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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 4 (February 15), 1999:
pp. 1157-1163
Endogenous Interleukin-8 (IL-8) Surge in Granulocyte
Colony-Stimulating Factor-Induced Peripheral Blood Stem Cell
Mobilization
By
T. Watanabe,
Y. Kawano,
S. Kanamaru,
T. Onishi,
S. Kaneko,
Y. Wakata,
R. Nakagawa,
A. Makimoto,
Y. Kuroda,
Y. Takaue, and
J.E. Talmadge
From the Department of Pediatrics, Tokushima University School of
Medicine, Tokushima, Japan; the Department of Stem Cell
Transplantation, National Cancer Center Hospital, Tokyo, Japan; and the
Department of Pathology/Microbiology, University of Nebraska Medical
Center, Omaha, NE.
 |
ABSTRACT |
The relationship between stem cell mobilization with granulocyte
colony-stimulating factor (G-CSF) and the endogenous production of
interleukin-8 (IL-8), macrophage inflammatory protein-1 (MIP-1), tumor necrosis factor- (TNF-), and interferon- (IFN-) was studied in normal donors for allogeneic peripheral blood stem cell
(PBSC) transplantation. G-CSF was administered to 20 normal donors at a
dose of 10 µg/kg/d for 5 days with aphereses on days 5 and 6 of G-CSF
treatment. Cytokine serum levels were measured using an enzyme-linked
immunosorbent assay (ELISA) before and during G-CSF treatment. Before
treatment, the average level of IL-8 was 7.1 pg/mL, increasing to 207.0 pg/mL on day 5 and 189.1 pg/mL on day 6. Serum IL-8 levels correlated
CD34+ cell numbers (P = .0151 and P = .0005 on days 5 and 6, respectively) and colony-forming
unit-granulocyte-macrophage (CFU-GM) numbers (P = .0019 and
P = .0010 on days 5 and 6, respectively). Furthermore, preapheresis serum IL-8 levels correlated with the yield of
CD34+ cells (P = .0027). In contrast, before
treatment, the average levels of MIP-1, TNF-, and IFN- were
70.1, 4.03, and 3.84 pg/mL, respectively, and no significant changes in
the levels of these cytokines were observed during G-CSF treatment.
These studies suggest that IL-8 production may be critical to
G-CSF-induced stem cell mobilization, although the underlying
mechanism could not be clarified.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
GRANULOCYTE COLONY-stimulating factor
(G-CSF) is increasingly used to mobilize hematopoietic progenitor cells
from bone marrow to circulatory blood for stem cell rescue
products.1 Studies on the kinetics of circulating
progenitor cells mobilization have been critical to the development of
successful G-CSF mobilization protocols.2-6 These studies
have demonstrated that several hours after the initiation of G-CSF
administration, a leukocytosis is usually evident; however, a
substantial increase in circulating CD34+ cells and
colony-forming unit-granulocyte-macrophage (CFU-GM) does not occur
until day 4 or 5 of G-CSF treatment. In most patients, the peak of
progenitor cell mobilization occurs on day 5 or 6 of G-CSF treatment.
Based on the differences in kinetics between differentiated cells and
hematopoietic progenitors, we hypothesized that endogenous
cytokine-mediated regulation of hematopoiesis is involved in this
delayed appearance of circulating progenitor cells.
One of the most logical cytokines to have such a mechanism is
interleukin-8 (IL-8), a member of the CXC ( ) family of chemokines. Bioactivities of IL-8 include neutrophil chemotaxis and activation and
upregulation of integrin family adhesion molecules.7 In previous studies, we and others have found that integrins such as very
late antigen-4 (VLA-4) and leukocyte functioning antigen-1 (LFA-1) are
expressed on mobilized CD34+ cells and that their
expressions are involved in progenitor cell mobilization.8-10 Although most of the IL-8 data concerning
blood cell migration have been focused on mature neutrophils, it is still unclear whether similar mechanisms occur during progenitor cell
mobilization from the marrow. Alternative cytokines that might be
upregulated by G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) administration and contribute to mobilization include
tumor necrosis factor- (TNF-), macrophage inflammatory protein-1 (MIP-1) or MIP-1 (C-C chemokine), interferon-
(IFN-), IL-1, stem cell factor (SCF), or Flt-3. TNF-, MIP-1,
and IL-1 are members of a large family of cytokines that are secreted
by activated macrophages, T cells, and/or
fibroblast11,12 and are associated with inflammatory
responses that might occur during cytokine mobilization.13
These target cytokines, especially MIP-1 and IL-1, have previously
been reported as stem cell mobilizing cytokines.14-17
Similarly, IFN- is produced by T cells and has been shown to mediate
the suppression of lymphocyte proliferation in response to antigens.
IFN- also activates native mononuclear phagocytes to produce
proinflammatory cytokines, which also may be involved in
mobilization.18 SCF and Flt-3 are a family of the ligands
for the receptor protein tyrosine kinase and share a significant
degree of homology. Synergy between G-CSF and SCF or Flt-3 has also
been shown in enhancement of peripheral blood stem cell (PBSC)
mobilization, probably due to expansion of progenitor cells.19,20
To investigate the role of endogenous cytokine expression in
G-CSF-induced progenitor cell mobilization, we examined the serum levels of these cytokines in healthy normal donors who received G-CSF
for the harvest of PBSC.
| |
MATERIALS AND METHODS |
Donors, PBSC mobilization, and harvesting.
Twenty normal, healthy donors (median age, 30 years; range, 2 to 45 years) were evaluated in this study. All of the donors were related to
the recipients, were in stable medical condition, and met eligibility
criteria for PBSC donation. All donors or their parents provided
written informed consent and the protocol was approved by the
University Hospital of Tokushima ethics committee. Donors received
G-CSF (filgrastim [N = 16] or lenograstim [N = 4]) subcutaneously
at a dose of 10 µg/kg for 5 consecutive days and underwent apheresis
with a Fenwall CS3000 Plus continuous cell separator (Baxter Healthcare
Co, Irvine, CA) on days 5 and 6 of G-CSF treatment.
Two hundred to 300 mL/kg of donor's body weight of blood for children
or 10 L of blood for adults were processed at a time. Aphereses were
repeated two to five times to collect a sufficient number of cells for transplantation.
Blood sampling.
Donor blood samples were obtained daily by venopuncture before and
during G-CSF treatment and apheresis. Samples were withdrawn immediately before G-CSF injection or apheresis and centrifuged within
three hours to obtain the serum. Serum was kept at  80°C until assayed.
IL-8, MIP-1, TNF-, and
IFN- detection.
The serum cytokine levels measured in this study were IL-8, MIP-1,
TNF-, and IFN-. The level of IL-8 was measured using a specific
enzyme-linked immunosorbent assay (ELISA) kit (TFB, Inc, Tokyo, Japan)
following the manufacturer's instructions. The levels of MIP-1,
TNF-, and IFN- were measured using an ELISA kit available from
Amersham Life Science (Buckinghamshire, UK) following the
manufacturer's instructions. Each serum sample was analyzed in
duplicate and the average value was used for calculation. Standard
curves were prepared, plotting optical density versus known
concentrations. The concentration of each cytokine in the unknown
samples was determined from the respective standard curves. Samples
with a cytokine concentration higher than the upper range value
measured by the assay kit were diluted so that the concentration fell
within the standard range. No cross-reactivity or interference by other
cytokines was reported by the manufacturer. The minimum detectable
concentrations are estimated to be 1.1 pg/mL for IL-8, 46.9 pg/mL for
MIP-1, 5.0 pg/mL for TNF-, and 0.63 pg/mL for IFN-. In our
studies, serum cytokine levels that were below detection were reported
as 0 pg/mL.
CD34+ cell enumeration and in vitro progenitor cell
assay.
One hundred microliters of mononuclear cell (MNC) suspension (3 × 106 cells/mL) were stained with a phycoerythrin
(PE)-conjugated anti-CD34 monoclonal antibody (HPCA-2; Becton Dickinson
Labware, Lincoln Park, NJ) for 30 minutes at 4°C in the dark and
then analyzed by a FACScan flow cytometer (Becton Dickinson
Immunocytometry Systems, San Jose, CA) after washing twice. Antimouse
IgG1 conjugated with PE was used as a control. The percentage of the
CD34+ cell population was calculated in an ungauged MNC
population. Absolute numbers of CD34+ cells in 1 mL of
blood were then calculated using the following formula: MNC count in 1 mL blood × the percentage of CD34+ cells in MNC. The
MNC count was defined after Percoll separation.
For CFU-GM assay, MNC were cultured with 0.50 to 1 × 105/well in Iscove's modified Dulbecco's medium
containing 0.8% methylcellulose, 20% fetal bovine serum (FBS), 450 µg/mL human transferrin, and 1% deionized bovine serum albumin.
Recombinant human cytokines were added to cultures at various
prescreened concentrations (200 ng/mL for SCF, 200 ng/mL for IL-3, 2 U/mL for erythropoietin, and 200 ng/mL for G-CSF). Quadruplicate
cultures were plated in a volume of 0.4 mL in 24-well tissue culture
plate and the average value was used for calculation. The plates were
incubated at 37°C in a humidified atmosphere of 5% O2,
5% CO2, and 90% nitrogen for 14 days. Colonies were
scored at 14 days of culture using an inverted microscope. Absolute
numbers of CFU-GM in 1 mL of blood were then calculated using the
following formula: MNC count in 1 mL blood × the number of CFU-GM
in the well/the number of MNC plated in the well.
Statistical analysis.
The Student's t-test was used to compare differences between
baseline data and data collected during G-CSF treatment. Correlations between the value of serum IL-8 level and the number of
CD34+ cells or CFU-GM were evaluated by Spearman's rank
correlation and P values were calculated with Fisher's
Z-conversion. Significance was considered P < .05.
| |
RESULTS |
Kinetics of IL-8, MIP-1, TNF-, and
IFN- serum levels during G-CSF treatment.
The average serum IL-8 levels increased from 7.1 ± 2.6 pg/mL (mean ± standard deviation) at baseline to a maximum of 207.0 ± 46.7 pg/mL on day 5 of G-CSF treatment (Fig 1).
In addition, the serum IL-8 levels were significantly higher on days 5 and 6 of G-CSF treatment as compared with baseline and the levels observed on days 2 to 4 (P < .001). In contrast, before
treatment, the average levels of MIP-1, TNF-,
and IFN- were 70.1, 4.03, and 3.84 pg/mL, respectively.
The peak average levels of MIP-1 and TNF- were 79.0 pg/mL
on day 3 and 4.58 pg/mL on day 3, respectively. The levels of IFN-
decreased gradually during G-CSF treatment, with the lowest level of
1.76 pg/mL observed on day 6. However, these changes in secretion of
MIP-1, TNF-, and IFN- were not statistically significant. The serum IL-8 values on days 5 and 6 correlated with the numbers of CD34+ cells (r = .529, P = .0151 for day 5 and r = .687, P = .0005 for day 6) and the numbers of CFU-GM (r = .637, P = .0019 for day 5 and r=0.664, P = .0010 for day 6) in
the peripheral blood on days 5 and 6 (Fig
2). In contrast, there was no relationship between the number of
CD34+ cells and the MIP-1, TNF-, or IFN-
levels (data not shown).
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| Fig 1.
The kinetics of serum IL-8 (A), MIP-1 (B), TNF-
(C), and IFN- (D) before and during G-CSF treatment. Each solid
circle represents the value of a patient, and an open circle and bar is
the mean ± standard deviation. The levels of serum IL-8 were
significantly higher on days 5 and 6 of G-CSF treatment as compared
with baseline and those on days 2 to 4 (P < .001). No
significant change was observed in the kinetics of serum MIP-1,
TNF-, or IFN- secretion. *P < .001.
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| Fig 2.
Correlation between the serum IL-8 values and the number
of CD34+ cells or CFU-GM on days 5 and 6 of G-CSF
treatment. (A) Serum IL-8 levels versus the number of
CD34+ cells per milliliter on day 5. (B) Serum IL-8
levels versus the number of CFU-GM per milliliter on day 5. (C) Serum
IL-8 levels versus the number of CD34+ cells per
milliliter on day 6. (D) Serum IL-8 levels versus the number of CFU-GM
per milliliter on day 6. The serum IL-8 level correlated with the
number of circulating CD34+ cells or CFU-GM.
|
|
White blood cell (WBC) and progenitor cell kinetics during G-CSF
treatment.
The median value of WBC numbers increased from 6,000/µL (range, 4,500 to 12,000/µL) at baseline to 34,300/µL (range, 8,600 to
57,300/µL) on day 5 of G-CSF treatment. Eighteen donors achieved WBC
counts greater than 30, 000/µL. The remaining 2 donors had peak WBC
values of 26,100 and 28,000/µL, respectively. The WBC median reached
27,500/µL (range, 19,800 to 38,500/µL) on the second day of G-CSF
treatment and was greater than 30,000/µL on days 3 to 6 (Table 1). The median number of
CD34+ cells in 1 mL of blood increased from 825 (range, 340 to 4,290) at baseline to the maximum number observed, ie, 27,331 (range, 3,200 to 184,000) on day 5. The increase of CD34+
cells was maximal on day 5. The median number of CFU-GM in 1 mL of
blood increased from 61 (range, 0 to 390) at baseline to 6,420 (range,
10 to 32,000) on day 6. There was no relationship between WBC count on
days 5 and 6 and the numbers of CD34+ cells and CFU-GM in
the blood on day 5 and 6 (Fig 3).
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| Fig 3.
Correlation between peripheral WBC count and the number
of CD34+ cells or CFU-GM on days 5 and 6 of G-CSF
treatment. (A) WBC count versus the number of CD34+ cells
per milliliter on day 5. (B) WBC count versus the number of CFU-GM per
milliliter on day 5. (C) WBC count versus the number of
CD34+ cells per milliliter on day 6. (D) WBC count versus
the number of CFU-GM per milliliter on day 6. No significant
correlation was observed.
|
|
Progenitor cell yield and serum IL-8 levels.
All donors underwent apheresis and PBSC were collected on days 5 and 6 or later if the target CD34+ cell dose of 2.5 × 106/kg of recipient body weight was not achieved. The
median number of apheresis was 3 (range, 2 to 5) and the median amount
of processed blood was 27 L (range, 9.5 to 40 L). The median number of
collected CD34+ cells and CFU-GM was 366.5 × 106 (range, 55 to 1,083 × 106) and 855 × 105 (range, 0 to 6,679 × 105), respectively. Because of donor variation, the number
of progenitor cells that were collected was also calculated per liter
of processed blood, and the median number of collected
CD34+ cells per liter and CFU-GM per liter was 15.3 × 106 (range, 2.0 to 39.3 × 106) and 30.5 × 105 (range, 0 to 247.4 × 105),
respectively. A significant correlation was observed between preapheresis serum IL-8 levels, ie, sampled immediately before the
first apheresis on day 5, and the yield of CD34+ cells
(r = .621, P = .0027; Fig
4). In addition, there was a weak correlation between preapheresis
serum IL-8 levels and the yield of CFU-GM (r = .468, P = .0366).
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| Fig 4.
Correlation between the preapheresis serum IL-8 level and
CD34+ cell yield (A) or CFU-GM yield (B). A significant
correlation was observed between the preapheresis serum IL-8 level and
CD34+ cell yield.
|
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| |
DISCUSSION |
This study indirectly examined the involvement of endogenous IL-8 in
G-CSF-induced progenitor cell mobilization from human marrow. The
levels of IL-8 secretion increased significantly on days 5 and 6 of
G-CSF treatment and correlated with the increased numbers of
circulatory CD34+ cells and CFU-GM. Furthermore, there was
a direct correlation between IL-8 levels and the numbers of circulatory
CD34+ cells and CFU-GM per milliliter of blood on days 5 and 6 of G-CSF treatment. No similar correlation was found with other
cytokines (MIP-1, TNF-, and IFN-), which suggests that the
observed response was specific to IL-8 levels and is not due to
nonspecific monocyte activation. Taken together, these results suggest
that IL-8 may have a mechanistic role in mobilization and that a period
of activation is needed for an increase in IL-8 levels and subsequent
effects on circulatory stem cells. IL-8 is a well-known chemotactic
agent for neutrophils, whose function is mediated by its effects on adhesion molecules, including L-selectin and
-integrins.21 The hypothesis that progenitor cell
mobilization may be a consequence of an alternation in the expression
of cellular adhesion molecules is supported by several
studies.22 The same adhesion molecules found on neutrophils
are also expressed on progenitor cells, and similar mechanisms of
neutrophils and progenitor cell mobilization from the marrow occur.
Preclinical studies of IL-8's effect on progenitor cell mobilization
have shown that IL-8 is a powerful mobilizing agent in animals.23,24 The maximal effect of exogenous IL-8 on the
number of circulating progenitors occurs from minutes to hours after its administration, before any proliferative effects have
occurred.25 Based on these studies and our study, we
speculate that increased IL-8 levels may trigger the migration of
progenitor cells from the marrow to the circulation. A previous report
demonstrated that the overproduction of IL-8 impaired neutrophil
migration and prolonged vascular neutrophil circulation
time.26 Thus, secreted IL-8 might also contribute to a
prolonged intravascular progenitor cell circulation time.
Alternatively, the increased endogenous IL-8 release may be the
consequence of enhanced differentiation of committed progenitor cells.
The mechanism of IL-8 induction and the cellular origin during G-CSF
treatment were not examined in this study and are currently under
investigation. Furthermore, the production of IL-8 in normal donors and
patients treated with G-CSF and IL-8's mechanistic role in progenitor
cell mobilization should be confirmed.
In addition, the possibility of synergistic effects of G-CSF and IL-8
in progenitor cell mobilization awaits further investigation. Stem cell
donors, particularly autologous donors who respond poorly to G-CSF
administration, might have an increased frequency of mobilized
progenitor cells with IL-8 administration. This is particularly important in the subset of patients from whom it is difficult to
collect a sufficient number of progenitor cells for transplantation. Because of this problem, several cytokine combinations have been used
with variable success to improve the progenitor cell
yield.27,28 In addition, anti-integrin antibody has been
used to enhance progenitor cell mobilization in mice and
baboons.29 In this regard, it is noteworthy that high IL-8
secretion levels were not observed in our studies with donors who
mobilized poorly. Thus, we speculate that serum IL-8 measurement may be
useful to prospectively identify donors or patients who will mobilize
poorly and subsequently lead to the use of more effective mobilization
protocol, including higher dose of mobilizing cytokines, cytokine
combination, or potentially the use of monoclonal antibodies directed
against cell adhesion molecules. Based on these results, future
strategies to improve the yield of progenitor cells from poor
responders to G-CSF treatment could include the sequential
administration of G-CSF and IL-8. Because the systemic administration
of IL-8 did not induce hemodynamic and metabolic aberrations or acute organ damage in primate study,30 the addition of IL-8 or
another chemokine to a mobilization protocol might be indicated and should be considered.
In this study, as in other studies,31 a correlation between
WBC count and the frequency of CD34+ cells or CFU-GM was
not observed, and a high WBC count was not a prerequisite for an
acceptable stem cell collection. In contrast, preapheresis serum IL-8
levels (those sampled immediately before the first apheresis on day 5 of G-CSF treatment) correlated with the yield of CD34+
cells, suggesting that serum IL-8 measurement might provide an additional tool for defining the exact timing of PBSC harvest, supplementing the current technologies for measuring blood
CD34+ cell levels that are accepted tools for predicting
yields.32
In conclusion, our data demonstrate that the sharp increase in serum
IL-8 levels that are present on days 5 and 6 of G-CSF treatment are
correlated with the number of circulating progenitor cells (ie,
CD34+ cells and CFU-GM). Although no underlying mechanism
was studied, this suggests that the endogenous surge in the IL-8 level
may be an important mechanism in progenitor cell mobilization and one
mechanism for G-CSF-induced PBSC mobilization might be the enhanced
exogenous IL-8 levels. To further characterize this possible mechanism
of mobilization, we are currently investigating the combination effects
of sequential administration of G-CSF and IL-8 on progenitor
mobilization in mice. In these studies, the direct source and mechanism
of IL-8 secretion during G-CSF treatment will also be investigated.
| |
ACKNOWLEDGMENT |
The authors thank Lisa Chudomelka for preparation of the manuscript and
Toshiko Yasuda for excellent technical assistance.
| |
FOOTNOTES |
Submitted June 5, 1998; accepted October 15, 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 Tsutomu Watanabe, MD, Department of
Pediatrics, Tokushima University School of Medicine, Kuromoto-cho
3-18-15, Tokushima 770-8503, Japan; e-mail:
twatanab{at}clin.med.tokushima-u.ac.jp.
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Abstract
Introduction