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Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3225-3232
Chemotactic Response Toward Chemokines and Its Regulation by
Transforming Growth Factor- 1 of Murine Bone Marrow Hematopoietic
Progenitor Cell-Derived Different Subset of Dendritic Cells
By
Masafumi Ogata,
Yi Zhang,
Yong Wang,
Meiji Itakura,
Yan-yun Zhang,
Akihisa Harada,
Shin-ichi Hashimoto, and
Kouji Matsushima
From the Department of Molecular Preventive Medicine and CREST,
School of Medicine, The University of Tokyo, Tokyo, Japan; and the
Department of Ophthalmology, Faculty of Medicine, Kanazawa University,
Kanazawa, Japan.
 |
ABSTRACT |
Dendritic cells (DCs) are highly specialized antigen-presenting
cells that distribute widely in all organs. DCs initiate the primary
immune response and activate naive T cells and B cells responsible for
the acquired immunity. In this study, CCR7 mRNA was proved to be
expressed in DCs and their precursors derived from murine bone
marrow-derived hematopoietic progenitor cells (HPCs), whereas CCR1 mRNA
was expressed in both CD11b /dullCD11c+ and
CD11b+hiCD11c+ DC precursors. CCR6 mRNA was
not detected in any murine DC populations. In agreement with the
chemokine receptor mRNA expression by each population in the DC
differentiation pathway, SLC (also termed as MIP-3 ), one of the
ligands for CCR7, strongly and selectively chemoattracted both
CD11b/dullCD11c+ and
CD11b+hiCD11c+ DC precursors (days 6 to 7)
and more mature DCs (days 13 to 14). We have recently found that
transforming growth factor-1 (TGF-1), a cytokine that is
essential for the appearance of Langerhans cells in the skin, polarizes
murine HPCs to generate Langerhans-like cells through
monocyte/macrophage differentiation pathway. We observed here that
TGF-1 not only inhibited the expression of CCR7 in DCs and DC
precursors derived from HPCs, but also inhibited the migration of these
cells in response to SLC. This is the first report describing the
chemokine and chemokine receptors responsible for murine DC migration
and downregulation of DC migration by TGF-1.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
DENDRITIC CELLS (DCs) are characterized
by their unique ability to take up, process, and present antigens to T
lymphocytes, which control the primary immune response. A variety of
DCs with distinct differences in phenotypes and functions are widely
distributed in peripheral blood, skin, lymphoid organs, liver, mucoid
organs, and various other tissues. This suggests that the origin and
development of DCs might be diverse.1,2
Accumulating evidence suggests that DCs can be generated in vitro when
human blood monocytes, human CD34+, and murine
Linc-kit+ hematopoietic progenitor cells
(HPCs) are cultured with appropriate combinations of
cytokines.3-6 According to our previous
study,6,7 murine Linc-kit+
HPCs differentiated in response to granulocyte-macrophage
colony-stimulating factor (GM-CSF) + stem cell factor (SCF) + tumor
necrosis factor- (TNF-) into two distinct DC precursors with the
immunophenotype of CD11b/dullCD11c+ and
CD11b+hiCD11c+ at days 4 to 6. These two
populations could differentiate into CD11b/dullCD11c+ mature DCs at days 10 to 14 with the characteristic phenotype.7 On the other
hand, transforming growth factor-1 (TGF-1) differentiated these
bone marrow-derived HPCs to generate Langerhans cell-like DCs with high
expression of E-cadherin through macrophage differentiation pathway8,9 (Fig 1). During
development and maturation of DCs, bone marrow-derived progenitors of
DCs are destined to distribute to the nonlymphoid tissues, where they
acquire the considerable ability to capture antigens. After inciting
stimuli that activate the host defense system, DCs at the immature
stage will be mobilized from the periphery to T-cell area of the
regional lymph nodes or spleen to present antigens to naive T
cells.10,11
The molecular mechanism accounting for leukocyte trafficking is imposed
upon seven transmembrane-spanning G-protein-coupled receptors and
their ligands.12 Chemokines, a rapid expanding family of 8 to 10 kD, and heparin-binding proteins are the most likely candidates
to regulate the migration of DCs. Monocyte chemoattractant protein-1
(MCP-1), MCP-2, MCP-3, macrophage inflammatory
protein-1 (MIP-1), MIP-1, and RANTES have been
shown to induce migration of human CD34+ umbilical
vein-derived DCs.13 fMLP, C5a, MCP-3, MIP-1,
RANTES,14 and macrophage-derived chemokine
(MDC)13 have also been shown to
chemoattract human peripheral blood mononuclear cells (PBMC)- or
monocyte-derived DCs that express chemokine receptors, such as CXCR1,
CXCR2, CXCR4, CCR1, CCR2, and CCR5.14 Recently, Dieu et
al15 have reported that CCR7 mRNA expression was
upregulated in human CD34+ cord blood-derived DC during
maturation, whereas CCR6 mRNA expression was concomitantly
downregulated. But, in human studies, the HPC for DCs has not yet been
precisely identified, or the differentiation pathway of DCs has not yet
been explored in detail. In this study, we have investigated not only
the expression pattern of chemokine receptors by murine DCs, but also
the migration capacity of DCs in the three differentiation pathways.
Furthermore, we also studied the effect of TGF-1 on the expression
of chemokine receptors and on the migration of DCs and their precursors
in vitro.
| |
MATERIALS AND METHODS |
Cytokines and antibodies.
Recombinant murine SCF and GM-CSF were kindly provided by Kirin Brewery
Co (Tokyo, Japan) and Dr T. Sudo (Basic Research Institute of Toray Co,
Kanagawa, Japan), respectively. Morinaga Milk Industry Cooperation
(Kanagawa, Japan) kindly provided macrophage colony-stimulating factor
(M-CSF). Mouse TNF- was produced as described
previously.16 Endotoxin was not detected in these cytokine
preparations using a Toxicolor assay kit (Seikagaku-Kogyo, Tokyo,
Japan). These cytokines were used at the optimal concentrations as
previously described.6 An anti-c-kit antibody (ACK-2) was
kindly provided by Dr Sudo and conjugated with biotin by using a
NHS-biotin kit (Amersham Pharmacia Biotech, Uppsala, Sweden) according
to the manufacturer's instructions.17 A rat monoclonal
antibody (MoAb) to murine DC marker, DEC-205 (NLDC145), was a generous
gift of Dr R.M. Steinman (Rockefeller University, New York,
NY).18,19 MoAb to mouse E-cadherin was purchased from
Dainippon Pharmaceutical Co (Osaka, Japan). Other MoAbs and reagents
used for immunostaining were obtained from PharMingen (SanDiego, CA),
unless otherwise indicated.
For migration assay, MIP-1, MIP-1, MCP-3 and TGF-1 were
purchased from R&D Systems Inc (Minneapolis, MN). RANTES was obtained from PeproTech Inc (Rocky Hill, NJ). Recombinant SLC was prepared as
follows. An expression vector pSCFV-1 (a generous gift from Chugai
Pharmaceutical Co, Tokyo, Japan) that contained a tryptophane promoter
and a leader sequence of the bacterial pelB gene was chosen to express
murine SLC. Complementary DNA for SLC was kindly provided by T. Imai
(Shionogi Institute for Medical Science, Osaka, Japan) and cloned into
pSCFV-1 and used to transform Escherichia coli BL21. The
transformant was precultured in a 40-mL LB medium for 12 hours, and the culture fluid was centrifuged at 3,000g for
10 minutes. The pellet was then cultured in 200 mL modified M9 medium
for 4 hours at 30°C and cultured with 3-indole acrylic acid for 4 hours. The culture fluids were centrifuged at 3,000g for 10 minutes, and the pellet was washed with TES buffer (0.2 mol/L
Tris, 0.5 mmol/L EDTA, 0.5 mol/L sucrose, pH 8.0) and
subsequently washed again with 5 mmol/L
MgSO4.20 All of the supernatants during these
procedures were pooled and applied to heparin column (Hi-Trap, Heparin;
Amersham Pharmacia Biotech) equipped with GradiFrac system (Amersham
Pharmacia Biotech). The sample was eluted by a linear gradient of
sodium chloride in the range of 0 to 1 mol/L in 0.02 mol/L sodium
phosphate buffer (pH 7.0). The fractions containing murine
SLC were monitored by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (SDS-PAGE) analysis. The final product showed a single band on SDS-PAGE stained with Coomassie brilliant blue dye,
and its amino acid sequence of amino terminus was identical to the
mature murine SLC. The concentration was finally determined by BCA kit
(Pierce, Rockford, IL).
Mice.
C57BL/6 mice were obtained from Clea Animal Co (Tokyo, Japan) and
maintained under pathogen-free conditions in the Animal Facility of
Department of Molecular Preventive Medicine, School of Medicine, The
University of Tokyo (Tokyo, Japan). All animal experiments complied
with the standards set out in the Guidelines for Care and Use of
Laboratory Animals of The University of Tokyo.
Suspension culture of Linc-kit+
HPCs.
Bone marrow cells were obtained by aspirating femurs and tibiae of 8- to 10-week-old female mice. Linc-kit+
HPCs were isolated from nonadherent bone marrow mononuclear cells (MNCs) using an EPICS ELITE cell sorter (Coulter Electronics, Hialeah,
FL), as previously described.7,8 In brief, nonadherent MNCs
were stained with an indirect staining process consisting of
biotin-conjugated anti-c-kit MoAb and phycoerythrin (PE)-labeled streptavidin followed by a set of fluorescein isothiocyanate
(FITC)-labeled MoAbs to CD3 (145-2C11), CD4 (H129.19), CD8 (53-6.7),
B220 (RA3-6B2), Gr-1 (Ly-6G), CD11c (2D7), and CD11b (M1/70). The
contamination by other types of cells in these preparations was
consistently less than 0.5%, as shown by an immunofluorescence analysis.
Purified Linc-kit+ HPCs were prepared as
previously described.7,8 Briefly, purified HPCs were
incubated at 1 × 104 cells/mL in Iscove's modified
Dulbecco medium (IMDM; GIBCO, Rockville, MD) supplemented with 10%
fetal bovine serum (FBS), 5 × 105 mol/L
2-mercaptoethanol, penicillin G (100 U/mL), and streptomycin (100 µg/mL) in the presence of GM-CSF + SCF + TNF-. TGF-1 was added
in the cultures in various combinations, as indicated. Optimal conditions were maintained by splitting these cultures at day 4, and
the medium containing fresh cytokines was exchanged every 3 to 4 days.
In some experiments, CD11b/dullCD11c+
and CD11b+hiCD11c+ DC precursor subsets were
sorted at day 6 from Linc-kit+ HPCs
cultures stimulated with GM-CSF + SCF + TNF-, as previously described.7,8 In other experiments, TGF-1-treated
Linc-kit+ HPC cultures stimulated with
GM-CSF + SCF were collected at day 13, washed twice, and recultured in
the presence of GM-CSF + TNF- for an additional 3 to 5 days. All of
the staining and sorting procedures were performed in the presence of 1 mmol/L EDTA to avoid cell aggregation. Reanalysis of the sorted
populations showed purity greater than 98%.
Reverse transcription-polymerase chain reaction (RT-PCR).
Total RNAs were extracted from 2 × 105 indicated
cells using RNAzolB (Biotex Laboratories Inc, Houston, TX),
according to the manufacturer's instructions. First-strand cDNA was
synthesized at 37°C for 1 hour from 200 ng of total RNA in 25 µL
reaction volume using random primers (Promega, Madison, WI).
Thereafter, cDNA was amplified for 35 cycles consisting of 94°C for
45 seconds, 60°C for 45 seconds, and 72°C for 2 minutes, with a
pair of oligonucleotide primers corresponding to each chemokine
receptor. As control, mouse -actin transcript was amplified in
parallel, as previously described.7 The oligonucleotide
primers for chemokine receptors were as follows:
5'-GTGTTCATCATTGGAGTGGTG-3' and
5'-GGTTGAACAGGTAGATGCTGGTC-3' were designed for murine
CCR1, 5'-ACTCTTTGTCCTCACCCTACCG-3' and 5'-ATCCTGCAGCTCGTATTTCTTG-3' for murine CCR6, and
5'-CATCAGCATTGACCGCTACGT-3' and
5'-GGTACGGATGATAATGAGGTAGCA-3' for murine CCR7. The PCR
products were fractionated on 1.5% agarose gel or 5% polyacrylamide
gel and visualized either by ethidium bromide staining or Cyber Green staining.
Migration assay.
Cell migration was assessed using a 96-well chemotaxis chamber
(Neuroprobe, Pleasanton, CA) with polycarbonate filter (5-µm pore
size). Cell suspension (0.5 to 1.0 × 106/mL) was
incubated at 37°C for the indicated time. Based on the number
measured by Coulter counter, the migration efficiency was calculated by
dividing the number of the migrated cells into the lower chamber by
that of the initially loaded cells onto the upper chamber. Each
experiment was performed in triplicate.
Statistical analysis.
Differences were evaluated using the Student's t-test.
P values of less than .05 were considered to be statistically significant.
| |
RESULTS |
Expression of chemokine receptors on distinct DCs and DC precursors.
We have recently identified three distinct DC differentiation pathways
from murine bone marrow HPCs (Fig 1). These DCs and their
precursors could be classified based mostly on the expression pattern
of CD11b and CD11c.6,7 To identify the chemokines responsible for the migration of DCs, we first examined the expression of chemokine receptor mRNA in the subpopulations derived from murine
Linc-kit+ HPCs. Using RT-PCR, the
expression of CCR1 mRNA was shown to be expressed in
CD11b/dullCD11c+ and
CD11b+hiCD11c+ precursors of DC (days 6 to 7)
and was not detected in either mature DCs derived from
CD11b/dullCD11c+ or
CD11b+hiCD11c+ DC precursors. To negate the
possibility that PCR products of chemokine receptors were attributable
to the misamplification from genomic DNA as template instead of mRNA,
the expression of a housekeeping gene, -actin, was visualized
exclusively with reverse transcription performed before PCR. In
addition, CCR7 mRNA was detected specifically in both
CD11b/dullCD11c+ and
CD11b+hiCD11c+ DC precursors and all types of
mature DCs, including TGF-1-induced macrophage-derived ones,
whereas CCR6 mRNA was not detected at all in any populations
(Fig 2). All of other chemokine receptor mRNAs tested, including CCR2, CCR3, CCR5, CXCR2, CXCR3, and CXCR5, were
not detected by RT-PCR in any population.
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| Fig 2.
Differential chemokine receptor expression on DCs and
their precursors derived from murine HPCs. Levels of mRNAs in every
stage of the differentiation pathway demonstrated in Fig 1 were
assessed by RT-PCR. For the positive control, genomic DNA extracted
from murine tail was used as the template. PCR product not preceded by
reverse transcription to exclude the amplification from genomic DNA was
also shown. The results represent three independent experiments.
|
|
Identification of chemokines for DCs and DC precursors.
To explore which chemokine receptors are playing a fundamental role in
DC migration, we evaluated the migration capacity of DCs and their
precursors in response to several corresponding chemokines. The
responsiveness to MIP-1 was rather limited to the
CD11b/dullCD11c+ DC precursors (10.8% ± 1.3%, n = 3; Fig 3), and
this was no longer active on mature DCs
(Fig 4A). Either MIP-1 or
RANTES was ineffective on any population of DCs (Figs 3 and 4A and B).
Comparing distinct populations with each other, a larger number of
CD11b/dullCD11c+-derived DCs or their
precursors were chemoattracted by SLC than were
CD11b+hiCD11c+-derived DCs or their precursors.
CD11b/dullCD11c+ precursors acquired
higher capacity to migrate in response to SLC in the course of
maturation, whereas CD11b+hiCD11c+ DC
precursors behaved similarly (Fig 4A and B). However, M-CSF-induced macrophages derived from CD11b+hiCD11c+ did not
show any chemotactic response toward SLC because they were lacking in
expression of CCR7 (data not shown).
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| Fig 3.
The effect of the various chemokines on the migration of
CD11b/dullCD11c+ and
CD11b+hiCD11c+ DC precursors. Optimal
concentrations of chemokines (100 ng/mL), TNF- (10 ng/mL), and
fMLP (107 mol/L) were tested as the ligand for
chemotaxis. ( ) CD11b/dullCD11c+ DC
precursors; ( ) CD11b+hiCD11c+ DC
precursors. The data represent the mean value ± SD of percentage. The
results are representative of more than three experiments.
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| Fig 4.
The comparison of the migration toward several chemokines
between () precursor and () mature DC in (A)
CD11b/dullCD11c+ and in (B)
CD11b+hiCD11c+ populations. The data
represent the mean value ± SD of percentage. The results are
representative of more than three experiments.
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Inhibition of CCR7 expression by TGF-1 on the
cytokine-stimulated HPCs.
The differentiating effect of TGF-1 on macrophages into
Langerhans-type cells has been described.8,9 We
investigated here whether TGF-1 affects the expression of chemokine
receptors in vitro. GM-CSF+SCF- and GM-CSF+SCF+TNF--stimulated
HPCs at days 6 to 7 expressed CCR1 and CCR7
(Fig 5), consistent with the results
described in Fig 2. Surprisingly, CCR7 induction was inhibited by the
addition of TGF-1 to cytokine-stimulated HPCs during the first 6 to
7 days, although CCR1 expression was not affected by TGF-1.
Downregulation of CCR7 expression by TGF-1 was no longer seen at
days 13 to 14 once TNF- was added to the culture.
Inhibition of chemotactic response of DCs and DC precursors to SLC by
TGF-1.
SLC attracted CD11c+ DC precursors in GM-CSF+SCF- and
GM-CSF+SCF+TNF--stimulated HPCs at days 6 to 7 (25.36% ± 2.87% and 35.27 ± 0.61%, respectively), on which no other
chemokines such as MIP-1 or MIP-1 could efficiently act
(Table 1 and
Fig 6A).
However, selective migration by SLC was no longer observed in the
presence of TGF-1, as shown in flow cytometric analysis (Fig 6A).
TGF-1-induced macrophages at day 13 responded weakly to SLC
compared with cell population (day 13) derived from GM-CSF + SCF alone,
analogous to the other chemokines (Fig 6B). However, mature DCs derived from TGF-1-induced macrophages completely restored the
responsiveness to SLC (Fig 6C) but lost the responsiveness to other
chemokines.
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|
Table 1.
Comparison of the Migration Efficiency (Mean
Value ± SD) in Response to Chemokines Between Combined
Cytokine-Induced DC Precursors (Day 6)
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| Fig 6.
Selective chemoattraction of DC precursors derived from
murine HPCs by SLC and its regulation by TGF-1. (A) Selective
migration of DC precursors from GM-CSF+SCF- and
GM-CSF+SCF+TNF--stimulated HPCs was abrogated by TGF-1. The
profiles in the uppermost row indicate the preloaded populations, and
those in the rest of the rows indicate the population in the lower
chamber after migration assay. (B) TGF-1-induced macrophages (at
day 13; ) were less sensitive to SLC than HPC stimulated with
GM-CSF+SCF (). (C) LC-like mature DCs successively generated with
GM-CSF+TNF- from TGF-1-induced macrophages (at day 13)
exhibited high selective migration toward SLC. The values in (B) and
(C) represent the mean value ± SD of percentage. The results are
representative of more than three experiments.
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| |
DISCUSSION |
We have recently established a culture system to generate DCs through
three distinct precursors from murine HPC (Fig 1). Either CD11b/dullCD11c+ or
CD11b+hiCD11c+ DC precursor, which appears 6 to
7 days after stimulation with GM-CSF + SCF + TNF-, becomes
phenotypically distinct mature DCs. TGF-1-induced macrophages (day
13) also differentiate into mature DCs, which resemble Langerhans cells
expressing high levels of Ia, CD86, DEC-205, CD40, and E-cadherin,
within another 5 days by culturing with GM-CSF + TNF-.7
We speculated that DCs from bone marrow might migrate to distinct
organs, due to different expression of chemokine receptors and their
responsiveness to chemokines destined by their ontogeny and
differentiation pathway. CD11b/dullCD11c+ DC precursors seemed to
be attracted by SLC more efficiently than
CD11b+hiCD11c+ precursors. The migration
capacity might decrease as
CD11b/dullCD11c+ DC precursors acquire
the characteristics of macrophages, represented by the expression of
markers such as CD11b and c-fms. In this context, M-CSF-induced
macrophages derived from CD11b+hi CD11c+
precursors never migrated toward SLC.
The expression of CCR7 on human DCs was induced during the maturation
elicited by various stimuli, eg, CD40L, lipopolysaccharide (LPS),
interleukin-1 (IL-1), and TNF-.15,21 Although we could not observe the difference in the expression of CCR7 mRNA between murine DCs and their precursors, the responsiveness to SLC, a ligand
for CCR7, increased as CD11b/dullCD11c+
and CD11b+hiCD11c+DC precursors became mature
DCs. Furthermore, SLC had chemotactic activity for both DCs and their
precursors. Surprisingly, CCR6, one of the candidates mediating the
chemotaxis of DC,22 was not expressed on any stage of the
differentiation pathway of murine DC tested so far, in line with the
results that LARC/MIP-3 never caused the chemotaxis in our system.
In contrast, in humans, a peculiar lineage of DCs such as
CD34+ cord blood cells-derived premature DCs, but not DC
progenitors in peripheral blood or monocytes, preferentially expresses
CCR6 and responds to LARC/MIP-3.10,15 This discrepancy
might be due to the species difference. CCR1, which is preferentially
expressed on DC precursors, might function instead of CCR6 in mice. A
recent study indicated that CXCR3 had the binding affinity to
SLC23; however, no populations in our DC differentiation
pathway expressed CXCR3. Human macrophage progenitors that form
granulocyte-macrophage-colony-forming unit (CFU-GM) have been
demonstrated to express CCR7 and also to migrate to
ELC/MIP-3,24 unlike murine HPCs used in this study.
Murine Linc-kit+ HPCs used in our study
could be more undifferentiated cells than CFU-GM forming cells in humans.
In our previous work,8 TGF-1 could suppress DC
maturation from murine Linc-kit+ HPCs
based on the decreased expression of MHC class II and CD86 and on the
reduced capacity of enhancing allogenic MLR. TGF-1-induced DCs in
vitro could prolong murine cardiac allograft survival by inhibiting
cellular immunity.25 In addition, infiltrating DCs in colon
and basal cell skin cancers25 and the progressing melanoma metastases26 are lacking in CD86 and in the capacity to
stimulate T cells because of massive production of TGF-1 by these
tumors.26,27 Collectively, TGF-1 may regulate immune
response negatively through modulating DCs' development and function.
In addition, to examine the effect of TGF-1 on the migration of DCs
was of great interest in acquired immunity and the tumor immunity,
besides the immunophenotype and the function of DC. The migration of DC
precursors in response to SLC was completely inhibited by TGF-1.
Therefore, it is possible that TGF-1 not only downregulates the
capacity of antigen presentation by DC, but also inhibits the migration
of immature DCs that process antigen. Because SLC is expressed on high
endothelial venules (HEV) in lymph node and Payer's
patch,28 SLC might recruit DCs at the entry site of the
regional lymph node, before the interaction with naive T cell. The
situation in which TGF-1 is produced massively, such as in tumor,
may interfere with the establishment of acquired immunity through
recruiting less number of sensitized DCs. But, once TNF- is produced
in an inflammatory situation, downregulation of CCR7 expression in
immature DCs is deprived. Subsequently, DC matures and is recruited
into T-cell area of regional lymph nodes to sensitize naive T lymphocytes.
| |
ACKNOWLEDGMENT |
The authors express our sincere gratitude to Dr R.M. Steinman for his
kind gift of MoAb to DEC-205 (NLDM145); to Dr T. Sudo for his generous
gift of anti-c-kit MoAb, GM-CSF, and SCF; and to Dr T. Imai and Dr O. Yosie (Kinki University, Osaka, Japan) for kindly providing murine SLC
cDNA and murine LARC. We also highly appreciate Dr J.J.
Oppenheim (NCI-FCRDC, Frederick, MD), Dr K. Kawasaki (Kanazawa
University, Kanazawa, Japan), and Dr C. Vestergaard for
their critical review of the manuscript.
| |
FOOTNOTES |
Submitted October 23, 1998; accepted December 31, 1998.
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 Kouji Matsushima, MD, PhD, Department of
Molecular Preventive Medicine, School of Medicine, The University of
Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; e-mail:
koujim{at}m.u-tokyo.ac.jp.
| |
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TOP
ABSTRACT
INTRODUCTION
