56bright NK cell.
NK Cell Receptors
NK cells do not have the capacity to rearrange genes encoding
for antigen recognition. However, NK cells express their own
repertoire of several classes of receptors (NKRs) that bind to MHC
class I or class I-like molecules or targets that regulate whether NK
cells will be activated or inhibited [2,18]. It is the balance of signals
from stimulation or inhibition through NKRs that determines the
ability of NK cells to lyse specific targets (Fig. 2). NKRs can be
classified in a number of ways, such as activating/inhibitory, killer
immunoglobulin like receptor (KIR)/C-lectin/other or MHC class I
dependent/MHC class I independent/other (Table I) [2,18].
—
—————
1
Department of Pediatrics, Columbia University, New York, New
York; 2Department of Medicine, Columbia University, New York, New
York; 3Department of Pathology, Columbia University, New York,
New York
Evan Shereck and Prakash Satwani Contributed equally to this
manuscript and should be considered co-primary or first authors.
Grant sponsor: Pediatric Cancer Research Foundation; Grant sponsor:
Bevanmar Foundation; Grant sponsor: Marisa Fund; Grant sponsor:
Scaramella fund.
*Correspondence to: Mitchell S. Cairo, Professor of Pediatrics,
Medicine and Pathology, Division of Pediatric Hematology and
Blood and Marrow Transplantation, Morgan Stanley Children’s
Hospital of New York-Presbyterian, Columbia University, 3959
Boardway, CHC 1114, New York, NY 10032.
E-mail: [email protected]
Received 20 April 2006; Accepted 5 December 2006
616
Shereck et al.
Fig. 1. Human natural killer (NK)-cell subset development. NK-cell development can be divided into three discrete stages based on in vitro
models. A CD34þ NK-cell progenitor, negative for lineage markers (Lin), that expresses the receptor tyrosine kinases fit-3 and c-kit, and is
responsive to fit-3 ligand (FL) and/or c-kit ligand (KL) differentiates into a CD34þ IL-15 receptor (IL-15R)þ NK precursor that is responsive to
IL-15 for maturation into a functionally mature CD56bright NK cell. The developmental relationship between CD56bright and CD56dim NK cells has
never been established definitively, and CD56dim NK cells have not been generated in vitro. Potential hypotheses for the development of CD56dim
NK cells include (a) the existence of a unique CD56dim NK-cell precursor. b: An alternate signal (e.g., a novel cytokine) that could induce the
differentiation of CD56dim cells from a common NK-cell precursor: or (c) maturation of CD56bright cells into CD56dim NK cells. Reprinted from
Trends in Immunology, Volume 22, Cooper M.A., Fehniger T.A., and Caligiuri M.A., The biology of human natural killer-cell subsets, 633–640,
2001, with permission from Elsevier.
Activating NKRs include KIRs, C-lectins, natural cytotoxicity
receptors (NCR), and other activating co-receptors (Table I) [2].
Inhibitory receptors on the NK cell surface recognize and engage
their ligands, MHC class I molecules (human leukocyte antigen
[HLA]) on the surface of the target tumor cell, thereby initiating an
inhibitory signal. Activating receptors bind ligands on the target cell
surface and trigger NK cell activation and target cell lysis. When
inhibitory receptors engage HLA in the absence of an activating
receptor/ligand interaction, a net negative signal is generated,
resulting in no target cell lysis. Conversely, when activating
receptors engage their ligands on target cells in the absence of
inhibitory receptor/ligand interaction, a net activation signal is
generated, resulting in target cell lysis. This scenario is likely
operative in NK alloreactivity in the setting of KIR epitope
mismatch (Fig. 2).
Another common class of NK receptors is the C-lectin NKG2
family [2,19,20]. There are at least five members of the NKG2
family, including NKG2A, NKG2C, NKG2D, NKG2E, and NKG2F
[21,22]. Other than CD94/NKG2A, which is an NK inhibitory
receptor, the remaining NKG2 receptors are NK activating receptors
(Table I). Target cell ligands for NKG2D are different than other
NKRs and include two families of ligands, MHC class I chainrelated antigens (MIC) and UL16 binding proteins (ULBPs)
[23,24]. MIC expression by several malignant solid tumors and
leukemias as recently demonstrated [2]. We have also demonstrated
expression of NKG2D ligands such as ULBP 1, 2, 3 and/or MIC
A and B in pediatric acute lymphoblastic leukemia, chronic
myeloid leukemia, non-Hodgkin lymphoma, and neuroblastoma
cell lines [25].
Pediatr Blood Cancer DOI 10.1002/pbc
The NCRs, which are NK activating receptors, have no apparent
specificity for MHC class I molecules. Three NCRs have been
identified that appear to be expressed on all NK cell subsets,
including NKp46, NKp44, and NKp30 [18,26,27]. NKp44 is not
expressed on resting NK cells but is significantly upregulated after
IL-2 stimulation and is also expressed on gamma/delta T cells [28].
Lastly, there are a number of other NK receptors known as coreceptors, which appear to activate NK cells after initial NKR
binding, and they include CD16 (FcgRIII), CD2, LFA-1, 2B4,
Nkp80, and CD40 ligand [2].
NK cells can be activated by various cytokines such as
interferon-g(IFN-g), IL-2, IL-12, IL-15, or IL-18, increasing their
number and cytotoxic activity and thereby killing a broader
spectrum of targets, including some that are generally not affected
by NK cells. This is probably related to the change in cytokine
environment that can induce specific molecules on both NK as well
as target cells to support cell adhesion and to mediate cytolysis of
NK cell-resistant targets [29].
The resistance of cancer cells to NK cell activity can be
overcome by genetic modification resulting in transduction of
chimeric receptors on NK cells targeted against specific ligands on
malignant cells. The stimulatory signals triggered by the receptors
on contact with target cells can induce powerful cytotoxicity against
NK-resistant leukemic cell lines [30].
Mechanisms of NK Cytotoxicity
When NK cells fail to interact with the MHC class I molecule and
the activating receptor is activated, NK cell mediated lysis will occur
Natural Killer Cells in Health and Disease
617
Fig. 2. Regulation of NK cell response by activating and inhibitory receptors. Inhibitory receptors (e.g., inhibitory KIR, CD94/NKG2A)
recognize and engage their ligands, MHC class I molecules (HLA), on the surface of the target tumor cell, thereby initiating an inhibitory signal.
Activating receptors (e.g., activating KIR, CD94/NKG2C, NKG2D) bind ligands on the target cell surface and trigger NK cell activation and target
cell lysis. A: When inhibitory receptors engage HLA in the absence of an activating receptor/ligand interaction, a net negative signal is generated,
resulting in no target cell lysis. B: Conversely, when activating receptors engage their ligands on target cells in the absence of inhibitory receptor/
ligand interaction, a net activation signal is generated, resulting in target cell lysis. This scenario is likely operative in NK alloreactivity in the setting
of KIR epitope mismatch. More complex physiologic scenarios are shown in C and D with both inhibitory and activating receptor/ligand signals
being generated when an NK cell interacts with a target cell. C: Here, the activating receptor/ligand interactions predominate over weaker inhibitory
receptor/ligand signals with the net result of NK cell activation and target cell lysis. This net result may occur when activation receptors and ligands
are upregulated, thereby amplifying the net activation signal to exceed the inhibitory signal. For example, the activating ligands MICA/B and ULBPs
are expressed highly in stressed or transformed cells, thereby activating NKG2D/P13K pathways that are not susceptible to inhibitory signals.
Alternatively, when expression of self-MHC class I ligands is decreased in the setting of viral infection or transformation, the net signal may be
positive, also resulting in target cell lysis. D: Here, inhibitory receptor/ligand interactions result in a net negative signal that prevents NK cell lysis of
the target cell. This process may occur constantly as NK cells survey normal host tissues. Not shown is the scenario of absence of both inhibitory and
activating signals that results in no NK cell activation. From: Farag SS, Fehniger TA, Ruggeri L, Velardi A, and Caligiuri MA. Natural killer cell
receptors: new biology and insights into the graft-versus-leukemia effect. Blood 2002; 100:1935–1947. Copyright American Society of
Hematology, used with permission.
[31]. For example, when CMV invades a host cell it causes
downregulation of MHC class I molecules, which stops the
inhibition of cell killing that usually occurs [31]. After activation,
lysosome-like vesicles containing perforin, serine esterases, and
sulfated proteoglycans are secreted toward the target cell. Perforin
causes pore formation in the target cell causing an osmotic lysis of
the target cell [32]. The serine esterases, including granzymes,
stimulate apoptosis [1,33]. Tumor necrosis factor-a (TNF-a)
activates a target cell endonuclease which degrades genomic DNA
[1]. Proteoglycans appear to protect the granzymes from inactivation by protease inhibitors [34].
Whether NK cells kill their targets with perforin or recruit other
cells by producing cytokines, the NK cells seem to require
Pediatr Blood Cancer DOI 10.1002/pbc
stimulation by conventional dendritic cells. Andoniou et al. [35]
demonstrated that NK cells alone with CMV or NK cells with
dendritic cells not exposed to CMV were not enough for the NK
cells to mount a response. Only when the NK cells were placed with
CMV and dendritic cells exposed to CMV was the cytotoxic
function enhanced and IFN-g produced [35]. The dendritic cells can
enhance NK cell cytotoxicity directly by activating the NKG2D
receptor or indirectly by producing IFN-g [35]. The dendritic cells
also produce IL-12 and IL-18 which enhance IFN-g production by
NK cells [35].
After stimulation with cytokines, the CD56bright are able to
produce IFN-g, TNF-a, and granulocyte-macrophage colony
stimulating factor [36]. These cytokines provide positive feedback
618
Shereck et al.
TABLE I. Human Activating and Inhibitory NK Cell Receptors (NKR) and Their Corresponding Ligands
Type
Killer immunoglobulin
receptors
C-type lectin receptors
Natural cytotoxicity
receptors
Activating
receptor
Activating receptor
ligand specificity
Inhibitory
receptors
Inhibitory receptor
ligand specificity
KIR2DS1
Group 2 HLA-CAsn77 Lys80
KIR2DL1 (CD158a)
Group 2 HLA-C Asn77Lys80
KIR2DS2
KIR2DL4
KIR2DS4
KIR2DS5
KIR3DS1
CD94/NKG2C
CD94/NKG2E/H
NKG2D
NKp46, NKp44,
NKp30
Group 1 HLA-CSer 77 Asn80
HLA-G
Unknown
Unknown
Unknown
HLA-E
Unknown
MIC-A, MIC-B, ULBP-1, 2 & 3
Unknown
KIR2DL2 (CD158b)
KIR2DL3 (CD158b)
KIR3DL1
KIR3DL2
KIR3DL7
CD94/NKG2A/B
CIRU
CIRU
Unknown
Group 1 HLA-C Ser77Asn80
Group 1 HLA-C Ser77Asn80
HLA-Bw4
HLA-A3, -A11
Unknown
HLA-E
CIRU
CIRU
CIRU
KIR, killer immunoglobulin like receptor; NK, natural killer; HLA, human leukocyte antigen; MIC, MHC class I chain related antigens; ULBP,
UL16 binding proteins; KIR, killer immunoglobulin like receptor; CIRU, corresponding inhibitory receptor unknown.
to macrophages and other antigen presenting cells for more efficient
control of infection [8].
NK cells can also act independently of perforin by NK celldependent death receptor mediated apoptosis. These molecules
and receptors are part of the TNF family of ligands and receptors.
Two of these ligands, the FAS (APO-1, CD95) ligand (FasL) [37]
and TNF-related apoptosis-inducing ligand (TRAIL/APO-2L) [38],
are found on NK cells and both have corresponding receptors on the
target cell. In a resting state NK cells intracellularly express
significant levels of FasL [39]. However, after activation of the
NK1.1 (CD161) receptor, FasL is upregulated on the cell surface
in a dose-dependent fashion [39]. Oshimi et al. [40] demonstrated
that target cells with high levels of Fas underwent apoptosis when
placed in a calcium free medium that inhibits the use of perforin
after NK cells were added. These apoptotic changes were not seen
when an anti-Fas monoclonal antibody (Mab) was added [40].
TRAIL has been shown to play an important role in tumor
surveillance [41].
Role of NK Cells in Adoptive Cellular Immunotherapy
Several investigators have used immunotherapy with IL-2 alone
or in combination with activated NK cells in patients with various
malignant hematologic diseases and breast cancer [42–44].
Rosenberg et al. treated 25 adult patients with refractory metastatic
cancer with systemic administration of autologous lymphokine
activated killer cells (ex-vivo expanded) and IL-2. Although this
approach induced nearly 15–20% partial and complete responses
(CR) in their initial trials, subsequent studies showed that a similar
anti-tumor effect could be achieved with high-dose IL-2 alone
[45,46]. Several non-randomized trials with different patient
eligibility and experimental designs have been performed with the
aim of evaluating the safety and efficacy of immunotherapy with IL2 with and without autologous hematopoietic stem cell transplant
(HSCT) in adult patients with lymphoma and breast cancer. These
trials have suggested a potential clinical benefit using an IL-2 based
immunotherapy approach [47–50].
An immuno-targeting approach has been tested in pediatric
patients with refractory neuroblastoma. Using immunotherapy with
Pediatr Blood Cancer DOI 10.1002/pbc
a Mab targeting a tumor-associated antigen, GD2, has been shown
to be uniformly expressed by neuroblastoma cells. Therapeutic
responses have been obtained in Phase I and Phase II studies using
murine IgG3 Mab, 3F8 [51], murine IgG2 Mab, 14G2a [52,53] and
human-mouse chimeric Mab, ch14.18 [54,55]. The biological
activities of ch14.18 are mediated by complement dependent
cytotoxicity [55] and ADCC, in part mediated by innate cellular
immunity of NK cells. Various non-randomized studies have been
conducted in children with refractory solid tumors and hematological malignancies using IL-2. In these studies only small number
of patients achieved clinical remission [56–62]. In a recently
conducted Phase III trial (CCG-2961) for newly diagnosed children
with acute myeloid leukemia (AML) administration of IL-2 had no
impact on overall survival and disease free survival (P ¼ 0.606)
[63].
Role of NK Cells in Allogeneic
Stem Cell Transplantation
Cure of leukemia by allogeneic HSCT relies on the action of
donor T-cells in the allograft, which is vital for promoting
engraftment, eradicating malignant cells (graft-versus- leukemia
[GVL] effect), and reconstituting immunity. Unfortunately, donor
T cells also mediate GVHD. In full haplotype-mismatched transplantation a high dose (approximately 20 106 CD34þ cells/kg) of
purified hematopoietic stem cells from NK alloreactive donors are
infused. The transplanted stem cells quickly give rise to NK cells.
The potential beneficial role of NK cells in haploidentical stem cell
transplant (haplo-SCT) is possible through the following theoretical
mechanisms: (1) targeting host T lymphocytes that may result in
lower rates of graft rejection; (2) targeting host dendritic cells
resulting in decrease antigen presentation by host dendritic cells and
hence decreasing the risk of GVHD; (3) targeting leukemic cells
which may decrease relapse; and (4) improving immune reconstitution which may decrease the risk of opportunistic infections
[64,65].
Donor selection for haplo-SCT requires a search for the donor
who is able to mount donor-versus-recipient NK cell alloreactivity.
Natural Killer Cells in Health and Disease
Search for haploidentical NK alloreactive donors may require
extension from the immediate family to other family members such
as aunts, uncles, and cousins. While patients who express the three
major HLA class I KIR ligands may not find an alloreactive donor,
patients who express one or two of these ligands may [66].
Ruggeri et al. [67] demonstrated that donor-versus-recipient NK
cell alloreactivity reduced the risk of leukemia relapse in 57 AML
patients at high risk of relapse, while improving engraftment and
protecting against GVHD. Similarly, in children with acute
leukemia, HSCT from haploidentical donors with potential for
NK cell alloreactivity was reported to decrease the risk of relapse
[68]. An updated analysis of 93 haplo-SCT for AML included
40 recipients (25 transplanted in remission, 15 in relapse) who
received HSCT from haploidentical donors who were able to mount
donor-versus-recipient NK alloreactions and 53 AML recipients
(26 transplanted in remission, 27 in relapse) who received HSCT
from haploidentical donors who were unable to mount donorversus-recipient NK alloreactions [69]. The analysis confirms that
grafts from NK alloreactive donors enhance engraftment and appear
to protect against GVHD. The probability of relapse was 15% for the
40 patients transplanted from NK alloreactive donors versus 68%
for the 53 patients transplanted from non-NK alloreactive donors
(P < 0.005). The probability of survival was correspondingly much
better after NK alloreactive donor transplantation (55% vs. 12%,
P < 0.005). In 62 haploidentical transplants in patients with
leukemia, Bishara et al. demonstrated that potential NK alloreactivity in the GVHD direction (MHC class I KIR ligand is absent in
the recipient but present in the donor) was associated with an
increased incidence of severe GVHD and poorer patient survival.
Furthermore, this approach had no impact on engraftment or
leukemic relapse and that lack of extensive T-cell depletion in haploSCT was associated with high GVHD rates and diminished the
benefits of NK cell alloreactivity [70].
T cells in the allograft may affect NK cell reconstitution in vivo.
In 77 patients with chronic myeloid leukemia who received
allografts from unrelated donors, Cooley et al. demonstrated that
NK cells expressed fewer KIRs and produced more IFN-g after
unmanipulated BM compared to T-cell depleted transplants.
Increased NK cell IFN-g production correlated with more acute
GVHD and decreased KIR expression correlated with inferior
survival [71]. Nguyen et al. [72] demonstrated that NK cells
generated after haplomismatched SCT are blocked at an immature
state characterized by specific phenotypic features and impaired
functioning.
Leung et al. demonstrated that the NK cells derived from highly
purified CD34þ cells acquired a donor-specific pattern of KIR
expression independent of self-HLA within the first 3 months of
transplantation. However, subsets of NK cells may express only one
of the KIRs which may potentially provide alloreactivity if the
corresponding ligand was absent in the recipient’s cells.
These findings might help to select a perfect mismatch donor on
the basis of a single evaluation of the donor’s KIR repertoire before
transplantation [68].
NK cell alloreactivity may be expected to occur in >60% of
unrelated donor transplants with one or more HLA allele-level
mismatches [73]. However, it remains to be determined whether
alloreactive donor-derived NK cells display GVL reactions after
unmodified unrelated HSCT. Some of the retrospective studies have
failed to demonstrate any advantage of transplantation from
unrelated donors with the potential to exert NK cell alloreactivity
Pediatr Blood Cancer DOI 10.1002/pbc
619
(Table II) [74–76]. These reports lacked functional assessment
of donor-versus-recipient NK cell alloreactivity, utilized heterogeneous conditioning regimens, immunosuppressive therapy, and
infused smaller stem cell doses. Other studies have documented an
increased GVL effect in transplants from unrelated donors, this
theoretically had the potential to exert NK cell alloreactivity
(Table II) [77–80].
Donor NK Cell Infusion
Donor lymphocyte infusion is limited by the development of
acute and chronic GVHD in up to 60% of the patients, which has
been associated with significant morbidity and mortality. Several
groups have investigated the preparation and infusion of purified,
T-cell-depleted, donor NK lymphocytes with the aim to consolidate
engraftment and induce GVL effects in patients after HSCT from
haploidentical or other donors. Despite demonstrating CRs in some
studies, most of these investigations include small numbers of
patients with short follow-up. Hence, it is difficult to assess the
potential benefit of this approach. However, these studies demonstrated that ex vivo purification of donor NK cells from
leukapheresis products is technically feasible and that large
numbers of CD56þ highly CD3 depleted cells can be obtained.
These purified NK cells have been infused without immediate
adverse events and without inducing GVHD. Clinical data on
efficacy are very limited. Whether NK donor lymphocyte infusion
will prevent graft rejection and/or promote a GVL effect requires
additional studies.
Future Considerations
Adequately powered prospective and/or randomized studies are
required to determine the usefulness of NK cells as adoptive
immunotherapy, optimal NK cell doses, and timing of administration. Furthermore, appropriate selection of donors and recipients
based on NKR matching/mismatching following haploidentical and
unrelated HSCT, requires further study. The use of NK cells as
adoptive immunotherapy will help to better define the clinical
impact of NK cell alloreactivity, including the importance of KIR
and other NKR matching and mismatching. Whether these cells
should be used preemptively or as salvage treatment is unknown.
Purging and enrichment technology using magnetic beads for
clinical application is technologically feasible but expensive.
Strategies for blocking KIR-MHC class I Ag interaction so that
inhibitory receptors are not activated should be further tested. Other
approaches might include the induction of activating receptors and
its ligands on malignant cells, infusion of autologous genetically
engineered NK cells to recognize specific tumor receptors and costimulation of NK cells through dendritic cell activation [81]. Other
considerations should include the investigation of various cytokines
(IL-15, IL-18, and IL-21) to increase in vivo or ex vivo expansion
and activation of NK cells. There is a need to better understand the
mechanisms that impact KIR expression and influence of T cells on
NK cell repertoire after unmanipulated BM and haplo-SCT. Further
understanding of the biology of NK cells and the mechanisms that
govern target cell sensitivity and resistance, together with clinical
investigations, will hopefully result in optimal exploitation of this
class of cytotoxic cells for the benefit of leukemia patients and
possibly patients with other malignancies [82].
Pediatr Blood Cancer DOI 10.1002/pbc
CML, ALL, AML,
MDS, others
CML, AML, MDS
CML, ALL, AML,
MDS, MM, NHL
CML
AML, MDS, CML
CML, ALL,
AML, MDS
[100]
[102]
[103]
[116]
[106]
[99]
66
89
49
49
103
113
112
48
29
20
15
62
KIR ligand
incompatibility
(Group B) (n)
NA
2.3 vs. 6.3
4 vs. 7
8 vs. 0
10 vs. 13
7 vs. 8
Graft Failure
Group
A vs. B %
TCD 100
vs. 100
None
ATG 20 vs.
13
ATG 100
vs. 100
None
TCD 37 vs.
29
TCD/ATG
Group
A vs. B %
15 vs. 24
58 vs. 55
49 vs. 52
43 vs. 30
46 vs. 69
50 vs. 61
Grade II-IV
AGVHD Group
A vs. B %
NA
11 vs. 4
20 vs. 0
21 vs. 6
30 vs. 60
12 vs. 9
Relapse
rate Group
A vs. B %
NA
53 vs. 58
52 vs. 66
48 vs. 87
46 vs. 33
40 vs. 32
5-year OS
Group
A vs. B %
Unrelated donors, Retrospective study.
Heterogeneous patients and conditioning
and immunosuppression, includes
pediatric patients
Unrelated donors, Retrospective study.
Older patients
Unrelated donors, Prospective study.
Younger patients
Unrelated donors, Prospective study.
Decreased RR with KIR incompatibility
but no survival advantage
Unrelated donors, Prospective study.
Decreased RR with KIR incompatibility
but no survival advantage
Matched sibling donors only AML and MDS
patients with inhibitory KIR mismatch had
significantly higher DFS and OS
Remarks
CML, chronic myeloid leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; MM, multiple myeloma; NHL, non-Hodgkin’s lymphoma;
KIR, killer immunoglobulin like receptor; aGVHD, acute graft-versus-host disease; OS, overall survival; RR, relapse rate; ATG, anti-thymocyte globulin; TCD, T cell depletion; DFS, disease free
survival; NA, not available.
Diagnosis
Study
No KIR ligand
incompatibility
(Group A) (n)
TABLE II. Outcomes of Non-Haploidentical Myeloablative Allogeneic Stem Cell Transplantation in Recipients With and Without Killer Immunoglobulin-Like Receptor Ligand
Incompatibility
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Shereck et al.
Natural Killer Cells in Health and Disease
ACKNOWLEDGMENT
The authors would like to thank Linda Rahl for expert editorial
assistance in the development of this manuscript.
21.
22.
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