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Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 765-769
RAPID COMMUNICATION
FLT-3 Ligand Provides Hematopoietic Protection From Total Body
Irradiation in Rabbits
By
A. Gratwohl,
L. John,
H. Baldomero,
J. Roth,
A. Tichelli,
C. Nissen,
S.D. Lyman, and
A. Wodnar-Filipowicz
From the Division of Hematology, the Department of Research,
Hematology Laboratory, and the Department of Radiation Physics,
Kantonsspital, Basel, Switzerland; and Immunex Corp, Seattle, WA.
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ABSTRACT |
Several hematopoietic cytokines have been investigated for their
potential to provide protection from the lethal consequences of bone
marrow aplasia after total body irradiation (TBI). Some can increase
the dose of irradiation tolerated by the animals; none allow endogenous
recovery after doses such as administered in clinical blood or marrow
transplantation. We tested the radioprotective potential of FLT-3
ligand, an early acting hematopoietic cytokine, alone and in
combination with a late acting cytokine, granulocyte-colony stimulating
factor (G-CSF). Adult outbred New Zealand White rabbits were submitted
to TBI of 1,200 or 1,400 cGy by a Co60 source. Recombinant
human (rh) FLT-3 ligand at a dose of 500 µg/kg and/or rhG-CSF
at a dose of 10 µg/kg were administered for 14 days subcutaneously daily, beginning either 2 days before or the day after TBI. All control
animals given no growth factors died of aplasia at day 10 (range, 5 to
16). All 8 animals given G-CSF had severe aplasia and 7 died at day 8 (range, 5 to 10); 1 animal survived, with G-CSF being administered
before TBI. In contrast, 11 of 12 animals given FLT-3 ligand, with or
without G-CSF, survived. Radioprotection was best in the group given
FLT-3 ligand together with G-CSF before TBI. In these animals median
platelet counts were never <10 × 109/L and median white
blood cell counts never <0.5 × 109/L. These data show
that hematopoietic recovery can occur after 1,400 cGy TBI in rabbits,
if protected by FLT-3 ligand, and suggest a radioprotective clinical
potential of this cytokine.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
SEVERE BONE MARROW (BM) aplasia with
bleeding and infection is the first dose-limiting toxicity of total
body irradiation (TBI).1-3 In animal models, toxicity is
expressed as LD50/30, the dose at which 50% of animals
survive at day 30 postirradiation. LD50/30 is influenced by
dose rate and number of radiation fractions. It depends on the number
of stem cells surviving and varies from species to species with a
higher dose tolerated by smaller animals.4,5 The
LD50/30 ranges from 300 to 400 cGy in dogs to about 700 cGy in mice, and is estimated in humans at 300 to 600 cGy.2,5 The maximal tolerated dose, ie, the dose without early mortality, is
less well defined but considerably lower. With stem cell support it is
increased to about 1,400 to 1,600 cGy, limited then by central nervous,
pulmonary, and gastrointestinal toxicity.2,6,7
Hematopoietic growth factors and a variety of cytokines have become
available over the last decade and have been tested for their potential
to protect BM from the lethal consequences of TBI.8-11 Some
have been shown to promote recovery when administered after sublethal
TBI, others were only effective when given before TBI or combined with
other cytokines. Improvements in all experiments were marginal.
Importantly, with the exception of stem cell factor,12 none
of the single cytokines or their combinations provided for recovery
after doses such as were administered in the clinical setting for blood
or marrow transplantation (BMT).13
FLT-3 ligand is a novel hematopoietic cytokine, involved in regulation
of early hematopoiesis.14-16 It stimulates alone, or in
combination with other growth factors, the proliferation of highly
enriched human and murine hematopoietic stem cells in vitro and leads
to expansion and mobilization of progenitor cells in animals and humans
in vivo.17-22 Serum levels of FLT-3 ligand are highly
upregulated in patients with acquired or induced BM aplasia, suggesting
that ligand plays a role in a compensatory hematopoietic response to
stimulate or protect the stem cell compartment.23,24 Based
on preliminary data in mice,25 we were therefore interested in testing the potential of FLT-3 ligand to protect animals submitted to TBI at a dose equivalent or higher to the dose used for allogeneic BMT. The present data show that FLT-3 ligand effectively promotes recovery and protects animals from otherwise lethal TBI.
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ANIMALS AND METHODS |
Animals.
Adult outbred New Zealand White rabbits (Biological Research
Laboratories Ltd, Füllinsdorf, Switzerland) of both sexes were used. Animals were housed in single cages with standard pellet diet and
water ad libitum in the supervised Animal Care Facility Center of the
Department of Research at the Kantonsspital Basel.
Experimental design.
Animals were treated with TBI in groups of two to four animals each,
given either no growth factors (control animals) or growth factors for
a period of 14 days, beginning 2 days before TBI (pre) or the day after
TBI (post), as outlined in Table 1. The
protocol was approved by the Ethical Committee for Animal Care of the
Canton of Basel-Stadt.
TBI.
TBI was administered from a Co60 source at a dose rate of
20 cGy/min in general anesthesia in two doses on 2 consecutive days, as
previously described in our transplant protocol.26,27 Total doses of 1,200 and 1,400 cGy were examined. TBI was applied as a
lateral beam from the top to animals lying on the floor. Animals were
anesthetized by intramuscular (im) injection of Hypnorm
(Janssen-Cilag Pharmaceutica, Baar, Switzerland) and were
administered 0.2 mg of dexamethason to protect from immediate central
nervous toxicity. Supportive care after TBI was comprised of Bactrim
(Roche, Ltd, Basel, Switzerland) administered orally daily and an
injection of normal saline subcutaneously (sc) if required. No red
blood cell or platelet transfusions were given.
Growth factors.
Recombinant human granulocyte colony-stimulating factor (rhG-CsF)
(Neupogen; kindly provided by Roche Pharma, Reinach, Switzerland) at a
dose of 10 µg/kg and FLT-3 ligand (kindly provided by Immunex Corp,
Seattle, WA) at a dose of 500 µg/kg were used. These doses of human
growth factors had been previously tested and shown to stimulate
hematopoiesis in vitro and to synergize in vivo in the mobilization of
hematopoietic precursor cells in rabbits.19 Growth factors
were injected daily sc in the shaved back of the animal. FLT-3 ligand
and G-CSF were administered either singly or combined, as outlined in
Table 1.
Laboratory examinations.
Animals were inspected daily and their weight was recorded. Whole blood
cell counts, including hemoglobin, reticulocyte, platelet counts, and
white blood cell differential counts, were determined three times
weekly.28 A postmortem examination was performed in all the
deceased animals.
Statistical analysis.
Mean, median, and range of numerical variables were calculated by the
Excel spreadsheet program. Survival of the groups was compared by
Fisher's exact t-test, the blood values at nadir by unpaired
t-test.
| |
RESULTS |
Survival.
The outcome of animals following TBI is summarized in Table 1 and
illustrated in Fig 1. All 8 control
animals, subjected to 1,200 or 1,400 cGy but given no growth factors,
died of aplasia between days 5 and 16 after TBI (median, day 10). No
higher dose was considered because of excessive early toxicity of the
central nervous system observed in previous studies.27
Seven of 8 animals given 1,400 cGy TBI and treated with G-CSF alone
died between days 5 and 10 (median, day 8). In this treatment group,
only one animal administered G-CSF before TBI recovered from severe
pancytopenia and survived. In contrast, 11 of 12 animals treated with
FLT-3 ligand survived. The survivors included all 10 animals given
FLT-3 ligand, with or without additional G-CSF, before TBI. Of the two animals subjected to 1,200 cGy and administered FLT-3 ligand and G-CSF
after TBI, one animal failed to recover and died at day 8 in aplasia.
The difference in survival between the control group or the G-CSF group
and the FLT-3 ligand-treated group is highly significant
(P < .01).
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| Fig 1.
Survival of animals subjected to TBI. Rabbits were given
no growth factors ( ), G-CSF ( ), or FLT-3 ligand with or without additional G-CSF ( ). For experimental details, see Animals and Methods. Difference in survival between the three groups of animals was
highly significant (P < .01, see text).
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Extent of aplasia.
As a result of TBI, all control animals entered severe pancytopenia
with platelet counts <10 × 109/L and white blood cell
counts <0.2 × 109/L (Table 1). The extent of
pancytopenia was no different in animals treated with G-CSF alone. Even
the 1 surviving animal had a nadir of 8 × 109/L for
platelets and 0.1 × 109/L for white blood cell counts. In
contrast, none of the 4 animals given the combination of FLT-3 ligand
and G-CSF before 1,400 cGy TBI had white blood cell counts <0.2 × 109/L at any time point and only 1 animal had a white blood
cell count <0.5 × 109/L for 1 day. A platelet count was
<10 × 109/L in only 1 animal on 1 day. Remarkably, 2 of
4 animals never had platelet counts <20 × 109/L nor white blood cell counts <1.0 × 109/L. The values of white blood cell counts and platelets
at the time of nadir are significantly different between the control group and the FLT-3 ligand + G-CSF pretreated animals
(P < .05).
The kinetics of entering and recovering from aplasia in terms of median
leukocyte, platelet, reticulocyte counts, and hemoglobin values are
illustrated in Fig 2. Control animals and
those administered G-CSF alone entered rapid aplasia and failed to
recover. Among animals given FLT-3 ligand alone and those given the
combination of FLT-3 ligand and G-CSF, there was a difference
concerning white blood cell kinetics. In animals administered FLT-3
ligand alone, median white blood cell counts were already <1 × 109/L at day 2 and recovered to >1 × 109/L at day 11 only. In contrast, in the combined
treatment group, white blood cell counts went to <1 × 109/L at day 4 and recovered to >1 × 109/L
at day 8.
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| Fig 2.
Hematological values of animals subjected to TBI. Rabbits
were given no growth factors (), G-CSF (), FLT-3 ligand ( ),
and FLT-3 ligand with G-CSF ( ). For experimental details, see
Animals and Methods. Differences in hematological values at nadir
between the control and the FLT-3 ligand with G-CSF-treated animals
were significant (P  .05, see text).
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| |
DISCUSSION |
The data from this study show that FLT-3 ligand, alone or in
combination with G-CSF, can consistently rescue animals from otherwise
lethal aplasia when administered before TBI. G-CSF alone is
insufficient. All animals pretreated with FLT-3 ligand survived high-dose irradiation. The best results in terms of survival and the
speed of recovery from aplasia were achieved when the two cytokines
were combined and given before, not after, irradiation. With the
combination, the nadir of white blood cell and platelet count was
reduced in both intensity and duration. These remarkable radioprotective effects of FLT-3 ligand are by far superior to the
effects of other growth factors and cytokines tested previously for
their potential to protect animals against the toxicity of TBI. Of the
hematopoietic cytokines, G-CSF was shown to have some radioprotective
effect in mice when administered before TBI. Sixty percent of mice
given high-dose G-CSF (40 µg/kg) before 700 cGy TBI survived in
contrast to control animals. No protection was observed at 800 cGy.29 Similarly, modest effects were observed with
granulocyte-macrophage colony-stimulating factor (GM-CSF) and
interleukins (IL)-3 and -6, in sublethally, but not in lethally, irradiated animals.8,9,30 Most data have been accumulated using IL-1 alone or in combination with G-CSF, GM-CSF, stem cell factor
or tumor necrosis factor- (TNF-) or
interferon- .8,22,31,32 Better results were obtained with
the combination of IL-1 and stem cell factor administered before
TBI.32 Even there, effects on protection were relatively
marginal with an increase in LD50/30 by factors of 1.2 to
1.3 from 800 to 950 cGy. In only one of the models tested did total
doses of tolerated TBI exceed 1,000 cGy when mice were given stem cell
factor before and after 1,150 cGy TBI.13
The mechanism of radioprotection by growth factors is unknown and the
results appear, in part, surprising. In clinical studies of leukemia
treatment, cytokines are used to prime target cells for higher
susceptibility to chemotheraphy.33 Therefore, an even more
rapid decline in peripheral blood values could have been expected in
cytokine-pretreated animals. To the contrary, in irradiated animals
receiving FLT-3 ligand and G-CSF the decrease of peripheral blood
values was not only less pronounced but also delayed. In addition,
decline in whole blood leukocyte counts was significantly slower in
animals given FLT-3 ligand and G-CSF than in animals given FLT-3 ligand
alone. Dose of G-CSF and FLT-3 ligand and the timing of administration
were selected on the basis of previous experiments in the same animal
model.21 We found that FLT-3 ligand and G-CSF
synergistically mobilize hematopoietic precursor cells in rabbits and
have their most pronounced effect at 10 to 12 days'
administration, ie, at the time when aplasia after radiation is most
severe. Effects of both cytokines on the kinetics of entry into and
recovery from hematopoietic aplasia cannot be explained solely by
expansion and proliferation of stem and progenitor cells.
Several decades ago, the property of bacterial lipopolysacharides to
protect animals from lethal irradiation was described and for a long
time provided the basis for considerations in
radioprotection.34 It is now known that lipopolysaccharides
elicit an inflammatory reaction by releasing a variety of cytokines,
including IL-1, IL-6, CSFs, TNF, IFNs, and transforming growth factor,
all shown to have some radioprotective activity of their own. Based on
these effects, Neta and Oppenheim8 postulated that an
inflammatory response would assist in recovery from radiation by the
removal of damaged tissue and by promoting restoration of normal
function. Later, it was postulated that growth factors induce or
enhance repair mechanisms and, thus, may protect stem cells from an
irradiation insult.9,31 Radiation is a powerful stimulator
of apoptosis.35,36 Aplasia after TBI might be the
consequence of radiation-induced apoptosis in hematopoietic precursor
cells. It has been shown that FLT-3 ligand promotes the maintenance of
hematopoietic progenitors in vitro37 and has antiapoptotic
effects.38 Protection of radiation-induced apoptosis by
combined FLT-3 ligand, stem cell factor, and IL-3 has recently been
shown for human and primate hematopoietic precursor cells in
vitro.39 We postulate that similar mechanisms might take
place in vivo in animals subjected to TBI.
Our data illustrate the profound radioprotective effects of FLT-3
ligand and extend information from previous studies concerning the
potential of cytokine therapy in the treatment and prevention of
radiation injury. The results of this study open the way for further
analyses of radioprotective effects of FLT-3 ligand in growth factor
combinations which should also include stem cell factor,
thrombopoietin, and erythropoietin. The clinical goal is to design
optimized radioprotective regimens to allow high-dose radiation for
cancer patients or as intensive immunosuppression for solid-organ
transplant recipients without the need for stem cell rescue.
| |
FOOTNOTES |
Submitted February 9, 1998;
accepted May 13, 1998.
Supported in part by the Swiss National Research Foundation
Grant No. 3200-042431-94/1.
Address reprint requests to A. Gratwohl, MD, Division of
Hematology, Department of Internal Medicine, Kantonsspital, CH-4031 Basel, Switzerland; e-mail: hematology{at}ubaclu.unibas.ch.
| |
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Abstract
Introduction
Abstract