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Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 333-339
By
From the Division of Hematology and Clinical Immunology, the
Department of Clinical and Experimental Medicine, University of
Perugia, Perugia, Italy; and the Division of Bone Marrow
Transplantation, the Department of Medicine, Stanford University,
Stanford, CA 94305.
Because of the expression of inhibitory receptors (KIR) for major
histocompatibility complex (MHC) class I allotypes, a person's natural
killer (NK) cells will not recognize and will, therefore, kill cells
from individuals lacking his/her KIR epitopes. This study investigated
the role of NK cell alloreactivity in human HLA haplotype-mismatched
hematopoietic stem cell transplantation and, specifically, the role of
the three major NK specificities, ie, those for HLA-C group 1, HLA-C
group 2, and HLA-Bw4 alleles. In 20 of 60 donor-recipient pairs, KIR
epitope incompatibility and functional analyses of donor NK cell clones
predicted donor NK cells could cause graft-versus-host
(GVH)/graft-versus-leukemia (GVL) reactions. NK cell clones of donor
origin were obtained from transplanted recipients and tested for lysis
of recipient's cryopreserved pretransplant lymphocytes. Despite the
absence of GVH disease, we detected high frequencies of NK clones which
killed recipient's target cells. Lysis followed the rules of NK cell alloreactivity, being blocked only by the MHC class I KIR epitope which
was missing in the recipient. The alloreactive NK clones also killed
the allogeneic leukemia. Transplants from these KIR epitope
incompatible donors had higher engraftment rates. Therefore, a GVL
effector and engraftment facilitating mechanism, which is independent
of T-cell-mediated GVH reactions, may be operational in HLA mismatched
hematopoietic cell transplants.
INHIBITION OF natural killer (NK) cell
lysis is signaled through specific receptors which bind to polymorphic
determinants of major histocompatibility complex (MHC) class I
molecules.1,2 In humans, one receptor is the lectin-like
heterodimer CD94-NKG2A, which recognizes human leukocyte antigen
(HLA)-E, a nonclassical MHC class Ib molecule whose expression is, in
turn, upregulated by the binding of signal sequence peptides of other
MHC class I molecules.3,4 Other receptors are a family of
Ig-like molecules known as killer cell inhibitory receptors
(KIR).5-7 The KIRs with two Ig domains (KIR2D) identify
HLA-C allotypes: KIR2DL2 (formerly designated p58.1) recognizes an
epitope shared by group 1 HLA-C allotypes (Cw2, 4, 5, and 6), whereas
KIR2DL1 (p58.2) recognizes an epitope shared by the reciprocal group 2 HLA-C allotypes (Cw1, 3, 7, and 8). One KIR with three Ig domains
KIR3DL1 (p70) recognizes an epitope shared by HLA-Bw4 alleles. Finally,
a homodimer of molecules with three Ig domains KIR3DL2 (p140)
recognizes HLA-A3 and -A11.8
KIR genes, each expressed by some of the individual's NK cells, vary
considerably among individuals.9 It is believed that during
development each NK cell precursor makes a random choice of which KIR
genes it will express, and the different combinations of HLA class I
molecules select NK cells that express receptors for self HLA class I. Consequently, the NK cells from any given individual will be
alloreactive toward cells from others which lack their KIR ligands and,
conversely, will be tolerant of cells from another individual who has
the same or additional KIR ligands.
Although KIR epitope mismatches are well-known causes of NK cell
alloreactivity,10-17 their role in human transplantation
have not been evaluated. Full haplotype-mismatched hematopoietic stem cell transplants have recently been used for treatment of bad-risk leukemia patients lacking a matched donor.18,19 In this
context, host and/or donor NK cells may be responsible for three
situations: (1) a potential for graft-versus-host (GVH) reactions, ie,
when the recipient fails to express the donor's KIR epitopes; (2) a potential for NK cell-mediated graft rejection, ie, when the donor fails to express the recipient's KIR epitopes; (3) no NK cell alloreactions, ie, when the donor and recipient mismatched alleles express the same KIR epitopes. One aim of the present study was, therefore, to evaluate whether mismatches for the three major KIR
epitopes, ie, those of the HLA-C group 1, HLA-C group 2, and HLA-Bw4
alleles, have any impact on transplantation outcome.
Moreover, the very fast donor-type NK cell recovery20 (and
this report) strongly suggests that postgrafting NK cells derive, not
from expansion of mature NK cells contaminating the stem cell graft,
but from large-scale maturation of the engrafted stem cells. This
maturation occurs under the influence of KIR epitopes expressed in the
donor's hematopoietic cells and the host's marrow stromal cells.21 Because little is known about the cell types which drive selection of the NK cells, KIR epitope mismatched transplants appear to be a convenient model for analyzing the selection of human NK
cell repertoires.
Patients
HLA Typing
Transplantation
Assessment of Chimerism Starting on day +12 after transplantation, chimerism of peripheral blood and bone marrow cells was determined by bimonthly assessment of polymerase chain reaction (PCR) amplification of a panel of variable number tandem repeat regions with different DNA polymorphism patterns in donor and recipient cells. All postengraftment blood samples used for the NK cell studies shown here exhibited 100% donor chimerism.Immunofluorescence and Flow Cytometry Indirect immunofluorescence with primary monoclonal antibodies (MoAbs) plus secondary fluorochrome-conjugated goat anti-mouse Ig antibodies (Southern Biotechnology Associates, Birmingham, AL) and flow cytometry (FACSCalibur; Becton Dickinson, San Jose, CA) determined NK cell phenotypes. NK cell clones were identified using an anti-CD16 MoAb (Immunotech, Marseille, France). Expression of KIRs recognizing group 1 HLA-C alleles (KIR2DL2), group 2 HLA-C alleles (KIR2DL1), and HLA-Bw4 alleles (KIR3DL1) was determined with MoAbs EB6, GL183 and Z27 respectively22 (kindly provided by L. Moretta, University of Genova, Genova, Italy). LFA-1 expression by allogeneic NK targets was measured by indirect immunofluorescence and flow cytometry with an anti-CD11a MoAb from Immunotech.Preparation of NK Cell Clones Peripheral blood mononuclear cells depleted of T cells by negative immuno-magnetic selection with anti-CD3 MoAb (OKT3 obtained from American Tissue Culture Collection [ATCC], Manassas, VA) were plated at the concentration of 10 cells per well in 96-well microtiter plates, activated with phytohemagglutinin (PHA), and cultured with interleukin-2 (IL-2) and irradiated feeder cells as described elsewhere.20 Cloned NK cells were used as effectors in standard 51Cr release cytotoxicity assays using as targets allogeneic PHA lymphoblasts or Epstein-Barr virus-transformed B-lymphoblastoid cell lines (BLCL), leukemia cells, and cell lines expressing single class I alleles. Effector to target (E:T) ratio was 10:1.Analysis of NK Cell Allospecificity Standard 51Cr release cytotoxicity assays against cell lines transfected with class I genes (kindly provided by L. Moretta) determined the three main NK allospecificities. Specificities for group 1 (Cw4-related) and group 2 (Cw3-related) HLA-C allotypes were analyzed using the HLA class I-negative cell line 721.221 and the same cell line transfected with Cw*0401 or Cw*0302 genes, respectively.23 Specificity for HLA-Bw4 allotypes (such as HLA-B27) was analyzed using untransfected C1R cells and C1R cells transfected with the B*2705 gene.22 Specificity for the nonclassical MHC class Ib molecule HLA-E was analyzed using C1R cells expressing HLA-B7 (Bw6)21 (cell-surface expression of HLA-E is regulated by the binding of peptides derived from the signal sequence of some other MHC class I molecules, such as HLA-B7).3,4 E:T ratio was 10:1. Results are presented as percentage inhibition compared with lysis of the untransfected 721.221 or C1R cells. NK clones lysed the untransfected cells at levels exceeding 60%, and were considered specific for a given allotype when this was reduced by at least 50%.
Transplantation Into Recipients Failing to Express the Donor's KIR Epitopes, ie, With a Potential for NK Cell-Mediated GVH Reactions Eight of the 20 patients in this group had AML, 5 CML, and 7 ALL. All patients engrafted successfully and reached 1,000 neutrophils/µL in 8 to 19 days (median, 11 days) and 50,000 platelets in 13 to 124 days (median, 29 days). No GVHD was observed. One hundred percent donor-type chimerism was detected in peripheral blood and bone marrow on all assessments (except at relapse). At a median follow-up of 6 months (range, 1 to 39 months), 0 of 8 AML, 0 of 5 CML, and 5 of 7 ALL patients relapsed.Postgrafting emergence of donor-versus-recipient alloreactive NK
cells.
Table 2 illustrates the HLA typing of these
20 donor-recipient pairs. Specific donor KIR ligands were missing in
the recipient. Some of the donor's NK cells could, therefore, lyse the
recipient's cells and cause GVHD. GVHD potential was assessed directly
in 14 pairs by pretransplant analysis of donor NK cell clones. Table 3 (left column) shows some donor NK cell
clones killed recipient target cells (PHA lymphoblasts or BLCLs),
indicating that donors possessed antirecipient NK cells in their
repertoires before transplant. Lysis by these clones could only be
blocked by transfected cell lines expressing the donor's MHC class I
allotypic group which was missing in the recipient (data not shown).
MHC specificity of donor-versus-recipient alloreactive NK cells.
Posttransplant killing of recipient cells might be triggered by
nonrecognition of recipient MHC. To test this hypothesis, clones were
analyzed for MHC specificity using target cells expressing the HLA-Bw4
allele B27, the group 2 HLA-C allele Cw3, and the group 1 HLA-C allele
Cw4. Expression of the corresponding KIR was determined by
immunofluorescence. Control targets, not recognized by KIRs, were cells
expressing the HLA-Bw6 allele B7 (see refs 3 and 4). As illustrated in
Fig 2 for the alloreactive NK clones from
transplants 7 and 9 (shown as examples), lysis could only be blocked by
target cells expressing the donor allele group that was missing in the
recipient. If the missing allele belonged to HLA-C group 1 (as in
transplant 7), the postgrafting donor-versus-recipient alloreactive NK
clones were only equipped with KIR2DL2, the receptor for HLA-C group 1. Their lysis could be blocked only by cells expressing an HLA-C group 1 allele (such as Cw4), and not by cells expressing allele groups
recognized by other KIRs, such as HLA-C group 2, or HLA-Bw4 (and
obviously not by cells bearing alleles, such as B7, which are not
recognized by KIRs). This phenomenon was observed in all cases
analyzed, ie, in transplants no. 7 and 9 (shown in the figure), as well
as in transplants 12, 13, and 14 (not shown).
Antileukemic effect of alloreactive NK cells.
To test the hypothesis that NK allorecognition may serve as a
graft-versus-leukemia (GVL) effector, we evaluated the susceptibility to allogeneic NK lysis of a set of leukemic cells and compared it with
reference targets (PHA lymphoblasts and BLCLs from the same leukemia
patients). NK clones that lysed allogeneic PHA lymphoblasts or BLCLs
from leukemia patients were tested for their ability to lyse leukemic
cells from the same individuals. Leukemia cells from 4 CML, 4 AML, and
5 ALL (calla+) patients were used as targets. The
alloreactive NK clones efficiently killed all the acute and chronic
myeloid leukemias (top panel in Fig 3). Only two of five ALLs were
killed (bottom left panel Fig 3). Killing
of susceptible leukemias followed the rules of NK cell allorecognition,
as leukemias were killed by 100% of the alloreactive NK clones (24 of
24, E:T ratio = 10:1), and were not killed by 50 of 50 nonalloreactive NK clones (even at E:T ratio of 50:1).
Immunofluorescence analysis of several adhesion molecules showed all
NK-resistant ALLs exhibited lower surface expression of lymphocyte
function antigen-1 (LFA-1) compared with the NK-susceptible ALLs and
with all the CMLs and AMLs (bottom right panel in Fig 3).
Transplantation From Donors Failing to Express the Recipient's KIR
Epitopes, ie, With a Potential for NK Cell-Mediated Graft Rejection
KIR Epitope-Matched Transplants, ie, With No Potential for NK Cell Alloreactions Twenty-three donor-recipient pairs were matched for all known KIR ligands, that is, HLA-A3/A11 in addition to HLA-C group 1, HLA-C group 2, HLA-Bw4. Six rejections (2 reversed by a second transplant) occurred. However, (1) none of 208 NK cell clones obtained before conditioning from three recipients who afterward rejected the graft lysed the donor's target cells; (2) at the end of conditioning, no host NK cells were detected by immunofluorescence, nor could they be cultured even by processing large (100 mL) samples of the recipient's blood; (3) at the time of rejection, no NK cells could be identified by immunofluorescence nor could they be cultured from the bone marrow or peripheral blood (not shown). Consequently, these tests failed to detect any role for NK cells in rejection in KIR epitope-matched transplants.
This study investigated the role of NK cell alloreactivity in clinical hematopoietic cell transplantation and, specifically, the role of the three major NK allospecificities, ie, those for the KIR epitopes of the HLA-C group 1, HLA-C group 2, and HLA-Bw4 alleles. Rejection and GVHD mediated by these NK specificities could have occurred in 37 of 60 high-risk leukemia patients who underwent mismatched hematopoietic stem cell transplants.
We thank Lorenzo Moretta (University of Genova, Genova, Italy) for antibodies and cell lines, Antonella Santucci for statistical analyses, and Geraldine Ann Boyd for assistance in the writing of the manuscript.
Submitted October 19, 1998; accepted February 18, 1999.
Supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC). L.R. and I.V. are supported by fellowships from Fondazione Italiana per la Ricerca sul Cancro (FIRC).
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
Address reprint requests to Andrea Velardi, MD, Sezione di Ematologia e Immunologia Clinica, Università di Perugia, Policlinico Monteluce, 06122-Perugia, Italy; e-mail: velardi{at}unipg.it.
1. Moretta A, Moretta L: HLA class I specific inhibitory receptors. Curr Opin Immunol 9:694, 1997[Medline] [Order article via Infotrieve] 2. Lanier LL: NK cell receptors. Annu Rev Immunol 16:359, 1998[Medline] [Order article via Infotrieve] 3. Braud VM, Allan DS, O'Callaghan CA, Soderstrom K, D'Andrea A, Ogg GS, Lazetic S, Young NT, Bell JI, Phillips JH, Lanier LL, McMichael AJ: HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391:795, 1998[Medline] [Order article via Infotrieve]
4.
Lee N, Liano M, Carretero M, Ishitani A, Navarro F, Lopez-Botet M, Geraghty DE:
HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A.
Proc Natl Acad Sci USA
95:5199, 1998 5. Wagtmann N, Biassoni R, Cantoni C, Verdiani S, Malnati M, Vitale M, Bottino C, Moretta L, Moretta A, Long EO: Molecular clones of the p58 natural killer cell receptor reveal Ig-related molecules with diversity in both the extra- and intra-cellular domains. Immunity 2:439, 1995[Medline] [Order article via Infotrieve]
6.
Colonna M, Samaridis J:
Cloning of immunoglobulin-superfamily members associated with HLA-C and HLA-B recognition by human natural killer cells.
Science
268:405, 1995 7. D'andrea A, Chang C, Franz-Bacon K, McClanahan T, Phillips JH, Lanier LL: Molecular cloning of NKB1: A natural killer cell receptor for HLA-B allotypes. J Immunol 155:2306, 1995[Abstract]
8.
Pende D, Biassoni R, Cantoni C, Verdiani S, Falco M, di Donato C, Accame L, Bottino C, Moretta A, Moretta L:
The natural killer cell receptor specific for HLA-A allotypes: A novel member of the p58/p70 family of inhibitory receptors that is characterized by three immunoglobulin-like domains and is expressed as a 140-kD disulphide-linked dimer.
J Exp Med
184:505, 1996 9. Uhrberg M, Valiante NM, Shum BP, Shilling HG, Lienert-Weidenbach K, Corliss B, Tyan D, Lanier LL, Parham P: Human diversity in killer cell inhibitory receptors genes. Immunity 7:753, 1997[Medline] [Order article via Infotrieve]
10.
Ciccone E, Viale O, Pende D, Malnati M, Biassoni R, Melioli G, Moretta A, Long EO, Moretta L:
Specific lysis of allogeneic cells after activation of CD3
11.
Ciccone E, Pende D, Viale O, Tambussi G, Ferrini S, Biassoni R, Longo A, Guardiola J, Moretta A, Moretta L:
Specific recognition of human CD3
12.
Ciccone E, Colonna M, Viale O, Pende D, Di Donato C, Reinharz D, Amoroso A, Jeannet M, Guardiola J, Moretta A, Spies T, Strominger JL, Moretta L:
Susceptibility or resistance to lysis by alloreactive natural killer cells is governed by a gene in the human major histocompatibility complex between BF and HLA-B.
Proc Natl Acad Sci USA
87:9794, 1990
13.
Ciccone E, Pende D, Viale O, Di Donato C, Tripodi G, Orengo AM, Guardiola J, Moretta A, Moretta L:
Evidence of a killer (NK) cell repertoire for (allo) antigen recognition: Definition of five distinct NK-determined allospecificities in humans.
J Exp Med
175:709, 1992
14.
Ciccone E, Pende D, Viale O, Di Donato C, Orengo AM, Biassoni R, Verdiani S, Amoroso A, Moretta A, Moretta L:
Involvement of HLA class I alleles in natural killer (NK) cell-specific functions: Expression of HLA-Cw3 confers selective protection from lysis by alloreactive NK clones displaying a defined specificity (specificity 2).
J Exp Med
176:963, 1992
15.
Colonna M, Spies T, Strominger JL, Ciccone E, Moretta A, Moretta L, Pende D, Viale O:
Alloantigen recognition by two human natural killer cell clones is associated with HLA-C or a closely linked gene.
Proc Natl Acad Sci USA
89:7983, 1992
16.
Colonna M, Brooks EG, Falco M, Ferrara GB, Strominger JL:
Generation of allospecific natural killer cells by stimulation across a polymorphism of HLA-C.
Science
260:1121, 1993 17. Colonna M, Borsellino G, Falco M, Ferrara GB, Strominger JL: HLA-C is the inhibitory ligand that determines dominant resistance to lysis by NK1- and NK2-specific natural killer cells. Proc Natl Acad Sci USA 90:1200, 1993
18.
Aversa F, Tabilio A, Terenzi A, Velardi A, Falzetti F, Giannoni C, Jacucci R, Zei T, Martelli MP, Gambelunghe C, Rossetti M, Caputo P, Latini P, Aristei C, Raymondi C, Reisner Y, Martelli MF:
Successful engrafment of T-cell-depleted haploidentical, "three loci" incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum.
Blood
84:3948, 1994
19.
Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F, Ruggeri L, Barbabietola G, Aristei C, Latini P, Reisner Y, Martelli MF:
Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype.
N Engl J Med
339:1186, 1998
20.
Albi N, Ruggeri L, Aversa F, Merigiola C, Tosti A, Tognellini R, Grossi CE, Martelli MF, Velardi A:
Natural killer (NK)-cell function and anti-leukemic activity of a large population of CD3+/CD8+ T cells expressing NK receptors for MHC class I after "three-loci" HLA-incompatible bone marrow transplantation.
Blood
87:3993, 1996
21.
Laver J, Jhanavar SC, O'Reilly RJ, Castro-Malaspina:
Host origin of the human hematopoietic microenvironment following allogeneic bone marrow transplantation.
Blood
70:1966, 1987
22.
Vitale M, Sivori S, Pende D, Agugliaro R, Di Donato C, Amoroso A, Malnati M, Bottino C, Moretta L, Moretta A:
Physical and functional independency of p70 and p58 natural killer (NK) cell receptors for HLA class I: Their role in the definition of different groups of alloreactive NK cell clones.
Proc Natl Acad Sci USA
93:1453, 1996
23.
Biassoni R, Falco M, Cambiaggi A, Costa P, Verdiani S, Pende D, Conte R, Di Donato C, Parham P, Moretta L:
Amino acid substitutions can influence the natural killer (NK)-mediated recognition of HLA-C molecules. Role of serine-77 and lysine-80 in the target cell protection from lysis mediated by "group 2" or "group 1" NK clones.
J Exp Med
182:605, 1995
24.
Sykes M, Harty MW, Karlhofer FM, Pearson DA, Szot G, Yokoyama W:
Hematopoietic cells and radioresistant host elements influence natural killer cell differentiation.
J Exp Med
178:223, 1993 25. Salcedo M, Andersson M, Lemieux S, Van Kaer L, Chambers BJ, Ljunggren HG: Fine tuning of natural killer cell specificity and maintenance of self tolerance in MHC class I-deficient mice. Eur J Immunol 28:1315, 1998[Medline] [Order article via Infotrieve] 26. Yu YYL, Kumar V, Bennett M: Murine natural killer cells and marrow graft rejection. Annu Rev Immunol 10:189, 1992[Medline] [Order article via Infotrieve] 27. Galandrini R, Albi N, Zarcone D, Grossi CE, Velardi A: Adhesion molecule-mediated signals regulate MHC-unrestricted and CD3/TCR-triggered cytotoxicity. Eur J Immunol 22:2047, 1992[Medline] [Order article via Infotrieve]
28.
Hauch M, Gazzola MV, Small T, Bordignon C, Barnett L, Cunningham I, Castro-Malaspina H, O'Reilly RJ, Keever CA:
Anti-leukemia potential of interleukin-2-activated natural killer cells after bone marrow transplantation for chronic myelogenous leukemia.
Blood
75:2250, 1990
29.
Cervantes F, Pierson BA, McGlave PB, Verfaillie CM, Miller JS:
Autologous activated natural killer cells suppress primitive chronic myelogenous leukemia progenitors in long-term culture.
Blood
87:2476, 1996 30. Uharek L, Glass B, Gaska T, Zeiss M, Gassmann W, Loeffler H, Mueller-Ruchholtz W: Natural killer cells as effector cells of graft-versus-leukemia activity in a murine transplantation model. Bone Marrow Transplant 12:S57, 1993 (suppl) 31. Glass B, Uharek L, Zeis M, Loeffler H, Mueller-Ruchholtz, Gassmann W: Graft-versus-leukemia activity can be predicted by natural cytotoxicity against leukemia cells. Br J Haematol 93:412, 1996[Medline] [Order article via Infotrieve] 32. Zeis M, Uharek L, Lass B, Steinmann J, Dreger P, Gassmann W, Schmitz N: Allogeneic MHC-mismatched activated natural killer cells administered after bone marrow transplantation provide a strong graft-versus-leukemia effect in mice. Br J Haematol 96:757, 1997[Medline] [Order article via Infotrieve] 33. Asai O, Longo DL, Tian Z, Hornung RL, Taub DD, Ruscetti FW, Murphy WJ: Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation. J Clin Invest 101:1835, 1998[Medline] [Order article via Infotrieve]
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  M. Stern, L. Ruggeri, A. Mancusi, M. E. Bernardo, C. de Angelis, C. Bucher, F. Locatelli, F. Aversa, and A. Velardi Survival after T cell-depleted haploidentical stem cell transplantation is improved using the mother as donor Blood, October 1, 2008; 112(7): 2990 - 2995. [Abstract] [Full Text] [PDF]
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 C. Vitale, F. Cottalasso, E. Montaldo, L. Moretta, and M. C. Mingari Methylprednisolone induces preferential and rapid differentiation of CD34+ cord blood precursors toward NK cells Int. Immunol., April 1, 2008; 20(4): 565 - 575. [Abstract] [Full Text] [PDF]
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J. Shi, G. J. Tricot, T. K. Garg, P. A. Malaviarachchi, S. M. Szmania, R. E. Kellum, B. Storrie, A. Mulder, J. D. Shaughnessy Jr, B. Barlogie, et al. Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma Blood, February 1, 2008; 111(3): 1309 - 1317. [Abstract] [Full Text] [PDF]
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G. M. Spaggiari, A. Capobianco, H. Abdelrazik, F. Becchetti, M. C. Mingari, and L. Moretta Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2 Blood, February 1, 2008; 111(3): 1327 - 1333. [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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 J. Yu, G. Heller, J. Chewning, S. Kim, W. M. Yokoyama, and K. C. Hsu Hierarchy of the Human Natural Killer Cell Response Is Determined by Class and Quantity of Inhibitory Receptors for Self-HLA-B and HLA-C Ligands J. Immunol., November 1, 2007; 179(9): 5977 - 5989. [Abstract] [Full Text] [PDF]
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TOP
ABSTRACT
INTRODUCTION
), and of the autologous donor's cells (
). E:T ratio = 10:1.
Shown are cytotoxicity assays with NK cell clones from four
representative recipients (see Table 
) were tested for their ability to
lyse pretransplant crypreserved leukemic cells from the same
individuals (
lymphocytes in mixed lymphocyte culture.
J Exp Med
168:2403, 1988