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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 2 (July 15), 1999:
pp. 825-831
Keratinocyte Growth Factor Separates Graft-Versus-Leukemia Effects
From Graft-Versus-Host Disease
By
Oleg I. Krijanovski,
Geoffrey R. Hill,
Kenneth R. Cooke,
Takanori Teshima,
James M. Crawford,
Yani S. Brinson, and
James L.M. Ferrara
From the Department of Pediatric Oncology, Dana Farber Cancer
Institute, Children's Hospital, and Harvard Medical School, Boston,
MA; the Department of Pathology, Yale University School of Medicine,
New Haven, CT; and the Departments of Internal Medicine and Pediatrics,
Division of Hematology and Oncology, University of Michigan Cancer
Center, Ann Arbor, MI.
 |
ABSTRACT |
The major obstacles to successful outcome after allogeneic bone
marrow transplantation (BMT) for leukemia remain graft-versus-host disease (GVHD) and leukemic relapse. Improved survival after BMT therefore requires more effective GVHD prophylaxis that does not impair
graft-versus-leukemia (GVL) effects. We studied the administration of
human recombinant keratinocyte growth factor (KGF) in a well- characterized murine BMT model for its effects on GVHD. KGF
administration from day -3 to +7 significantly reduced GVHD mortality
and the severity of GVHD in the gastrointestinal (GI) tract, reducing serum lipopolysaccharide (LPS) and tumor necrosis factor (TNF) levels, but preserving donor T-cell responses (cytotoxic T lymphocyte [CTL] activity, proliferation, and interleukin [IL]-2
production) to host antigens. When mice received lethal doses of P815
leukemia cells at the time of BMT, KGF treatment significantly
decreased acute GVHD compared with control-treated allogeneic mice and
resulted in a significantly improved leukemia-free survival (42%
v 4%, P < .001). KGF administration thus offers a
novel approach to the separation of GVL effects from GVHD.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
ALLOGENEIC BONE MARROW transplantation
(BMT) remains the treatment of choice for a number of malignant
conditions. Much of the therapeutic potential of this procedure relates
to the graft-versus-leukemia (GVL) effect, which eradicates host malignancy after BMT and is mediated by donor T and natural killer (NK)
cells.1 GVL effects are closely associated, however, with graft-versus-host disease (GVHD), the major limitation of allogeneic BMT. During GVHD, the skin, gastrointestinal (GI) tract, and liver are
damaged by both cellular and inflammatory cytokine
effectors.2 The separation of beneficial GVL effects from
destructive GVHD remains a prerequisite to improving allogeneic BMT for
hematologic malignancies.
Depletion of T cells from the graft effectively prevents GVHD, but it
results in the loss of the GVL effect and increases the rate of graft
failure.3 An alternative approach to the prevention of
acute GVHD is to retain mature T cells in the bone marrow graft, but to
disrupt the amplification of inflammatory cytokine effectors. GI tract
injury is critical in this regard to subsequent systemic
GVHD,4,5 and a pharmacological agent such as keratinocyte
growth factor (KGF), which can shield the GI tract, offers an
attractive approach to GVHD prophylaxis. KGF is a fibroblast growth
factor family member (FGF-7) with a specificity for epithelial tissues
expressing its receptors including gut epithelial cells,
hepatocytes,6 skin keratinocytes,7 alveolar type II cells,8 mammary epithelium,9 and
urothelium.10 In previous studies, KGF administration
before autologous BMT dramatically protected the gut epithelium from
injury by lethal chemoradiotherapy.11 This protection
appears to be due to a potent trophic effect on intestinal
epithelium6 and an improved survival of crypt stem
cells,12 perhaps through the regulation of genes that
reduce oxidative damage (nonselenium glutathione peroxidase)13 and enhance DNA repair (DNA polymerases- ,
- , and - ).14
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MATERIALS AND METHODS |
Mice.
Female C57BL/6 (B6,H-2b, Ly-5.2+) and B6D2F1
(H-2b/d, Ly-5.2+) mice were purchased from the
Jackson Laboratories (Bar Harbor, ME). B6 Ly-5a
(H-2b, Ly-5.1+) mice were purchased from
Frederick Cancer Research Facility (Frederick, MD) and used as donors
to document engraftment. The age of recipients ranged between 12 to 14 weeks. Mice were housed in sterilized microisolator cages and received
filtered water and normal chow, or autoclaved hyperchlorinated drinking
water for the first 2 weeks after BMT.
BMT.
Mice were transplanted according to standard protocol as has been
described previously.15 Briefly, on day 0, mice received 1,550 cGy or 1,300 cGy total body irradiation (TBI)
(137Cs source), split into two doses separated by 3 hours
to minimize GI toxicity. A total of 5 × 106 bone
marrow cells and 0.5 × 106 or 2 × 106 nylon wool purified splenic donor T cells were
resuspended in 0.25 mL of Leibovitz's L-15 media, (GIBCO BRL,
Gaithersburg, MD) and injected intravenously into recipients after TBI.
Studies of T-cell function (see Table 3) were performed after 1,300 cGy of TBI to ensure sufficient number of surviving control mice. In some
experiments, Ly-5.2a (H-2b,
Ly-5.1+) animals were used as donors (see below). Survival
was monitored daily, recipient's body weight and GVHD clinical score
were measured weekly. The degree of systemic GVHD was assessed by a
scoring system, which sums changes on a scale from 0 to 2 in five
clinical parameters: weight loss, posture (hunching), activity, fur
texture, and skin integrity (maximum index = 10).16
KGF treatment.
Recombinant human KGF was supplied by Amgen (Thousand Oaks, CA). KGF
was reconstituted in supplied carrier (Amgen) and diluted in 0.1%
bovine serum albumin/phosphate-buffered saline (BSA/PBS) before injection. Mice were injected subcutaneously with KGF (5 mg/kg/dose) once daily from either day -3 to 0 or day -3 to day +7
after BMT. Mice from the control groups received injection of diluent only.
Fluorescence-activated cell sorting (FACS) analysis.
Fluorescein isothiocyanate (FITC)-conjugated monoclonal antibody (MoAb)
to mouse Ly 5.1 and Ly 5.2 antigens, FITC-conjugated CD4 and
phycoerythrin (PE)-conjugated CD8 were purchased from PharmMingen (San
Diego, CA). Cells were stained and analyzed as previously
described.15 Donor cell engraftment was determined by
examining a percentage of Ly-5.1+ cells in peripheral blood
at day 56 after transplantation.
Cell cultures.
All culture media and incubation conditions were as previously
described.4,15 Splenocytes were removed from animals 14 days after transplant and three to six spleens combined from each group. Mononuclear cells were isolated by ficoll separation as previously described.15 The percentage of CD4+
and CD8+ T cells was estimated and cells were plated at a
concentration 105 CD4+ plus CD8+ T
cells/well with 105 irradiated (2,000 rad) peritoneal
macrophages lavaged from naive B6D2F1 (allogeneic) or B6 (syngeneic)
animals in 96-flat bottomed plates (Falcon Labware, Lincoln Park, NJ).
The ratio of CD4 to CD8 was similar in respective allogeneic splenocyte
populations. At 40 hours, cultures were pulsed with 3[H]
thymidine (1 µCi per well), and proliferation was determined 20 hours
later on a 1205 Betaplate reader (Wallac, Turku, Finland). Cytotoxic T
lymphocyte (CTL) assays were performed using the same splenic T-cell
populations for effector:target ratios as described above in standard
51Cr release assays.15 P815, a mouse
mastocytoma cell line (H-2d, American Type Culture
Collection, Rockville, MD), was carried in RPMI/10% fetal
calf serum (FCS) at 37°C, 5% CO2 and was
used for both GVL experiments in vivo and as a target for CTL assays.
Cytokine enzyme-linked immunosorbent assay (ELISA) and
lipopolysaccharide (LPS) assays.
The antibodies and standards used in tumor necrosis factor (TNF) and
interleukin (IL)-2 ELISAs were purchased from Genzyme (Cambridge, MA)
and PharMingen, respectively. All assays were performed according to
the manufacturer's protocol. LPS concentrations in serum were detected
using the Limulus Amebocyte Lysate (LAL) assay (Bio Whittaker,
Walkersville, MD) according to the manufacturer's protocol.
Histology.
Formalin-preserved distal small and transverse large bowel were
embedded in paraffin, and 5-µm thick sections were stained with
hematoxylin and eosin for histologic examination. Slides were coded and
examined in a blinded fashion by one individual (J.M.C) using a
semiquantitative scoring system for abnormalities known to be
associated with GVHD.15 In the small bowel, the eight
parameters scored were crypt loss, villus blunting, lamina propria
inflammatory cell infiltrate, mucosal atrophy, enterocyte vacuolization, loss of microvillus brush border, epithelial
attenuation, and lymphocytic infiltrate. In the large bowel, the
parameters scored were mucosal atrophy, goblet cell mucus depletion,
and lymphocytic infiltration. The scoring system for each parameter denoted 0 as normal; 0.5 as focal and rare; 1 as focal and mild; 3 as
diffuse and moderate; and 4 as diffuse and severe, as previously described in human17 and experimental4 GVHD
histology. Scores were added to provide a total maximum score of 32 in
the small bowel and 12 in the large bowel.
Statistical analysis.
Survival curves were plotted using Kaplan-Meier estimates and compared
with the Mantel-Cox log-rank test. The Mann-Whitney U test was used for
the statistical analysis of cytokine data, LPS levels, clinical scores,
weight loss, and histology. P < .05 was considered
statistically significant.
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RESULTS |
KGF reduces intestinal injury, serum LPS, and TNF levels after
allogeneic BMT.
We tested the effects of KGF in a well established murine BMT system
where GVHD is induced by both minor and major histocompatibility antigens (B6 B6D2F1). We hypothesized that KGF may protect
the GI tract epithelium from damage inflicted by cellular and
inflammatory cytokine effectors of GVHD that occur in addition to that
from radiation and chemotherapy. BMT recipients were conditioned with 1,550 cGy of TBI and transplanted with 2 × 106
splenic T cells and 5 × 106 bone marrow cells from B6
(allo) or B6D2F1 (syn) mice. KGF was given to allogeneic BMT recipients
from day -3 to day +5 at a dose 5 mg/kg/day subcutaneously. The
severity of GI histopathology was examined on day 5 after BMT, a time
of maximal GI damage in this model, according to a standard scoring
system.15 Macroscopic evaluation of control-treated
allogeneic recipients showed dilated and edematous bowel, while the
intestine in both syngeneic and KGF-treated allogeneic mice appeared
normal (data not shown). Microscopically, the small bowel in allogeneic
BMT controls was more severely damaged than in syngeneic controls, with
significant differences in several features of mucosal architecture and
epithelial cytology (Table 1). The large
majority of these parameters was reduced by KGF treatment (Table 1 and
Fig 1) to the level found in syngeneic BMT
recipients, completely abrogating the damage specific to GVHD.
Interestingly, KGF treatment given before BMT only did not
significantly protect the GI tract from GVHD (Table 1). KGF
administration from day -3 to +5 also significantly reduced damage to
colonic mucosa in allogeneic animals as determined by semiquantitative
scoring of histologic features, which were specific for GVHD as
described in Materials and Methods (KGF allo v control allo:
1.8 ± 0.5 v 9.0 ± 0.8, P < .001).
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| Fig 1.
Small bowel histology 5 days after BMT. (A) Allogeneic
control mouse, exhibiting severe villus blunting, extensive crypt
destruction with no appreciable regenerative response, and a moderate
lamina propria inflammatory infiltrate. (B) Allogeneic mouse treated
with KGF from day -3 to +5 exhibiting moderate villus blunting,
prominent crypt regenerative features, and minimal lamina propria
inflammatory infiltrate. Features in syngeneic control mice (not shown)
were identical to those in KGF allogeneic animals.
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Damage to gut mucosa is believed to be critical for the translocation
of LPS into the systemic circulation.4,5,18 Consistent with
the anatomic evidence of GI protection, KGF dramatically reduced serum
LPS levels in allogeneic BMT recipients to levels detected in syngeneic
controls (Table 2). It is interesting to note that allogeneic damage in controls accounted for nearly 90% of
the LPS translocated to the systemic circulation, and thus this entire
increase was prevented by KGF, correlating with the histologic
improvement. LPS plays an important role in GVHD pathophysiology by
inducing the production of inflammatory cytokines such as
TNF,18 which is secreted by both host4 and
donor5 macrophages. Consistent with reduced serum LPS
levels, KGF administration reduced serum TNF levels by 60% compared
with allogeneic BMT controls (Table 2).
KGF treatment reduces GVHD mortality and morbidity.
The ability of KGF to protect the GI tract from GVHD-mediated damage
and to reduce systemic TNF levels led us to hypothesize that KGF
administration would improve survival and decrease the morbidity of
acute GVHD. KGF or control diluent was injected from day -3 to day +7
after allogeneic BMT (0.5 × 106 splenic T cells and 5 × 106 bone marrow cells) and GVHD was assessed
(Fig 2A). A total of 81% of allogeneic BMT
controls died of GVHD by day 50, whereas mice identically transplanted
and treated with KGF had only 22% mortality. KGF also protected
animals from lethal GVHD when the donor T-cell dose was escalated
fourfold to 2 × 106 per animal (100% v 25%
mortality at day 50 in control-v KGF-treated groups, P
< .01). Surviving animals were evaluated weekly for clinical GVHD
severity using a standard scoring system of five parameters (weight
loss, skin integrity, fur texture, mobility, and posture) as detailed
in Materials and Methods. As shown in Fig 2B, surviving allogeneic BMT
controls developed significantly more severe clinical GVHD from day 21 onwards than KGF-treated animals, although mild GVHD was clearly
evident. In pilot studies, recipients of KGF both before and after BMT
had significantly less GVHD compared with cohorts treated before BMT
only (Fig 2B). Among the clinical parameters of GVHD, weight loss was
the most dramatically improved by KGF treatment and was similar to
syngeneic controls (data not shown). Analysis of Ly 5 alleles on
peripheral blood cells at day 56 after BMT showed complete (100%)
donor hematopoietic engraftment in all allogeneic animals, excluding
mixed chimerism as a cause of tolerance and reduced GVHD in KGF-treated
recipients.
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| Fig 2.
KGF reduces GVHD mortality and morbidity in allogeneic
BMT. Recipients were transplanted with 5 × 106 bone
marrow cells and 0.5 × 106 splenic T cells from
allogeneic (B6) or syngeneic (B6D2F1) donors after 1,550 cGy of TBI.
KGF (Amgen) or control diluent was given subcutaneously from either day
-3 to day 0 or day -3 to +7. Syngeneic BMT (n = 22, - - - ), control diluent-treated allogeneic BMT (n = 26, - · · - ), KGF-treated (day - 3 to 0) allogeneic BMT (n
= 16, ), KGF-treated (day -3 to
+7) allogeneic BMT (n = 18, ).
(A) Survival. Control-treated allogeneic BMT recipients versus
KGF-treated (both treatment schedules) and syngeneic BMT recipients
(P < .01 by Mantel Cox logrank test). (B) GVHD
clinical score. Animals were scored for clinical GVHD by five
parameters as described in Materials and Methods. GVHD severity (mean ± standard error [SE]) was significantly less in animals receiving
KGF from day -3 to +7 than those receiving KGF from day -3 to 0 and
control-treated animals from day 21 onwards (P < .05) and
significantly higher than in syngeneic BMT recipients (P < .05). Data represent results combined from two similar experiments.
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KGF preserves donor T-cell responses to host alloantigens.
Alloreactive donor T cells are critical mediators of acute
GVHD.2,3 We therefore investigated whether the inhibition of GVHD by KGF treatment was associated with decreased donor T-cell responses to host alloantigens. Serum interferon (IFN)- levels were
measured 5 days after BMT and were similarly increased in KGF and
control-treated allogeneic animals (79 ± 8 U/mL v 87 ± 9 U/mL, P = .75), suggesting equivalent T-cell expansion early after BMT. On day 14 after allogeneic BMT as described in Materials and
Methods, donor splenic T cells from KGF- and control-treated allogeneic
BMT recipients showed equivalent proliferation to host alloantigens in
mixed lymphocyte culture (MLC), although the differences in
proliferation to syngeneic stimulators resulted in a twofold reduction
of the stimulation index in the KGF-treated group
(Table 3). IL-2 production and CTL activity
to host antigens was similar in control- and KGF-treated recipients.
Splenocytes from both groups showed equivalent lysis of P815
(H-2d) leukemia cells (syngeneic to host) and only
background lysis of EL-4 (H-2b) leukemia targets (syngeneic
to donor). Thus, KGF treatment in vivo produced little or no alteration
of critical T-cell responses to host antigens despite dramatic
attenuation of GI tract GVHD and improved survival after allogeneic
BMT.
KGF administration preserves GVL effects.
The vigorous donor T-cell activity against host antigens in vitro
suggested that KGF treatment might preserve GVL effects of allogeneic
BMT. We therefore evaluated the effects of KGF treatment in this BMT
model when 5,000 host type P815 leukemia cells were injected with the
donor inoculum on the day of BMT. Injection of 2,000 cells of this
aggressive leukemia produces 100% mortality by day 30 after syngeneic
BMT (data not shown). KGF treatment dramatically improved leukemia-free
survival in allogeneic BMT recipients compared with T-cell depleted
(TCD) BMT recipients treated either with KGF or control diluent
(Fig 3). Mortality due to leukemia began to
occur from day 10 onwards in all groups and all animals that died after
this time point had gross evidence of tumor on necropsies. Eradication
of leukemia was confirmed in all surviving animals by macroscopic
examination of the spleen and liver at day 65 after BMT. The incidence
of death from leukemia after day 10 was similar in both KGF- and
control-treated allogeneic groups (6 from 14 v 2 from 4). In
addition, KGF- and control diluent-treated TCD recipients died at
similar rates, confirming that KGF did not alter the kinetics of
leukemic growth after BMT.
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| Fig 3.
Preservation of allogeneic GVL effects in KGF-treated
mice. B6D2F1 recipients were conditioned and transplanted as in Fig 1
with the addition of 5,000 P815 tumor cells to the bone marrow inoculum
at day 0. Recipients of TCD bone marrow or bone marrow plus T cells
from allogeneic B6 donors were treated with KGF or control diluent from
day -3 to +7 as described in Materials and Methods. Results are
represented as Kaplan-Meier cumulative survival estimates from two
similar experiments. Control diluent-treated TCD recipients
(, n = 11), KGF-treated TCD
recipients ( - - - , n = 6), control allogeneic BMT
recipients ( - · · - , n = 28), KGF allogeneic BMT
recipients (, n = 17). KGF versus control
(allogeneic BMT groups), P < .0001.
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DISCUSSION |
We have shown that KGF administration reduces GVHD mortality and
long-term morbidity in an experimental BMT model, primarily by
protecting the GI tract from GVHD damage and subsequent inhibition of
LPS translocation and TNF generation. KGF did not suppress T-cell
responses to host tissue and preserved a GVL response, resulting in a
significant increase in leukemia-free survival.
The ability of KGF to protect the GI tract from injury due to
chemotherapy and radiation is maximal when it is administered before
chemoradiotherapy.11 The protective mechanisms include enhanced crypt survival11 due to increased intestinal stem
cell survival,12 goblet cell hyperplasia, and enhanced
mucin secretion.6 KGF also promotes TGF secretion from
intestinal epithelial cells,19 which is an important
mediator of mucosal healing.20 In the current study, the
maximal protection from GVHD morbidity occurred when KGF was given both
before and after BMT rather than before BMT only. This observation
confirms and extends a recent study in which KGF, given before BMT
only, did not protect the large bowel from GVHD damage.21
Limiting the administration of KGF before BMT did delay GVHD mortality,
but it produced significantly less protection than observed in this
study. The importance of continuing KGF administration after allogeneic
BMT suggests that KGF may promote recovery of the GI tract after
injury, a phenomenon demonstrated in models of colitis.22
Damage to GVHD target organs is mediated by both inflammatory cytokines
(IL-1, TNF, IFN) and cellular effectors (CTL and NK
cells).23 Injury to the GI tract is mediated predominantly by TNF, while the Fas-dependent CTL pathway is important in the development of hepatic GVHD.24 GVHD histopathology in the
GI tract has been described in three phases,25 and we have
included discriminatory parameters from each phase in our histological scoring system. The initial proliferative phase results in increased crypt cell mitotic activity, crypt lengthening, and increased intraepithelial lymphocytes. However, the histological features of GI
tract GVHD in this model are consistent with the destructive and
atrophic phases, characterized by villus blunting, lamina propria
inflammation, crypt destruction (with crypt stem cell loss), and
mucosal atrophy (Table 1). These features together with epithelial
vacuolization and attenuation are induced by inflammatory cytokines
such as TNF26 and IL-1.27 The dramatic
amelioration of these histological features in KGF-treated recipients
is therefore consistent with the reduction in serum TNF levels in
these animals. Disruption of the GI mucosal barrier facilitates the
translocation of LPS, a normal constituent of endogenous bowel flora,
into the systemic circulation.4 LPS is a potent stimulus
for inflammatory cytokine production18 and augments donor
T-cell activation,28 thereby amplifying both inflammatory
and cellular effectors of GVHD. In this study, KGF administration
inhibits TNF generation, most likely by protecting the GI epithelium
from GVHD injury, which is mediated by both TBI and alloreactive T
cells.4 Disruption of LPS leakage suppresses TNF
generation that mediates ongoing gut injury4 and thus the
"indirect" blockade of inflammatory cytokines by KGF provides
dramatic protection from GVHD.
It should be noted that KGF did not entirely prevent clinical GVHD, as
evidenced by the elevated clinical scores throughout the transplant
period (Fig 2B) and the typical findings of atrophy in the thymus and
spleen at day 56 (data not shown). This GVHD probably reflects the
persistent responses of allospecific donor T cells to host antigens in
animals treated with KGF. The KGF receptor has not been described on
cells of hematopoietic origin29,30 and the preservation of
T-cell function after KGF administration is therefore not surprising.
In contrast to other systems where GVL effects appear to depend on
CD8+ T cells,31 depletion of either
CD4+ or CD8+ populations before BMT compromises
GVL in our model, showing that both these subsets play a critical role
in the expansion of GVL effector cells (manuscript in
preparation). It is important to note that the proportion
of mice dying of leukemia was similar in control-and KGF-treated
recipients, confirming that mechanisms of alloreactive leukemia
eradication are not impaired by KGF administration. Studies, which
further escalate the dose of leukemia, are ongoing to quantify the
magnitude of GVL effects preserved after KGF treatment. Finally, KGF
does not appear to protect malignant cell lines from chemoradiotherapy
in models studied to date,11,32,33 suggesting reductions in
the leukemic burden by BMT conditioning will not be adversely affected
by KGF administration. The favorable clinical toxicity profile of
KGF,34 as well as these compelling preclinical data, make
KGF an attractive candidate to study in clinical trials as an adjunct
to standard GVHD prophylaxis.
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FOOTNOTES |
Submitted December 23, 1998; accepted March 22, 1999.
O.I.K and G.R.H. contributed equally to this work and should be
regarded as cofirst authors.
Supported by Grants No. CA39542 and HL55162 from the National
Institutes of Health (to J.L.M.F.). J.L.M.F. is a scholar of the
Leukemia Society of America.
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 James L.M. Ferrara, MD,
Departments of Internal Medicine and Pediatrics, Division of Hematology
and Oncology, University of Michigan Cancer Center, Ann
Arbor, MI 48109-0560; e-mail: ferrara{at}umich.edu.
| |
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ABSTRACT
INTRODUCTION