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*
Division of Infectious Diseases, Centre Hospitalier Universitaire Vaudois-Lausanne, Lausanne, Switzerland;
Pharma Research, Novartis, Basel, Switzerland; and
Laboratory of Immunopharmacology of Microbial Products, Tokyo University of Pharmacy and Life Science, Tokyo, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production and died of overwhelming infection within 24 h, after a
challenge with 250 CFU of virulent Klebsiella
pneumoniae. Blockade of TNF- also increased lethality,
whereas pretreatment with TNF- protected mice, even in the presence
of LBP and CD14 blockade. Anti-LBP or anti-CD14 mAbs did not
improve or decrease lethality with a higher inoculum (105
K. pneumoniae) and did not affect outcome following
injections of low or high inocula of Escherichia coli
O111. These results point to the essential role of LBP/CD14 in innate
immunity against virulent bacteria. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The role of LBP and CD14 in bacterial infections is not clearly defined. LBP and CD14 have been postulated to be a prerequisite in the mechanisms involved in initiation of host defense against Gram-negative bacteria, alarming the host to the presence of minute amounts of LPS (1). In favor of this hypothesis, LBP-/- mice, although resistant to LPS, were susceptible to Salmonella typhimurium (3), and the intestinal mucosa of rabbits treated with a neutralizing anti-CD14 mAb exhibited a 50-fold increase in Shigella invasion and more severe injury compared with controls (10).
The role of excess of proinflammatory cytokines in pathogenic events
triggered by systemic injections of LPS or high numbers of bacteria has
been well documented (11, 12). Yet, in the presence of a
low inoculum of bacteria, endogenous production of cytokines and of
TNF- appears pivotal for normal innate immune responses against an
invading organism. Ab-mediated blockade of TNF- or disruption of the
TNF- gene or of the TNFp55 receptor gene was
detrimental in models of intracellular facultative bacteria
(13, 14, 15, 16). This was also shown for extracellular bacteria,
in models of cecal ligation puncture (17), of pneumonia
(18, 19, 20), or of peritonitis (21). Conversely,
treatment with TNF- improved survival of mice injected with S.
typhimurium or undergoing cecal ligation puncture (22, 23). Importantly, LPS-hyporesponsive C3H/HeJ mice were found to
be more susceptible to lethal infection with Escherichia
coli than normal LPS-responsive mice, a defect that was corrected
by administration of TNF- (24).
Thus a body of data emphasizes the need for an intact mechanism of
recognition of LPS leading to cytokine production in initiating host
defense mechanisms against Gram-negative infections. In the present
study, we investigated the contribution of LBP, CD14, and TNF- in
bacterial sepsis. We hypothesized that blocking of the innate immune
responses with Abs to LBP, CD14, or TNF- may impair the development
of normal innate responses to low doses of bacteria, and thus augment
lethality.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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An encapsulated strain of Klebsiella pneumoniae isolated from a bacteriemic patient was used in the present experiments (25). This strain was selected among other Klebsiella strains for its high virulence in mice. Bacteria were grown for 2 h in tryptic soy broth (Difco, Detroit, MI) and collected in the exponential growth phase at an OD of 0.18, corresponding to 5.5 x 107 ± 0.15 CFU/ml. Bacteria were then diluted to the desired concentration in saline before injection into mice. E. coli O111:B4 was cultivated as described (26).
Reagents and Abs
Two rat mAbs to mouse LBP described in (6) were
studied: 1) the neutralizing mAb (clone M330-9, referred thereafter as
to anti-LBP mAb), preventing the binding of LPS to LBP, suppressing
LPS-induced TNF- production and blocking LBP activity in vivo up to
7 h after injection in mice; and 2) the control anti-LBP mAb
(clone M306-5, referred thereafter as to control mAb), which does not
neutralize LBP activity. 4C1 is a rat mAb that neutralizes mouse CD14
(27). MAbs were purified by protein G chromatography,
dialyzed into PBS, and stored at -80°C. Anti-TNF Abs were raised in
rabbits and polyclonal IgG from immunized rabbits or control rabbits
isolated by protein G chromatography. Recombinant murine TNF- was a
gift from G. Grau (University of Marseille, Marseille, France).
Presence of LPS in reagents was determined with the Limulus
assay (Chromogenix, Embrach, Switzerland). The LPS content of the mAbs
and of the IgG was 1 pg/µg of protein.
Galactosamine model
Because 4C1 Ab has never been evaluated in vivo, we assessed
whether 4C1 prevented endotoxemia in mice sensitized with
D-galactosamine. Mice were injected i.v. with 200 µg of
the neutralizing anti-CD14 mAb 4C1 2 h before an i.p.
challenge of 50 ng of E. coli O111 LPS (Sigma, St. Louis,
MO) given in combination with 20 mg
D-galactosamine (Sigma). Mice were bled 1.5
h after LPS challenge to measure plasma TNF- concentration.
The injection of 4C1 reduced TNF- production, and prevented death (0
deaths/5 mice) compared with injection of saline (5/5) (data not
shown). Similarly to neutralizing anti-LBP mAb, anti-CD14 mAb
was effective at blocking LPS-induced cell activation and death for
5–7 h (data not shown).
Bacterial challenge
OF1 female mice, 5- to 6-wk old, were purchased from IFFA Credo
(Lyon, France). OF1 mice were injected i.v. with saline or with 100
µg/mouse of rat mAbs in a volume of 250 µl of saline, and with
K. pneumoniae or E. coli suspended in 250 µl
saline. Plasma was obtained via the tail vein to determine plasma
TNF- concentrations, bacterial counts, and neutrophil counts. To
avoid excess bleeding, most of the mice were bled only once (50-µl
aliquots), occasionally twice.
TNF bioassay
TNF- was measured in plasma by bioassay using WEHI
clone 13 as targets, as previously described (28).
Neutrophil count determination
Türck Blue (Sigma) was added to whole blood samples, and the total number of white blood cell counts was determined by microscopy. For neutrophil count determination, plasma samples were lysed on ice with 0.1 M NH4Cl/0.1 M KHCO3 and cytocentrifuged. The percentage of polymorphonuclear neutrophils (PMN) was determined with May-Grünwald-Giemsa staining. The number of PMN per milliliter of blood was determined taking into account the total number of white blood cells and the percentage of neutrophils.
Statistics
The 
2 test was used to assess the
significance of differences between treatment groups. The ANOVA test on
ranks was used to assess the significance of intergroup differences for
the various markers (bacteria, PMN cell, TNF-).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in mice injected i.v. with a low inoculum of K.
pneumoniaeIn preliminary experiments, the LD50 for K. pneumoniae was found to be between 50 and 250 CFU/mouse. We thus used this inoculum to investigate the role of LBP and CD14 in the early steps of infection leading to death.
To investigate the effect of LBP activity blockade on TNF-
production induced by bacterial sepsis, mice were injected with
anti-LBP mAbs before a challenge with <250 CFU of K.
pneumoniae (Fig. 1
). Bioactive
TNF- was not detectable in the blood within the first 5 h,
irrespective of treatment (control or anti-LBP mAb). Five hours
after infection, TNF- levels were 0.8 ± 0.4 ng/ml in mice
treated with control mAb, and undetectable in mice treated with
anti-LBP mAb. There was a 1- to 2-h delay in TNF- production in
mice treated with anti-LBP mAb compared with mice treated with
control mAb. Six hours after infection, TNF- levels were 1 ±
0.5 ng/ml in mice treated with control mAb, and 0.2 ± 0.1 ng/ml
in mice treated with anti-LBP mAb. Yet, 7 h after infection,
TNF- levels were higher thereafter in mice treated with
anti-LBP mAb.
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production was obtained in mice treated with
anti-CD14 mAb (Fig. 1
). Yet, TNF- levels were still higher in
mice treated with anti-CD14 mAb than in mice treated with
anti-LBP mAb, 7 h after infection. LBP and CD14 blockade is associated with impairment of neutrophil recruitment in mice injected i.v. with a low inoculum of K. pneumoniae
In the early hours after infection with K. pneumoniae,
neutrophil counts doubled in the first 30 min, irrespective of
treatment (Fig. 2). In mice treated with
control mAb, neutrophil counts continued to increase to a 4-fold level
over basal levels, peaking at 1.5 h, then progressively
decreasing to basal levels at 6 h. In contrast, animals treated
with anti-LBP mAb did not show any increase of neutrophils from 30
min to 6 h. The same observation was made during the first 3
h after infection, in mice treated with anti-CD14 mAb. Yet, in
those mice, numbers of bacteria were similar to controls from 3 to
6 h.
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Death was associated with elevated bacteremia, and moribund mice
had bacterial counts higher than 107 CFU/ml of
blood (Fig. 3). Kinetics of bacterial
counts were similar in mice receiving saline or control mAb for the
first 24 h after bacterial challenge. Fig. 3A
illustrates the kinetics of bacterial counts in mice treated with
control mAb. Blood bacterial counts increased in survivors and
nonsurvivors from 100 to 250 CFU/ml to 
104
CFU/ml during the first 12 h, then plateaued until 48 h, with
slightly higher numbers in nonsurvivors than in survivors. From day 3,
bacteria were cleared from the circulation in survivors, whereas blood
bacterial counts progressively increased until death in nonsurvivors.
Fig. 3B shows the kinetics of blood bacterial counts in mice
injected with anti-LBP mAb (nonsurvivors). Blood bacterial counts
were similar (no statistically significant difference) to those
measured in survivors or nonsurvivors receiving control mAb for the
first 6 h. However, between 7 and 12 h, mice that were
moribund all had increased numbers of circulating bacteria than
survivors found either in this group of mice or in the group of mice
receiving saline or control mAb. Under this condition, bacterial counts
remained elevated until death. Kinetics of blood bacterial counts was
even more accelerated when mice were treated with anti-CD14 mAb
(Fig. 3C, nonsurvivors). All mice had similar numbers of
bacteria until 4 h (survivors and nonsurvivors). However, 7 h
after bacterial challenge, bacterial numbers were at least 2 logs
higher than those of controls (103 vs
105 CFU/ml, p < 0.0001).
Bacterial numbers corresponding to those observed in moribund mice were
found in all mice, 14 h after challenge.
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levels in
mice treated with anti-LBP or anti-CD14 mAb and injected i.v.
with a low inoculum of K. pneumoniae
We next analyzed whether blood TNF- levels were related to
numbers of bacteria (Fig. 4). TNF- was
not detected in samples containing <104 CFU/ml,
irrespective of treatment. Mice treated with control mAb had detectable
levels of blood TNF-, from 60 to 10,000 pg/ml, irrespective of the
number of circulating bacteria detected in these samples (from
104 to 106 CFU/ml). Yet, in
mice treated with anti-LBP mAb (or anti-CD14 mAb, data not
shown), TNF- was not detectable or barely detectable in samples in
which bacterial counts were <105 CFU/ml.
However, when blood bacterial counts exceeded 5 x
105 CFU/ml, blood TNF- levels were higher than
those found in animals receiving control mAb (p
< 0.001). Thus, it appeared that LBP or CD14 blockade induced a delay
in early TNF- production that was associated both with time and
number of bacteria (<105 CFU/ml). However, as
soon as bacteria reached 5 x 105 CFU/ml in
the blood, TNF- was produced in higher amounts in mice treated with
anti-LBP or anti-CD14 mAb, suggesting LBP- and CD14-independent
mechanisms of TNF- production at high bacterial loads.
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The Klebsiella strain was very virulent, because
<250 CFU induced a death rate of >50% in 5 days in control mice
receiving saline (Fig. 5). Injection with
control mAb had no effect on survival rates. In contrast, injection of
anti-LBP or anti-CD14 mAb increased lethality, with a striking
increase during the first 24 h.
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). In most mice, TNF- measured at
6 h after infection was not detected; TNF- was only detectable
in mice presenting bacterial counts 105 CFU/ml
at 6 h (data not shown).
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in mice challenged i.v with a low inoculum of
K. pneumoniae
Experiments with a low inoculum of bacteria indicated a delay in
TNF- production in animals receiving anti-LBP or anti-CD14
mAb, compared with that of controls. This was observed during the
initial steps of infection, when bacterial numbers were low. Thus we
hypothesized that the absence of TNF- production may be associated
with a defective innate immune response. We investigated the role of
TNF- in that model. As shown in Fig. 6, pretreatment of mice with neutralizing
anti-TNF- Abs augmented early deaths.
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treatment reverses the effect of LBP or CD14 blockade in
mice challenged with a low inoculum of K. pneumoniae
We next investigated whether pretreatment with rTNF- would
improve survival. As shown in Fig. 7, administration of rTNF-, given at the time of bacterial challenge,
induced a good degree of protection in mice challenged with a low
inoculum of K. pneumoniae. Yet, TNF has to be given in the
early hours after infection, with a failure to protect mice when
administered 6 or 10 h after infection (Table II).
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, induced a defective immune response leading to
uncontrolled bacterial multiplication. Thus, we investigated whether
pretreatment with rTNF- would also improve outcome in mice treated
with anti-LBP or anti-CD14 mAb. Fig. 8 indicates that administration of
rTNF- almost fully protected mice treated with anti-LBP mAb,
that otherwise died rapidly (80% survival compared with 0% survival).
Addition of TNF- also partially restored outcome in mice receiving
anti-CD14 mAb (Fig. 9), but
protection was less than in mice treated with anti-LBP
mAb.
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We next investigated how LBP and CD14 blockade affected outcome in
mice challenged with high inocula of bacteria. Data obtained ex vivo
indicated LBP- and CD14-independent mechanisms of TNF- production
with 105 heat-killed K. pneumoniae
(data not shown). Mice were pretreated with the three mAbs and injected
with 105 live K. pneumoniae. Lethality
was extremely rapid with this high inoculum. Yet, death rates and
bacterial numbers were similar in all groups of mice (Table III), indicating that LBP and CD14 did
not contribute to the worsening of infection under these conditions.
Plasma TNF- levels were also not different in the three groups
of mice.
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Finally, we investigated whether LBP and CD14 played a similar
role in a systemic challenge of mice with the less virulent
Gram-negative bacterium E. coli O111. The
LD50 for this particular strain is
108 CFU/mouse. Mice were injected with a
nonlethal inoculum (105/mouse) to assess whether
blockade of the innate system would impair the natural defense
mechanisms of mice. As shown in Table IV,
in mice receiving the nonlethal inoculum, blockade of LBP or CD14 with
Abs did not worsen outcome, nor did it alter bacterial clearance. We
also injected mice with a high inoculum (109),
which we knew from ex vivo experiments was LBP- and CD14- independent.
In mice receiving the high and lethal inoculum, death was very rapid.
Anti-LBP or anti-CD14 mAb did not modify TNF- levels, did not
reduce the number of circulating bacteria, and did not prevent or delay
death.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mechanisms responsible for aggravation of the disease imply that a
vigorous inflammatory response likely triggered by LPS through LBP and
CD14 was necessary to eliminate low numbers of virulent bacteria. For
this response, TNF- stands as a key cytokine, and neutrophil
activation and recruitment is of paramount importance. In the
Klebsiella model with a low inoculum, TNF- was
determinant, as 1) treatment with anti-LBP or anti-CD14 mAb
delayed TNF- appearance in the blood; 2) treatment of mice with
anti-TNF- Abs was found to aggravate infection; 3) treatment of
mice with rTNF- was protective; 4) treatment of mice with rTNF-
almost totally protected mice treated with anti-LBP mAb, and
partially restored survival in mice treated with anti-CD14 mAb,
indicating that blockade of CD14 induced more profound alterations of
host defense than the sole prevention of TNF- production; and 5)
TNF- had to be present early to prevent death, because
administration of rTNF- was not effective when given 5–10 h after
bacterial challenge.
Bioactive TNF- was not detectable when bacterial numbers were
<104 CFU/ml in the blood, and not before 4
h following infection. Determinant mechanisms for elimination of
bacteria (that remain to be defined) happen between 5 and 6 h
after infection, and are dependent on host activation by
TNF-. During this 2-h period, anti-CD14- and
anti-LBP-treated mice had no detectable bioactive TNF-. Yet,
1 h later, at 7 h, TNF- levels were higher in
anti-LBP- and anti-CD14-treated mice than in controls, in
relation with the fact that bacterial counts higher than in controls
were present in these mice. This suggests that TNF- production is
dependent on LBP/CD14 in the initial steps, when LPS-triggered monocyte
activation occurs. Prophylactic blockade of LBP and CD14 led to the
most severe effects. Yet, experiments with a delayed blockade of LBP or
CD14 up to 6 h after the start of infection also indicate that
these molecules were required during a sustained period of time to
protect the mice. From 6 h on, two pathways may be responsible
for cell activation, either 1) LPS-dependent (but LBP- and
CD14-independent, because concentrations of LPS are too high)
mechanisms; or 2) mechanisms dependent on other bacterial products.
Mechanisms responsible for aggravation of the disease following LBP/CD14 blockade are likely not due to prevention of phagocytosis by the Abs, because bacterial numbers were similar in control mice or in mice treated with anti-LBP or anti-CD14 mAbs in the initial steps of infection, whatever the strain of bacteria used. Earlier reports have suggested that phagocytosis of Gram-negative bacteria may occur via a CD14-dependent pathway (29, 30). Yet, these experiments have been performed with heat-killed bacteria, a treatment that breaks capsules and likely allows binding of LBP or CD14 to Gram-negative bacteria. We previously reported that LBP bound efficiently to heat-killed Gram-negative bacteria, but did not bind to most live bacteria, including Klebsiella species, whereas it binds to rough live bacteria (31). Binding to CD14 was not observed for the Klebsiella strain used in the present study (data not shown). Thus indirect mechanisms, other than prevention of phagocytosis, are responsible for the failure of anti-LBP- and anti-CD14-treated mice to control infection.
Blockade of innate immune responses by anti-LBP or anti-CD14 mAb was associated with an impairment of optimal neutrophil recruitment during the initial steps of infection, which is necessary for host defenses. Concentrations of chemokines have not been measured, but one may speculate that they would also be diminished. Cytokines and chemokines are known to potentiate the function of neutrophils and macrophages, resulting in activation of microbial mechanisms, including generation of superoxide production, reactive oxygen and nitrogen intermediates, or enhancement of phagocytosis, with an increased ability to kill microorganisms (32, 33, 34, 35).
It has been largely documented that activation of myelomonocytic cells by LPS via LBP/CD14 occurs only at low doses of LPS, and that LBP or CD14 blockade does not prevent cell activation by high doses of LPS. We approached this question by comparing the effect of CD14 or LBP blockade in mice challenged with a low vs a high bacterial inoculum. The present study indicated a role for LBP and CD14 almost exclusively for low inocula of virulent bacteria. With a high inoculum of bacteria, virulent or not, cytokine synthesis occurred that was LBP- and CD14-independent. Yet, despite triggering host response, bacteria were not eliminated and death occurred rapidly. The present study indicates that under these conditions, administration of anti-LBP or anti-CD14 mAb did not decrease the proinflammatory response.
The detrimental contribution of LBP in models of endotoxemia has been clearly defined (3, 4, 5, 6). Its role in infection has been examined in only one study so far. It was reported that LBP was necessary to combat a low-dose infection induced by an i.p. challenge of S. typhimurium, presumably because LBP-deficient animals were unable to trigger an adequate response mediating phagocytosis and killing of the microorganism (3). S. typhimurium is an intracellular organism, and the present study now extends this observation to extracellular Gram-negative bacteria. With regard to CD14, the present study confirms and extends the conclusion of a recent report showing that blockade of CD14 aggravates experimental shigellosis in rabbits (10). These data as well as the present data may appear at variance with an earlier study that showed that CD14 knockout mice had a better survival than wild-type mice following challenge with E. coli (7). There is no explanation for these discrepant results. In the aforementioned study (7), CD14-deficient mice survived to an i.p. inoculum of 5 x 106 E. coli O111, which was lethal to control mice. In the present study, administration of anti-LBP or anti-CD14 mAbs did not alter outcome with a similar inoculum of the same E. coli strain given systemically. Studies using gene-deficient animals or animals treated with Abs are not similar.
To conclude, the present study is in agreement with the concept proposed many years ago by Ulevitch and colleagues (1, 2, 36), that LPS shed from Gram-negative bacteria binds to LBP and that the LPS/LBP complexes are presented to CD14 to trigger monocyte activation, leading among other mechanisms to cytokine synthesis, necessary for the host response. This study also stresses the need for critical evaluation of novel therapeutic approaches for the management of patients with severe sepsis or shock.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Didier Heumann, Division of Infectious Diseases, BH19, CHUV 1011 Lausanne, Switzerland. E-mail address: dheumann{at}hola.hospvd.ch
3 Abbreviations used in this paper: LBP, LPS-binding protein; PMN, polymorphonuclear neutrophil.
Received for publication January 29, 2001. Accepted for publication June 27, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in innate resistance to mouse pulmonary infection with Pseudomonas aeruginosa. Infect. Immun. 63:3272.[Abstract]
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protects rats against the lethality, hypotension, and hypothermia of Gram-negative sepsis. J. Clin. Invest. 88:34.
/cachectin and murine interleukin 1 protects mice from lethal bacterial infection. J. Exp. Med. 169:2021. and to LPS. J. Immunol. 148:1890.[Abstract]
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), anti-LBP mAb (
), or
anti-CD14 mAb (
) 5 min before i.v. infection. Data are the mean
of five different experiments (42 mice/group). p <
0.05, by ANOVA comparing anti-LBP mAb vs control mAb (*) or
anti-CD14 mAb vs control mAb (#).
),
with 100 µg/mouse of control mAb (•), anti-LBP mAb (
) 5 min before i.v. infection. Data are the mean
of five different experiments (42 mice/group). No deaths were recorded
after 6 days. Survival was assessed by the 
