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IMMUNOBIOLOGY
From the Unité d'Immunologie des Tumeurs
Département d'Hématologie, Institut Paoli-Calmettes;
Unité d'Immuno-Génétique, Centre de Transfusion
Sanguine, and Unité INSERM U119, Université de la
Méditerranée, Marseille, France; Laboratorio di Immunologia
Molecolare, Dipartimento di Medicina Sperimentale, Sezione Istologia,
Università degli Studi di Genova, Italy; and U.O. Immunologia,
Istituto Scientifico Tumori, Genova, Italy.
The cytolytic function of natural killer (NK) cells is induced by
the engagement of a series of activating receptors and coreceptors some
of which have recently been identified and collectively termed natural
cytotoxicity receptors (NCRs). Here, we analyzed the cytolytic function
of NK cells obtained from patients with acute myeloid leukemia (AML).
In sharp contrast with healthy donors, in most (16 of 18) patients
with AML the majority of NK cells displayed low NCR surface density
(NCRdull). This phenotype correlated with a weak cytolytic
activity against autologous leukemic cells that could not be reversed
by the monoclonal antibody-mediated disruption of HLA class I/killer
immunoglobulinlike receptor interaction. The remaining 2 patients were
characterized by NK cells having an NCRbright phenotype.
Surprisingly, although displaying NCR-mediated cytolytic activity,
these NCRbright NK cells were unable to kill autologous
leukemic blasts. Importantly, the leukemic blasts from these 2 patients
were also resistant to lysis mediated by normal NCRbright
allogeneic NK cells. Our study suggests that in most instances the
inability of NK cells to kill autologous leukemic blasts is consequent
to low NCR surface expression. In few cases, however, this failure
appears to involve a mechanism of tumor escape based on down-regulation
of ligands relevant for NCR-mediated target cell recognition.
(Blood. 2002;99:3661-3667) Human natural killer (NK) lymphocytes are potent
effector cells involved in clearance of virus-infected cells and
tumors. Their cytolytic function is regulated by the expression of a
series of surface receptors that either block or enhance the
NK-mediated cytotoxicity. Under physiologic conditions, target cells
are protected from NK-mediated cytotoxicity because they express an
adequate amount of HLA class I molecules. Indeed, NK cells express at
the cell surface HLA-specific inhibitory receptors (including killer immunoglobulinlike receptors [KIRs] and CD94/NKG2A heterodimers) that
on recognition of the ligands on normal target cells down-regulate the
NK-mediated cytolytic activity.1,2 In the absence of these
inhibitory interactions, target cells become susceptible to NK-mediated
killing.3-5 As recently demonstrated, this
susceptibility is due to the expression by NK cells of
different non-HLA-specific activating receptors that are involved in
the induction of cytotoxicity.4 Three of these molecules,
NKp46, NKp30, and NKp44 (collectively termed natural cytotoxicity
receptors [NCRs]), are selectively expressed by NK cells, and their
engagement results in a strong enhancement of the NK-mediated cytolytic
activity.6 Importantly, NCRs play a crucial role in
NK-mediated recognition and killing of most target cells because
monoclonal antibody (mAb)-mediated disruption of the NCR/ligand(s)
interactions may abrogate the NK-mediated killing of tumor-transformed
cells of autologous, allogeneic, or (in the case of NKp46) xenogeneic
origin.7 Interestingly, the NCR surface density, as
measured by the brightness of immunofluorescence, varies among
individuals. Thus, NK cells from some donors express a homogeneously
high density of NCR (NCRbright), whereas in other
individuals 2 subsets of NK cells expressing either high
(NCRbright) or low (NCRdull) receptor densities
were detected.7,8 Importantly, a strict correlation exists
between NCR density and NK-mediated cytolytic activity.7
Thus, although NCRbright NK cell clones display strong
cytolytic activity, those expressing low NCR surface density
(NCRdull) are poorly or even noncytolytic against most
target cells.
Another surface receptor playing a role in the induction of NK-mediated
cytotoxicity is represented by NKG2D, a receptor that, different from
NCRs, is also expressed by virtually all T-cell receptor
(TCR) An altered HLA class I phenotype has been observed in most human
tumors,5,14,15 More particularly, a deficient HLA class I
expression has been described in leukemia,16-18 with a
quite variable level of expression for specific alleles.19
Moreover, allogeneic bone marrow transplantation suggests that NK cells may have potent antileukemia activity.20-23 Previous
reports have focused on the role of NK cells in the control of chronic
myelogenous leukemia (CML).24-26 For example, it has been
shown that in CML the NK cell number and the NK cell function
progressively decrease during the spontaneous course of the
disease27 and that both recover on interferon- Altogether these data suggest that NK cells may play an important role
in the control and clearance of leukemic cells. So far, however, little
is known regarding the direct role of the various activating
receptors/coreceptors in the NK-mediated control of leukemia.
The aim of the present study was to analyze the NK cell function in
patients affected by AML and, in particular, to define the role of the
various activating receptors in the recognition and killing of leukemic cells.
Cells
Peripheral blood mononucleated cells (PBMCs) from healthy donors or
leukemic patients were isolated on Ficoll-Hypaque gradients and viably
frozen in liquid nitrogen until use. For cytotoxicity experiments using
leukemia cells as targets, only samples with 95% or more leukemic
cells were used; the purity of the preparation was assessed by flow
cytometry analysis and Giemsa stain of cytocentrifuge preparations.
Monoclonal antibodies
Flow cytometry analysis When using our own produced mAbs, we performed indirect staining; briefly, cells were incubated with the appropriate mAb followed by PE- or FITC-conjugated isotype-specific goat antimouse secondary reagent (Southern Biotechnology Associated, Birmingham, AL). Directly coupled commercially available mAbs were used in one-step direct staining. Samples were analyzed by one- or 2-color cytofluorimetric analysis (FACScan; Becton Dickinson, Mountain View, CA). In all experiments, isotype-matched controls were used to set up the negative values.NK cell lines derived from healthy and leukemic patients To obtain NK cell lines from healthy donors or leukemic patients, PBMCs were depleted of plastic-adherent cells. Then, CD3 CD4DR cells were obtained
by incubating peripheral blood lymphocytes with anti-CD3
(JT3A), anti-CD4 (HP2.6), and anti-HLA DR (D1.12) mAbs (30 minutes at
4°C) followed by immunomagnetic depletion with goat antimouse-coated
Dynabeads (Dynal, Oslo, Norway) (30 minutes at 4°C).
CD3CD4DR cells were cultured
on irradiated feeder cells in the presence of 100 U/mL recombinant
interleukin 2 (rIL-2; Proleukin; Chiron, Emeryville, CA) and 1.5 ng/mL
phytohemagglutinin (PHA; Gibco, Paisley, Scotland) to obtain activated
polyclonal NK cell population.8
Cell culture and cytolytic activity Cell cultures were performed in RPMI 1640 (Bioproducts, Walkersville, MD) with 10% fetal bovine serum (Bioproducts). The cytotoxic assays were performed as previously described8 by means of a 4-hour 51chromium-release assay. The concentrations of the various mAbs were 10 µg/mL for the masking experiments and 0.5 µg/mL for the redirected killing experiments. All experiments were performed in triplicate in at least 2 independent experiments.
Phenotypic analysis of NK cells derived from patients with AML at diagnosis Fresh NK cells were isolated from 18 patients with AML at diagnosis and before any chemotherapy. In most patients these cells (CD56+/CD3) represented less than 1% of the
PBMC population. Purified CD3 cells were cultured in
vitro in the presence of rIL-2 to obtain polyclonal-activated NK cell
populations, thereafter termed AML-NK cells. These cells were then
analyzed for surface phenotype by indirect immunofluorescence and
cytofluorimetric analysis (Figure 1). No
significant differences could be observed between AML-NK cells and NK
cells derived from healthy donors regarding the expression of surface
molecules such as CD16, 2B4, CD94, and NKG2D. However, most (16 of 18)
of the patients analyzed displayed a rather homogeneous weak expression
of the NKp46 receptor. Moreover, in all instances the low expression of
NKp46 was paralleled by low expression of NKp30 and NKp44. Cells
characterized by this surface phenotype were previously described in
healthy individuals as NK cells with NCRdull
phenotype.7 It is of note, however, that in healthy donors the NCRdull phenotype is found in a subset of NK cells and
only in rare cases (< 1 of 20) corresponds to the majority of NK
cells. Thus, it appears that in patients with AML the
NCRdull phenotype is significantly more represented than in
healthy individuals. The remaining 2 patients with AML expressed an NCR
surface density that was comparable to the NCRbright
phenotype observed in most healthy individuals. Moreover, in line with
previous reports on NK cells derived from healthy
individuals,7 the expression of NKG2A was confined to
AML-NK cells expressing the NCRbright phenotype.
Analysis of the cytolytic activity mediated by AML-NK cells Previous studies demonstrated that the ability of human NK cells to kill murine targets correlates with the surface density of the NKp46 receptor.4,7 Indeed, in healthy individuals, killing of murine target cells such as the (Fc R+) P815 mastocytoma
cell line is mainly confined to NK cells expressing the
NCRbright phenotype, and mAb-mediated blocking of the NKp46
receptor is sufficient to abrogate this cytolytic effect.
AML-NK cells were analyzed for spontaneous cytolytic activity against
P815 target cells (Figure 2A). In line
with results obtained in healthy donors, NK cells derived from AML
patients characterized by NCRdull phenotype displayed poor
cytolytic activity against these target cells. On the contrary, NK
cells derived from AML patients characterized by NCRbright
phenotype displayed a cytolytic activity comparable in magnitude to
that of NCRbright NK cells derived from healthy donors.
AML-NK cells were also evaluated against P815 in a redirected killing assay in the presence of anti-CD16 or anti-NKp46 mAbs (Figure 2B). In agreement with previous data7 obtained with NK cells from healthy individuals, anti-CD16 mAb induced a comparable enhancement of cytotoxicity both in NCRdull and NCRbright AML-NK cells. However, the enhancement of cytotoxicity induced by anti-NKp46 mAb was confined to NCRbright AML-NK cells, whereas only little effects were observed in NCRdull AML-NK cells. Altogether these results suggest that AML-NK cells expressing different NCR surface densities display functional properties comparable to the corresponding NCRdull and NCRbright NK cells derived from healthy individuals. Analysis of the cytolytic activity mediated by AML-NK cells against autologous leukemic target cells AML-NK cells from patients displaying NCRdull or NCRbright phenotype were analyzed for cytolytic activity against autologous leukemic cells. These target cells, as determined by the use of mAb directed to a monomorphic determinant of HLA class I, expressed HLA class I molecules, although, in most instances, the level of fluorescence was slightly lower as compared with B-lymphocyte cell lines (B-LCLs) derived from the same individuals (not shown). These findings suggested that in these patients the expression of HLA class I may, at least in part, protect leukemic cells from NK-mediated cytotoxicity. As predicted by their surface phenotype, NCRdull AML-NK cells displayed poor spontaneous cytotoxicity against both autologous (Figure 2C) and allogeneic (not shown) leukemic cells. Moreover, the low levels of cytolytic activity were only moderately (from 3%-4% to 15%-18% lysis) incremented in the presence of anti-HLA class I mAbs, indicating that the poor cytolytic effect was not simply consequent to inhibitory signals generated by KIR/HLA class I interactions (Figure 2C).In line with their ability to kill murine P815 target cells, AML-NK
cells characterized by the NCRbright phenotype displayed
strong cytolytic activity against allogeneic leukemic blasts derived
from NCRdull patients (not shown). Surprisingly, however,
these NCRbright AML-NK cells were poorly cytolytic against
autologous leukemic cells even in the presence of anti-HLA class I mAbs
(Figure 2C). Moreover, an NK cell population derived from a healthy
individual (used as a control) was able to kill autologous PHA blasts
in the presence of anti-HLA class I mAb. Thus, AML-NK cells,
independent from their NCR phenotype, are characterized by the
inability to kill autologous AML blasts. In the same set of experiments
we also evaluated whether AML-NK cells derived from
NCRbright patients were able to kill autologous AML blasts
under conditions in which the need for NCR ligands is substituted by
anti-NCR mAbs. Thus, we performed a redirected killing assay in which
different AML-NK cell populations were assessed for cytolytic activity
against autologous (Fc Susceptibility of AML blasts to killing mediated by normal allogeneic NK cells Altogether, the above results suggested that the low levels of cytolytic activity displayed by AML-NK cells against the autologous leukemia may reflect the existence of insufficient NCR/ligand interactions. In NCR[dull] AML-NK cells this defect may be easily explained by the low number of NCR molecules at the NK cells surface. On the contrary, in the case of AML-NK cells characterized by an NCRbright phenotype, the inability to kill autologous leukemic blasts may be due to an insufficient expression of NCR ligands on leukemic blasts.To verify this possibility we analyzed the different leukemic cells for
susceptibility to killing by NK cells derived from unrelated healthy
individuals. A representative experiment is shown in Figure
3A in which the cytolytic activity
against leukemic blasts was evaluated in the absence or in the presence
of anti-HLA class I mAb (to prevent KIR/HLA interactions). It is
evident that under these conditions, unlike autologous AML-NK cells
(Figure 2C), normal NCRbright allogeneic NK cells displayed
strong cytolytic activity against leukemic cells derived from
NCRdull patients. On the contrary, the same normal NK cells
displayed poor cytotoxicity against leukemic cells derived from
NCRbright patients even in the presence of anti-HLA class I
mAb. In line with data presented in Figure 2C, AML blasts
(Fc
To directly evaluate the involvement of NCRs in AML killing by
allogeneic NCRbright normal NKs, these cells were assessed
for cytolytic activity either in the absence or in the presence of mAbs
specific for NCRs. In this case, the mAbs used to block the
NCR-mediated recognition of AML target cells were of IgM isotype. This
isotype was necessary to avoid redirected killing effects against the
Fc NK-mediated killing of B-LCLs derived from patients with AML Further studies were performed by using as target cells B-LCLs derived from the various AML patients. These cells were first analyzed for susceptibility to killing by NK cells derived from healthy donors either in the absence or in the presence of anti-HLA class I mAb. As shown in Figure 4A in the presence of anti-HLA class I mAb, all B-LCLs were susceptible to killing mediated by normal NK cells. Moreover, in line with previous reports4 killing could be inhibited by the use of anti-NCR mAbs (not shown). These results suggest that, unlike leukemic cells, B-LCLs derived from all the AML patients analyzed normally express ligand(s) able to activate NCR functions. This finding was confirmed by experiments in which B-LCLs were analyzed for susceptibility to killing by autologous AML-NK cells (in the presence of anti-HLA class I mAb). As shown in the representative experiment reported in Figure 4B, AML-NK cells displaying the NCRdull phenotype were poorly cytolytic against autologous B-LCLs, whereas those characterized by the NCRbright phenotype displayed strong cytotoxicity.
In the present study we show that leukemic cells derived from patients with AML are generally poorly susceptible to lysis mediated by autologous NK cells and that this defect is likely due to insufficient numbers of NCR/ligand(s) interactions. In most of the patients analyzed, this defect is consequent to the low (dull) expression of NCR, ie, the receptors that are crucial for target cell recognition and for induction of NK-mediated cytotoxicity.4,6 In the remaining patients the poor NK-mediated cytotoxicity against autologous leukemia blasts appears to be the result of a mechanism of tumor escape based on a defective expression of surface ligands by leukemic cells. In most instances no dramatic down-regulation of HLA class I expression has been detected in the AML blasts analyzed. However, it is well established that transformed cells may selectively down-regulate only one or few alleles and that, in this case, the use of anti-HLA class I mAb specific for monomorphic determinants may not be sufficient to reveal a partial HLA class I-deficiency.3,5,19 Thus, it is possible that at least some of the leukemic blasts analyzed are carrying a HLA class I-defective phenotype. If this is the case, in principle AML blasts should become susceptible to cytotoxicity mediated by NK cells expressing the relevant HLA-specific inhibitory receptor.1,2 However, our present data suggest that the protective role of HLA class I may be incremented by additional mechanisms that are based on defective NCR/ligand(s) interactions. Indeed, in most cases our functional analysis of AML-NK cells against leukemic blasts has been performed both in the absence and in the presence of anti-HLA class I mAb. The disruption of the interaction between HLA class I and the inhibitory receptors expressed at the AML-NK cell surface should allow these cells to kill autologous leukemic blasts.1,2 Because our results indicate that killing of autologous AML blasts cannot significantly be incremented in the presence of anti-HLA class I mAb, we may conclude that the mechanism of protection of AML blasts from autologous AML-NK cells is not simply based on "inhibition of lysis." Rather, our present data suggest an additional mechanism that renders AML-NK cells unable to attack autologous leukemia is based on "lack of NK cell triggering." The latter mechanism, however, is likely to be relevant especially in those leukemias that have first lost HLA class I expression. A possible approach to the analysis of HLA class I down-regulation in patients with AML is provided by the study of NK clones expressing inhibitory surface receptors for one or another HLA class I molecules. Along this line we observed that in most instances NK clones derived from healthy donors and expressing CD94/NKG2A as the unique HLA class I-specific inhibitory receptor were capable of killing AML blasts. Moreover, their cytolytic activity could not be significantly increased by anti-HLA class I mAb (not shown). The same NK clones were unable to kill target cell transfectants expressing appropriate HLA class I ligands (used as controls), and, in this case, lysis could be reverted by anti-HLA class I mAb. This finding suggests that the surface density of the "nonclassical" HLA-E molecules may be, at least in part, decreased in the various AMLs analyzed possibly consequent to down-regulation of one or more "classical" HLA class I molecules. In this context we also observed that a NK clone expressing the p58.1 (KIRD2L1) receptor (but lacking other inhibitory receptors) was able to kill at least 2 AMLs expressing the appropriate HLA-C alleles (not shown). However, the same AML blasts appeared to express sufficient amounts of other HLA class I alleles as suggested by the observation that NK clones expressing other inhibitory receptors (p70/KIR3DL1 or p140/KIR3DL2) were unable to kill AML blasts expressing the appropriate HLA class I ligands. Importantly, in this case, lysis could be reverted by anti-HLA class I mAbs. These data would indicate that one or more (but not all) HLA class I alleles may be defective in the AML blasts of the patients analyzed. This in turn would allow NK cells expressing adequate amounts of NCR to kill AML blasts because of insufficient interactions between HLA class I and their inhibitory receptors. Remarkably, in most (16 of 18) patients analyzed in this study the lack of NK cell triggering was consequent to the dull expression of NCR. Indeed, normal NK cells were able to kill leukemic blasts derived from this group of patients, whereas autologous NK cells characterized by the NCRdull phenotype were not. Previous studies indicated that in normal NK cells the NCRdull phenotype is stable and is not modified on in vitro culture.7 However, no information is available so far on the mechanisms regulating the level of NCR expression in NK cells and whether the NCR surface densities may be under the control of the microenvironment by cell-to-cell contacts and/or cytokine secretion. In this context, we performed cocultures of NCRbright AML-NK with leukemic cells from NCRdull patients; no substantial changes in NCR surface density could be detected in 4 independent experiments (data not shown). Identical results were obtained by using supernatants from cultured leukemias (data not shown). These experiments suggest that leukemic blasts are not directly involved in NCR down-regulation by cell-to-cell contact or by the release of soluble factors (not shown). Moreover, we excluded the leukemic origin of AML-NKs by performing interphase nuclei fluorescent in situ hybridization on cytospin preparations of NKs from 3 patients selected for the presence of trisomy 8 in their blast cells at diagnosis. In the 3 patients with trisomy 8, all AML-NK cells presented with 2 fluorescent signals, thus excluding the presence of trisomy 8 (data not shown). The down-regulation of the TCR-associated CD3- A minor group of the patients analyzed in this study was characterized by AML-NK cells that expressed adequate amounts of NCRbright molecules. This characterization allowed these NK cells to kill allogeneic leukemic cells derived from NCRdull patients (not shown) as well as autologous B-LCLs and murine P815 target cells (Figures 4 and 2). On the contrary, such NCRbright AML-NK cells were unable to kill autologous leukemic blasts. This finding may suggest that these tumor cells have evolved a mechanism of escape from NK-cell mediated recognition based on the down-regulation of target cell ligands. This finding is further supported by the fact that NK cells derived from normal individuals also did not display cytotoxicity against leukemic blasts from this group of patients. A possible interpretation of these findings is that leukemic cells express inadequate amounts of NCR-specific ligands. In this context, although NCRs appear to represent the main NK receptors involved in killing of AML blasts, the nature of their specific ligands remains to be identified.4 An alternative possibility could be that these leukemic cells are not killed because of the lack of molecules involved in cell adhesion. In this context, however, the surface expression of LFA3 and ICAM-1 was comparable to that of leukemic cells derived from patients characterized by NCRdull NK cells (data not shown). In conclusion, we have identified in patients with AML 2 possible mechanisms of tumor escape from NK cell-mediated recognition. The first mechanism, found in a small proportion of the patients analyzed, appears to be based on the in vivo selection of leukemic cells lacking the ligands involved in NK cell triggering. The second mechanism, found in the majority of cases, is based on the down-regulation of NCRs, ie, the main receptors involved in NK-mediated recognition and killing of tumor targets. In this case, because of the low NCR surface density on AML-NK cells, there would be no need for a selection of the leukemic blasts toward a NCR ligand(s)-deficient phenotype.
We thank F. Mallet, M. Illiano, and J. Viscardi for excellent technical assistance and T. Baffi for secretarial assistance.
Submitted August 10, 2001; accepted December 19, 2001.
Supported by Groupement Entreprise Français Lutte Cancer, Association pour la Recherche contre le Cancer, Ligue contre le Cancer de Bastia, Fédération Nationale des Centres de Lutte Contre le Cancer, Fondation Contre la Leucémie, European Association for Cancer Research, Etablissement Français des Greffes, Fondation pour la Recherche Médicale, Société Française contre le Cancer, Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.), Istituto Superiore di Sanità (I.S.S.), and Ministero dell'Università e della Ricerca Scientifica e Tecnologica (M.U.R.S.T.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Régis T. Costello, Unité d'Immunologie des Tumeurs & Département d'Hématologie, Institut Paoli-Calmettes, Université de la Méditerranée, Marseille, France; e-mail: regis.costello{at}free.fr.
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  M. Carlsten, H. Norell, Y. T. Bryceson, I. Poschke, K. Schedvins, H.-G. Ljunggren, R. Kiessling, and K.-J. Malmberg Primary Human Tumor Cells Expressing CD155 Impair Tumor Targeting by Down-Regulating DNAM-1 on NK Cells J. Immunol., October 15, 2009; 183(8): 4921 - 4930. [Abstract] [Full Text] [PDF]
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 F. Romagne, P. Andre, P. Spee, S. Zahn, N. Anfossi, L. Gauthier, M. Capanni, L. Ruggeri, D. M. Benson Jr, B. W. Blaser, et al. Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells Blood, September 24, 2009; 114(13): 2667 - 2677. [Abstract] [Full Text] [PDF]
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 F. Bozzano, P. Costa, G. Passalacqua, F. Dodi, S. Ravera, G. Pagano, G. W. Canonica, L. Moretta, and A. De Maria Functionally relevant decreases in activatory receptor expression on NK cells are associated with pulmonary tuberculosis in vivo and persist after successful treatment Int. Immunol., July 1, 2009; 21(7): 779 - 791. [Abstract] [Full Text] [PDF]
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 M. E.D. Chamuleau, T. M. Westers, L. van Dreunen, J. Groenland, A. Zevenbergen, C. M. Eeltink, G. J. Ossenkoppele, and A. A. van de Loosdrecht Immune mediated autologous cytotoxicity against hematopoietic precursor cells in patients with myelodysplastic syndrome Haematologica, April 1, 2009; 94(4): 496 - 506. [Abstract] [Full Text] [PDF]
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R. Castriconi, A. Daga, A. Dondero, G. Zona, P. L. Poliani, A. Melotti, F. Griffero, D. Marubbi, R. Spaziante, F. Bellora, et al. NK Cells Recognize and Kill Human Glioblastoma Cells with Stem Cell-Like Properties J. Immunol., March 15, 2009; 182(6): 3530 - 3539. [Abstract] [Full Text] [PDF]
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G. G. Halfteck, M. Elboim, C. Gur, H. Achdout, H. Ghadially, and O. Mandelboim Enhanced In Vivo Growth of Lymphoma Tumors in the Absence of the NK-Activating Receptor NKp46/NCR1 J. Immunol., February 15, 2009; 182(4): 2221 - 2230. [Abstract] [Full Text] [PDF]
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 L Moretta, F Locatelli, and A Moretta Alloreactive natural killer cells in targeting high-risk leukaemias Ann Rheum Dis, December 1, 2008; 67(Suppl_3): iii39 - iii43. [Abstract] [Full Text] [PDF]
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N. Nausch, I. E. Galani, E. Schlecker, and A. Cerwenka Mononuclear myeloid-derived "suppressor" cells express RAE-1 and activate natural killer cells Blood, November 15, 2008; 112(10): 4080 - 4089. [Abstract] [Full Text] [PDF]
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S. Diermayr, H. Himmelreich, B. Durovic, A. Mathys-Schneeberger, U. Siegler, U. Langenkamp, J. Hofsteenge, A. Gratwohl, A. Tichelli, M. Paluszewska, et al. NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities Blood, February 1, 2008; 111(3): 1428 - 1436. [Abstract] [Full Text] [PDF]
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S. Sivori, M. Falco, S. Carlomagno, E. Romeo, L. Moretta, and A. Moretta Heterogeneity of TLR3 mRNA transcripts and responsiveness to poly (I:C) in human NK cells derived from different donors Int. Immunol., December 1, 2007; 19(12): 1341 - 1348. [Abstract] [Full Text] [PDF]
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H. Harlin, M. Hanson, C. C. Johansson, D. Sakurai, I. Poschke, H. Norell, K.-J. Malmberg, and R. Kiessling The CD16 CD56bright NK Cell Subset Is Resistant to Reactive Oxygen Species Produced by Activated Granulocytes and Has Higher Antioxidative Capacity Than the CD16+CD56dim Subset J. Immunol., October 1, 2007; 179(7): 4513 - 4519. [Abstract] [Full Text] [PDF]
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P. K. Epling-Burnette, F. Bai, J. S. Painter, D. E. Rollison, H. R. Salih, M. Krusch, J. Zou, E. Ku, B. Zhong, D. Boulware, et al. Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors Blood, June 1, 2007; 109(11): 4816 - 4824. [Abstract] [Full Text] [PDF]
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C. Fauriat, S. Just-Landi, F. Mallet, C. Arnoulet, D. Sainty, D. Olive, and R. T. Costello Deficient expression of NCR in NK cells from acute myeloid leukemia: evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction Blood, January 1, 2007; 109(1): 323 - 330. [Abstract] [Full Text] [PDF]
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M. Brune, S. Castaigne, J. Catalano, K. Gehlsen, A. D. Ho, W.-K. Hofmann, D. E. Hogge, B. Nilsson, R. Or, A. I. Romero, et al. Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial Blood, July 1, 2006; 108(1): 88 - 96. [Abstract] [Full Text] [PDF]
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J. O. Richards, X. Chang, B. W. Blaser, M. A. Caligiuri, P. Zheng, and Y. Liu Tumor growth impedes natural-killer-cell maturation in the bone marrow Blood, July 1, 2006; 108(1): 246 - 252. [Abstract] [Full Text] [PDF]
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N. Hanaoka, T. Kawaguchi, K. Horikawa, S. Nagakura, H. Mitsuya, and H. Nakakuma Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP Blood, February 1, 2006; 107(3): 1184 - 1191. [Abstract] [Full Text] [PDF]
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K. Mazodier, V. Marin, D. Novick, C. Farnarier, S. Robitail, N. Schleinitz, V. Veit, P. Paul, M. Rubinstein, C. A. Dinarello, et al. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome Blood, November 15, 2005; 106(10): 3483 - 3489. [Abstract] [Full Text] [PDF]
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B. Le Maux Chansac, A. Moretta, I. Vergnon, P. Opolon, Y. Lecluse, D. Grunenwald, M. Kubin, J.-C. Soria, S. Chouaib, and F. Mami-Chouaib NK Cells Infiltrating a MHC Class I-Deficient Lung Adenocarcinoma Display Impaired Cytotoxic Activity toward Autologous Tumor Cells Associated with Altered NK Cell-Triggering Receptors J. Immunol., November 1, 2005; 175(9): 5790 - 5798. [Abstract] [Full Text] [PDF]
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C. Fauriat, A. Moretta, D. Olive, and R. T. Costello Defective killing of dendritic cells by autologous natural killer cells from acute myeloid leukemia patients Blood, September 15, 2005; 106(6): 2186 - 2188. [Abstract] [Full Text] [PDF]
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J. D. Coudert, J. Zimmer, E. Tomasello, M. Cebecauer, M. Colonna, E. Vivier, and W. Held Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells Blood, September 1, 2005; 106(5): 1711 - 1717. [Abstract] [Full Text] [PDF]
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 A. P. Williams, A. R. Bateman, and S. I. Khakoo HANGING IN THE BALANCE: KIR and Their Role in Disease Mol. Interv., August 1, 2005; 5(4): 226 - 240. [Abstract] [Full Text] [PDF]
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N. C. Fernandez, E. Treiner, R. E. Vance, A. M. Jamieson, S. Lemieux, and D. H. Raulet A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules Blood, June 1, 2005; 105(11): 4416 - 4423. [Abstract] [Full Text] [PDF]
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R. Biassoni, M. Fogli, C. Cantoni, P. Costa, R. Conte, G. Koopman, A. Cafaro, B. Ensoli, A. Moretta, L. Moretta, et al. Molecular and Functional Characterization of NKG2D, NKp80, and NKG2C Triggering NK Cell Receptors in Rhesus and Cynomolgus Macaques: Monitoring of NK Cell Function during Simian HIV Infection J. Immunol., May 1, 2005; 174(9): 5695 - 5705. [Abstract] [Full Text] [PDF]
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P. Nowbakht, M.-C. S. Ionescu, A. Rohner, C. P. Kalberer, E. Rossy, L. Mori, D. Cosman, G. De Libero, and A. Wodnar-Filipowicz Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias Blood, May 1, 2005; 105(9): 3615 - 3622. [Abstract] [Full Text] [PDF]
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D. Pende, G. M. Spaggiari, S. Marcenaro, S. Martini, P. Rivera, A. Capobianco, M. Falco, E. Lanino, I. Pierri, R. Zambello, et al. Analysis of the receptor-ligand interactions in the natural killer-mediated lysis of freshly isolated myeloid or lymphoblastic leukemias: evidence for the involvement of the Poliovirus receptor (CD155) and Nectin-2 (CD112) Blood, March 1, 2005; 105(5): 2066 - 2073. [Abstract] [Full Text] [PDF]
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 R. Castriconi, A. Dondero, M. V. Corrias, E. Lanino, D. Pende, L. Moretta, C. Bottino, and A. Moretta Natural Killer Cell-Mediated Killing of Freshly Isolated Neuroblastoma Cells: Critical Role of DNAX Accessory Molecule-1-Poliovirus Receptor Interaction Cancer Res., December 15, 2004; 64(24): 9180 - 9184. [Abstract] [Full Text] [PDF]
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M. Jinushi, T. Takehara, T. Tatsumi, T. Kanto, T. Miyagi, T. Suzuki, Y. Kanazawa, N. Hiramatsu, and N. Hayashi Negative Regulation of NK Cell Activities by Inhibitory Receptor CD94/NKG2A Leads to Altered NK Cell-Induced Modulation of Dendritic Cell Functions in Chronic Hepatitis C Virus Infection J. Immunol., November 15, 2004; 173(10): 6072 - 6081. [Abstract] [Full Text] [PDF]
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T. I. Arnon, H. Achdout, N. Lieberman, R. Gazit, T. Gonen-Gross, G. Katz, A. Bar-Ilan, N. Bloushtain, M. Lev, A. Joseph, et al. The mechanisms controlling the recognition of tumor- and virus-infected cells by NKp46 Blood, January 15, 2004; 103(2): 664 - 672. [Abstract] [Full Text] [PDF]
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E. S. Doubrovina, M. M. Doubrovin, E. Vider, R. B. Sisson, R. J. O'Reilly, B. Dupont, and Y. M. Vyas Evasion from NK Cell Immunity by MHC Class I Chain-Related Molecules Expressing Colon Adenocarcinoma J. Immunol., December 15, 2003; 171(12): 6891 - 6899. [Abstract] [Full Text] [PDF]
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 S. R. Archacki, G. Angheloiu, X.-L. Tian, F. L. Tan, N. DiPaola, G.-Q. Shen, C. Moravec, S. Ellis, E. J. Topol, and Q. Wang Identification of new genes differentially expressed in coronary artery disease by expression profiling Physiol Genomics, September 29, 2003; 15(1): 65 - 74. [Abstract] [Full Text] [PDF]
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R. Zambello, M. Falco, M. D. Chiesa, L. Trentin, D. Carollo, R. Castriconi, G. Cannas, S. Carlomagno, A. Cabrelle, T. Lamy, et al. Expression and function of KIR and natural cytotoxicity receptors in NK-type lymphoproliferative diseases of granular lymphocytes Blood, September 1, 2003; 102(5): 1797 - 1805. [Abstract] [Full Text] [PDF]
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C. P. Kalberer, U. Siegler, and A. Wodnar-Filipowicz Human NK cell development in NOD/SCID mice receiving grafts of cord blood CD34+ cells Blood, July 1, 2003; 102(1): 127 - 135. [Abstract] [Full Text] [PDF]
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 R. Castriconi, C. Cantoni, M. Della Chiesa, M. Vitale, E. Marcenaro, R. Conte, R. Biassoni, C. Bottino, L. Moretta, and A. Moretta Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: Consequences for the NK-mediated killing of dendritic cells PNAS, April 1, 2003; 100(7): 4120 - 4125. [Abstract] [Full Text] [PDF]
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D. Pende, P. Rivera, S. Marcenaro, C.-C. Chang, R. Biassoni, R. Conte, M. Kubin, D. Cosman, S. Ferrone, L. Moretta, et al. Major Histocompatibility Complex Class I-related Chain A and UL16-Binding Protein Expression on Tumor Cell Lines of Different Histotypes: Analysis of Tumor Susceptibility to NKG2D-dependent Natural Killer Cell Cytotoxicity Cancer Res., November 1, 2002; 62(21): 6178 - 6186. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
+ and CD8+ TCR
+
cells.
chains is one
of the mechanisms leading to abnormal immune responses in hematologic malignancies, including chronic lymphocytic leukemia,