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*
Departments of Immunology and Cell Biology and
Immunochemistry and Biochemical Microbiology, Research Center Borstel, Center for Medicine and Biosciences, Borstel, Germany
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The aim of this study was to define the role of monocytes and accessory costimulatory signals in more detail. We investigated the role of CD14/LPS interactions, the effects of lysosomotropic agents, MHC restriction, and the role of costimulatory signals via CD28 and/or CTLA-4. Additionally, we examined whether B7.1 (CD80) or B7.2 (CD86) are differentially up-regulated on monocytes from LPS responders and nonresponders. We also investigated the role of IL-12 and IL-15 during the LPS-induced T cell proliferation. It will be shown that the accessory cell activity of monocytes during LPS-induced T cell proliferation is dependent on CD14/LPS interactions and is sensitive to ammonia. The T cell/monocyte interaction during LPS-induced T cell proliferation is MHC unrestricted and strongly dependent on costimulatory signals through CD28/CTLA-4. We demonstrate that the CD28/CTLA-4 ligand CD80 is crucial for LPS-induced T cell proliferation since it is induced by LPS on monocytes of LPS responders, but not of LPS nonresponders. Furthermore, we show that addition of anti-IL-12 mAb but not anti-IL-15 mAb inhibit the LPS-induced T cell proliferation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LPS of Salmonella friedenau and Salmonella minnesota R7 was prepared by the phenol-water method as described (14), purified by repeated ultracentrifugation, and converted to the sodium salt after electrodialysis, as reported previously (15). Such preparations contain <0.1% of protein and nucleic acid, as determined by chemical analysis.
Azide-free tetanus toxoid (TT)3 was obtained from Behringwerke AG, Marburg, Germany, and azide-free purified protein derivatives of Mycobacterium tuberculosis (PPD) was obtained from Statens Serum Institut, Copenhagen, Denmark. The superantigen staphylococcal enterotoxin B (SEB) was obtained from Sigma, Munich, Germany.
Isolation of cells
PBMC were isolated from heparinized blood of healthy human donors by density centrifugation, as described by Böyum (16). Purified monocytes and lymphocytes were isolated from PBMC by counterflow centrifugation using a Beckman JE-6B elutriator (Beckman Instruments, Munich, Germany). The monocyte fraction collected consisted of >95% monocytes, as determined by FACS analysis after staining with anti-CD14 (Leu-M3, Becton Dickinson, Heidelberg, Germany). T cells were isolated from the elutriated lymphocyte fraction by nylon wool filtration (nylon wool fiber, Polysciences, Eppelheim, Germany) according to the methods described by Julius et al. (17). The nonadherent cells consisted of >95% of CD2+ T lymphocytes (Leu-5b, Becton Dickinson). The concentration of monocytes within these purified T cells was below the detection limit (<0.1%, as determined by chemiluminescence) (18). The content of B cells was 0.5 to 3%, as determined by FACS analysis after staining with anti-CD20 (Leu-16, Becton Dickinson).
Cell culture
Purified monocytes were primed with LPS from S. friedenau (1 µg/ml), TT (1 limes flocculation dose (Lf)/ml), or SEB (10 ng/ml) by incubation in RPMI 1640, supplemented with 10% heat-inactivated human serum (HS) and antibiotics for 1 h at 37°C. Monocytes were then washed intensively and added to autologous or heterologous T cells (1 x 106/ml) at a final concentration of 1 x 105/ml. They were cultured in flat-bottom plates (Nunc, Roskilde, Denmark) at a final volume of 200 µl. Cells were cultured for 4 days, if stimulated with SEB, or for 7 days in case of LPS- or TT-induced proliferation. For the last 8 h of stimulation, cells were labeled with [3H]TdR (sp. act. 2 Ci/mmol, 0.2 µCi/culture, Amersham Buchler, Braunschweig, Germany) and harvested on glass-filter mats for measurement of incorporated radioactivity.
Binding studies with LPS-primed monocytes
For these studies, purified monocytes were treated with LPS from S. minnesota R7 (1 µg/ml) for different time intervals. One part of these primed monocytes (1 x 105/ml) was added to purified autologous T lymphocytes (1 x 106/ml) to determine their capacity to induce T cell proliferation. Another portion of primed monocytes was labeled with an anti-S. minnesota LPS mAb as described below to detect membrane-bound LPS.
Inhibition of LPS priming by anti-CD14 mAb
In some experiments, purified monocytes were incubated for
1 h at 4°C with the azide-free anti-CD14 mAb MEM-18 (7
µg/ml, a kind gift of V. Ho
ej
i, Czechoslovak Academy of
Sciences, Prague, Czech Republic) (19) and then washed twice over a FCS
gradient. Thereafter, monocytes were treated for 1 h at 37°C
with the stimuli and washed again twice over a FCS gradient. The
culture medium in these experiments was RPMI 1640, supplemented with
10% HS. Primed monocytes (1 x 105/ml) were
added to purified T cells (1 x 106/ml) and cultured
for 7 days. Then, TdR incorporation was measured as described
above.
Treatment of monocytes with ammonium chloride
Purified monocytes (2 x 106/ml, 1 ml/glass tube) were incubated with ammonium chloride (NH4Cl, Merck, Darmstadt, Germany) in concentrations as indicated in the figure legends for 30 min at 37°C in serum-free RPMI 1640. The stimuli (LPS 2 µg/ml, SEB 20 ng/ml, TT 2 Lf/ml) were added in 1 ml RPMI 1640, supplemented with 20% HS. Cells were incubated at 37°C for further 2 h and then washed intensively. Of these pretreated monocytes (2 x 105/ml) 100 µl were added to 100 µl autologous T lymphocytes (2 x 106/ml) and cultured for 4 days (SEB-stimulated cultures), or 7 days (LPS- or TT-stimulated cultures), respectively. DNA synthesis was measured as described above.
Studies with anti-MHC class II mAb, CTLA-4Ig, anti-IL-12 mAb, or anti-IL-15 mAb
For blocking experiments, PBMC (1 x 106/ml) were stimulated with LPS (1 µg/ml), TT (1 Lf/ml), PPD (10 µg/ml), or SEB (10 ng/ml) in the presence of 10 µg/ml anti-MHC class II mAb (anti-HLA-DP, -DQ, and -DR, clone Tü39, PharMingen, Hamburg, Germany), the chimeric protein of human CTLA-4 and murine Ig (CTLA-4Ig, a kind gift of Dr. P. Lane, Basel Institute, Basel, Switzerland), blocking anti-IL-12 mAb (10 µg/ml, clone C8.6, Endogen, Woburn, MA), or blocking anti-IL-15 mAb (10 µg/ml, clone M111, Genzyme, Cambridge, MA). The final concentrations of CTLA-4Ig are indicated in the figure legends.
Induction of CD80/CD86
PBMC (1 x 106/ml, 1 ml/well) were cultured in 24-well culture plates (Nunc) for 48 h in the presence or absence of LPS (1 µg/ml) in RPMI 1640, supplemented with 10% heat-inactivated HS. Cells were collected after careful rubbing, to yield all adherent monocytes. Cells were then stained with mAb as described below.
Immunofluorescence staining of cells
The following mAb were obtained from PharMingen, Hamburg, Germany: anti-CD86-biotin (anti-B7.2, clone IT2.2, IgG2b) and isotype controls IgG2b-FITC and IgM-FITC. Anti-CD80-biotin (anti-B7.1, clone BB.1, IgM) was obtained from Ancell, Bayport, MN, and streptavidin-Red670 was obtained from Life Technologies, Berlin, Germany. The anti-LPS Ab S3232 (IgG2a) is specific for the sugar core of LPS from S. minnesota R7 (20). Indirect immunofluorescence staining of PBMC was performed in ice-cold PBS (containing 0.1% sodium azide) with the different Ab in concentrations as recommended by the producers. S3232 was used in a 1:25 (culture supernatant) dilution. After incubation for 20 min at 4°C, cells were washed by centrifugation on a FCS gradient (200 x g for 10 min). Biotinylated antibodies were detected by further incubation for 20 min with streptavidin-Red 670. Unbound streptavidin-Red 670 was again removed by centrifugation over a FCS gradient. Labeled cells were analyzed in a Cytofluorograf (System 50H, Ortho Diagnostic Systems, Westwood, MA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As described in a previous study, LPS-primed monocytes are able to
stimulate the proliferation of human T lymphocytes (12). In first
experiments of the present study, the time-kinetics of priming
monocytes by LPS were analyzed. Monocytes were incubated for 5, 20, 60,
or 120 min with LPS of S. minnesota R7. After this
pretreatment, unbound LPS was removed by washing the monocytes. These
primed monocytes were used as stimulatory cells for autologous T
lymphocytes. In addition, we investigated the presence of
membrane-bound LPS on the primed cells with a LPS-specific mAb. As a
control for the stimulatory capacity of primed monocytes, the
proliferative response of T cells in unseparated PBMC was measured. In
these cultures with PBMC, the LPS was present during the entire culture
period. Typical results are shown in Figure 1
. With increasing time of priming, the
number of surface-bound LPS, as well as the stimulatory capacity of
primed monocytes, increased and reached optimal levels after 
60 min
of preincubation. Interestingly, only monocytes with saturated
LPS-binding sites were able to induce optimal T cell proliferation. In
additional experiments, therefore, monocytes were primed for 1h
with LPS.
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CD14 is a well-documented LPS receptor on monocytes. To
investigate whether CD14 also acts as a LPS receptor during priming of
monocytes, we examined the effects of anti-CD14 mAb. For this
purpose, monocytes were first preincubated with anti-CD14 mAb and
then primed with LPS, TT, or SEB as described in Materials and
Methods. These primed monocytes were added to purified T cells,
and [3H]TdR incorporation was determined after 4 days
(with SEB-primed monocytes) or 7 days (TT- or LPS-primed monocytes,
respectively) of culture. Typical results of such experiments are shown
in Table I. Pretreatment of monocytes
with anti-CD14 mAb resulted in a significant inhibition of T cell
proliferation induced by LPS-primed monocytes, whereas stimulation of T
cells with TT- or SEB-primed monocytes was not affected.
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Next, we investigated the effects of the lysosomotropic agent
ammonium chloride. In these experiments, priming of monocytes by the
different stimuli was performed in the presence of different
concentrations of ammonia. Typical results of such experiments are
shown in Figure 2. While stimulation of T
lymphocytes with the superantigen SEB was not affected by any
concentration of ammonia tested, there was a clear dose-dependent
reduction in T cell proliferation induced by the Ag TT. Interestingly,
LPS-induced T cell proliferation was also inhibited by ammonia at a
dose effect comparable with the inhibition of Ag-driven proliferation.
This finding indicates that the stimulatory effect of LPS is sensitive
to inhibition by ammonia.
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Next we investigated whether or not the interaction of LPS-primed
monocytes and T cells was MHC restricted. We compared the stimulatory
activity of primed autologous as well as primed heterologous monocytes.
Monocytes and T lymphocytes were isolated from two different donors,
and T cells were stimulated with LPS-, TT-, or SEB-primed monocytes,
respectively. As a control, [3H]TdR incorporation in
unstimulated cultures was determined. The results of these experiments
are shown in Table II. As expected,
[3H]TdR incorporation of T cells stimulated with
TT-primed monocytes was slightly over background levels, when
heterologous monocytes were used, indicating MHC restriction in
antigenic T cell stimulation. On the other hand, SEB-primed monocytes
induced T cell proliferation also in the presence of heterologous
monocytes (Table II). In the case of LPS-primed monocytes, both
autologous and heterologous monocytes effectively activated T cell
proliferation, indicating that the LPS-induced T cell proliferation is
MHC unrestricted.
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To further confirm that the LPS-induced T cell proliferation is
MHC unrestricted, we investigated whether anti-MHC class II Ab are
able to block T cell proliferation. We therefore stimulated PBMC with
LPS, PPD, or TT in the presence of anti-HLA-DP, -DQ, and -DR Ab. As
shown in Table III, the PPD- or
TT-induced T cell proliferation was inhibited by anti-MHC class II
Ab, while the LPS-induced T cell proliferation was not affected. Again,
these results confirm that LPS induces T cell proliferation by a
mechanism that is independent of MHC/T cell receptor interactions.
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As shown in our previous reports (12, 13), only PBMC of 50% of
healthy donors show a T cell proliferative response to LPS. Thus,
healthy donors can be grouped into LPS responders and nonresponders. T
cells of LPS responders showed a good proliferative response to LPS in
the presence of autologous monocytes, while T cells of LPS
nonresponders failed to respond in the presence of autologous
monocytes. Thus, we repeated the experiments described above with
donors of these two groups. We cocultured primed monocytes of a LPS
responder with T cells of a nonresponder and vice versa. Typical
results of such experiments are shown in Figure 3. Although T lymphocytes of the LPS
nonresponder were unable to proliferate in the presence of LPS-pulsed
autologous monocytes, they showed a remarkable proliferative response,
when cocultured with LPS-pulsed monocytes from a LPS responder (Fig. 3B). On the other hand, T cells of a LPS responder
showed a clear response in the presence of LPS-pulsed autologous
monocytes, but only a weak response when cocultured with pulsed
monocytes of a LPS nonresponder (Fig. 3A).
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We previously found that LPS-induced T cell proliferation is
strongly dependent on direct cell-to-cell contact between viable
monocytes and T lymphocytes. These observations made it likely that
interactions of membrane-bound ligand/receptor pairs on monocytes and T
lymphocytes were delivering costimulatory signals necessary for
activation. CD28 and/or CTLA-4 on T cell with their ligands CD80 (B7.1)
and/or CD 86 (B7.2) on monocytes are such ligand/receptor pairs. To
investigate the role of these costimulatory molecules during
LPS-induced T cell proliferation, blocking experiments were performed
with soluble CTLA-4. For this purpose, the chimeric product of CTLA-4
and murine Ig (CTLA-4Ig) was added in different concentrations to LPS-,
SEB-, or TT-stimulated cultures. As shown in Figure 4A, LPS-induced T cell
proliferation was strongly inhibited by CTLA-4Ig in a dose-dependent
manner. With a concentration of 0.3 µg of CTLA-4Ig/ml, only
background levels of proliferation were observed. Control experiments
showed that the antigenic stimulation of T cells by TT was also
inhibited in a dose-dependent manner by CTLA-4Ig but that higher
amounts of CTLA-4Ig were required for total inhibition (Fig. 4B). The T cell proliferation induced by the
superantigen SEB was not affected by CTLA-4Ig (Fig. 4C).
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The experiments described above show that interactions of CD28
and/or CTLA-4 on T lymphocytes with their ligands CD80 and/or CD86 on
accessory monocytes were necessary for stimulation of human T
lymphocytes by LPS. This finding caused us to compare the expression of
CD80 and CD86 on monocytes of LPS responders and nonresponders after
LPS stimulation. Figure 5 shows the
experimental results obtained with different donors, i.e., LPS
responders as well as LPS nonresponders. As already described by others
(21), CD80 is not or only slightly expressed on resting monocytes (Fig. 5). When PBMC were cultured for 2 days in medium alone, only a slight
increase of CD80 expression was observed (Fig. 5). In LPS-stimulated
cultures, expression of CD80 correlated well with the induction of
proliferation of T cells by LPS; CD80 expression was clearly enhanced
only on monocytes of LPS responders (Fig. 5A), while
there were no or only small changes in CD80 expression on monocytes of
LPS nonresponders (Fig. 5B). In contrast to CD80, no
reproducible and significant changes of CD86 expression on monocytes
induced by LPS were found (data not shown).
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Next, we investigated the role of IL-12 and/or IL-15 in
LPS-induced T cell proliferation. Thus, we stimulated PBMC with LPS (1
µg/ml) or PPD (10 µg/ml) in the presence of neutralizing Ab against
IL-12, IL-15, or a combination of both. As shown in Table IV, neutralizing anti-IL-12 mAb
clearly inhibited LPS-induced T cell proliferation between 50 and 80%.
Less marked were the effects of anti-IL-15 mAb; addition of
neutralizing anti-IL-15 mAb reduced LPS-induced T cell
proliferation by only 20 to 30%. Addition of anti-IL-12 mAb
together with anti-IL-15 mAb did not further increase the effects
of anti-IL12 mAb alone. In contrast, neutralizing the biologic
activities IL-12 or IL-15 by adding blocking mAb had more or less no
effect in PPD stimulated cultures.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, A and B,
accessory monocytes within PBMC can be replaced by LPS-primed
monocytes. These primed monocytes were active in stimulating T
lymphocytes even in the absence of supplemental LPS. On the other hand,
we could show a correlation between the stimulatory capacity of primed
monocytes and the amount of surface-bound LPS on these monocytes (Fig. 1, A and C). Only monocytes with saturated
LPS-binding sites on their surface were able to induce optimal T cell
proliferation. In additional experiments, we investigated the different
steps involved in the priming of monocytes by LPS.
In the first step, interaction of LPS with monocytes was strongly
dependent on membrane-bound CD14, as preincubation of monocytes with
anti-CD14 mAb totally blocked the ability of LPS-primed monocytes
to promote T cell proliferation (Table I). These blocking effects of
anti-CD14 mAb could not be observed in TT- or SEB-primed monocytes
and are therefore specific for LPS/monocyte interactions. CD14 is
described to be responsible for specific binding of LPS to monocytes
and is, beside CD11/CD18 (22), one of the functionally LPS receptors
known thus far (23). Furthermore, it is known that the specific binding
of LPS to monocytes can be blocked by the anti-CD14 mAb MEM-18
(24, 25, 26). Therefore, we conclude from our results that binding of LPS
to CD14 on monocytes is necessary to induce their T cell-stimulatory
capacity.
As shown in Figure 2, further steps of LPS/monocyte interactions were
sensitive to the lysosomotropic agent ammonium chloride. Ammonia has
been shown to alkalinize lysosomal intracellular compartments and thus
to prevent proteolysis of proteins (27). As already described,
stimulation of T cells by protein recall Ag, like TT, requires Ag
processing (27), while in case of T cell stimulation by the
superantigen SEB Ag processing is not necessary (28). Surprisingly, T
cell stimulation by the nonprotein compound LPS was also sensitive to
ammonium chloride. Whether this sensitivity to ammonia reflects
processing steps of LPS or whether ammonia is simply inhibiting the
endosomal traffic and processing of secretory products requires further
investigations.
Next, we investigated whether or not interaction of T cells with
LPS-primed monocytes is MHC restricted. Thus, we cocultured purified T
lymphocytes with primed autologous or heterologous monocytes. As shown
in Table II, the interaction of LPS-primed monocytes with T cells was
not MHC restricted, since primed autologous monocytes could be replaced
effectively by primed heterologous monocytes. These results were
confirmed by the finding that Ab against MHC class II had no effect on
LPS-induced T cell proliferation (Table III).
Interestingly, only LPS-primed monocytes of LPS responders were able to
induce T cell proliferation (Fig. 3). Thus, it is not the T cell
repertoire that is the limiting factor for a healthy donor to become a
LPS responder, but the capability of the monocytes to provide optimal
help in the form of costimulatory signals for LPS-induced T cell
proliferation.
Beside MHC/T cell receptor interactions, several ligand/receptor pairs
are described that deliver costimulatory signals for optimal T cell
proliferation. Interaction of CD28 and/or CTLA-4 on T lymphocytes with
their ligands CD80 (B7.1) and CD86 (B7.2) on monocytes deliver such
costimulatory signals (29, 30). In blocking experiments, we
investigated the role of these costimulatory signals during LPS-induced
T cell proliferation by the use of soluble CTLA-4Ig. As shown in Figure 3, T cell proliferation induced by LPS or TT was inhibited by CTLA-4Ig
in a dose-dependent manner, while superantigen-induced T cell
proliferation was not affected. These experiments indicate that
costimulatory signals through CD28 and/or CTLA-4 are required for
optimal stimulation of human T lymphocytes by LPS and by the recall Ag
TT. On the other hand, superantigenic stimulation of T cells was not
dependent on B7 costimulatory interactions (28).
The finding that interactions between CD28/CTLA-4 on T lymphocytes with
their ligands CD80/CD86 on monocytes were necessary for optimal T cell
stimulation made it reasonable to assume that these ligands were
differentially regulated on monocytes of LPS responders and LPS
nonresponders. Thus, we compared the expression of CD80 or CD86,
respectively, on monocytes of LPS responders and nonresponders before
and after LPS stimulation (Fig. 5). Indeed, there was a clear
correlation of CD80 expression on monocytes after LPS stimulation and
their capacity to support T cell proliferation. The expression of CD80
was only enhanced in the group of LPS responders. On the other hand,
there was no significant enhancement of the CD86 expression on
monocytes either of LPS responders or of nonresponders. It has recently
been shown that CD80 is inducible on monocytes by LPS (31). In these
studies, it was also demonstrated that healthy donors, with regard to
the induction of CD80 expression by LPS, can be separated into two
groups: one, in which CD80 expression could not be induced by LPS; and
another, in which CD80 was inducible by LPS. These observations
therefore correlate well with the data presented here.
Blocking of the biologic activity of IL-12 by neutralizing anti-IL-12 mAb resulted in a clear reduction of T cell proliferation, while blocking with neutralizing anti-IL-15 mAb had only minor effects. Thus, beside B7/CD28 interactions, IL-12 also seems to play a crucial role in LPS-induced T cell proliferation, while IL-15 plays a minor role. IL-12 is a strong immunoregulator (26) that synergizes with B7/CD28 interaction in inducing proliferation of human T lymphocytes (32). However, it was shown that IL-12 alone is not able to induce proliferation in resting T lymphocytes but stimulates activated T cells or T cell clones (33). Whether LPS, in our experimental system, induces T cell proliferation of in vivo preactivated T lymphocytes by inducing the expression of CD80 on monocytes and their IL-12 secretion is therefore of main interest in our future studies.
In conclusion, LPS-induced T cell activation seems to be based on thus far unknown mechanisms with MHC-unrestricted accessory cell requirements different from classical antigenic or superantigenic stimulation. Recognition of endotoxin by LPS-primed monocytes depends on CD14, and LPS-primed monocytes provide costimulatory signals through CD28 and/or CTLA-4, CD80 interactions, and presumably IL-12 secretion. Whether the status of LPS responders or nonresponders regarding the induction of CD80 expression and T cell activation is of clinical significance, e.g., during Gram-negative sepsis or endotoxemia, remain to be investigated.
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Acknowledgments |
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reji. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Artur J. Ulmer, Department of Immunology and Cell Biology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany.
3 Abbreviations used in this paper: TT, tetanus toxoid; HS, human serum; PPD, purified protein derivatives of M. tuberculosis; SEB, staphylococcal enterotoxin B.
Received for publication April 28, 1997. Accepted for publication December 1, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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secretion in the presence of endothelium. J. Surg. Res. 63:73.[Medline]
stimulated monocytes: A potential mechanism for amplification of T cell activation through the CD28 pathway. Cell. Immunol. 137:429.[Medline]
ß+, TCR-
+ T lymphocytes, and NK cells. J. Immunol. 149:3495.[Abstract]
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C. Forestier, E. Moreno, J. Pizarro-Cerda, and J.-P. Gorvel Lysosomal Accumulation and Recycling of Lipopolysaccharide to the Cell Surface of Murine Macrophages, an In Vitro and In Vivo Study J. Immunol., June 1, 1999; 162(11): 6784 - 6791. [Abstract] [Full Text] [PDF]
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 D. W. Beelen, A. Elmaagacli, K.-D. Muller, H. Hirche, and U. W. Schaefer Influence of Intestinal Bacterial Decontamination Using Metronidazole and Ciprofloxacin or Ciprofloxacin Alone on the Development of Acute Graft-Versus-Host Disease After Marrow Transplantation in Patients With Hematologic Malignancies: Final Results and Long-Term Follow-Up of an Open-Label Prospective Randomized Trial Blood, May 15, 1999; 93(10): 3267 - 3275. [Abstract] [Full Text] [PDF]
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 T. Mattern, G. Girroleit, H.-D. Flad, E. T. Rietschel, and A. J. Ulmer CD34+ Hematopoietic Stem Cells Exert Accessory Function in Lipopolysaccharide-induced T Cell Stimulation and CD80 Expression on Monocytes J. Exp. Med., February 15, 1999; 189(4): 693 - 700. [Abstract] [Full Text] [PDF]
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