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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 96 No. 1 (July 1), 2000:
pp. 218-223
IMMUNOBIOLOGY
Impaired antigen presentation by human monocytes during endotoxin
tolerance
Kerstin Wolk,
Wolf-Dietrich Döcke,
Volker von Baehr,
Hans-Dieter Volk, and
Robert Sabat
From the Institute of Medical Immunology, Medical School
Charité, Humboldt University, Berlin, Germany
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Abstract |
Endotoxin tolerance (ET) has been described as a temporary
alteration in the lipopolysaccharide (LPS) response of monocytic cells
after an initial LPS exposure with respect to the production of soluble
immunomodulators. Apart from the LPS response, monocytic cells play an
important role in initiation of the specific immune response as
antigen-presenting cells. This study investigated the capacity of human
blood monocytes to induce T-cell stimulation in ET. First, the
expression of monocyte surface molecules, important for T-cell
interaction, was analyzed by flow cytometry. In vitro priming of
peripheral blood mononuclear cells with LPS clearly down-regulates
major histocompatibility complex class II molecules and the
costimulatory molecule CD86. Both changes were dependent on the
endogenous interleukin (IL)-10 and less so on the transforming growth
factor- . In contrast, other accessory molecules on monocytes were
only marginally down-regulated (CD58), were not significantly changed
during ET (CD40), or even remained up-regulated after initial LPS
priming (CD54, CD80). Second, an impact of these phenotypic alterations
on the accessory function of monocytes was observed. This was
manifested as diminished T-cell proliferation and interferon (IFN)-
release in response to the presence of different recall antigens.
Neutralizing IL-10 during LPS priming prevented the diminished T-cell
IFN- production but had little effect on T-cell proliferation. These
data confirm that ET is an appropriate model of the monocyte functional
state in immunoparalysis, which is frequently observed in patients
after septic shock, trauma, or major surgery.
(Blood. 2000;96:218-223)
© 2000 by The American Society of Hematology.
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Introduction |
Endotoxin tolerance (ET) was first described as
the temporary insensitivity of a host to a repeated lipopolysaccharide
(LPS) challenge with respect to systemic inflammation parameters. This phenomenon is associated with functional alterations to the monocytic cells1 and can be imitated in vitro. After pretreatment
with a first activating LPS dose, a second LPS stimulation of monocytic cells causes a reduced production of proinflammatory cytokines, including tumor necrosis factor (TNF)- , interleukin (IL)-1, IL-12, IL-6, as well as nitric oxide and IL-10 when compared with non-LPS prestimulated controls.2-6
However, we and others have shown that this monocytic state does not
represent a complete deactivation but rather a specific reorientation
in the reaction of the cells to LPS. In response to a second LPS
stimulation the production of IL-1 receptor antagonist (IL-1RA) was not
altered,5 and TNF receptor II gene expression was actually
increased.7
We recently demonstrated that the reduced monocyte TNF- production
capacity observed during ET is mediated by IL-10 and transforming growth factor (TGF)- produced during the primary LPS stimulation. In
fact, neutralization of endogenous IL-10 and TGF- during LPS priming prevented the loss of LPS-induced TNF- production in peripheral blood mononuclear cells (PBMCs).5 Furthermore,
exposure to IL-10 in combination with TGF- could mimic ET in
terms of the reduced production of TNF- and IL-10.5,8
In contrast, neutralization of endogenous IL-10 and
TGF- failed to prevent reduced monocytic IL-12 production capacity,
indicating other factors are involved in the initiation of
ET.6
In contrast to previous studies, which defined the functional state of
monocytic cells during ET only in terms of the altered capacity to
produce soluble immunomodulators, we intended to characterize LPS-tolerized monocytes in terms of their antigen-presenting capacity. Here we show the differentially altered expression of human monocyte molecules important for T-cell stimulation after an initial in vitro
exposure of total PBMCs to LPS. We also determined the capacity of
these primed monocytes to stimulate various T-cell responses. Furthermore, we tested the role of endogenous mediators produced during
the initial LPS exposure in the alterations expressed by the monocytes.
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Materials and methods |
Preparation and culture of PBMCs
Human PBMCs from various healthy donors were isolated from citrated
venous blood by density gradient centrifugation using Ficoll-Paque
(Pharmacia, Freiburg, Germany). Cells were usually cultured at a
concentration of 106 cells/mL in RPMI 1640 medium tested
for very low (< 0.01 EU/mL) endotoxin content (Biochrom KG, Berlin,
Germany) supplemented with 10% (v/v) fetal bovine serum and 2 mmol/L
glutamine (both from Biochrom KG). For inhibiting monocyte adherence,
culture vessels were coated with use of 100 µL/cm2 of 1%
(w/v) poly(2-hydroxyethylmethacrylate) (ICN Biomedicals, Eschwege,
Germany) as described elsewhere.9
If not otherwise indicated, PBMCs were primed with 2 ng/mL LPS from
Escherichia coli 0127 B8 (Sigma-Aldrich Chemie, Deisenhofen, Germany) or were cultured without stimulation (control group) for the
first 24 hours. For neutralization experiments either 5 µg/mL
anti-IL-10 monoclonal antibody (MoAb) (clone CB/RS/1),10 anti-TGF- MoAb (clone 1D11.16; Genzyme, Munich,
Germany),5 or control murine immunoglobulin (Ig)G1 MoAb
(clone 11 711.11; R&D Systems, Wiesbaden-Nordenstadt, Germany), were
present during priming period.
For the following experiments cells were extensively washed and
recultured under secondary culture conditions:
1. For flow cytometric analysis at 36, 48, 72, and 120 hours,
reculturing was performed without any stimulation on coated culture
vessels in medium as described previously.
2. For detection of monocyte TNF- production capacity, PBMCs were
cultured for another 12 hours without stimulation and subsequently exposed to LPS (100 ng/mL) for 6 hours, afterward culture supernatant was recovered for TNF- measurement.
3. To assay T-cell stimulation, PBMCs were recultured as
described below.
Flow cytometric analysis
To quantify the expression of monocyte surface molecules, PBMCs from
primary culture (12 and 24 hours) and secondary culture (36, 48, 72, 96, and 120 hours) were stained with the following antibodies:
R-phycoerythrin (PE)-labeled antihuman leukocyte antigen (HLA)-DR MoAb
(clone L243; Becton Dickinson, Heidelberg, Germany), fluorescein
isothiocyanate (FITC)-labeled anti-CD40 MoAb (clone 5C3; Pharmingen,
Hamburg, Germany), PE-labeled anti-CD86 MoAb (clone 2331; Pharmingen),
FITC-labeled anti-CD80 MoAb (clone BB1; Pharmingen), PE-labeled
anti-CD58 MoAb (clone AICD58; Coulter Immunotech, Hamburg, Germany),
FITC-labeled anti-CD54 MoAb (clone 84H10; Coulter Immunotech), or the
respective isotype controls: FITC-labeled mouse IgG1 MoAb (clone
679.1Mc7; Coulter Immunotech), PE-labeled mouse IgG2a MoAb (clone X39;
Becton Dickinson). To discriminate the monocyte population, additional
staining with R-phycoerythrincyanin (PE-Cy5)-labeled anti-CD14 MoAb
(clone RMO52; Coulter Immunotech) was performed.
To assess the major histocompatibility complex (MHC) class II
expression patterns on monocytes at 36 hours, the following antibodies were used in addition to anti-HLA-DR MoAb and
the respective isotope control: anti-HLA-DP MoAb (clone B7/21; Becton
Dickinson), control murine IgG1 MoAb (clone 11711.11; R&D
Systems) and PE-labeled goat antimouse IgG (H, L)
F(ab')2 (Jackson ImmunoResearch Laboratories, West
Groove, PA), FITC-labeled anti-HLA-DQ MoAb (clone SK10; Becton Dickinson) and FITC-labeled mouse IgG1 MoAb (clone X40; Becton Dickinson).
The flow cytometric analyses were performed by means of a FACScan
instrument with LYSYS II software (Becton Dickinson); 30,000 to 40,000 PBMCs per measurement were analyzed, and monocytes were gated based on
their CD14 expression and light-scatter properties.
T-cell stimulation assay
To determine the capacity of monocytes to induce antigen-dependent
T-cell stimulation, PBMCs were recultured in triplicate assays at
106 cells/mL in RPMI 1640 medium (see above) supplemented
with 10% (v/v) human AB serum (Sigma-Aldrich Chemie) and 2 mmol/L
glutamine (Biochrom KG) in the presence of either 2.5 µg/mL candidin
(Allergopharma, Reinbek, Germany), 0.08 IU/mL tetanus toxoid
(Tetasorbat SSW; SmithKline Beecham Pharma, Munich, Germany), 5 purified protein derivative (PPD)-S/mL tuberculin (Tuberkulin GT 100 Behring; Chiron Behring & Co, Marburg, Germany), or medium. To assay
T-cell DNA synthesis, cells were labeled after 3 days or (in kinetic
assays) after the indicated times for a further 15 hours with 1 µCi/mL [5'-3H]thymidine (Amersham Buchler & Co KG,
Braunschweig, Germany) in the continued presence of antigen. After
harvesting cells, the incorporated radioactivity was measured using a
beta counter (Inotech; Dunn Labortechnik, Asbach, Germany). For
detection of T-cell interferon (IFN)- production, supernatant was
recovered after 4 days of antigen stimulation. Of note, at the onset of each T-cell proliferation assay the ratio of CD4+
and CD14+ cells was verified to be similar in all
groups (data not shown).
Cytokine quantification assays
Detection of TNF- and IFN- concentrations in PBMC culture
supernatant was realized by the commercially available enzyme-linked immunosorbent assay (ELISA) kits from Medgenix (Ratingen, Germany).
Statistical analysis
Statistical analyses were performed either by Wilcoxon matched-pairs
signed-ranks test (Figure 1, Tables
1 and 2),
Friedman 2-way ANOVA (Figure 2), or
Mann-Whitney U test (Figure 1) using SPSS software (SPSS, Chicago, IL).
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| Fig 1.
LPS differentially alters surface expression of HLA-DR
and accessory molecules in monocytes in a time-dependent manner.
PBMCs were cultured for the first 24 hours with 2 ng/mL or without LPS
in the presence of either control murine IgG1, anti-IL-10, or
anti-TGF- MoAb and recultured afterward without further stimulation.
Surface molecule expression as assessed by flow cytometry is presented
as the ratio of the mean fluorescence intensities (MFI) between cells
treated with or without LPS for each of the 3 antibodies. Mean data
(± SEM) from 5 independent experiments are shown. Statistical
analyses were performed for LPS/IgG1-treated groups by Wilcoxon
matched-pairs signed-rank test (*P < .05 versus cultures at
0 hours) or for LPS/neutralizing MoAb-treated groups by Mann- Whitney U
test (#P < .05, ##P < .01 for
LPS/anti-IL-10 MoAb versus LPS/IgG1 MoAb-treated group at the same time
point; +P < .05 for LPS/anti-TGF- MoAb-
versus LPS/IgG1 MoAb-treated group at the same time point),
respectively.
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Table 1.
Expression of different MHC class II species on
monocytes is down-regulated during ET; a comparison with
monocyte TNF- production capacity
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| Fig 2.
LPS priming alters surface expression of HLA-DR and
costimulatory molecules in monocytes in a dose-dependent fashion.
PBMCs were cultured with different concentrations of LPS for 24 hours,
and monocyte HLA-DR (A), CD86 (B), and CD80 (C) expression was assessed
by flow cytometry. Mean (± SEM) data from 3 independent experiments
are shown. Dark columns indicate the respective isotypic controls. For
the expression of all 3 surface molecules, significant dose dependency
was demonstrated by Friedman test (P < .05). Note the
different scales for the 3 markers.
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Results and discussion |
Isolated human PBMCs, primed with a low-dose (2 ng/mL) of LPS during
24 hours and washed afterward, were LPS-tolerant for some days as
assessed by the clearly reduced LPS-induced TNF- production when
compared with PBMCs with no LPS priming (Table 1). We investigated
whether monocytes, rendered tolerant this way, demonstrated an altered
expression of surface molecules important for T-cell activation.
The prerequisite for any antigen-specific activation of T
cells is recognition of MHC-bound antigenic peptides expressed on antigen-presenting cells (APCs) by the T-cell receptor
complex.11 In addition, costimulatory interactions, which
complement signals transduced from the T-cell receptor complex, as well
as adhesive interactions, which enable intimate intercellular contacts,
are necessary for effective T-cell stimulation. One major costimulatory signal of resting T cells is provided through engagement of T-cell CD28
by B7 molecules (CD86, CD80). This interaction promotes T-cell IL-2
production and proliferation, and its absence inhibits T-cell responses
and induces T-cell anergy or death.12,13 T-cell receptor signaling leads to the induction of CD154, the ligand of the accessory molecule CD40 on APCs. Expression of CD154 is further enhanced by CD28
engagement.14 The CD40/CD154 interaction seems to be especially important for T-cell activation if the APCs are B
cells.15 Adhesion molecules like CD58 (leukocyte
function-associated antigen-3) and CD54 (intercellular adhesion
molecule-1) have been implicated not only in intercellular adhesion,
but also in direct costimulation of T cells.16
CD54-mediated costimulation was more effective in CD8+ than
in CD4+ cells.17
In this study, therefore, we analyzed the expression of the surface
molecules MHC class II, CD86, CD80, CD40, CD58, and CD54 on LPS-primed
human monocytes using flow cytometry. We recently demonstrated the
participation of IL-10 and TGF- in the initiation of
ET.5 Therefore, we simultaneously tested the influence of endogenous IL-10 and TGF- during LPS priming on the expression of
the monocyte surface molecules listed above using neutralizing MoAbs.
Figure 1 shows the time course of monocyte expression patterns before
(0 hour), during (12 and 24 hours), and after (36-120 hours) LPS
priming in the presence of either control MoAb, anti-IL-10 MoAb, or
anti-TGF- MoAb. Expression patterns of LPS-primed monocytes are
presented relative to the expression patterns of monocytes with no LPS
priming at the same time point.
After an initial up-regulation within the first 12 hours, the
expression of the MHC class II molecule HLA-DR had already decreased by
the end of the LPS priming period and was strongly depressed during the
following 4 days tested. The CD86 expression was moderately down-regulated after 12 hours of LPS exposure and further decreased until 48 hours. It had not recovered by the 4th or 5th day
of culture. CD58 expression on monocytes was only moderately
down-regulated after LPS priming. After an increase during initial LPS
priming, monocyte CD40 expression corresponded to untreated controls;
however, CD54 and CD80 expression remained up-regulated moderately and strongly, respectively. Similar LPS-induced alterations of surface expression were observed in purified monocytes (data not shown). The
relative up-regulation of CD80 expression reflects the presence of only
a small number of surface molecules because freshly isolated monocytes
are weakly if at all positive for CD80 (Figure 2). Taking the
down-regulation of CD86 into account, the totality of T-cell CD28
ligands was decreased in ET.
The effects were already evident with a few picograms per milliliter of
LPS, that is, at concentrations below those found in plasma of patients
with septic shock.18 Figure 2 shows the alterations of
monocyte HLA-DR, CD86, and CD80 expression in a LPS dose-dependent manner.
Because we observed the strongest down-regulating effect of LPS priming
on HLA-DR expression, we examined whether the expression of other
monocyte MHC class II molecules was also diminished during ET. PBMCs
were rendered tolerant by exposing them for the first 24 hours to 2 ng/mL LPS. As shown in Table 1, the down-regulation of HLA-DR
at 36 hours was accompanied by a reduction of HLA-DP and HLA-DQ
expression. No down-regulation of the expression of MHC class II
molecules on B cells was observed in our study (data not shown).
The down-regulation of CD86 and CD58 expression could be prevented
completely if endogenous IL-10 was neutralized during LPS priming
(Figure 1). Anti-IL-10 MoAb increased and prolonged initial HLA-DR
up-regulation but failed to fully prevent its down-regulation at later
time points. The expression of CD40, CD80, and CD54 was further
increased after IL-10 neutralization. The use of anti-TGF- MoAb
increased levels of all surface molecules tested during the LPS priming
period but had marginal effect afterward. The combination of
anti-TGF- MoAb and anti-IL-10 MoAb did not amplify the effect of
IL-10 neutralization alone, when tested with respect to HLA-DR and CD86
expression (data not shown).
IL-10 is produced by activated monocytes at high levels and has been
described to act in a negatively autoregulatory fashion to limit the
activation-induced proinflammatory state.19 The extent to
which IL-10 counteracts the initial LPS-induced increase in expression
of the analyzed monocyte surface molecules (Figure 1) reflects the
differential sensitivity of these molecules toward IL-10 signaling in
resting monocytic cells. In fact, IL-10 strongly down-regulates
monocyte HLA-DR and CD86 expression but has only minor inhibitory
effect on CD58, CD40, and CD54 expression (references 20-23 and our
unpublished data). In contrast, IL-10 has been shown to moderately
up-regulate monocyte CD80 expression.21 Thus, the
differentially altered expression of monocyte surface molecules participating in T-cell interaction during ET reflects, at least partly, the autoregulatory action of endogenous IL-10.
We also investigated whether these changes in monocyte expression had
an effect on their capacity to present antigen to autologous T cells in
an MHC class II-dependent manner. If this were the case, reduction of
monocytic MHC class II and CD86 expression should limit monocyte
accessory function in ET. After LPS priming, PBMCs were recultured in
the presence or absence of the recall antigen candidin for 1, 2, 3, and
4 days. Induction of T-cell proliferation was determined by measuring
cellular incorporation of 3H-thymidine, which is a direct
indicator of DNA synthesis. Figure 3 shows
reduced antigen-specific DNA synthesis in LPS-primed PBMC cultures
compared to unprimed controls, which was observed after 3 days.
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| Fig 3.
The capacity of monocytes to stimulate T-cell DNA
synthesis in response to the protein recall antigen candidin is
diminished during ET; study of different kinetics.
PBMCs were cultured in the presence or absence of 2 ng/mL LPS. Cells
were washed and recultured at 24 hours with (2.5 µg/mL) or without
candidin. After the time periods indicated, cells were pulsed with
[5'-3H]thymidine for a further 15 hours. Results of the
cellular radioactive labeling are presented as specific cpm (the
difference between cpm of culture in the presence of antigen and cpm of
culture in the absence of antigen). Representative data from 1 of 3 independent experiments in triplicate assays (mean ± SEM) are
given.
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To further verify the diminished antigen-presenting activity of
monocytes during ET, we tested different T-cell responses after
challenge with the recall antigens candidin, tetanus toxoid, and
tuberculin. The proliferation (Table 2A) and IFN- secretion (Table
2B) of T cells were strongly diminished in ET following challenge with
each of the 3 antigens for 3 or 4 days, respectively. Similarly,
LPS-primed purified monocytes showed reduced capacity to stimulate T
cells in the presence of these antigens. In contrast, LPS priming of T
cells did not impair their antigenic response when cocultured with
nonprimed monocytes (data not shown).
Finally, we investigated whether IL-10 neutralization during LPS
priming could prevent the suppression of T-cell responses. PBMCs were
primed with LPS or not in the presence of either anti-IL-10 MoAb or a
control MoAb. After extensive washing, stimulation with candidin,
tetanus toxoid, or tuberculin was performed. Figure 4 presents the individual antigen-specific
3H-thymidine incorporation and IFN- production in
cultures of 2 different donors after 3 or 4 days of antigen
stimulation, respectively. Depending on the individual, the T-cell
reactivity toward the different antigens varied considerably.
Neutralization of endogenous IL-10 only marginally reduced LPS-induced
suppression of antigen-specific T-cell DNA synthesis (Figure 4A). In
contrast, neutralization of endogenous IL-10 completely repressed
down-regulation of antigen-induced IFN- production (Figure 4B). No
IFN- was detectable in any of the groups in the absence of antigen
exposition.
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| Fig 4.
Neutralization of endogenous IL-10 during LPS priming
completely ameliorates the ET-associated suppression of T-cell
IFN- production but not the suppression of T-cell proliferation in
response to different protein recall antigens.
PBMCs from 2 donors were cultured for the first 24 hours with (2 ng/mL)
or without LPS in the presence of either a control murine IgG1 or
anti-IL-10 MoAb and recultured with either 2.5 µg/mL candidin (Can),
0.08 IU/mL tetanus toxoid (TT), 5 PPD-S/mL tuberculin (Tbc), or without
stimulation. (A) Cellular [5'-3H]thymidine incorporation
after 3 days of antigen stimulation is given from experiments in
triplicate assays (mean ± SEM). (B) IFN- production after 4 days
of antigen stimulation was assessed by ELISA.
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In summary, these data demonstrate for the first time that ET of
monocytic cells not only diminishes their proinflammatory action but
also their ability to elicit antigen-specific T-cell responses. IL-10,
which is involved in this phenomenon, is known to suppress T-cell
stimulation by altering monocyte accessory function.20,21
The reduction of monocyte MHC class II expression and T-cell
stimulation capacity after LPS priming were even stronger than after
IL-10 (10 ng/mL) priming (manuscript in preparation). These results are
consistent with ET being associated with incomplete repression of MHC
class II down-regulation in monocytes and decreased antigen-specific
T-cell responses, if endogenous IL-10 is neutralized during LPS priming
(Figures 1 and 4). Our data indicate that IL-10-independent factors are
involved in mediating the impaired accessory function of LPS-primed
monocytes, as is also known for IL-12 suppression in ET.6
TGF- does not appear to be one of these factors.
Neutralization of IL-10 during LPS priming of PBMCs was sufficient to
completely prevent decreased T-cell IFN- production but not to
normalize T-cell DNA synthesis. T cells can effect distinct biologic
responses as a function of the level of T-cell receptor occupancy, as
has been previously described.24 Consistent with our data,
the induction of T-cell proliferation requires a greater number of MHC
molecule-peptide complexes to interact with the T cell than is required
for the release of T-cell IFN-.
LPS is well known as an activator of monocytic cells. It induces the
expression of monokines and cytotoxic agents25,26 and
up-regulates the accessory function of monocytic cells.27 The latter is consistent with the initially increased expression of MHC
class II, and several accessory molecules, by LPS seen in our study
(Figure 1). After the LPS-induced proinflammatory state, however, the
ET state follows where monocytic cells do not adequately express
cytokines when reexposed to LPS. Here we demonstrate that ET is also
associated with impaired monocyte accessory function.
Massive LPS-induced release of proinflammatory cytokines in vivo has
been associated with induction of acute septic shock.28,29 We have observed that subsequent to septic shock, as well as to major
surgery or polytrauma, there often follows a clinical state called
immunoparalysis.30-32 Although immunoparalysis can be
induced by multiple mechanisms, it is accompanied by common functional abnormalities of the blood monocytes: (1) a drastically decreased expression of surface MHC class II and CD86 molecules, which is associated with a diminished antigen presentation capacity, and (2) a
reduced ex vivo LPS-induced production of TNF-, IL-10, and reactive
oxygen species, whereas the capacity to produce IL-1RA was not altered
(references 5, 33, and 34 and our unpublished data). The diminished
HLA-DR expression on peripheral blood monocytes is regarded as a
diagnostic indicator of immunoparalysis, whose persistence correlates
with a high risk for persistent infections and fatal
outcome.34-36 IL-10, systemically released during septic events and injury-induced neuroendocrine stress, seems to be essential in the pathogenesis of immunoparalysis.32,37 Therefore, the monocyte functional state in patients with immunoparalysis is similar
to that observed in experimental ET. Modern medicine is now able to
potentially control acute hyperinflammatory situations, but there is no
established therapy to deal with the high risk associated with
immunoparalysis. We propose that the monocyte functional state during
in vitro ET is an appropriate model of the monocyte alterations
observed during immunoparalysis and may help in the development of
novel therapeutic strategies.
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Acknowledgments |
The authors especially thank Christa Liebenthal for technical
help and Dr Nigel E. A. Crompton for accurately proofreading the manuscript.
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Footnotes |
Submitted July 29, 1999; accepted February 23, 2000.
Supported in part by the Deutsche Forschungsgemeinschaft (SFB 421, TP-B2 Volk).
Reprints: Robert Sabat, Institut für Medizinische
Immunologie, Charité, Schumannstr. 20/21, D-10098 Berlin; e-mail: robert.sabat{at}charite.de.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Abstract
Introduction