Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3467-3472
Additive Effects of Human Recombinant Interleukin-11 and Granulocyte
Colony-Stimulating Factor in Experimental Gram-Negative Sepsis
By
Steven M. Opal,
Jhung W. Jhung,
James C. Keith Jr,
Samuel J. Goldman,
John E. Palardy, and
Nicolas A. Parejo
From the Infectious Disease Division and the Pathology Department,
Memorial Hospital of Rhode Island and Brown University School of
Medicine, Providence, RI; and Genetics Institute, Cambridge, MA.
 |
ABSTRACT |
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is
widely used to promote granulocyte recovery from a variety of
pathologic states. Recombinant human interleukin-11 (rhIL-11) has
recently become available clinically as a platelet restorative agent
after myelosuppressive chemotherapy. Preclinical data has shown that
rhIL-11 limits mucosal injury after chemotherapy and attenuates the
proinflammatory cytokine response. The potential efficacy of
combination therapy with recombinant human forms of rhIL-11 and rhG-CSF
was studied in a neutropenic rat model of Pseudomonas
aeruginosa sepsis. At the onset of neutropenia, animals were
randomly assigned to receive either rhG-CSF at a dose of 200 µg/kg subcutaneously every 24 hours for 7 days; rhIL-11 at 200 µg/kg subcutaneously every 24 hours for 7 days; the combination of
both rhG-CSF and rhIL-11; or saline control. Animals were orally colonized with Pseudomonas aeruginosa 12.4.4 and then given a myelosuppressive dose of cyclophosphamide. rhG-CSF resulted in a slight
increase in absolute neutrophil counts (ANC), but did not provide a
survival advantage (0 of 12, 0% survival) compared with the placebo
group (1 of 12 , 8% survival). rhIL-11 was partially protective (4 of
10, 40% survival); the combination of rhG-CSF and rhIL-11 resulted in
a survival rate of 80% (16 of 20; P < .001). rhIL-11 alone
or in combination with rhG-CSF resulted in preservation of
gastrointestinal mucosal integrity (P < .001), lower
circulating endotoxin levels (P < .01), and reduced
quantitative levels of P. aeruginosa in quantitative organ
cultures. These results indicate that the combination of rhIL-11 and
rhG-CSF is additive as a treatment strategy in the prevention and
treatment of experimental Gram-negative sepsis in immunocompromised
animals. This combination may prove to be efficacious in the prevention of severe sepsis in neutropenic patients.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
THE MANAGEMENT OF septic complications
associated with intensive cytoreductive chemotherapy has improved
significantly with the introduction of hematopoietic growth factors in
clinical medicine.1,2 Nonetheless, patients with prolonged
periods of neutropenia continue to suffer considerable febrile
morbidity and remain at risk for potentially lethal systemic
infections.3 Recent advances in the understanding of the
protective role of the intestinal epithelium against microbial
invasion4 and the interactions between multiple cytokines
and growth factors offer the possibility that additional levels of
protection may be afforded immunocompromised patients from septic
complications.5
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) has
become the standard adjunctive therapy to promote granulocyte recovery
after intensive chemotherapy.1 In clinical trials in cancer
patients, rhG-CSF has been shown to significantly reduce the duration
of fever and neutropenia after cytoreductive
chemotherapy.6,7 In addition to its effects as a
granulocytic growth factor, rhG-CSF has immunomodulatory effects that
may benefit severely septic patients. rhG-CSF has been shown to promote
neutrophil phagocytic and oxidative bactericidal
activity.8-11 rhG-CSF may have some antiinflammatory
properties as well. There is evidence that rhG-CSF can decrease the
synthesis of proinflammatory mediators such as interleukin-12 (IL-12),
interferon 
, and tumor necrosis factor (TNF)-
and increase the
synthesis antiinflammatory mediators such as IL-10 and IL-1 receptor
antagonist.812 The clinical relevance of these
antiinflammatory activities of G-CSF in neutropenic patients are not
clear at the present time.
IL-11 is a 178-amino acid, nonglycosylated multifunctional cytokine
that belongs to the IL-6 family of GP130 receptor
ligands.13 IL-11 binds to a unique alpha
receptor14-16 and activates cells via the ubiquitous GP-130
signal transduction pathway.14,17,18 The recombinant human
form of IL-11 (rhIL-11) has recently been approved for clinical use as
a platelet restorative agent after chemotherapy-induced
myelosuppression.19-21 This cytokine has a number of other
potential therapeutic indications that are under preclinical and
clinical development at the present time. IL-11 has the capacity to
limit chemotherapy and radiation therapy-induced apoptosis of
epithelial cells22 and maintain gastrointestinal mucosal
integrity in a variety of pathologic states.4,23,24 This
activity may be of particular value in the prevention of gut-derived
bacterial translocation and sepsis in immunocompromised patients.
Our laboratory has previously shown that IL-11 given intravenously in
high doses can rescue neutropenic animals from otherwise lethal sepsis
from Pseudomonas aeruginosa.25 The current series of experiments were designed to test the hypothesis that IL-11 could
provide additive benefit in combination with G-CSF after cytoreductive
chemotherapy. This combination of growth factors was tested in an
experimental system designed to mimic the pathophysiologic events that
may occur in neutropenic sepsis in humans.26
| |
MATERIALS AND METHODS |
Reagents and bacterial strains.
The chemicals and reagents used in these experiments were obtained from
Sigma (St Louis, MO) except for cefamandole, which was purchased from
Eli Lilly (Indianapolis, IN). rhIL-11 was provided by Genetics
Institute (Cambridge, MA) as the 177 amino acid human protein produced
in Escherichia coli (E. coli). The rhG-CSF was obtained
from Amgen (Thousand Oaks, CA). The bacterial challenge strain was
Pseudomonas aeruginosa 12.4.4. This strain was initially obtained as a gift from A. McManus (United States Army Institute of
Surgical Research, San Antonio, TX). This strain is a serum-resistant, human blood isolate belonging to Fisher-Devlin-Gnabasik immunotype 6.25
Animal model.
The details of the neutropenic rat model have been published in detail
previously.25 In brief, female, Albino,
specific-pathogen-free, Sprague-Dawley rats (Charles River
Breeding Laboratories, Wilmington, MA) weighing 150 to 200 g were used in these experiments. The protocol was reviewed and
approved by the Brown University Animal Care Committee and was
conducted under National Research Council animal care guidelines. The
animals were kept in biosafety cabinets and allowed to feed and drink
water ad libitum.
The animals were first treated with cefamandole (100 mg/kg
intramuscular [IM]) to disrupt bacterial colonization resistance within the rat gastrointestinal tract. Animals were then colonized with P. aeruginosa 12.4.4 by orogastric feeding of
106 bacterial colony-forming unit (CFU)/mL at
time 0, 48, and 96 hours. Cyclophosphamide (Bristol-Myers, Evansville,
IN) was given intraperitoneally at 150 mg/kg at time 0 and 50 mg/kg
intraperitoneally at 72 hours.
Animals were monitored daily for evidence of overt illness and had
temperature readings performed with a noncontact, digital, infrared
thermometer (Horiba Instruments, Markson Sciences, Phoenix, AZ). At the
onset of neutropenia (between 120 and 148 hours), blood samples were
taken and treatment was instituted with rhIL-11 (200 µg/kg)
subcutaneously every 24 hours for 7 days; rhG-CSF (200 µg/kg)
subcutaneously every 24 hours for 7 days; the combination of rhIL-11
and rhG-CSF; or saline for the control group. Animals were randomly
assigned to the saline control group (n = 12), rhG-CSF + saline (n = 12), rhIL-11 + saline (n = 10), or the combination of rhG-CSF + rhIL-11
(n = 20).
Periodic blood sampling was performed from the retro-orbital plexus
under light CO2 anesthesia. Blood was obtained for white blood cell counts (by Coulter counter, Coulter Corp, Miami, FL) and
serum endotoxin (by quantitative turbidimetric Limulus Amebocyte Lysate
assay, Associates of Cape Cod, Woods Hole, MA). Blood cultures were
obtained at the onset of fever and quantitative bacteriology was
performed by standard methods (Pseudomonas isolation agar and serotypic
methods [Difco, Detroit, MI]).
Animals were observed several times daily for up to 14 days after the
cyclophosphamide dose when bone marrow recovery was complete. Each
animal that succumbed from infection and those animals that survived
the experiment were killed and subjected to necropsy examination.
Histologic examination of the lung, liver, kidney, adrenal, and the
small and large intestine was performed by a pathologist who was
unaware of the treatment given to each animal. A histologic score for
gastrointestinal pathology was developed as follows: 0, normal;
1, minimal thinning of mucosa; 2, moderate thinning and
inflammation; 3, marked thinning and inflammation with focal areas of
necrosis; 4, diffuse thinning and necrosis.
Statistical analysis.
Numeric values are presented as mean ± standard deviation.
Continuous variables were analyzed by a one-way analysis of variance (ANOVA) followed by the Tukey-Kramer multiple comparisons test for
multiple groups or Mann-Whitney U-test for two groups. Survival functions are presented as a Kaplan-Meier plot and differences in
survival time were determined by the ANOVA. P values less than .05 were considered significant.
| |
RESULTS |
Effects of combination therapy on survival.
Kaplan-Meier plot of the survival function for each group in these
experiments is provided in Fig 1. Animals
that succumbed over the experimental period had histopathologic
evidence of multisystem infection with the challenge strain of
Pseudomonas aeruginosa 12.4.4 and pathologic findings of acute
tubular necrosis, adrenal hemorrhage, pulmonary congestion, and diffuse
interstitial edema. rhG-CSF even at doses of 200 µg/kg was not able
to salvage these animals from lethal infection from Pseudomonas
aeruginosa. rhIL-11 alone was partially protective (40% survival;
P < .05) and the combination of rhG-CSF and rhIL-11 resulted
in the most favorable outcome (16 of 20 or 80%; P < .001).
The combination was superior to rhIL-11 alone (P < .05).
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| Fig 1.
Kaplan-Meier survival plot of animals treated with
rhG-CSF, rhIL-11, combination of both growth factors, or the control
group.
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Pathologic and microbiologic findings.
Pathologic findings in the small and large intestine were strikingly
different depending on the treatment group.
Figure 2A shows a representative pathologic
sample from an animal assigned to the control group. Marked thinning of
the bowel wall and extensive areas of epithelial cell sloughing was
noted. Animals randomized to rhG-CSF treatment had minimal improvement
in histologic findings with focal regions of preserved epithelium (Fig
2B). Animals randomized to the rhIL-11 group showed substantial
improvement with thickening of the epithelial layer and preservation of
mucosal cell integrity (Fig 2C). Animals receiving both rhG-CSF and
rhIL-11 had the most favorable histologic findings with normal mucosal
thickness, minimal inflammatory changes, and preserved tissue
architecture (Fig 2D). The composite analysis of the gastrointestinal
pathology is provided in Table 1.
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| Fig 2.
Histopathology of small intestinal mucosa cut in
transection from an animal in each treatment group (study day 8). The
upper panel (row 1) is a low power view (original magnification × 57); the lower panel (row 2) is a high power view (original
magnification × 144). Note the diffuse thinning and necrosis of the
mucosa with sloughing of intestinal epithelial cells in the control
animal (A). There is progressive recovery of the thickness of the
mucosa, reduction in inflammatory changes, and improved epithelial
architecture with rhG-CSF (B), rhIL-11 (C), and combination therapy
with rhG-CSF+IL-11 (D).
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|
The microbiological findings from blood cultures and organ cultures are
found in Table 1. Bacteremia from the challenge strain of
Pseudomonas aeruginosa was detected in one or both quantitative blood cultures obtained at the onset of fever in over 75% of the animals. Treatment with either rhG-CSF or rhIL-11 or the combination did not significantly reduce the frequency of bacteremia. There is a
trend towards reduced quantitative levels of bacteremia in the animals
treated with rhIL-11 or the combination of rhIL-11 and rhG-CSF, but
these differences did not reach statistical significance. The tissue
levels of bacterial densities and circulating levels of bacterial
endotoxin were significantly reduced by rhIL-11 alone or the
combination of rhIL-11 and rhG-CSF. The rhG-CSF alone treatment group
had a trend towards reduced tissue concentrations of P. aeruginosa compared with the control group, but this difference did not reach statistical significance.
The effects of rhG-CSF and rhIL-11 on the ANC over the course of the
experiments are provided in Fig 3. In
preliminary dose-finding experiments, rhG-CSF at this dose regimen was
capable of significant improvements (fivefold increase over control) in
neutrophil counts (data not shown). In the current set of experiments,
rhG-CSF resulted in a twofold to threefold increase in neutrophil
counts during the nadir of severe neutropenia (day 5; P < .05); however, only the combination of rhIL-11 and rhG-CSF exhibited a
sustained increase in neutrophil counts throughout the entire
neutropenic period (P < .01).
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| Fig 3.
ANC/mm3 over the course of the 14-day
experimental period in each treatment group. Neutrophil recovery was
significantly accelerated by the combination treatment (rhG-CSF + rhIL-11) compared with each treatment alone or the control group
(P < .01).
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| |
DISCUSSION |
Recombinant human IL-11 has consistently afforded protection in
neutropenic animals whether given intravenously alone,27 with antimicrobial agents,25 or subcutaneously as observed
in the current trial. In addition to its hematopoietic effects, rhIL-11 has antiinflammatory properties that attenuate the production of the
proinflammatory cytokines. rhIL-11 has been shown to decrease the
production of TNF-, IL-12, interferon , and the synthesis and
release of nitric oxide.17 rhIL-11 limits the hemodynamic effects of endotoxin challenge in an experimental sepsis
model28 and provides a survival advantage in animals
exposed to an otherwise lethal challenge with Gram-positive bacteria or
superantigen-induced shock.29
The mechanism of inhibition of proinflammatory cytokine synthesis by
rhIL-11 appears to be related to its ability to induce the synthesis of
I
B in monocytes. IB binds to NFB in the cytoplasm of cells and
prevents its nuclear translocation. NFB is an important transcriptional activator for a large number of proinflammatory cytokines including TNF- and IL-1
. Inhibition of nuclear
translocation of NFB by rhIL-11 downregulates cytokine synthesis by
CD14+ mononuclear cells.30 Moreover, recent
evidence suggests that rhIL-11 also directly affects T-cell function.
rhIL-1I promotes a Th2-type cytokine response in experimental animal
models after allogeneic bone marrow transplantation.31
rhIL-11 has been shown to have marked effects on gastrointestinal
epithelial surfaces. rhIL-11 blocks apoptosis of epithelial cells
exposed to radiation and chemotherapy in mice.22 rhIL-11 is
protective in a variety of mucositis models and in models of intestinal
inflammation.4,23,24 rhIL-11 has been shown to prolong the
G-0 phase of growth of intestinal epithelial cells. The precise
mechanism of action is not known, but it has been observed that rhIL-11
decreased pRB (retinoblastoma protein) phosphorylation (an
important signaling event in cell cycling) within intestinal epithelial
cells.32 rhIL-11 has protective effects on gastrointestinal mucosa in transgenic rats, which possess HLA-B27 antigens.4 These animals develop an inflammatory colitis that is similar in many
respects to human inflammatory bowel disease. rhIL-11 treatment in
these animals decreases intestinal inflammation and chronic diarrhea.
Based on these preclinical findings, rhIL-11 is currently in clinical
trials in both inflammatory bowel disease and chemotherapy-induced
mucositis.33 The remarkable capacity of rhIL-11 to protect
the gastrointestinal mucosal integrity after chemotherapy is apparent
in the current series of experiments (Fig 2).
The beneficial effects of rhIL-11 in the neutropenic rat model may be
mediated by its activity as a hematopoietic growth factor, an
antiinflammatory cytokine, or its ability to maintain gastrointestinal epithelial integrity.25,33 The results of the current study would favor rhIL-11 protective effects on the intestinal epithelium as
the principal mechanism protection in these animals. Maintenance of the
gastrointestinal barrier function should diminish the frequency of gut
translocation-derived bacterial infection after chemotherapy-induced myelosuppression and epithelial injury.25 The remarkable
preservation of membrane integrity found on the gastrointestinal
pathologic samples, the reduced circulating levels of endotoxin, and
the reduced bacterial load in organ cultures support a dominant role for epithelial protective effects by rhIL-11 treatment in this animal model.
The modest effects of rhG-CSF in the granulocyte recovery observed in
these animals did not result in a survival advantage in the presence of
Pseudomonas aeruginosa sepsis. This may be attributed to some
species differences in the avidity of human recombinant G-CSF in the
rat. It is of interest to note that rhG-CSF has previously been shown
to be efficacious in neutropenic mice with experimental
sepsis11,34 and rats with intraabdominal sepsis.12 The lack of protection observed in the current
study may be a consequence of the intrinsic virulence of the infecting
strain of P. aeruginosa,26 the route of the septic
challenge, the duration of neutropenia, and the absence of
antimicrobial agents directed against the challenge strain in this
series of experiments.25
The combination of rhIL-11 and rhG-CSF was additive and potentially
synergistic in the prevention against lethality in the neutropenic rat
model. The combination treatment resulted in 80% survival, while less
than 10% of animals in the control group survived. rhIL-11 may reduce
accumulation of pulmonary edema fluid that has been associated with the
rhG-CSF treatment given as a single agent.1 This may be the
result of the antiinflammatory effects of rhIL-11. rhIL-11 attenuates
the excess production of proinflammatory cytokines that may be
deleterious in systemic inflammatory states such as septic
shock.35
The explanation for the added benefit of rhG-CSF to rhIL-11 therapy
alone has not been identified in this study. It may be related to the
promotion of phagocytic activity and oxidative bactericidal capacity
neutrophils by rhG-CSF therapy.8-11 It is also possible
that the combination of rhIL-11 and rhG-CSF expanded the neutrophil
pool in these animals. rhIL-11 promotes early progenitor stem cell
differentiation and acts in concert with other growth factors such as
rhG-CSF to promote granulocyte development. The two hematopoietic
growth factors have been shown to be synergistic in the promotion of
granulopoiesis.36 It is possible that the expansion of the
absolute neutrophil population within the animal may not have been
detected from measurements of circulating granulocyte populations in
these septic animals with severe chemotherapy-induced neutropenia.
In summary, the results indicate that the combination of rhG-CSF and
rhIL-11 was additive in the prevention of mortality in this
experimental model of neutropenic sepsis. The model is designed to
mimic the pathophysiologic events that may occur in patients after
cytoreductive chemotherapy.25,26 The animals are colonized by the opportunistic bacterial pathogen, Pseudomonas
aeruginosa. The animals subsequently develop Gram-negative sepsis
as a result of translocation of bacteria across a damaged
gastrointestinal mucosal barrier. The presence of neutropenia prevents
the rapid clearance of microbial pathogens and multisystem infection
and sepsis results. Animals develop bacteremia and endotoxemia and succumb from multiorgan failure unless specific therapy is instituted.
Recent evidence indicates that the salutary effects of IL-11 on
gastrointestinal membrane integrity may extend to the respiratory epithelium as well.37 Transgenic mice that express
increased amounts of IL-11 on respiratory epithelial surfaces were
protected from hyperoxia-induced lethality and had reduced expression
of IL-1 and TNF in airways exposed to 100% oxygen. IL-11 also protects the mucous membranes of the oropharnynx for chemotherapy-induced mucositis in experimental animal systems.4 The mucosal
protection afforded by rhIL-11 may prove to be generally applicable in
a wide range of potential therapeutic indications.
The advantageous effects of the combination rhG-CSF and rhIL-11 in this
experiment suggests that a similar approach might be useful in the
management of chemotherapy-induced myelosuppression in patients. The
desirable attributes of rhIL-11 combined with the established capacity
of rhG-CSF to promote granulocyte recovery may diminish infection risk
in neutropenic patients. The combination strategy will need to be
studied in clinical trials to determine if additive or synergistic
effects accrue from rhG-CSF and rhIL-11 therapy in the management of
neutropenic patients.
| |
FOOTNOTES |
Submitted August 10, 1998; accepted January 7, 1999.
Supported by Genetics Institute, Cambridge, MA.
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.
Presented in part at the 37th Annual Interscience Conference on
Antimicrobial Agents and Chemotherapy, held in Toronto, Ontario,
Canada, September 30, 1997.
Address reprint requests to Steven M. Opal, MD, Infectious
Disease Division, Memorial Hospital of Rhode Island and Brown
University School of Medicine, 111 Brewster St, Providence, RI 02860.
| |
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TOP
ABSTRACT
INTRODUCTION
