Molecular Human Reproduction, Vol. 8, No. 3, 255-261,
March 2002
© 2002 European Society of Human Reproduction and Embryology
Implantation and pregnancy |
Th1- and Th2-like cytokine production by first trimester decidual large granular lymphocytes is influenced by HLA-G and HLA-E
1 Department of Obstetrics and Gynaecology, Julius-Maximilians-University, Wuerzburg and 2 Institute of Anthropology and Human Genetics, Ludwig-Maximilians-University, Munich, Germany
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During normal early pregnancy, a particular immune environment in the decidua and the expression of non-classical HLA-G and HLA-E molecules on the invading trophoblast are assumed to be essential for the tolerance of the fetus. To assess whether HLA-G and HLA-E influence the cytokine production of their putative target cells [large granular lymphocytes (LGL)], we analysed the concentrations of tumour necrosis factor (TNF-
), interferon (IFN)-
, interleukin (IL)-10, IL-13 and granulocyte-macrophage colony stimulating factor (GM-CSF) in supernatants of isolated first trimester LGL co-cultured with HLA-G or HLA-E transfected K-562 leukaemia cells lacking the classical HLA class I and II molecules. In comparison with that observed with untransfected K-562 cells, co-culture of LGL with HLA-G-expressing cells significantly reduced the concentration of all cytokines investigated (TNF-, IL-10 and GM-CSF, P < 0.01; IFN- and IL-13, P < 0.05). In contrast, co-culture of LGL with HLA-E-expressing cells significantly (P < 0.01) decreased only IL-10 production, although a strong tendency towards reduced IL-13 levels was also observed. In the co-culture system presented, membrane-bound HLA-G and, to a lesser extent, HLA-E expression affected cytokine release by decidual LGL in a manner not consistent with the Th1/Th2 paradigm. In conclusion, our data are indicative of a general immune-suppressive effect of HLA-G on LGL activity. cytokine/HLA-E/HLA-G/K-562/LGL
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Introduction |
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Successful human pregnancy seems to be an immunological paradox, in that the semi-allogenic fetus develops in the potentially hostile environment of the maternal immune system. Cytokines, produced by different immunocompetent cells such as macrophages, natural killer (NK) cells and thymus-derived (T) cells are thought to be important mediators in the communication between the mother and the developing fetus.
The majority of the lymphoid cells present in human first trimester decidua are large granular lymphocytes (LGL) exhibiting the unusual phenotype CD56++, CD3–, CD16– and NK cell function (Starkey et al., 1988
). It has been suggested that LGL are involved in the control of fetal trophoblast (FTB) invasion during early human pregnancy, e.g. as cytotoxic effector cells or as producers of specific cytokines (Loke and King, 2000), but the biological functions of these cells are not yet completely understood. Several studies indicate that in normal pregnancy, there is a shift in the cytokine pattern from Th1 towards Th2, suggesting that successful pregnancy is a Th2 phenomenon (Wegmann et al., 1993). Members of the Th1 cytokine family are tumour necrosis factor (TNF)-, interleukin (IL)-2, IL-12 and interferon (IFN)-. TNF- has been shown to inhibit FTB invasion by impairing trophoblast cell motility (Todt et al., 1996). IFN- is a known up-regulator of major histocompatibility complex (MHC) class I and MHC class II antigen expression on human trophoblast cells (Grabowska et al., 1990). In contrast, cytokines of the Th2 family such as IL-4, IL-6, IL-10 and IL-13 mainly exhibit immunosuppressive properties, which are considered to be of particular importance for the survival of the fetus (Wegmann et al., 1993). Uterine lymphocytes as well as FTB produce granulocyte-macrophage colony-stimulating factor (GM-CSF) (Jokhi et al., 1994). GM-CSF is believed to support pregnancy, in that the administration of GM-CSF in mice at risk of abortion reduces the fetal death rate (Clark et al., 1994).
Cytokine production by different decidual immunocompetent cells could be regulated by the expression of specific antigens on the surface of trophoblast cells. HLA-G and HLA-E are both non-classical MHC class I molecules exhibiting limited polymorphism. Within the human decidua, HLA-G expression is mainly restricted to the invasive extravillous FTB (McMaster et al., 1995), which are in direct contact with maternal immunocompetent cells, in particular decidual LGL. HLA-G could be important for the survival of the fetus by inhibiting NK-mediated lysis and/or modulating the cytokine release of decidual cells (Loke et al., 2000). HLA-E is an ubiquitous antigen that has also been detected on trophoblast cells (King et al., 2000a). The function of HLA-E in the decidual cell network is still poorly characterized; it has been shown that interaction of HLA-E with CD94/NKG2 receptors on NK cells diminishes the cytoxicity of NK cells lines (Borrego et al., 1998). Whether the expression of HLA-G or HLA-E on FTB modulates the cytokine production of decidual LGL is still unknown. In our study, we used co-cultures of HLA-G- or HLA-E-positive K-562 transfectant cells with isolated decidual LGL as a model to study the influence of HLA-G and HLA-E expression on the cytokine production of decidual LGL.
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Materials and methods |
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Patients and tissue specimens
Samples of decidual tissues (decidua basalis and parietalis) were obtained by curettage from 11 healthy women undergoing voluntary therapeutic abortion of a viable pregnancy at 7–9 weeks gestation. Tissue was stored in phosphate-buffered saline (PBS) for subsequent cell isolation. All women gave informed consent to the contribution of uterine tissue to the present study. These studies were approved by the Ethics Committee of the medical faculty of the University of Wuerzburg.
LGL isolation and flow cytometry
Decidual LGL were isolated from the 11 decidual samples as previously described and immediately used for co-culture (Kammerer et al., 1999). After isolation, reanalysis in a FACScan fluorescence-activated cell sorter (Becton Dickinson, Heidelberg, Germany) was performed as described (Rieger et al., 2001) and, using fluorescein-labelled anti-CD56 antibodies, revealed a purity of >95% CD56++ in the LGL fraction.
Cell lines
K-562 leukaemia cells were obtained from the American Type Culture Collection (Rockville, USA) and cultured in RPMI 1640 medium (Life Technologies, Karlsruhe, Germany) supplemented with 10% heat inactivated fetal calf serum (FCS) and 25 µg/ml gentamycin-sulphate (R10 medium; Biochrom, Berlin, Germany). The HLA-E transfectant was established as previously described (Maier et al., 2000). Briefly, a hybrid HLA-E cDNA encoding exon 1 of HLA-A2 was subcloned in the vector pcDNA3 and HLA class I-positive K-562 transfectants were selected by FACS and cloned (M.Ulbrecht, Department of Biology II, University (LMV) of Munich, Germany; personal communication). The HLA-G-positive K-562 cells were established with the HLA-G1m cDNA subcloned in the vector pcDNA3.1 (Invitrogen, Groningen, The Netherlands). Clones were selected and maintained in RPMI 1640 medium supplemented with 1 mmol/l sodium pyruvate, penicillin (100 IU/ml), streptomycin (100 µg/ml; all BioWhittaker, Verviers, Belgium), 10% FCS (Biochrom) and 0.4 mg/ml G418 (PAA, Linz, Austria). Cells were selected for high HLA-G and HLA-E expression respectively by cell sorting in a FACScan fluorescence-activated cell sorter (Becton Dickinson). For immunofluorescence, 2x105 cells were incubated with 40 µl of hybridoma supernatant W6/32 for 30 min on ice. Cells were washed twice with PBS/5% FCS and incubated with 30 µl secondary reagent phycoerythrin-conjugated goat anti-mouse immuno-globin G H+L F(ab')2-fragment (1:150 in PBS/5% FCS; Immunotech, Marseille, France) for 20 min on ice in the dark. After three washes with PBS/5% FCS, samples were fixed with 1% paraformaldehyde in PBS and analysed on a FACScan fluorescence-activated cell sorter (Becton Dickinson). The results are shown in Figure 1.
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As effector cells for the cytotoxicity assay, the NK cell leukaemia cell line NKL was used.
Lanthanide cytotoxicity assay
A total of 3x106 target cells (HLA-G and HLA-E transfected K-562 cells respectively) were washed in RPMI medium (RPMI 1640 supplemented with 5% FCS) and labelled at a concentration of 1x106 cells/ml with 5 µl BATDA reagent (Perkin Elmer Wallac GmbH, Freiburg, Germany) for 10 min at 37°C. Labelled cells were washed three times in RPMI/5% FCS and stored in aliquots at –80°C or used immediately. The cytolytic activity of the cell line NKL was assessed in a 2 h TDA-release assay in which effector cells were mixed with 5x103 BATDA-labelled and washed target cells at various effector:target ratios (E:T = 5:1, 2.5:1 and 1.25:1) in a total volume of 200 µl. After co-incubation of the effector and target cells for 2 h at 37°C in a humidified 5% CO2 incubator, 20 µl of the supernatant was mixed with 180 µl europium solution (Perkin Elmer Wallac GmbH) and incubated for 15 min at room temperature while shaking in a flat-bottom 96-well microtitre plate (Perkin Elmer Wallac GmbH). Time-resolved fluorometry was carried out with a VictorTM 1420 Multilabel Counter (Perkin Elmer Wallac GmbH). The percentage of specific lysis was calculated as (experimental release – spontaneous release)/(maximal release – spontaneous release)x100%. The maximal release was determined by addition of TritonX100 in an end concentration of 0.25%. The spontaneous release was never >20%. The assay was performed in triplicates. The results are shown in Figure 2.
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Co-culture experiments
Isolated CD56++ LGL were resuspended in R10 medium at a concentration of 5x106 viable cells/ml and directly used for co-culture. Trypan Blue staining revealed 95% of LGL to be viable. For co-culture experiments, 5x106 K-562 cells were seeded per well in 1 ml of R10 medium in 24-well cluster plates (Costar, Bodenheim, Germany) and then irradiated with UV-C (8 mW/cm2; 10 min). Subsequently, each well was overlaid by 1 ml R10 medium with 5x106 LGL to be tested to a total volume of 2 ml/well. For each decidual sample, the following co-culture experiments were performed in the settings described above: isolated LGL were co-cultured with K-562, HLA-G1-transfected K-562 (K-562-G) or HLA-E-transfected K-562 cells (K-562-E). LGL as well as untransfected and transfected K-562 cells (each 5x106 cells/well in 2 ml R10 medium) alone served as a control. After incubation for 48 h at 37°C and 5% CO2, the culture supernatant was centrifuged to remove remaining cells. Aliquots of supernatant were snap-frozen in liquid nitrogen and stored at –80°C until the cytokine measurements were performed.
Enzyme-linked immunosorbent assay (ELISA)
The concentrations of TNF-, IFN-, IL-10, IL-13 and GM-CSF were determined twice in each supernatant using the OptEIA human matched antibody pair sets (BD Pharmingen, Heidelberg, Germany). All cytokine ELISAs were established following the manufacturer's instructions to a sensitivity of 2–4 pg/ml (lowest cytokine concentration that gives 2 SD above the mean background signal value). For all ELISA systems the tetramethylbenzidine substrate reagent set (BD Pharmingen) was used to detect horse-radish peroxidase reactivity.
Statistical analysis
Because the basic levels of cytokines among the patients did not conform to a normal distribution pattern as assessed by the Shapiro–Wilkins test for normality, we used the non-parametric Wilcoxon matched pair log rank test (two-tailed) for statistical analysis. We compared the cytokine concentrations in the supernatant of all cultured cells (co-cultures and single culture controls).
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Functional expression of the transfected HLA molecules
Analysis of functional expression of the transfected HLA molecules was performed by a lanthanide cytotoxicity assay. As shown in Figure 2
, the HLA-E-positive K-562 cells were protected from NKL cell line-mediated lysis, whereas the HLA-G-positive cells as well as the original K-562 cell line were lysed.
Cytokine concentrations in the supernatant
We compared the cytokine production of isolated decidual LGL and co-cultures of LGL with K-562 cells, and co-cultures of LGL with K-562 cells transfected with either HLA-G or HLA-E. The results of these experiments for all 11 samples investigated are summarized in Tables I, II and Figure 3. None of the cytokines examined (TNF-, IFN-, IL-10, IL-13 and GM-CSF) could be detected in the supernatant of untransfected or transfected K-562 cells without the presence of decidual cells.
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Cultures of LGL with K-562 cells resulted in detectable cytokine secretion, as described in detail below.
TNF-
In 10 out of 11 cases, TNF- could be detected in the supernatant of decidual LGL alone and in co-cultures of decidual LGL with untransfected or transfected K-562 cells. Significantly more TNF- was detected in all supernatants of co-cultures of LGL with K-562 (P < 0.01), K-562-G (P < 0.01) and K-562-E (P < 0.01) cells than in the control LGL cultures. TNF- concentrations in LGL/K-562-G co-cultures were significantly lower than in LGL/K-562 (P < 0.01) co-cultures. The TNF- concentrations of LGL/K-562-G and LGL/K-562 did not differ significantly from LGL/K-562-E co-cultures (Figure 3A).
IFN-
In only two of the 11 cases, isolated decidual LGL produced detectable amounts of IFN- in the control cultures. In contrast, IFN- could be detected in eight out of 11 co-cultures of LGL with transfected or untransfected K-562 cells. IFN- concentrations in supernatants of LGL/ K-562-G were significantly lower than those in LGL/K-562 (P < 0.05) and LGL/K-562-E (P < 0.05) co-cultures. There was no significant difference in IFN- concentrations in the LGL/K-562 and LGL/K-562-E co-cultures (Figure 3B).
IL-10
IL-10 could only be detected in the supernatants of six out of the 11 LGL control cultures and in eight co-cultures. In those cases, the IL-10 concentration in the control cultures was significantly lower than in the co-cultures with K-562 (P < 0.01), K-562-G (P < 0.05) and K-562/E (P < 0.05). There was significantly less IL-10 secretion in co-cultures of both LGL/K-562-G (P < 0.01) and LGL/K-562-E (P < 0.01) in comparison with LGL/K-562, but the concentrations of IL-10 in LGL/K-562-G and LGL/K-562-E supernatants were similar (Figure 3C).
IL-13
IL-13 could only be detected in the supernatant of one of the 11 LGL control cultures. However, when the decidual LGL were co-cultured with K-562 cells, IL-13 could be detected in five co-culture experiments. In those five cases, IL-13 secretion was significantly reduced when HLA-G transfectants of K-562 were used for co-cultures compared with that when untransfected K-562 or transfected K-562-E cells were used (P < 0.05 in both cases; Figure 3D). Similar to HLA-G transfectants, the use of HLA-E-positive K-562 cells resulted in a marked reduction of IL-13. However, in those five cases, statistical significance was not reached.
GM-CSF
GM-CSF could be detected in the supernatant in eight of the 11 LGL control cultures. In all co-cultures of LGL with untransfected or transfected K-562 cells, GM-CSF was present in media. Amounts of GM-CSF were in all cases significantly higher than in the control cultures (P < 0.01 for all co-cultures). Co-cultures of LGL/K-562-G produced significantly less GM-CSF than co-cultures of LGL with untransfected K-562 (P < 0.01) or K-562-E cells (P < 0.05; Figure 3E). There was no significant difference between the co-cultures of LGL/K-562 and LGL/K-562-E.
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Discussion |
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Human FTB are known to express classical HLA-C (King et al., 2000b
), non-classical HLA-E (Ritson and Bulmer, 1987) and HLA-G (Kovats et al., 1990) antigens. It has been proposed that the expression of these MHC antigens on FTB is important to maintain the development of the fetus in the uterine environment which is, especially in the first trimester, seeded by a large number of decidual LGL. Several receptors which can interact with MHC class I antigens on FTB have been described on decidual LGL. Immunoglobin-like transcript 2 (ILT2), which is expressed on a fraction of decidual NK cells, is a known receptor for HLA-G (Colonna et al., 1997). Another receptor described to recognise HLA-G is the killer inhibitory receptor (KIR) p49 which is expressed by every NK cell (Cantoni et al., 1998). Decidual LGL have also been found to carry the CD94/NKG2 receptor complex, which specifically recognises HLA-E (King et al., 2000a) and confers protection from NK lysis (Lee et al., 1998). Since the human genome encodes a large number of ILT and KIR transcripts, it is possible that additional, not yet identified, class I receptors are present on LGL and could interact with HLA-G.
The role of uterine LGL in the immunoregulation of pregnancy is still unclear. One suggested role for decidual LGL is an NK cell function and the infiltrating FTB might be possible targets. HLA-G expression on FTB is discussed as one of the signals which protects them against NK cell lysis. It has been shown that K-562 cells, which are normally susceptible to NK-lysis, are protected from lysis by decidual LGL and peripheral blood NK cells when expressing HLA-G on their surface (Rouas-Freiss et al., 1997). However, our results (discussed below) showed that HLA-G expression did not protect K562 cells from NK cell-mediated lysis. Furthermore, it has been demonstrated that the MHC class I-negative choriocarcinoma cell line JAR is equally resistant to lysis by peripheral blood NK lymphocytes as the HLA-G- and HLA-C-positive JEG-3 chorioncarcinoma cell line. This and the fact that both cell lines are equally lysed by IL-2-stimulated peripheral blood lymphocytes (Avril et al., 1999) question that the biological function of HLA-G is merely protection of trophoblast cells against NK cell lysis. Thus, the biological significance of the expression of MHC class I molecules on FTB in the interaction with decidual LGL remains unclear.
Decidual LGL are not only known to have a cytotoxic function, but also to produce different cytokines. Therefore, LGL might have a role in the production of a local cytokine milieu which is protective for the FTB. It is assumed that the balance of Th1 and Th2 cytokines is important for the success of pregnancy and that HLA-G expression on FTB could modulate the cytokine release of decidual LGL (Loke and King, 2000). It has been shown that membrane-bound (mHLA-G) and soluble (sHLA-G) HLA-G influences the release of cytokines from allogenic peripheral blood mononuclear cells (Kanai et al., 2001a). Furthermore, Kanai et al. demonstrated that HLA-G expression on 721.221 B-lymphoblast cells modulates the ability of decidual and peripheral blood mononuclear cells to release cytokines which are relevant to Th2 polarization (Kanai et al., 2001b).
Previously, we have described that MHC class I-positive JEG-3 and MHC class I-negative JAR choriocarcinoma cells modulate the cytokine production of decidual LGL in different ways (Rieger et al., 2001). In the present study, we investigated whether HLA-G- or HLA-E-transfected K-562 cells, in comparison with untransfected K-562 cells, affect the production of TNF-, IFN-, IL-10, IL-13 and GM-CSF by isolated human decidual LGL. Co-cultures of LGL with untransfected K-562 cells dramatically increased the production of all the cytokines examined in this study compared with control LGL. MHC class I expression reduced extracellular cytokine levels when compared with co-culturing LGL with the untransfected class I-negative K-562 cells. Moreover, HLA-G and HLA-E differed with regard to their suppression of cytokine secretion. HLA-G significantly reduced the level of all cytokines measured, whereas HLA-E expression significantly decreased only IL-10 concentrations.
From these observations it can be assumed that HLA-G exerts a suppressive effect on cytokine secretion of decidual LGL, and that this effect is not restricted to members of the Th1 or Th2 families. However, it should be mentioned at this point that with the exception of IFN- and GM-CSF, the cytokines examined exert both Th1 and Th2 properties.
The role of HLA-E at the feto–maternal interface is even less defined than that of HLA-G. It is generally assumed that HLA-E expression allows the immune system to monitor normal biosynthesis of HLA class I molecules, a process that is hampered during viral infections and in some tumours (Lopez-Botet and Bellon, 1999). King et al. have shown that HLA-E expression on 721.221 cells inhibits the cytotoxic activity of decidual NK cells (King et al., 2000a), but to our knowledge, there is no information about the influence of HLA-E on cytokine production of other immunocompetent cells.
Similarly to HLA-G, HLA-E expression on K-562 cells in our model system resulted in a reduction of all cytokine concentrations, but, with the exception of IL-10, without statistical significance. The lack of significance for the effect of HLA-E on IL-13 may be due to the low number of supernatants with detectable concentrations of this cytokine and the use of a rank test.
Our observations lead to speculation of a general suppressive effect of the expression of HLA-G and HLA-E on the ability of decidual LGL to release cytokines. The difference in the degree of reduction of cytokine levels by HLA-G versus HLA-E can presumably be explained by their different receptors on LGL. Though the HLA-E transfectant cells have been selected for high surface expression, HLA-E expression was generally lower than that of HLA-G on K-562 cells (Figure 1) (Maier et al., 2000). Hence, the different effects that HLA-G and HLA-E exert might be explained by their different surface expression. However, with regard to the inhibition of NK cell-mediated lysis, the HLA-E-positive K-562 cells were protected, whereas the HLA-G-positive cells were lysed (Figure 2). The NKL cell line expresses CD94/NKG2A, the only known receptor for HLA-E, and ILT-2, one of the inhibitory receptors recognised by HLA-G. Thus, the HLA-E cell surface molecules suffice for negative signalling via CD94/NKG2A in NKL, whereas HLA-G on the cell surface engaging ILT-2 does not. These results point to a differential regulation of factors involved in cell lysis by HLA class I inhibitory receptors.
Taken together, our results suggest that HLA-G, more than HLA-E, expression on co-cultured K-562 cells can suppress the cytokine release of isolated decidual CD56++ LGL and thus may have a general immunosuppressive effect in addition to their NK-inhibitory function (Rouas-Freiss et al., 1997; King et al., 2000a). However, the understanding of the precise mechanism of the interaction between MHC molecules on the surface of FTB with decidual NK cells is still limited. Further investigations are needed to find out by which receptors the cytokine secretion of decidual LGL is regulated.
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We thank M.Lopez-Botet for kindly providing the cell line NKL and H.Pohla for the use of the VictorTM 1420 Multilabel Counter. These studies were supported by a grant from the Federal Ministry of Education and Research (01KS9603) and the Interdisciplinary Centre of Clinical Research Wuerzburg (IZKF) and by the SFB 571.
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3 To whom correspondence should be addressed at: Universitäts-Frauenklinik, Josef-Schneider-Str. 4, D-97080 Wuerzburg, Germany. E-mail: frak057{at}mail.uni-wuerzburg.de
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Submitted on July 30, 2001; accepted on November 22, 2001.
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 A. Blaschitz, H. Juch, A. Volz, H. Hutter, C. Daxboeck, G. Desoye, and G. Dohr The soluble pool of HLA-G produced by human trophoblasts does not include detectable levels of the intron 4-containing HLA-G5 and HLA-G6 isoforms Mol. Hum. Reprod., October 1, 2005; 11(10): 699 - 710. [Abstract] [Full Text] [PDF]
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H.G.M. Lukassen, I. Joosten, B. van Cranenbroek, M.J.C. van Lierop, J. Bulten, D.D.M. Braat, and A. van der Meer Hormonal stimulation for IVF treatment positively affects the CD56bright/CD56dim NK cell ratio of the endometrium during the window of implantation Mol. Hum. Reprod., July 1, 2004; 10(7): 513 - 520. [Abstract] [Full Text] [PDF]
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A. van der Meer, H.G.M. Lukassen, M.J.C. van Lierop, F. Wijnands, S. Mosselman, D.D.M. Braat, and I. Joosten Membrane-bound HLA-G activates proliferation and interferon-{gamma} production by uterine natural killer cells Mol. Hum. Reprod., March 1, 2004; 10(3): 189 - 195. [Abstract] [Full Text] [PDF]
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