By
From the * Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical
School, Boston, Massachusetts 02215; the Institut für Pathologie/Tumorimmunologie, Universität
Regensburg, D-93042, Regensburg, Germany; § Forschungszentrum für Umwelt und Gesundheit-Institut
für Experimentelle Hämatologie, D-81337, München, Germany; the
Department of Molecular
Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and ¶ Amgen Inc., Thousand Oaks,
California 91320
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Abstract |
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Mast cells are thought to contribute significantly to the pathology and mortality associated with
anaphylaxis and other allergic disorders. However, studies using genetically mast cell-deficient WBB6F1-KitW/KitW-v and congenic wild-type (WBB6F1-+/+) mice indicate that mast cells can also promote health, by participating in natural immune responses to bacterial infection.
We previously reported that repetitive administration of the c-kit ligand, stem cell factor
(SCF), can increase mast cell numbers in normal mice in vivo. In vitro studies have indicated
that SCF can also modulate mast cell effector function. We now report that treatment with
SCF can significantly improve the survival of normal C57BL/6 mice in a model of acute bacterial peritonitis, cecal ligation and puncture (CLP). Experiments in mast cell-reconstituted
WBB6F1-KitW/KitW-v mice indicate that this effect of SCF treatment reflects, at least in part,
the actions of SCF on mast cells. Repetitive administration of SCF also can enhance survival in
mice that genetically lack tumor necrosis factor (TNF)-, demonstrating that the ability of SCF
treatment to improve survival after CLP does not solely reflect effects of SCF on mast cell-
dependent (or -independent) production of TNF-
. These findings identify c-kit and mast
cells as potential therapeutic targets for enhancing innate immune responses.
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Introduction |
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Mast cells are thought of primarily as key effector cells
in IgE-dependent immune responses, such as those
involved in the pathogenesis of allergic disorders or in certain examples of immunity to parasites (1). However, recent work has identified another facet of mast cell effector
function, the promotion of innate, or "natural", immunity
to bacterial infection (2, 3). For example, Echtenacher et al.
(2) reported that genetically mast cell-deficient KitW/KitW-v
mice exhibited greatly increased mortality after cecal ligation and puncture (CLP)1 compared with wild-type mice,
and that the survival of KitW/KitW-v mice in this model of
septic peritonitis was improved if the KitW/KitW-v mice had
undergone adoptive repair of their peritoneal mast cell deficiency before CLP. The same study also showed that the
mast cell-dependent protective response to CLP could be
greatly diminished in mice treated with antibodies to TNF-
(2). Prodeus et al. (4) later reported that normal levels of
mast cell activation and TNF-
production in this CLP
model required an intact complement system, and that
complement C3 or C4 knockout mice had greatly increased
mortality after CLP compared with wild-type mice.
These findings indicated that a lack of mast cells, or deficits in other components of innate defense mechanisms
(e.g., TNF-, complement), can result in impaired natural
immunity to bacterial infection (2). However, these
studies did not evaluate whether, in normal animals, manipulations that can increase mast cell numbers and/or enhance mast cell function might improve the animals' ability to express innate immunity.
We therefore investigated whether repetitive administration of the c-kit ligand, stem cell factor (SCF [references 6, 7]; also known as kit ligand [reference 8], mast cell growth factor [MGF, reference 9], or steel factor [reference 10]), could influence the survival of mice subjected to CLP. By acting synergistically with other growth factors, SCF can promote the proliferation and further differentiation of hematopoietic progenitor cells; SCF is also critical for the normal development of germ cells, melanocytes, and interstitial cells of Cajal (6, 7). However, interactions between SCF and c-kit are especially important in promoting mast cell survival (11), proliferation (14, 15), and maturation (14, 15), and can also enhance certain mast cell effector functions (16). We previously reported that the daily subcutaneous administration of E. coli-derived recombinant rat SCF164 (rrSCF164) to normal mice or rats can increase mast cell numbers in many anatomical sites, including the peritoneal cavity (13, 15, 20). We now report that repetitive treatment of mice with SCF can markedly improve their survival after CLP, and that this effect of SCF treatment reflects, at least in part, its actions on mast cells.
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Materials and Methods |
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Animals.
C57BL/6 mice, genetically mast cell-deficient WBB6F1-KitW/KitW-v (KitW/KitW-v) mice, and the congenic normal WBB6F1-+/+ (Kit+/+) mice were purchased from The Jackson Laboratory, Bar Harbor, ME. Adult KitW/KitW-v mice ordinarily contain <1.0% of the number of dermal mast cells present in the skin of the congenic normal (+/+) mice, and have no detectable mature mast cells in the gastrointestinal tract or peritoneal cavity (21). TNF-Treatment with SCF.
Mice received 21 daily subcutaneous injections into the same area of back skin of vehicle alone (sterile 0.9% NaCl containing 0.1% BSA, fraction V, fatty acid-free [ICN Immunobiologicals, Lisle, IL]), Escherichia coli-derived recombinant rat SCF164 (rrSCF164) at 50, 100, or 200 µg/kg per day in 150-250 µl of vehicle, or rrSCF164 that had been modified by the covalent attachment of polyethylene glycol (rrSCF164-peg) to increase the biological half-life of the cytokine, at 30 or 100 µg/kg per day in 150-250 µl of vehicle (13, 15, 25). rrSCF164 and rrSCF164-peg were from AMGEN Inc. (Thousand Oaks, CA).Peritoneal Lavage.
Mice were killed by CO2 inhalation, then the abdominal skin was washed with 70% ethanol, the peritoneum was exposed by a 1-2-cm midline abdominal incision, and 2.0 ml of sterile, pyrogen-free 0.9% NaCl and 8.0 ml of air were injected into the peritoneal cavity via a 25-gauge needle. The abdomen was massaged gently for ~3 min and the peritoneal fluid was recovered via a 22-gauge needle, stained for mast cells by Kimura stain, and counted in a Neubauer chamber; the lavage fluid was then cytospun and stained by May Grünwald-Giemsa stain (26).Cecal Ligation and Puncture.
CLP was performed as previously described (2, 27). In brief, mice were deeply anesthetized and the cecum was exposed by a 1-2-cm midline incision on the anterior abdomen and subjected to ligation of the distal half followed by a single puncture with a 0.7- or 0.9-mm (for TNF-Selective Mast Cell Reconstitution of KitW/KitW-v Mice.
Kit W /KitW-v mice (male, 4-6 wk old) were repaired of their mast cell deficiency selectively and locally by the injection of growth factor- dependent bone marrow-derived cultured mast cells (BMCMCs) into the peritoneal cavity (2, 23). In brief, femoral bone marrow cells from Kit+/+ mice were maintained in vitro for ~4 wk in IL-3-containing, Con A-stimulated mouse spleen cell-conditioned medium until mast cells represented >95% of the total cells according to staining by Giemsa (6, 16, 22). Mast cells (106 in 200 µl of Hanks' MEM containing 0.47 g/liter Pipes instead of NaHCo3 [HMEM-Pipes]) or HMEM-Pipes alone were injected intraperitoneally and mice were used for experiments, together with gender- and age-matched mast cell-deficient KitW/KitW-v and Kit+/+ mice, 4 wk after adoptive transfer of cultured mast cells. The selectivity of the repair of the mast cell deficiency of the KitW/KitW-v mice was assessed before using the mice in experiments by confirming that the adoptive transfer of BMCMCs failed to improve the recipients' anemia (6, 22, 23).Histologic Studies.
After the mice had been killed, biopsy specimens of the back skin at SCF or vehicle injection sites were fixed in Carnoy's fixative, processed into paraffin-embedded, Alcian blue-stained sections, coded so that the observer was not aware of the identity of the individual specimens, and then examined at 400× by light microscopy to quantify mast cells per squared millimeter of dermis (15).Statistical Analysis.
The significance of differences in the survival rates after CLP was assessed using the Mantel-Cox Logrank test. All other data were tested for statistical significance using the unpaired two-tailed Student's t test. Unless otherwise specified, all data are presented as the mean ± SEM. ![]() |
Results and Discussion |
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We first administered various doses of non-peg-derivatized rrSCF164 (rrSCF) or peg-derivatized rrSCF164 (rrSCF-peg), or vehicle alone subcutaneously to C57BL/6 mice daily for 21 d, then killed some of the mice for quantification of mast cells in the peritoneal cavity and in the rrSCF or vehicle cutaneous injection sites, whereas other, identically treated, mice underwent CLP; the CLP-treated mice continued to receive daily subcutaneous injections of rrSCF, rrSCF-peg, or vehicle for as long as they survived.
We found that rrSCF-peg was more effective than rrSCF in increasing numbers of mast cells at the cutaneous injection sites (Fig. 1 A) or in the peritoneal cavity (Fig. 1 B). Both rrSCF-peg and rrSCF exhibited a positive dose- response effect on mast cell numbers at the skin injection sites (Fig. 1 A), whereas rrSCF-peg gave high, but statistically indistinguishable, enhancement of numbers of peritoneal mast cells (PMCs) at either 30 or 100 µg/kg per day (Fig. 1 B).
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Survival after CLP was significantly better in all SCF treatment groups (compared with that in the vehicle-treated group) except for the one that had been treated with rrSCF at 50 µg/kg per day (Fig. 1 C). Even mice treated with rrSCF at 100 µg/kg per day, a dose that had little or no effect on numbers (Fig. 1 A) or percentages (data not shown) of PMCs, exhibited ~2× the survival after CLP as did vehicle-treated mice (P = 0.01). However, the best survival after CLP (~2.5× the level in the vehicle-treated group, i.e., 53 vs. 15% survival at 14 d, P < 0.0001) was observed in mice treated with rrSCF-peg at 30 µg/kg per day (Fig. 1 C). This was also the treatment protocol that had the greatest effect on numbers of PMCs (Fig. 1 B). Accordingly, we used this dose of rrSCF-peg in the rest of our studies.
Repetitive Treatment with SCF Improves Survival after CLP in Mast Cell-reconstituted WBB6F1-KitW/KitW-v Mice, but Not in Mast Cell-deficient KitW/KitW-v Mice.Mast cells are
distinct from virtually all other hematopoietic lineages in
that mature cells continue to express relatively high levels
of c-kit (6, 7). Moreover, at the doses tested in this report,
rrSCF has modest or no effects on numbers of circulating leukocytes in normal mice (6). Nevertheless, it is possible that some of the protective effects of SCF treatment in
CLP in normal mice might reflect actions of SCF on the
numbers or function of c-kit+ cell types other than mast
cells. To address this possibility, we performed two experiments in which rrSCF-peg-(30 µg/kg per day) or vehicle-treated mast cell-deficient KitW/KitW-v mice were subjected
to CLP after some of the mice had undergone adoptive
repair of their peritoneal mast cell deficiency (i.e., +/+
BMCMC KitW/KitW-v mice) by the intraperitoneal
transfer of BMCMCs of Kit+/+ origin. The data from these
two experiments, which gave very similar results, are
pooled in Fig. 2.
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SCF treatment had no significant effects on PMC numbers (Fig. 2 A) nor on overall or late (after day 3) survival after CLP (Fig. 2 B and Table 1) in KitW/KitW-v mice; these
mice express kit derived from the KitW-v c-kit allele, which
exhibits markedly reduced tyrosine kinase activity upon
binding of SCF (28). By contrast, both overall and late
survival were significantly better in SCF-treated +/+ BMCMC KitW/KitW-v mice than in either SCF- or vehicle-treated mast cell-deficient KitW/KitW-v mice (Fig. 2 B
and Table 1). Moreover, SCF treatment not only increased
PMC numbers in +/+ BMCMC
KitW/KitW-v mice (by
~160%, P = 0.019; Fig. 2 A), but also increased CLP survival in these mice (from ~4 to ~21% at day 14, P = 0.0811 for overall survival, P = 0.0169 for survival after day 3, versus the corresponding values in the vehicle-treated +/+
BMCMC
KitW/KitW-v mice (Fig. 2 B and Table 1).
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Because the repair of the mast cell deficiency in +/+
BMCMC KitW/KitW-v mice is selective (2, 22, 23), the
adoptively transferred mast cells are the only cellular lineage
in these mice that express the wild-type kit. Accordingly,
the ability of SCF treatment to enhance survival after CLP
in +/+ BMCMC
KitW/KitW-v mice must reflect actions
of SCF treatment on mast cells. Indeed, CLP survival in
SCF-treated +/+ BMCMC
KitW/KitW-v mice was not
significantly different (albeit somewhat lower) than that in
SCF-treated wild-type mice (Fig. 2 B and Table 1). However, compared with results in C57BL/6 mice, treatment
of Kit+/+ mice with rrSCF-peg at 30 µg/kg per day had
more modest effects on both PMC numbers (compare Fig.
2 A with Fig. 1 B) and survival after CLP (compare Fig. 2
B with Fig. 1 C), perhaps reflecting strain differences in
these responses to SCF treatment. Note also that despite
having higher numbers of PMCs (Fig. 2 A), vehicle-treated +/+ BMCMC
KitW/KitW-v mice had significantly
poorer survival 14 d after CLP than did vehicle-treated
Kit+/+ mice (~4 vs. 30%, P < 0.0001 for overall survival
and P = 0.0846 for after day 3 survival). A number of factors may have contributed to this finding, including phenotypic/functional differences between the endogenous
PMCs in Kit+/+ mice and the adoptively transferred, in
vitro-derived mast cells in the +/+ BMCMC
KitW/
KitW-v mice (15, 23).
Several lines of evidence indicate that
TNF- represents one important mediator of mast cell-
dependent host resistance in CLP and other models of innate
immunity to bacteria (2). In support of this hypothesis,
we found that TNF-
/
mice exhibited significantly
impaired survival after the standard CLP procedure (50%
ligation, one needle puncture), in comparison to the corresponding wild-type mice (Fig. 3 A). To assess the extent
to which the effects of SCF treatment on CLP survival
might be TNF-
dependent, we performed two experiments in which survival after CLP was compared in vehicle- or rrSCF-peg- (30 µg/kg per day) treated TNF-
/
or +/+ mice. Both experiments gave very similar results,
which are pooled in Fig. 3, B-D.
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These experiments used a more severe CLP procedure
(80% ligation, two punctures with a 0.9-mm needle) in order to observe better any favorable effect of SCF treatment
on survival. In these experiments, in contrast to those
shown in Fig. 3 A, vehicle-treated TNF-+/+ mice exhibited only marginally enhanced overall survival (P = 0.0655)
compared with vehicle-treated TNF-
/
mice (Fig. 3 B).
However, SCF treatment resulted in improved survival after
CLP in both TNF-
/
mice (P < 0.0001 versus vehicle-treated TNF-
/
mice) and TNF-
+/+ mice (P = 0.0119 versus vehicle-treated TNF-
+/+ mice). Indeed, SCF treatment had an even more striking effect on survival after CLP
in TNF-
/
mice than in the wild-type controls (Fig. 3 B).
Notably, treatment with rrSCF-peg at 30 µg/kg per day did
not significantly increase numbers of PMCs in TNF-
/
or +/+ mice, possibly in part because "baseline" levels of
PMCs (e.g., in vehicle-treated mice) were already substantially higher in TNF-
/
or +/+ mice than in C57BL/6
mice (compare Fig. 3 C with Fig. 1 B). On the other hand,
SCF treatment did greatly increase mast cell numbers at skin
injection sites in TNF-
/
and +/+ mice (Fig. 3 D).
In C57BL/6 mice, repetitive treatment
with SCF significantly enhanced survival after CLP roughly
in parallel with the ability of such treatment to increase
numbers of PMCs. However, improved survival after CLP
was also seen in C57BL/6 mice treated with 100 µg/kg per
day of non-peg-derivatized rrSCF, and in TNF-/
or
TNF-
+/+ mice treated with 30 µg/kg per day of rrSCF-peg, even though these SCF-treated mice did not exhibit
significantly increased numbers of PMCs. The latter findings strongly suggest that actions of SCF treatment other
than simply the expansion of PMC numbers can contribute
to the ability of this agent to enhance survival in CLP.
These alternative consequences of SCF treatment in this model of innate immunity may include effects on mast cell
effector function (16); they also may include actions of
SCF on c-kit+ lineages other than mast cells. For example,
the CD56bright subset of human natural killer cells expresses
c-kit and can exhibit enhanced IFN-
production in response to stimulation with SCF (29, 30); however, we have
no data that would permit us to speculate about the relevance of these in vitro findings in human cells to our in
vivo study in mice.
On the other hand, the experiments with +/+
BMCMC KitW/KitW-v mice indicate that at least some
of the critical effects of SCF on CLP survival can reflect
actions of SCF on mast cells. Thus, KitW/KitW-v mice exhibited no protective effect of SCF treatment on survival after CLP unless the animals had first been repaired of their PMC deficiency; in this setting, only the adoptively transferred mast cells of wild-type origin expressed normal kit,
and therefore could have responded normally to SCF treatment.
Our studies also indicate that treatment with SCF can
enhance survival after CLP even in mice that genetically
lack TNF-, indicating that SCF treatment must be able to
augment mechanisms of host defense in innate immunity
that can be mobilized independently of TNF-
. Finally, in
confirmation of the results of our earlier experiments with
WCB6F1-+/+ mice (20), we found that mice treated with
rrSCF-peg (30 µg/kg per day for 21 d) did not appear to
be at substantially increased risk (versus vehicle-treated
mice) for death when IgE-dependent systemic anaphylaxis
was induced by intraperitoneal challenge with specific antigen (our unpublished data).
These findings are the first to show that survival in a model of innate immunity can be enhanced by treatment with SCF, a cytokine with diverse effects on mast cells, as well as many other cell types. These data are also the first to show that normal animals that have been treated to develop higher than baseline levels of mast cells can exhibit enhanced resistance to bacterial infection. Although great caution must be exercised when extrapolating from mouse studies to human medicine, our findings suggest a new approach for attempting to manage patients at risk for bacterial infection. It may be of particular interest to evaluate SCF treatment in patients with congenital or acquired immunodeficiency disorders, since such individuals have been reported to have greatly decreased numbers of mast cells in the gastrointestinal mucosa (31).
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Footnotes |
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Address correspondence to Stephen J. Galli, Department of Pathology/Division of Experimental Pathology, Research North 227, Beth Israel Deaconess Medical Center-East, PO Box 15707, Boston, MA 02215. Phone: 617-667-5970; Fax: 617-667-3616; E-mail: sgalli{at}bidmc.harvard.edu
Received for publication 9 September 1998.
B. Echtenacher and L. Hültner contributed equally to this paper.We thank Robert Parker of the Biometrics Center of the Beth Israel Deaconess Medical Center for consultation regarding the statistical analysis of the data; S. Fish, Z.-s. Wang, and H. Broszeit for technical assistance; and F.-T. Liu (La Jolla Institute of Allergy and Immunology, San Diego, CA) and D.H. Katz (Medical Biology Institute, La Jolla, CA) for H 1 DNP--26 hybridoma cells.
This work was supported by United States Public Health Science Grants CA/AI72074, AI/GM23990, and 5 U19 AI41995 (Project 1) (to S.J. Galli), by a grant of the Deutsche Forschungsgemeinschaft (to M. Maurer), and by AMGEN Inc. S.J. Galli performs research funded by AMGEN Inc., and consults for AMGEN Inc., under terms that are in accord with Beth Israel Deaconess Medical Center and Harvard Medical School conflict-of-interest policies.
Abbreviations used in this paper BMCMCs, mouse bone marrow-derived cultured mast cells; CLP, cecal ligation and puncture; PMCs, peritoneal mast cells; rrSCF, E. coli-derived recombinant rat stem cell factor164; rrSCF-peg, polyethylene glycol-derivatized rrSCF; SCF, stem cell factor.
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