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Blood, Vol. 95 No. 11 (June 1), 2000:
pp. 3473-3477
IMMUNOBIOLOGY
Acquisition of intact allogeneic human leukocyte antigen
molecules by human dendritic cells
Vincenzo Russo,
Dan Zhou,
Claudia Sartirana,
Patrizia Rovere,
Antonello Villa,
Silvano Rossini,
Catia Traversari, and
Claudio Bordignon
From the HSR-Telethon Institute of Gene Therapy
(TIGET) and the Cancer Immunotherapy and Gene Therapy Program, H.S.
Raffaele Scientific Institute, Milan, Italy, and the Microscopy and
Image Analysis, HSR, and Faculty of Medicine, the University of Milan
Bicocca, Milan, Italy, and Gen Era S.P.A.
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Abstract |
In an attempt to transduce monocyte-derived dendritic cells (DCs) by
a retroviral vector coding for a cell surface marker, we were
confronted by the observation of high transfer of the surface molecule
in the absence of vector proviral DNA in the treated cells. Indeed, DCs
acquired the surface marker by a mechanism independent of the vector
machinery, requiring cell-to-cell contact and involving transfer of
lipids and a variety of intact membrane proteins. Most important, this
property of DCs also includes acquisition of foreign human leukocyte
antigen (HLA) molecules. Consequently, DCs become immunological hybrids
as they display their own and foreign HLA molecules. The newly acquired
HLA is fully functional because it allows recognition by allo-specific
T lymphocytes and the binding and presentation of antigen peptides.
(Blood. 2000;95:3473-3477)
© 2000 by The American Society of Hematology.
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Introduction |
Dendritic cells (DCs) are central players in the immune
system. They present autologous antigens (Ags) during
T-cell development and foreign Ags during the induction of immune
responses.1 To stimulate an efficient T-cell response, DCs
located in the majority of tissues capture and process Ags
displaying major histocompatability complex-peptide (MHC-peptide)
complexes at their surface with high efficiency. This process allows
maturation of DCs2 that up-regulate costimulatory molecules
and migrate to lymphoid organs,3,4 where they
activate Ag-specific T cells.
All these properties suggest the potential role of DCs as an adjuvant
in immune approaches to cancer treatment. Indeed, in the last few years
great attention has been given to the role of DCs in inducing an
effective and long-lasting antitumor immunity in various murine tumor
systems.5 This has been obtained by pulsing DCs with both
synthetic and natural peptides6-8 or by genetically
engineering DCs for constitutive expression of a given antigen.9,10 The relevance of these preclinical experiments to the treatment of human cancer has been recently
confirmed.11,12
In addition to immune stimulation, DCs play a central role in the
induction of T-cell tolerance to autologous Ags. In the thymic medulla,
bone marrow-derived DCs present autologous Ags in the context of
autologous MHC molecules, thereby allowing deletion of high-affinity
autoreactive T cells by negative selection. Recently, an important role
for DCs in the induction of peripheral tolerance has been
suggested.13 Host antigen presenting cells
(APCs) acquire Ags in a form that is able to gain access to MHC class I
and II molecules. This process, which is fundamental for the induction of both immunity and tolerance, is referred to as
cross-presentation14,15 and can be facilitated by apoptotic
cell death of the Ag-expressing cells.16
A different mechanism involving direct cell-to-cell transfer of
self-determinants has been hypothesized for endogenous super Ags and
peptide fragments of self-proteins.17 Here, we provide evidence for a new property of monocyte-derived DCs that allows DC
acquisition of intact foreign human leukocyte antigen (HLA) molecules.
This phenomenon requires cell-to-cell contact and involves transfer of
membrane lipids and a variety of surface molecules.
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Materials and methods |
Cell lines and antibodies
DET-mel and MZ2-G43 are melanoma lines expressing HLA-A2
and HLA-DR*0101 respectively. MSR3-B52 was derived by transfection of
the MSR3-mel tumor line18 with HLA-B52 (Bw4). The
vector-producing line SFCMM2 has been previously
described.19 The 3T3- LNGFr was derived
by transduction of NIH/3T3 cells with the SFCMM2 vector. The cell lines
were maintained in Roswell Park Memorial Institute medium (RPMI 1640)
supplemented with 10% fetal calf serum (FCS). Monoclonal antibodies
(mAbs) used in the study included mAb 20.4 (HB8737; American Type
Culture Collection, Rockville, MD), which recognizes a truncated form
of the low-affinity nerve growth factor receptor (LNGFr);
anti-HLA-DR, anti-CD3, and anti-CD1a (Becton Dickinson,
Mountain View, CA); anti-CD83 (Immunotech, Marseilles, France);
HLA-A2/A28-specific 4B and 2A.1 (anti-Bw4) mAbs (Dr Soo Young Yang,
Memorial Sloan Kettering Cancer Center, New York, NY);
and HLA-DR*0101-specific mAb (gift from Dr G. B. Ferrara, Advanced
Biotechnology Center, Genoa, Italy).
We performed phenotypic analyses using either mAbs
directly labeled with phycoerythrin/fluorescein isothiocyanate
(PE/FITC) or uncoupled mAb revealed by antimouse immunoglobulin
(Southern Biotechnology Associates, Birmingham, AL) conjugated by PE,
FITC, Texas red, or Cyanin-5. Negative controls were performed by
staining with unrelated murine mAbs. Fluorescence analysis was
determined by a fluorescence-activated cell sorter (FACS) (Coulter
Elite; Coulter Electronics, Miami, FL), and 5000 to 10 000 events were collected for each staining.
Retroviral vector-mediated transduction of
monocyte-derived DCs
Peripheral blood mononuclear cells (5-6 × 107
cells) were allowed to adhere 1 hour at 37°C. The adherent cells
were then cultured in RPMI 1640 with 10% FCS supplemented with 10 ng/mL lipopolysaccharide (LPS); 800 U/mL
granulocyte-macrophage colony-stimulating factor (GM-CSF)
(Schering-Plough, Innishannon, County Cork, Ireland); 100 U/mL
interleukin-4 (IL-4) (gift from Dr P. Coulie, Ludwig Institute for
Cancer Research, Brussels, Belgium); 2 mmol/L L-glutamine; and 50 mmol/L 2 -ME. At day 2 of culture, differentiating DCs were
transduced by cocultivation with a monolayer of irradiated (100 Gy)
vector-producing cells in the presence of 4µg/mL
polybrene. The vector-encoded surface marker was the
LNGFr.19 After 72 hours, DCs were harvested and seeded
in fresh medium. DCs were analyzed 48 hours later for LNGFr
expression by flow cytometry with the specific mAb 20.4.
Transfer of cell surface molecules to DCs
DCs at day 5 of culture (CD14 , CD1a+ with 40%-80% CD83
expression) were seeded on a monolayer of nonirradiated donor cells (ie, 3T3-LNGFr or human melanoma cells) or cocultured with
phytohemagglutinin-activated (PHA-activated)
lymphocytes at a 2:1 (DC:lymphocyte) ratio. DCs were harvested 20 hours
later and stained for the transferred molecule using appropriate mAbs.
Confocal microscopy experiments were performed as above, seeding DCs on
adherent donor cells grown on poly-L-lysine-coated glass. After 20 hours of cocultivation, cells were fixed in cold ethanol for 1 minute, permeabilized in PBS/0.05% saponin/0.02% BSA
and incubated with FITC-labeled primary mAbs. Indirect staining was
performed by incubation with different primary mAbs, followed by
isotype Texas red- or FITC-labeled secondary mAbs. The
analysis was performed with a confocal laser scanning
microscope system (MRC-1024; BioRad Laboratories, Hercules,
CA) attached to a microscope (Axioplan; Carl Zeiss, Inc,
Thornwood, NY) equipped with a krypton/argon laser. Appropriate
controls were always included.
Transfer of plasma membrane lipids to DCs
3T3-LNGFr cells were labeled according to manufacturer's
protocol with the membrane red dye PKH26 (Sigma, St Louis, MO). The
labeled cells were cocultured with DCs for 20 hours as described above,
and further processed for confocal analysis using an HLA-DR-FITC mAb
and a Cy-5-labeled secondary mAb to detect LNGFr expression. In
Figure 1C, the Cy-5-labeled secondary mAb
is shown as a light blue color.
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| Fig 1.
DC acquisition of intact cell surface molecules displayed
on the plasma membrane of donor cells.
(A) DC acquisition of the cell surface marker LNGFr is
vector-independent. Monocyte-derived DCs were differentiated and
cocultured with (b) vector-producing cells19 or with (c)
the 3T3-LNGFr cell line expressing the LNGFr on its cell surface,
but unable to produce any vector particle. Transduction efficiency was
evaluated by immunofluorescence for the expression of the cell surface
marker LNGFr encoded by the retroviral vector. LNGFr expression
on (a) untreated and (b, c) treated DC populations is shown. (B) DC
acquisition of the LNGFr cell surface marker appears to require a
cell-to-cell interaction. DCs were cultured on glass cover slips on a
monolayer of nonirradiated 3T3-LNGFr. Cocultures were processed for
immunofluorescence and confocal microscopy 20 hours later. HLA-DR
molecules expressed by DCs were visualized using an HLA-DR-FITC mAb and
displayed as green staining. LNGFr surface marker was visualized by
the 20.4 specific primary mAb followed by a Texas red-conjugated
second antibody and displayed as red staining. Optically merged
confocal images showed the colocalization, displayed as yellow
staining, of the HLA-DR marker with LNGFr. The dependence of the
LNGFr transfer by intercellular contact between cell membranes of
DCs and donor cells is suggested by the observation that positive DCs
were always in close contact with donor cells, while negative DCs were
distant (arrow). (C) DC acquisition of LNGFr cell surface marker is
associated with the transfer of plasma membrane lipids. DCs were
exposed to 3T3-LNGFr cells previously labeled with PKH26, a stable
membrane-soluble red dye that does not exchange spontaneously between
membranes for prolonged periods. Cocultures were processed, 20 hours
later, for immunofluorescence and confocal microscopy by using an
HLA-DR-FITC mAb and a Cy-5-labeled secondary mAb to detect LNGFr
expression. The Cy-5-labeled secondary mAb is shown as a light blue
color. All DCs that acquired the cell surface marker from
LNGFr-expressing cells (arrows) also became positive for the PKH26
red dye. (D) Cell surface distribution of the acquired LNGFr
molecules. Cocultures of DCs and 3T3-LNGFr cells were analyzed by
double immunolabeling for LNGFr and HLA-DR expression. LNGFr
molecules (5-nm gold particles) are interspersed between HLA-DR
molecules (15-nm gold particles) on the cell surface of DCs.
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Electron microscopy analysis
DCs were cocultured with 3T3-LNGFr cells as described above and
further processed for electron microscopy analysis. The cells were
incubated at 4°C for 1 hour with anti-LNGFr and biotinylated HLA-DR-specific mAbs. After extensive washing, cells were incubated with 5-nm gold particle conjugated antimouse immunoglobulin G (IgG) and
15-nm gold particle conjugated antibiotin mAbs for 1 hour. After the
incubation, cells were washed, fixed in 2% glutaraldehyde, and then
harvested by scratching and centrifugation. The pellet was washed with
0.1 mol/L cacodylate buffer, postfixed with 2% osmium tetroxide
(OsO4), dehydrated, and embedded in Epon.
Ultrathin sections were stained with uranyl acetate and lead citrate
and examined in a Hitachi H7000 electron microscope (Hitachi, Japan).
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Results |
Transfer of vector-encoded surface marker into monocyte-derived DCs
To improve the current technology of retroviral vector-mediated
gene transfer9,20 into human monocyte-derived
DCs,21,22 we were confronted by the evident dissociation
between transfer of the vector-encoded surface marker,
LNGFr,19 and the absence of integrated viral genome into
the treated cells. In several independent experiments, upon
cocultivation with irradiated vector-producing cells, a high proportion
of DCs (50%-90%) expressed the LNGFr surface marker (Figure 1A).
However, the apparent high efficiency of gene transfer was in sharp
contrast to the inherited inefficiency of retroviral vectors in
transducing nondividing cells such as monocyte-derived
DCs.23 This discrepancy was confirmed by the failure to
detect any significant levels of integrated proviral vector into the
LNGFr-positive population of DCs (data not shown). Further
experiments clearly demonstrated that the mechanism involved in the
acquisition of the cell surface marker is independent of the retroviral
vector machinery.
DC acquisition of the cell surface marker
To demonstrate that DCs acquire the LNGFr surface molecules, even
in the absence of retroviral particles, we performed
coculture experiments using as donor cells the 3T3-LNGFr cell line,
which express the LNGFr on the cell surface but is unable to produce any vector particles. Indeed, nonirradiated 3T3-LNGFr cells were able to transfer the cell surface marker to DCs at frequencies similar
to those observed by the use of vector-producing cell lines (Figure
1A). These observations suggest that acquisition of the cell surface
marker by DCs is dependent upon membrane contact and transfer. Indeed,
serial confocal microscopy analysis showed that only DCs in close and
direct contact with the LNGFr-expressing cells acquire and display
the cell surface marker (Figure 1B).
To understand whether the surface marker acquisition by DCs was
associated with membrane transfer, DCs were exposed to
LNGFr-expressing cells previously labeled with the lipophilic red
dye PKH26. As shown in Figure 1C, all DCs that acquired the cell
surface marker from LNGFr-expressing cells (arrows) also became
positive for PKH26 red dye, demonstrating that LNGFr is acquired by
DCs as a component of the cell surface membrane. Moreover, exposure of DCs to culture supernatant of PKH26-labeled cells did not allow red dye
transfer, thus excluding the presence of an artifact due to dye leakage
in the medium (data not shown).
Once the exogenous plasma membranes were acquired by DCs, remodeling
and redistribution of the transmembrane proteins occurred, as
demonstrated by electron microscopy analysis (Figure 1D). This analysis
showed the acquired LNGFr molecules (5-nm gold particles) interspersed within the endogenous HLA-DR molecules (15-nm gold particles).
DC acquisition of foreign HLA molecules
To define whether the observed acquisition of cell surface molecules
is part of a more general property of DCs and whether this acquisition
may play a role in cross-presentation to immune effectors,
we investigated whether HLA molecules were involved in
this intercellular transfer. DCs obtained from an HLA-A2-negative individual were exposed to human melanoma cells expressing HLA-A2 (Figure 2A, right panel) or not expressing
HLA-A2 (Figure 2A, left panel). Following coculture, DCs were analyzed
by flow cytometry for CD83 and HLA-A2 expression and were found to have
acquired HLA-A2 molecules (Figure 2A). The amount of foreign HLA
molecules acquired by DCs was about 2 logs lower, in terms of
fluorescence intensity, compared with that naturally expressed by
HLA-A2 DCs and DET-mel melanoma cells (gated in Figure 2A, upper-left
quadrant).
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| Fig 2.
DC acquisition of allogeneic HLA class I molecules.
DCs from (A) HLA-A2-negative or (B) HLA-DR*0101-negative individuals
were cultivated on a monolayer of nonirradiated melanoma cells
expressing the HLA-A2 or the HLA-DR*0101 allele,
respectively (right panels). As a control, DCs were cocultured with
HLA-unrelated melanoma cells (left panels). After 20 hours of
cocultivation, the expression of the allogeneic HLA molecules on the
cell surface of DC populations was analyzed by flow cytometry using
mAbs specific for CD83 and (A) HLA-A2 or (B) DR0101 molecules.
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Similar results were reproduced for HLA class II molecules (Figure 2B)
by using a melanoma expressing HLA-DR*0101 (Figure 2B, right panel) as
donor cells. The efficiency of transfer seems to be higher for HLA
class I molecules compared with HLA class II. This could be related to
the molecular structure of the 2 HLA molecules or to their
concentration on donor cells. Indeed, transfer of
LNGFr molecules from highly expressing cells consistently allowed
high levels of transfer to DCs, while lower levels of transfer were
achieved using donor cells expressing intermediate amounts of LNGFr
(data not shown). However, the low efficiency of the class II transfer
could be in part dependent on a different sensitivity of the detection
system used (eg, different affinities of the 2 mAbs for their ligands).
Acquisition of the foreign HLA molecules is independent of the
maturation stage of the DC population because CD83+ and
CD83 DCs acquire HLA-A2 with the same efficiency (Figure 2).
CD83 is a surface marker specific for mature DCs expressed by 40%-80% of DCs at day 5 in our culture system. Dependence of the HLA transfer upon intercellular contact between cell membranes of DCs and donor cells was further confirmed by the confocal analysis. Transfer of
HLA-Bw4+ melanoma cells to DCs occurs in a 1-way direction, starting
from the point of contact and progressively diffusing to the entire DC
surface (Figure 3; highlighted, arrow in
lower panel). Transfer in the opposite direction (from DCs to tumor cells) never occurred.
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| Fig 3.
DC acquisition of HLA-Bw4 molecules.
DCs were cultured on glass cover slips on a monolayer
of nonirradiated melanoma cells. The cocultures were processed for
immunofluorescence and confocal microscopy 20 hours later. (A,
B) HLA-DR molecules expressed by DCs were visualized using an
HLA-DR-FITC mAb and displayed as green staining. (A, B) HLA-Bw4
molecules were visualized by specific primary mAbs followed by a Texas
red-conjugated second antibody and displayed as red staining. (A, B)
Optically merged confocal images showed the colocalization, displayed
as yellow staining, of the HLA-DR marker with HLA-Bw4 molecules on the
cell surface of DCs. The transfer of cell membrane molecules starts
from the point of contact between DCs and melanoma cells (B, indicated
by arrows).
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To evaluate the existence of such phenomenon in DC interaction with
nontumor cells, we analyzed the ability of DCs to acquire HLA molecules
from activated human T lymphocytes. The experiment was performed under
the conditions already described, using PHA-activated lymphocytes grown
in the presence of IL-2 as donor cells. Upon coculture, the mixture of
the 2 populations was analyzed with flow cytometry by gating the DC
population and using either CD83 or CD1a, which are not expressed by
activated T lymphocytes, as specific markers. Only DCs cocultured with
HLA-A2-expressing lymphocytes were found to have acquired HLA-A2
molecules (Figure 4, right panels).
Contaminating T cells, expressing high levels of HLA-A2, are shown in
the upper-left quadrants of Figure 4. Even in this system, transfer of
surface HLA class I molecules is independent of the maturation stage of
DCs.
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| Fig 4.
DC acquisition of allogeneic HLA class I from activated
human lymphocytes.
DCs from an HLA-A2-negative individual were cocultivated with
PHA-activated human lymphocytes expressing the HLA-A2 allele (right
panels). As a control, DCs were cocultured with HLA-unrelated
lymphocytes (left panels). After 20 hours, the expression of the
allogeneic HLA molecules on the cell surface of the DC populations was
analyzed by flow cytometry using mAbs specific for HLA-A2 and CD83
(upper panels) or CD1a (lower panels).
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Acquired foreign HLA molecules are targets of a specific T-cell
response
To confirm that foreign HLA class I molecules acquired by DCs are
fully functional, hybrid DCs, displaying both their own molecules and
the foreign HLA-A2 molecules, were used as targets in a cytotoxic
assay. HLA-A2-specific cytotoxic T cells killed DCs exposed to an
HLA-A2-positive melanoma line, while DCs untreated or cocultured with
HLA-A2-negative melanoma were not recognized (Figure
5). Analogous results were obtained by
loading A*6801-hybrid-DCs with an exogenous peptide
(TRP-2-INT2.222-231)24 and using a peptide-specific T-cell clone as an effector (data not shown). These
results strongly suggest that cell surface molecules are acquired by
DCs as intact proteins properly integrated into the cell membrane
rather than as proteolyzed fragments released by the donor cells and
bound by nonspecific or receptor-mediated mechanisms. This hypothesis
is further supported by the inability of culture supernatant from
LNGFr and HLA expressing cells to transfer the relevant surface
molecule (data not shown). Additionally, the half-life of the
transferred molecules was monitored to be in the same range as that
reported for endogenous HLA class I (ie, 10-20 hours).25 We
observed that after 24 hours, only 20% of the acquired HLA-A2
molecules were expressed on the DC cell surface, while 70% of LNGFr
molecules were still present.
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| Fig 5.
T-cell recognition of foreign HLA class I molecules
displayed by DCs.
DCs from an HLA-A2-negative individual were cultivated on a monolayer
of nonirradiated melanoma cells expressing the HLA-A2 allele ( ). As
a control, DCs were either untreated ( ) or cocultured with an
HLA-unrelated melanoma cell line ( ). After 20 hours, DCs were
harvested, purified from the potential melanoma contamination by CD45RO
microbead separation, and used as targets in a standard chromium
release assay. Only DCs exposed to the HLA-A2 melanoma are recognized
by anti-HLA-A2 cytotoxic T-cell effectors. Recognition of the
HLA-A2-positive melanoma cells is shown ( ).
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Discussion |
Our studies provide evidence of a new mechanism involving
intercellular transfer of intact proteins to DCs. The ability to acquire surface proteins by direct cell-to-cell contact is a unique feature of DCs. Other cell lines of hematopoietic origin (ie, CD8-activated T lymphocytes and Epstein-Barr virus-induced
(EBV-induced) lymphoblastoid cell lines) did not show this property
(data not shown). Acquisition of intact surface proteins by CD4+
lymphocytes has been recently described to occur in an in vitro
transendothelial migration model,26 and it has been
strongly correlated to the activation stage of the lymphocytic population.
Several lines of evidence obtained in this study suggest that the
acquisition of the surface molecules is mediated by a close interaction
between DCs and donor cells. In addition, this phenomenon seems not to
be the consequence of the classical pathway of phagocytosis of vesicles
or apoptotic bodies and recycling to the plasma membrane. First, the
cell surface molecules are transferred to DCs with the same efficiency
by both apoptotic and nonapoptotic donor cells (data not shown) and are
also acquired in the presence of the saturating concentration of
D-mannose (data not shown), suggesting that mannose receptor-mediated
endocytosis27 is not involved in the phenomenon. Moreover,
we never observed localization of the surface molecules within any
intracellular compartment (Figure 1B, 1C, and Figure 3). Additionally,
DCs exposed to culture supernatant of LNGFr expressing cells do not
acquire the surface marker (data not shown). Altogether these
observations suggest that if ectocytosis28 by donor cells
and up-take by DCs play a role in the transfer of surface molecules,
this process may occur locally in the context of a close DC-donor cell interaction.
We could speculate that DCs at certain stages of differentiation may
allow cell fusion with transfer of plasma membrane components by the
use of fusogenic proteins, as described to occur
during viral infection.29 The DCs may also induce locally
triggered shedding of membrane vesicles from the tissues they interact
with during their trafficking.
We believe that this mechanism, if confirmed in vivo, may provide an
additional pathway of cross-presentation that is also active in the
absence of tissue damage and apoptosis. Indeed, acquisition of
preformed MHC-peptide complexes from normal tissues and neoplastic
cells may allow efficacious cross-presentation by DCs in the absence of
inflammation and other signals of tissue damage. A unique feature of
this phenomenon may be occurring during allogeneic organ
transplantation. Here, DCs from the recipient could seed the
transplanted organ, up-take and display the intact HLA of the donor,
thus representing a continuous source of foreign HLA presentation.
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Acknowledgments |
We thank M.G. Roncarolo, A. Manfredi, and P. Panina for useful discussions.
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Footnotes |
Supported in part by grants from the Italian
Association for Cancer Research, Milan, Italy, and the Ministry of
Health (RF 98.51), Italy.
Submitted September 23, 1999; accepted January 28, 2000.
Reprints: Claudio Bordignon, TIGET, Istituto Scientifico H.S.
Raffaele, via Olgettina 58, 20132 Milano, Italy; e-mail: claudio.bordignon{at}hsr.it.
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.
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Abstract
Introduction