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1 Tulane University Health Science Center, New Orleans, Louisiana and 2 Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
Requests for reprints: Weiping Zou, Tulane University Health Science Center, Section of Hematology and Medical Oncology, 1430 Tulane Avenue, New Orleans, LA 70112-2699. Phone: 504-988-3562; Fax: 504-988-5483; E-mail: wzou{at}tulane.edu.
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Abstract |
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Introduction |
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Dendritic cells play a critical role in establishing tumor immunity. However, because of the rarity of dendritic cells in vivo, primary dendritic cell studies are confined to in vitro differentiated myeloid dendritic cells. Published, detailed studies of functional human dendritic cells in tumor environment are rare (9). Furthermore, another dendritic cell subset, plasmacytoid dendritic cells are technically more difficult to study. T cell activation pattern induced by plasmacytoid dendritic cells are largely determined in the allogeneic system. Little is known of the role of tumor environmental plasmacytoid dendritic cells in tumor immunity (9, 10). These limitations may significantly underestimate the impact of the dendritic cell system in tumor pathology. We have studied malignant ascites of patients with ovarian carcinoma. Malignant ascites contains viable tumor and immune cells, and serves as a model for the tumor microenvironment (9–13). We identified a significant population of plasmacytoid dendritic cells in malignant ascites. In an allogeneic system, normal blood plasmacytoid dendritic cells (14, 15) and tumor plasmacytoid dendritic cells (9) induce interleukin (IL)-10 expressing suppressive T cells. In this report, we further studied the pathologic interaction between tumor ascites T cells and tumor ascites plasmacytoid dendritic cells, and its impact on tumor-associated antigen–specific T cell immunity.
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Materials and Methods |
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Ascites, ascites cells, and tumor-draining lymph nodes. We collected and prepared single cells from ascites, blood, and lymph nodes as previously described (9, 16). CD3, CD14, CD16, CD19, and CD56-expressing cells were depleted using paramagnetic beads (Miltenyi, Auburn, CA), and plasmacytoid dendritic cells were sorted with FACSAria gating on CD4+CD123+HLA-DRbrightCD11c– cells. Cell populations were 
99% pure by flow cytometry analysis (fluorescence-activated cell sorting, FACS). Tumor ascites T cells were obtained by depleting CD14, CD16, CD19, CD56, and CD123-expressing cells using microbeads (Miltenyi), and sorting CD45+ cells by flow cytometry. Cellular purity was 98% as determined by FACS staining with anti-human CD3 antibody. Antibodies for flow cytometry and depletion were purchased from BD PharMingen, San Jose, CA. Autologous ascites cells were used throughout this study.
Peripheral blood cells. Peripheral blood was collected aseptically from normal volunteers or patients by venipuncture or by cytophoresis, and mononuclear cells were then obtained by Ficoll-Hypaque density centrifugation. Blood plasmacytoid dendritic cells were obtained as described for tumor ascites plasmacytoid dendritic cells. Cells were 98% pure as determined by FACS.
In vitro tumor-associated antigen–specific T cell stimulation. Tumor myeloid dendritic cells were differentiated from tumor macrophages as previously described (17). Tumor plasmacytoid dendritic cells were sorted from ascites as we previously described (9). Dendritic cells were activated with CD40L (200 ng/mL) for 24 hours (17), and loaded with three distinct HLA-A2-binding Her-2/neu peptides (13, 18) at 5 µg/mL each: p369-384 (KIFGSLAFLPESFDGDPA), p688-703 (RRLLQETELVEPLTPS), and p971-984 (ELVSEFSRMARDPQ). Peptide-loaded myeloid dendritic cells (tumor-associated antigen–myeloid dendritic cell) or peptide-loaded plasmacytoid dendritic cells (tumor-associated antigen–plasmacytoid dendritic cells; 102-104/mL) were used to stimulate autologous tumor ascites T cells (5 x 105/mL) in the presence of IL-2 (50 units/mL; R & D Systems, Minneapolis, MN) for 6 days (one round of stimulation). In some experiments, CD25+ or CCR7+ ascites T cells were initially depleted with magnetic beads, and CD25– T cells or CCR7– T cells were then stimulated with tumor-associated antigen–plasmacytoid dendritic cells. T cells might receive several rounds of the identical stimulation as noted. T cell phenotypes, tumor-associated antigen–specific T cell proliferation, cytokines and cytotoxic activity were detected as we described (9, 16). In some cases, T cells were stained with mouse anti-human CCR7-PE (clone 150503, mouse IgG2a, R & D), mouse anti-human CD8-APC (289-13804, IgG2a, PharMingen) and anti-human IL-10 (JES-19F1, rat anti-human IgG2a, PharMingen). At least 5,000 gated events per condition were analyzed using CellQuest software (Becton Dickinson, Mountain View, CA).
In vitro allogeneic T cell immunosuppression assay. Normal peripheral blood CD3+ T cells (4 x 105/mL) were stimulated with 2.5 µg/mL anti-human CD3 (BD PharMingen) and blood monocytes (1 x 105/mL) in the presence of different concentrations of freshly sorted allogeneic CCR7+CD45RO+CD8+ T cells from peripheral blood in normal donors or ascites in patients with ovarian cancer. Seventy-two hours after coculture, T cell proliferation was evaluated with thymidine incorporation.
In vitro tumor-associated antigen–specific immunosuppression assay. After two rounds of stimulation with tumor-associated antigen–plasmacytoid dendritic cells, ascites T cells (0.5-2 x 105/mL; on day 13) were added into tumor-associated antigen–myeloid dendritic cells (104/mL) and primary ascites T cell (5 x 105/mL) coculture for 6 days. Tumor-associated antigen–specific T cell proliferation and cytokines were detected as we described (9, 13, 16). In some cases, anti-human IL-10 receptor (250 ng/mL; 3F8, rat anti-human IgG2a, PharMingen) and anti-human IgG (250 ng/mL; R35-95, rat anti-human IgG2a, PharMingen) were added into the coculture.
Migration assay. After two rounds of stimulation with tumor-associated antigen–plasmacytoid dendritic cells, or tumor-associated antigen–myeloid dendritic cells, day 13 T cells (2 x 105) were initially incubated with 500 ng/mL mouse anti-human CCR7 monoclonal antibody (clone 150503, mouse IgG2a, R & D) or control monoclonal antibody (clone G155-178, mouse IgG2a, BD PharMingen) for 2 hours, and then subjected to in vitro migration assay as we have previously described (9). Recombinant, human chemokines (MIP-3
and MIP-3ß, 100 ng/mL each; R & D) were added to the lower chamber. The identity of migrating cells was confirmed by FACS for CD8 and CCR7.
T cell repetitive stimulation with tumor plasmacytoid dendritic cells and myeloid dendritic cells. Autologous tumor T cells were labeled with 10 µm 5,6-carboxyfluorescein diacetate succinimidyl ester (Molecular Probes, Eugene, OR) for 10 minutes in the dark at 37°C. 5,6-Carboxyfluorescein diacetate succinimidyl ester–labeled tumor T cells (5 x 105/mL) were divided into three groups. Group 1 received three rounds of identical stimulation with tumor-associated antigen–plasmacytoid dendritic cells. Group 2 received three rounds of identical stimulation with tumor-associated antigen–myeloid dendritic cells. Group 3 initially received one round of stimulation with tumor-associated antigen–plasmacytoid dendritic cells and followed two rounds of stimulation with tumor-associated antigen–myeloid dendritic cells. Tumor-associated antigen–specific T cell proliferation and cytokines were detected as we previously described (9, 13, 16). Autologous tumor-associated antigen–dendritic cells (103-104/mL) were used.
Real-time reverse transcriptase PCR. CCR7+CD45RO+CD8+ T cells were sorted from blood, tumor ascites, and tumor-draining lymph nodes. cDNA was prepared from CCR7+CD45RO+CD8+ T cells. Real-time reverse transcriptase-PCR was carried out for IL-10 (upstream 5'-atgcttcgagatctccgaga-3', downstream 5'-aaatcgatgacagcgccgta-3'), IFN-
(upstream 5'-gcagagccaaattgtctcct-3', downstream 5'-atgctcttcgacctcgaaac-3') and housekeeping gene gyceraldehyde-3-phosphate dehydrogenase (GAPDH). Complementary DNA was normalized against, and expressed as fold differences relative to, GAPDH (19) as we have previously described (13).
Statistical analysis. Differences in cell surface molecule expression were determined by 
2 test, and in other variables by unpaired t test, with P < 0.05 considered significant.
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Results |
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(Fig. 1C), and poor cytotoxic activity (Fig. 1D; n = 4; *, P < 0.001 for all, compared with myeloid dendritic cell). No significant T cell IL-4, IL-5, IL-13 and transforming growth factor-ß (TGF-ß) were detected in the culture. Primary tumor ascites tumor-associated antigen–plasmacytoid dendritic cells (without CD40L activation) did not induce important T cell proliferation (<1,000 c.p.m.) and cytokine production (IL-10, <30 pg/mL; IFN-, <0.1 ng/mL). The results indicate that tumor plasmacytoid and myeloid dendritic cells induced distinct T cell responses. Tumor ascites contain CD4+CD25+FOXP3+ T cells (CD4+ regulatory T cells; ref. 13). To determine whether CD4+ regulatory T cells affected IL-10 production induced by tumor plasmacytoid dendritic cells, we did similar experiments by initially deleting CD25+ ascites T cells with magnetic beads, and stimulated CD25– ascites T cells with tumor-associated antigen–plasmacytoid dendritic cells. We detected similar level of IL-10 (195 ± 73 pg/mL versus 221 ± 53 pg/mL, n = 4) in the supernatant from CD25– ascites T cell and tumor-associated antigen–plasmacytoid dendritic cell coculture (P = 0.078, compared with no CD25 depletion). The data suggest that CD4+ regulatory T cells are not essential for tumor plasmacytoid dendritic cells to induce IL-10-expressing T cells.
Tumor plasmacytoid dendritic cells induced IL-10+CCR7+CD45RO+CD8+ T cells. We next examined the phenotype of IL-10-expressing T cells induced by tumor plasmacytoid dendritic cells. Intracellular staining showed that tumor plasmacytoid dendritic cells induced IL-10+CD8+ T cells (n = 4; Fig. 2A). Multiple-color FACS analysis further showed that 100% of IL-10+ T cells (gate 1) were CCR7+CD45RO+CD8+ T cells and IL-10–CD8+ T cells (gate 2) were CCR7–CD45RO+ T cells, and IL-10–CD8– cells (gate 3) were largely CCR7–CD45RO+ cells (Fig. 2A).
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Tumor plasmacytoid dendritic cell–induced IL-10+CD8+ T cells migrate with MIP-3ß. To further determine whether CCR7 is functional in tumor plasmacytoid dendritic cell–induced IL-10+CD8+ T cells, we conducted a chemotaxis assay with MIP-3ß (CCL19), the ligand for CCR7. We observed that a fraction of tumor plasmacytoid dendritic cell–activated T cells efficiently migrated with MIP-3ß, but not with MIP-3 and medium (data not shown), and neutralizing mouse anti-human CCR7 monoclonal antibodies efficiently blocked this migration (n = 4; *, P < 0.001; Fig. 2B). FACS analysis revealed that the migrated cells were uniquely CCR7+CD8+ T cells (Fig. 2B). Tumor myeloid dendritic cell–activated T cells poorly migrated in these conditions. CCR7 was solely expressed on IL-10+CD8+ T cells (Fig. 2A). Thus, tumor plasmacytoid dendritic cell–induced IL-10+CD8+ T cells expressed functional CCR7, which would allow them to return to the tumor-draining lymph nodes.
Tumor plasmacytoid dendritic cell–induced IL-10+CCR7+CD8+ T cells are suppressive. We next studied whether tumor plasmacytoid dendritic cell–induced IL-10+CCR7+CD8+ T cells are suppressive. To this end, autologous tumor ascites T cells were initially activated with tumor-associated antigen–plasmacytoid dendritic cells as described (Fig. 1A). Then, different concentrations of tumor plasmacytoid dendritic cell–activated T cells were added into autologous tumor-associated antigen–myeloid dendritic cell and T cell coculture system. As expected, myeloid dendritic cells induced strong tumor-associated antigen–specific T cell proliferation in the absence of plasmacytoid dendritic cell–activated T cells (Fig. 3A and B). Interestingly, tumor plasmacytoid dendritic cell–activated T cells significantly inhibited myeloid dendritic cell–mediated, Her2/neu-specific T cell proliferation in a dose-dependent manner (n = 4; *P < 0.05, **P < 0.01, compared with controls; Fig. 3A). Tumor-associated antigen–specific T cell IFN- production was also suppressed (n = 4; *P < 0.01; Fig. 3C). Interestingly, mouse neutralizing anti-human IL-10 receptor antibody significantly recovered T cell functions (Fig. 3B and C). The data indicate that tumor plasmacytoid dendritic cell–induced CD8+ T cells are suppressive and that IL-10 is critical for this suppression.
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(0.12 ± 0.05 ng/mL), which was largely observed in the first two cell divisions (5 ± 2% IFN-+ T cells; Fig. 3E). The IL-10-expressing cells were CD8+ T cells, similar to tumor plasmacytoid dendritic cell stimulation alone (Fig. 2A). Whereas T cells stimulated with myeloid dendritic cells (without plasmacytoid dendritic cells), expressed strong T cell IFN- (total 55 ± 7%), 40% of IFN- expressing T cells were observed in the fourth cell division, indicating potent effector functions (Fig. 3E). Therefore, repetitive myeloid dendritic cell stimulation is unable to override the T cell–defective function initially induced by tumor plasmacytoid dendritic cells.
Primary tumor IL-10+CCR7+CD45RO+CD8+ T cells are suppressive. We next examined the functional characteristics of tumor primary CCR7+CD45RO+CD8+ T cells (Table 1). We sorted CCR7+CD45RO+CD8+ T cells from blood, ascites, and lymph nodes in the same individual patients (n = 8) and from peripheral blood in normal donors (n = 5). Direct intracellular straining revealed a negligible level of IL-10 protein in the sorted T cells. However, real-time reverse transcriptase-PCR showed high levels of IL-10 mRNA in CCR7+CD45RO+CD8+ T cells from peripheral blood, primary tumor ascites, and primary tumor-draining lymph node in patients with ovarian cancer, whereas normal blood CCR7+CD45RO+CD8+ T cells expressed a negligible level of IL-10 mRNA (*, P < 0.001, compared with normal blood; Fig. 4A). Furthermore, the level of IL-10 mRNA was at least 2-fold higher in CCR7+CD45RO+CD8+ T cells from tumor ascites than that from blood and lymph nodes (Fig. 4A). All the CCR7+CD45RO+CD8+ T cells expressed comparable, but low levels of IFN-, whereas activated normal T cells expressed high IFN- (Fig. 4B). Altogether, IL-10 is highly expressed in primary CCR7+CD45RO+CD8+ T cells in vivo in patients with ovarian carcinoma.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There are several proposals to explain why the immune system fails to control tumor progression, including deletions or mutations affecting the genes encoding proteins in the MHC class I pathway, or the antigen itself (21), altered TCR signal transduction or expression (22), triggering of Fas receptor on CD8+ T cells by Fas ligand expressed by tumor cells (23), and producing inhibitory cytokines such as TGF-ß and IL-10. We recently showed that tumor environmental CD4+CD25+FOXP3+ T cells contribute to tumor-associated antigen–specific immunosuppression (13). Apart from these possibilities, the dendritic cell system is thought to contribute to tumor immunopathogenesis. Tumor-derived cytokines, such as IL-6, IL-10, M-CSF, and vascular endothelial growth factor inhibit dendritic cell–differentiation, maturation, and function (8, 16, 24). Immature dendritic cells are found in tumor tissues (25), which might induce IL-10-expressing CD4+ regulatory T cells (26, 27). This report, in conjunction with our previous work (9), show for the first time that human tumors mediate plasmacytoid dendritic cell tumor trafficking and enable plasmacytoid dendritic cells to induce CD8+ regulatory T cells.
Normal blood plasmacytoid dendritic cells are shown to induce immunosuppressive T cells in an allogeneic T cell reaction (14, 15). We previously showed that tumor environmental plasmacytoid dendritic cells promoted tumor vascularization (10), and induced IL-10-expressing T cells (9). We now show that tumor plasmacytoid dendritic cells induce CD8 regulatory T cells in the context of tumor-specific immunity. Although the mechanisms whereby tumor plasmacytoid dendritic cells induce CD8 regulatory T cells remain to be defined, we have identified four characteristics for these plasmacytoid dendritic cell–induced IL-10+CD8+ T cells: (a) induction of CD8+ regulatory T cells is independent on CD4+ regulatory T cells; (b) CD8+ regulatory T cells significantly suppress myeloid dendritic cell–mediated tumor-associated antigen–specific T cell effector functions through IL-10; (c) tumor myeloid dendritic cells cannot recover the suppressive functions; (d) CD8+ regulatory T cells express functional CCR7 and efficiently migrate with lymphoid homing chemokine MIP-3ß. Furthermore, primary functional IL-10+CCR7+CD8+ T cells are found in blood, malignant ascites, and tumor-draining lymph nodes in patients with ovarian cancers. The data suggests that tumor plasmacytoid dendritic cells may induce IL-10+CCR7+CD8+ regulatory T cells in vivo.
CCR7 was used to categorize central memory T cells (CD45RO+CCR7+) versus effector memory T cells (CD45RO+CCR7–; ref. 28). Simultaneous staining of peripheral blood cells with CD45RO and CCR7 reveals a high heterogeneity in distribution of these markers (29). Functional variables are suggested to describe different T cell subsets (30). We show that tumor plasmacytoid dendritic cell–induced IL-10+ T cells exhibit a central memory T cell phenotype (CCR7+CD45RO+; ref. 28). These cells are functionally suppressive and migrate in response to MIP-3ß. Furthermore, the in vivo primary counterpart (IL-10+CD8+CD45RO+CCR7+ T cells) is found in patients with ovarian cancers. Analogously, IL-10+CD8+CD45RO+CCR7+ T cells may be termed as central regulatory memory T cells.
Notably, the tumor plasmacytoid dendritic cell in vitro induced CD8+CD45RO+CCR7+ T cells and primary in vivo tumor CD8+CD45RO+CCR7+ T cells in ovarian tumor–bearing patients are able to inhibit T cell activation. Based on the functional definition of regulatory T cells (31), ovarian tumor–associated CD8+CD45RO+CCR7+ T cells are regulatory CD8+ T cells. It remains to be defined whether this population is suppressive in patients with other tumors. Furthermore, normal blood CD8+CD45RO+CCR7+ T cells are not suppressive. Therefore, CD8+CD45RO+CCR7+ T cells are not a common phenotype and marker for defining CD8+ regulatory T cells. In fact, CD8+ regulatory T cells with distinct phenotypes have been reported. For instance, CD8+CD28– alloantigen-specific T suppressor cells were observed in human heart transplant recipients (32). Human CD8+CD25+ thymocytes are reported to mediate suppressive effects through CTLA4 and TGF-ß in normal donors (33). Murine CD8+ regulatory T cells with central memory phenotype were also reported to be a novel CD8+ regulatory T cell population (34). Our data suggest that tumor plasmacytoid dendritic cells would contribute to CD8+ regulatory T cell induction. CD8+ regulatory T cells may inhibit tumor-associated antigen–specific effector T cell immunity at the functional sites (tumor sites), and further home to lymph node and suppress tumor-associated antigen–specific naïve T cell central priming at the priming sites.
No immunogeneic (functionally mature) myeloid dendritic cells are detected in malignant ascites, suggesting that their absence is immunopathologically relevant, and means to introduce them into the tumor might be therapeutic. However, if myeloid dendritic cells cannot recover T cell effector functions after plasmacytoid dendritic cell induction, as shown in this study, blocking plasmacytoid dendritic cell tumor trafficking or functions may be essential prior to boosting tumor immunity by myeloid dendritic cells. Our data, in conjunction with the work from other groups (35–42), may at least partially explain why tumor-bearing hosts often have established weak tumor immunity, not sufficient to control disease progress, and why only moderate clinical benefits are observed in myeloid dendritic cell–based immunotherapy.
In summary, our study indicates that tumors manipulate tumor environmental dendritic cell subset distribution and functions to subvert tumor immunity (8). Multiple cellular and molecular layers of the suppressive network have been imposed in the tumor microenvironment in patients with cancers (8, 35–42). We suggest that a combination therapy with subverting immunosuppressive mechanisms, including blocking plasmacytoid dendritic cell tumor trafficking or function, is a promising, yet little-studied strategy for treating human cancers.
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Acknowledgments |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank Roy Weiner and Jules Puschett for their constant support.
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Footnotes |
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Received 11/11/04. Revised 3/14/05. Accepted 3/30/05.
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and ß expression in sporadic breast cancer. Oncogene 2001;20:8109–15.[CrossRef][Medline]
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C. Prevosto, M. Zancolli, P. Canevali, M. R. Zocchi, and A. Poggi Generation of CD4+ or CD8+ regulatory T cells upon mesenchymal stem cell-lymphocyte interaction Haematologica, July 1, 2007; 92(7): 881 - 888. [Abstract] [Full Text] [PDF]
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N. Suciu-Foca, N. Feirt, Q.-Y. Zhang, G. Vlad, Z. Liu, H. Lin, C.-C. Chang, E. K. Ho, A. I. Colovai, H. Kaufman, et al. Soluble Ig-Like Transcript 3 Inhibits Tumor Allograft Rejection in Humanized SCID Mice and T Cell Responses in Cancer Patients J. Immunol., June 1, 2007; 178(11): 7432 - 7441. [Abstract] [Full Text] [PDF]
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S. P. Bak, J. J. Walters, M. Takeya, J. R. Conejo-Garcia, and B. L. Berwin Scavenger Receptor-A-Targeted Leukocyte Depletion Inhibits Peritoneal Ovarian Tumor Progression Cancer Res., May 15, 2007; 67(10): 4783 - 4789. [Abstract] [Full Text] [PDF]
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M. R. Nazareth, L. Broderick, M. R. Simpson-Abelson, R. J. Kelleher Jr., S. J. Yokota, and R. B. Bankert Characterization of Human Lung Tumor-Associated Fibroblasts and Their Ability to Modulate the Activation of Tumor-Associated T Cells J. Immunol., May 1, 2007; 178(9): 5552 - 5562. [Abstract] [Full Text] [PDF]
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I. Perrot, D. Blanchard, N. Freymond, S. Isaac, B. Guibert, Y. Pacheco, and S. Lebecque Dendritic Cells Infiltrating Human Non-Small Cell Lung Cancer Are Blocked at Immature Stage J. Immunol., March 1, 2007; 178(5): 2763 - 2769. [Abstract] [Full Text] [PDF]
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T. Ito, M. Yang, Y.-H. Wang, R. Lande, J. Gregorio, O. A Perng, X.-F. Qin, Y.-J. Liu, and M. Gilliet Plasmacytoid dendritic cells prime IL-10-producing T regulatory cells by inducible costimulator ligand J. Exp. Med., January 22, 2007; 204(1): 105 - 115. [Abstract] [Full Text] [PDF]
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A. G. Jarnicki, J. Lysaght, S. Todryk, and K. H. G. Mills Suppression of Antitumor Immunity by IL-10 and TGF-beta-Producing T Cells Infiltrating the Growing Tumor: Influence of Tumor Environment on the Induction of CD4+ and CD8+ Regulatory T Cells J. Immunol., July 15, 2006; 177(2): 896 - 904. [Abstract] [Full Text] [PDF]
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D. Benitez-Ribas, G. J. Adema, G. Winkels, I. S. Klasen, C. J.A. Punt, C. G. Figdor, and I. J. M. de Vries Plasmacytoid dendritic cells of melanoma patients present exogenous proteins to CD4+ T cells after Fc{gamma}RII-mediated uptake J. Exp. Med., July 10, 2006; 203(7): 1629 - 1635. [Abstract] [Full Text] [PDF]
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H. Norell, M. Carlsten, T. Ohlum, K.-J. Malmberg, G. Masucci, K. Schedvins, W. Altermann, D. Handke, D. Atkins, B. Seliger, et al. Frequent Loss of HLA-A2 Expression in Metastasizing Ovarian Carcinomas Associated with Genomic Haplotype Loss and HLA-A2-Restricted HER-2/neu-Specific Immunity. Cancer Res., June 15, 2006; 66(12): 6387 - 6394. [Abstract] [Full Text] [PDF]
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A. B. Frey and N. Monu Effector-phase tolerance: another mechanism of how cancer escapes antitumor immune response J. Leukoc. Biol., April 1, 2006; 79(4): 652 - 662. [Abstract] [Full Text] [PDF]
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