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1 Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Germany
2 Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Germany
Correspondence
Susanne Beckebaum
susanne.beckebaum{at}uni-due.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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)-based antiviral therapy. Altered homing behaviour of DCs may be a possible mechanism for their ‘loss’ in peripheral blood in these clinical conditions. Systemic chemokine levels were measured by ELISA. Phenotypes and migratory properties of MDCs and PDCs from HCV patients were analysed by flow cytometry and chemotaxis assay. Compared with healthy controls, HCV patients had increased serum levels of inflammatory and constitutively expressed chemokines. Spontaneously generated MDCs from HCV patients were less mature, and both MDCs and PDCs showed intrinsic activation of receptors for inflammatory chemokines, thus suggesting an increased propensity to migrate towards inflammatory sites. IFN- treatment in vitro induced MDC maturation and skewed the migratory response of both MDCs and PDCs towards chemokines expressed constitutively in secondary lymphoid organs. In conclusion, our results hint at altered homing behaviour of DCs during chronic HCV infection. IFN- therapy may redirect DC migration from inflamed hepatic portal areas towards secondary lymphoid tissue. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). DC trafficking is an essential step for the establishment of specific immune responses. The migration ability of DCs is regulated by chemokines that control the mobilization of DCs from inflammatory sites and their homing to secondary lymphoid organs (Gunn, 2003). Immunophenotypic characterization of DC subtypes in humans is commonly based on the absence of a panel of leukocyte lineage-negative (Lin–) specific antigens (CD3, CD14, CD16, CD19, CD20 and CD56) and the presence of major histocompatibility complex (MHC) class II (such as HLA-DR) (Willmann & Dunne, 2000). These Lin–HLA-DR+ DCs were originally subdivided into two populations: CD11c+CD123low myeloid DCs (MDCs) and CD123highCD11c– plasmacytoid DCs (PDCs) (Banchereau et al., 2000). However, novel specific antigen markers that allow further characterization of distinct DC subsets in peripheral blood have been identified (Dzionek et al., 2000). The CD123 antigen is also expressed at low levels in circulating MDCs (Banchereau et al., 2000; Ho et al., 2002), whereas blood dendritic-cell antigen (BDCA)-4 is only expressed by CD123highCD11c– PDCs in peripheral blood (Dzionek et al., 2000). Conflicting experimental data about DC homeostasis in chronic HCV infection have been reported. Several reports have indicated DC dysfunction in patients with chronic HCV infection (Auffermann-Gretzinger et al., 2001; Bain et al., 2001; Kanto et al., 1999, 2004; Murakami et al., 2004; Ulsenheimer et al., 2005). Some groups found that HCV-infected patients had significantly lower levels of DC subsets in peripheral blood than healthy individuals (Della Bella et al., 2007; Goutagny et al., 2004; Kanto et al., 2004; Kunitani et al., 2002; Murakami et al., 2004; Nattermann et al., 2006; Wertheimer et al., 2004). However, a causal role of HCV has been questioned, as reduced levels of circulating DCs have also been observed in patients with other, non-HCV-associated, chronic liver diseases (Wertheimer et al., 2004). Furthermore, some reports even indicated normal functioning of MDCs in patients with chronic HCV infection (Longman et al., 2005; Piccioli et al., 2005). Altered DC-trafficking behaviour with intrahepatic compartmentalization during chronic HCV infection has been suggested (Dolganiuc et al., 2006; Kunitani et al., 2002; Nattermann et al., 2006; Wertheimer et al., 2004). Two recent reports showed a further reduction in levels of circulating MDCs in patients with chronic hepatitis C who were receiving alpha interferon (IFN-)-based antiviral therapy (Itose et al., 2007; Shiina et al., 2006).
IFN- is a type 1 IFN with potent antiviral and immunomodulatory properties (Bekisz et al., 2004). IFN- comprises at least 13 subtypes (1, 2, 4, etc.) of structurally similar glycoproteins that share a common receptor on eukaryotic cells, namely IFN-/β receptor (IFNAR) (Branca, 1988). Generation of cellular responses to IFN- is mediated by the coordination and cooperation of multiple distinct signalling cascades, including the Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathway (Platanias, 2005). The possible mechanism of action of IFN- on DC homeostasis in HCV patients is yet to be determined. Functional studies with purified blood DCs have been hampered by poor viability in cell cultures and by interference of exogenous DC growth factors with the cellular response to IFN- (Larner et al., 1993). Moreover, recent evidence indicates that receptor cross-linking during DC isolation procedures influences DC phenotype and function markedly (Fanning et al., 2006). However, the spontaneous generation and survival of blood DCs in mononuclear cell cultures without exogenous cytokines were highlighted previously (Ho et al., 2002). Thus, the effects of recombinant human IFN- on the immunophenotype of DCs derived from HCV patients were assessed by the use of mixed mononuclear cell cultures without further addition of exogenous DC growth factors. In addition, serum concentrations of inflammatory and constitutive chemokines and DC-trafficking properties were examined in patients with chronic HCV infection.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). Thus, bulk PBMCs were cultured in serum-free X-VIVO 15 medium (Cambrex BioScience) at a density of 4x106 cells ml–1 in round-bottomed 12-well culture plates without the addition of exogenous growth factors. Preliminary experiments with escalating doses of recombinant human IFN- (100–2000 IU ml–1; Sigma-Aldrich) and distinct times of exposure (24–72 h) indicated that the effect on DC subsets treated with IFN- for 48 h at a concentration of 1000 IU ml–1 reached a plateau. Thus, the following experiments were performed under these experimental conditions. In some experiments, blood MDCs and PDCs were sorted magnetically from PBMCs with BDCA-1 and BDCA-4 cell isolation kits (Miltenyi Biotec), respectively, to a purity of >90 % in both cases.
Flow-cytometric analysis.
Freshly isolated PBMCs, as well as cells harvested from in vitro cultures, were analysed by three- and four-colour flow cytometry for DC quantification and phenotyping, respectively. Briefly, a cocktail of fluorescein isothiocyanate-labelled mAbs against the lineage markers CD3, CD14, CD16, CD19, CD20 and CD56 (Lineage Cocktail 1; BD Biosciences) was used to identify Lin– PBMCs that were stained with anti-HLA-DR–peridinin chlorophyll protein (PerCP), anti-CD11c–phycoerythrin (PE) (BD Biosciences) or anti-BDCA-4–PE mAb (Miltenyi Biotec). DCs were also phenotyped after incubation with biotinylated anti-CC chemokine receptor (CCR)1, anti-CCR2 (RD Systems), anti-CD80, anti-CCR7 or allophycocyanin (APC)-labelled anti-CD40, anti-CD54, anti-CD62L, anti-CD83, anti-CD86, anti-CCR5 (BD Biosciences), anti-CXC chemokine receptor (CXCR)3 and anti-CXCR4 mAb (RD Systems). Streptavidin–APC (BD Biosciences) was used for indirect immunofluorescent staining with biotinylated antibodies. The respective isotype mAbs were used as controls. Cells were incubated with mAbs for 30 min on ice and washed twice in PBS containing 0.1 % (w/v) BSA and 0.1 % (w/v) NaN3. After staining, cells were fixed with 2 % (w/v) paraformaldehyde in PBS, and flow cytometry was performed by using a FACScalibur flow cytometer (BD Biosciences). At least 200 000 events were recorded for each sample. Data were analysed with the WinMDI program (version 2.8; Joe Trotter, Scripps Institute, La Jolla, CA, USA). Data are expressed as percentages of positively stained cells after subtraction of cells in the same gate that were stained with isotype controls, or as the mean fluorescence intensity (MFI) with values of the isotype control subtracted.
Chemotaxis assay.
DC-migration experiments were performed in 24-transwell chambers using 5.0 µm pore-size polycarbonate membranes (Corning, Inc.). Chemokines used were monocyte chemotactic protein (MCP)-1/CCL2 (10 ng ml–1), macrophage inflammatory protein (MIP)-1β/CCL4 (100 ng ml–1), regulated upon activation, normal T cell-expressed and -secreted (RANTES)/CCL5 (10 ng ml–1), monocyte chemotactic protein (MCP)-3/CCL7 (100 ng ml–1), EBV-induced molecule 1 ligand CC chemokine (ELC)/CCL19 (1 µg ml–1), secondary lymphoid tissue chemokine (SLC)/CCL21 (1 µg ml–1), myeloid progenitor inhibitory factor (MPIF)-1/CCL23 (1 µg ml–1), IFN-inducible T-cell chemoattractant (I-TAC)/CXCL11 (1 µg ml–1) and stromal-derived factor-1 (SDF-1)/CXCL12 (100 ng ml–1) (all from R&D Systems). Chemokines were diluted in X-VIVO 15 cell-culture medium (600 µl per well) and added to the lower chambers. The lower compartments of the control chambers contained culture medium alone. Then, untreated PBMCs or PBMCs that had been pretreated with IFN- were harvested, washed and resuspended in X-VIVO 15 medium (2.5x105 cells per 100 µl) and loaded into the upper chamber. The migration assay was carried out for 3 h at 37 °C in 5 % CO2. In preliminary experiments, different concentrations of chemokines (1 ng ml–1 up to 1 µg ml–1) were used to assess their effect on DC migration. Each assay was performed in triplicate. After incubation, the cells were harvested and the proportion of migrated DCs within the total number of PBMCs was characterized by three-colour flow cytometry, as described above. For each culture condition, the migration index (MI), expressed as mean±SD, was calculated as the percentage of DCs that migrated in response to the chemokines tested compared with the percentage of DCs that migrated in the culture medium alone.
Chemokine ELISA.
Blood from patients and healthy volunteers was centrifuged at 3500 r.p.m. for 5 min, and serum was collected, aliquotted and stored at –80 °C. The concentrations of MCP-1/CCL2, MIP-1β/CCL4, RANTES/CCL5, MCP-3/CCL7, ELC/CCL19, SLC/CCL21 and MPIF-1/CCL23 were measured by using sandwich ELISA kits specific for each cytokine (R&D Systems) according to the manufacturer's protocol. The minimum detectable concentrations were 31.25 pg ml–1 for MCP-1/CCL2, MIP-1β/CCL4, RANTES/CCL5 and ELC/CCL19, 15.60 pg ml–1 for MCP-3/CCL7 and MPIF-1/CCL23, and 125 pg ml–1 for SLC/CCL21. EvenCoat goat anti-mouse immunoglobulin G (IgG) microplates (R&D Systems) were used for MCP-1/CCL2, MIP-1β/CCL4, MCP-3/CCL7 and SLC/CCL21, whereas Costar EIA/RIA plates (Corning, Inc.) were used for RANTES/CCL5, ELC/CCL19 and MPIF-1/CCL23.
Statistical analysis.
Student's t-test (two-tailed) or Wilcoxon's test for paired samples was used to detect differences between IFN--treated and control samples. Multiple comparison procedures were performed with one-way analysis of variance (ANOVA) or ANOVA on ranks. Results are expressed as means±SD unless otherwise specified. For all analyses, a P value of <0.05 was defined as statistically significant. Statistical analyses were performed by using SPSS 12.0 (SPSS, Inc.) and JMP 5.0 (JMP, Inc.) statistical software.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). Similarly, the fraction of circulating BDCA-4+ PDCs was reduced significantly in HCV patients compared with controls, with median values of 0.04±0.05 % versus 0.12±0.23 %, respectively (Fig. 1b). There were no significant correlations between the percentages of DC subsets in the blood and gender, age, grade of hepatic inflammation, stage of fibrosis, presence or absence of cirrhosis, transaminases, bilirubin, HCV genotype or viral load (data not shown).
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/ribavirin (RBV) therapy (n=58) had a further reduction in levels of circulating MDC subsets. Median MDC levels were 0.09±0.09 % in HCV patients at baseline and 0.02±0.02 % after 16 weeks combined IFN-/RBV treatment (Fig. 1c
). Similarly, the percentages of PDCs were reduced significantly from 0.03±0.05 % in untreated patients to 0.01±0.02 % after 16 weeks antiviral treatment (Fig. 1d). No significant differences in the median percentages of circulating DC subsets were evident between patients receiving PEG-IFN-2a, PEG-IFN-2b or IFN-alfacon-1, each of which was administered in combination with RBV. Two patients receiving only PEG-IFN-2b monotherapy also showed marked reductions in the levels of DC subsets in peripheral blood (data not shown). Representative examples of direct ex vivo flow-cytometric analysis of DCs from a healthy volunteer and from a patient before and during antiviral therapy are shown in Fig. 2.
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MDCs derived from HCV patients display an immature phenotype
Spontaneously generated MDCs from untreated HCV patients showed a lower grade of maturation than MDCs from healthy volunteers. In particular, HCV-MDCs had significantly lower expression levels of HLA-DR, CD54 and CD86 than MDCs from healthy individuals (Table 2). In contrast, PDCs from patients and controls showed similar expression levels of co-stimulatory and adhesion molecules (Table 2).
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). Spontaneously generated PDCs from patients also displayed intrinsic activation of CCR2, whereas the expression levels of CCR1, CCR5 and CCR7 were similar between both study groups (Table 2).
IFN- treatment affects the phenotype of MDCs and PDCs differentially
Exposure to IFN- for 48 h in vitro induced a significant upregulation of the maturation marker CD83 and HLA-DR in MDCs from untreated HCV patients (Fig. 3a, b). Moreover, there were significant increases in the expression levels of co-stimulatory (CD40, CD80 and CD86) and adhesion (CD54 and CD62L) molecules (Fig. 3a, b). In PDCs, IFN- had no effect on the expression of CD40, CD80 or CD83 (Fig. 3d), whereas the expression levels of CD86 and HLA-DR were downregulated significantly (Fig. 3e). IFN--exposed PDCs had significantly increased expression levels of adhesion markers CD54 and CD62L (Fig. 3e). IFN- treatment induced downregulation of CCR1 in MDCs from healthy controls (data not shown), whereas the high expression level of CCR1 in HCV-MDCs was not affected by IFN- (Fig. 3c). However, IFN- exposure reduced the expression level of CCR2 and upregulated the expression of CCR7 significantly in HCV-MDCs. The level of CCR5 expression was not affected by IFN- (Fig. 3c). After IFN- exposure, the expression levels of receptors for inflammatory chemokines (CCR1, CCR2 and CCR5) were reduced significantly in PDCs (Fig. 3f), whereas those of CXCR3 and CXCR4 were upregulated. The expression level of CCR7 was unaffected by IFN- exposure (Fig. 3f). Similar results regarding the effects of IFN- on DC immunophenotype were obtained from experiments performed with magnetically isolated DC subsets (Table 3).
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alters the chemotactic response of MDCs and PDCs). In contrast, there was little or no migration of HCV-MDCs in response to chemokines that are expressed constitutively in secondary lymphoid organs, such as ELC/CCL19 and SLC/CCL21 (Fig. 4a). In comparison with controls, IFN--exposed HCV-MDCs showed a significant, nearly twofold reduction in the migratory response to inflammatory ligands (Fig. 4a). The same treatment increased the responsiveness to ELC/CCL19 and SLC/CCL21 significantly (Fig. 4a). The migratory response towards constitutively expressed MPIF-1/CCL23 was not affected further by IFN- treatment (Fig. 4a). Spontaneously generated PDCs from patients had a marked migratory response to inflammatory ligands, as well as to ELC/CCL19, SLC/CCL21 and MPIF-1/CCL23 (Fig. 4b). HCV-PDCs did not migrate in response to the CXCR3 ligands, such as monokine induced by IFN-
(Mig)/CXCL9 and IFN-inducible protein 10 (IP-10)/CXCL10 (data not shown). PDCs from HCV patients, however, migrated in response to I-TAC/CXCL11 and to SDF-1/CXCL12, which are CXCR3 and CXCR4 ligands, respectively (Fig. 4b). After IFN- exposure, the migratory response of PDCs to inflammatory chemokines was reduced significantly, and PDCs had an increased propensity to migrate in response to the CCR7 ligands ELC/CCL19 and SLC/CCL21, as well as to I-TAC/CXCL11 and SDF-1/CXCL12 (Fig. 4b). Magnetically isolated DC subsets exhibited a similar change of chemotactic-migration pattern after exposure to IFN- (Table 4).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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). Although the adaptive immune response is ineffective, the inflammatory response persists, resulting in intrahepatic retention of activated lymphocytes with low levels of HCV specificity (Valiante et al., 2000). Inflammatory chemokines promote fibrogenesis of the liver by controlling the distribution of activated hepatic stellate cells (Marra et al., 1998; Schwabe et al., 2003). In the course of chronic hepatitis C, chemokines are upregulated locally in the portal tracts, where most necro-inflammatory changes occur (Kusano et al., 2000; Shields et al., 1999). HCV can also directly upregulate the expression of inflammatory chemokines, such as MCP-1/CCL2 and RANTES/CCL5, in hepatic cells (Soo et al., 2002). In agreement with these findings, we found that patients with chronic HCV infection had higher serum levels of MCP-1/CCL2, MIP-1β/CCL4 and RANTES/CCL5 than healthy volunteers. These chemokines, which are produced not only by hepatic parenchymal cells, but also by resident lymphocytes (Adams et al., 1996; Afford et al., 1998; Nischalke et al., 2004), critically regulate the inflammatory process by promoting the transendothelial migration and localization of lymphocytes in the inflamed tissue (Mackay, 2001).
Immature MDCs express the receptors CCR1, CCR2 and CCR5, which allow their migration towards the respective ligands that are produced at sites of inflammation (Dieu et al., 1998). After antigen uptake in the periphery, MDCs become increasingly mature, as shown by upregulation of MHC class I and II, as well as by increased levels of adhesion and co-stimulatory molecules. Furthermore, during maturation, MDCs downregulate receptors for inflammatory chemokines and switch to increased expression of CCR7, thus allowing their migration towards constitutive chemokines that are expressed in secondary lymphoid organs for T-cell stimulation (Banchereau et al., 2000; Dieu et al., 1998; Sallusto et al., 1998; Sozzani et al., 1998).
Spontaneously generated MDCs from HCV patients showed intrinsic activation of CCR1 and CCR2, which indicates their increased propensity to migrate towards chemokines produced at the sites of inflammation (Dieu et al., 1998). In contrast to MDCs, most chemokine receptors on circulating PDCs, in particular those responding to inflammatory chemokines, have been reported not to be functional (Penna et al., 2001). Spontaneously generated PDCs from HCV patients, however, showed a marked migratory response towards several inflammatory chemokines, such as MCP-1/CCL2, MIP-1β/CCL4, RANTES/CCL5 and MCP-3/CCL7. This is in line with recently published findings indicating a critical role for PDCs in coordinating the inflammatory milieu and antiviral immune response during chronic HCV infection (Decalf et al., 2007). Compared with healthy controls, HCV patients had significantly higher serum levels of ELC/CCL19 and SLC/CCL21, which are expressed constitutively in secondary lymphoid organs, but are also upregulated in portal tracts, as well as sinusoids, during chronic inflammatory liver disease (Bonacchi et al., 2003; Heydtmann et al., 2006). In contrast to MDCs, spontaneously generated PDCs had a notable propensity to migrate towards ELC/CCL19 and SLC/CCL21. PDCs from HCV patients also migrated in response to I-TAC/CXCL11 expressed on the sinusoidal endothelium and on portal and hepatic vascular endothelium, particularly during hepatic inflammation (Goddard et al., 2001). Moreover, PDCs from patients showed a migratory response to the CXCR4 ligand SDF-1/CXCL12, which is expressed constitutively in lymph nodes (Krug et al., 2002), as well as in normal and inflamed biliary epithelium (Goddard et al., 2001). Thus, our results suggest that both MDCs and PDCs are retained in the liver during chronic hepatitis C.
Patients with chronic HCV infection had increased serum levels of MPIF-1/CCL23, which is expressed constitutively in liver, lung and bone marrow (Patel et al., 1997). Besides evoking a chemotactic response in both DC subsets, MPIF-1/CCL23 has also been reported to be a potent inhibitor of haematopoietic progenitors, which may indicate a dual mechanism of action for reducing the levels of circulating DCs. Dysfunctional MDCs in patients with chronic hepatitis C have been reported consistently (Auffermann-Gretzinger et al., 2001; Bain et al., 2001; Kanto et al., 1999, 2004; Murakami et al., 2004). In agreement with a recent report, our results indicated an immature phenotype of spontaneously generated MDCs derived from the blood of HCV patients (Averill et al., 2007). In contrast, two other reports have described a mature phenotype and an enhanced function of MDCs residing in the livers of patients with chronic HCV infection (Kunitani et al., 2002; Lai et al., 2007). The latter findings may reflect partial maturation of MDCs in the liver, owing to locally produced inflammatory cytokines that have integral roles in inflammation in chronic hepatitis C. These partially activated MDCs might be retained in the liver because the local inflammatory milieu is not sufficient to promote a full maturational chemokine-receptor switch and subsequent emigration of MDCs from inflamed tissue.
An important role of IFN for homing of lymphocytes has been suggested previously, as it has been noted that both T and B cells are retained in secondary lymphoid organs after treatment with IFN-inducing molecules (Shiow et al., 2006). It has been shown that IFNAR signalling leads to inhibition of a particular G protein-coupled receptor required for lymphocytes to egress from lymphoid tissue. Our study revealed that IFN- modulates the expression of G protein-coupled CC chemokine receptors, as well as adhesion molecules, which are all required for DC trafficking into secondary lymphoid tissue. IFN- is typically used in combination with RBV for treatment of chronic HCV infection (Stark et al., 1998). RBV at physiological doses has no effect on MDC phenotype, whereas IFN- has been shown consistently to induce MDC maturation (Barnes et al., 2004; Luft et al., 1998). Our results indicated that IFN--exposed MDCs from HCV patients acquired a mature phenotype, as defined by the upregulation of HLA-DR and of co-stimulatory and adhesion molecules, as well as of the maturation marker CD83. Additionally, IFN- exposure induced a maturational chemokine-receptor switch in MDCs from HCV patients, as evidenced by downregulation of CCR2 and upregulation of CCR7 expression. Consistent with their chemokine-receptor profile, IFN--exposed MDCs from patients had reduced migratory responses towards inflammatory chemokines, but increased migratory responses to ligands expressed constitutively in secondary lymphoid organs.
PDC entry into lymph nodes through high endothelial venules is dependent on the interaction of the selectin family of adhesion molecules with their respective ligands, and additionally on the presence of CXCL12, as well as that of CXCR3 ligands CXCL9, CXCL10 and CXCL11 (Cella et al., 1999; Krug et al., 2002; Luft et al., 1998; Penna et al., 2001). IFN--treated PDCs from HCV patients showed markedly increased expression levels of CD54 and CD62L, as well as an increased migratory response to CCL19, I-TAC/CXCL11 and SDF-1/CXCL12, suggesting an increased ability to migrate into peripheral lymph nodes through high endothelial venules. Decalf et al. (2007) showed that PDCs are able to coordinate a complex chemokine and cytokine network after activation with specific Toll-like receptor (TLR) agonists. In addition, the authors provide evidence that PDCs from HCV patients are neither infected directly nor impaired functionally. Thus, the combined use of IFN- and specific TLR agonists might produce synergistic effects facilitating the induction of the antiviral immune response.
In conclusion, our results hint at altered trafficking behaviour with intrahepatic compartmentalization as a mechanism for the reduction of circulating DC subsets during chronic hepatitis C. Moreover, our findings highlight the immune-modulating effects of IFN- on DCs in HCV patients and may indicate novel mechanisms of IFN--mediated antiviral and anti-inflammatory activity.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Received 13 October 2007;
accepted 7 January 2008.
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