Journal of Neuroimmunology 267 (2014) 105–110

Contents lists available at ScienceDirect

Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim

Short communication

The neurotrophic hepatocyte growth factor induces protolerogenic human dendritic cells Nicolas Molnarfi a,b,1, Mahdia Benkhoucha a,b,1, Catherine Juillard a, Kristbjörg Bjarnadóttir a,b, Patrice H. Lalive a,b,c,⁎ a b c

Department of Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology and Multiple Sclerosis, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Switzerland Department of Genetics and Laboratory Medicine, Laboratory Medicine Service, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland

a r t i c l e

i n f o

Article history: Received 10 September 2013 Received in revised form 2 December 2013 Accepted 4 December 2013 Keywords: Multiple sclerosis (MS) Hepatocyte growth factor Monocyte-derived dendritic cells Immune regulation Neuroinflammation

a b s t r a c t Hepatocyte growth factor (HGF) limits mouse autoimmune neuroinflammation by promoting the development of tolerogenic dendritic cells (DCs). Given the role played by DCs in the establishment of immunological tolerance, agents that coerce DCs to adopt a protolerogenic function are currently under investigation for multiple sclerosis (MS) therapy. Here, we studied the immunomodulatory effects of HGF on DCs derived from human monocytes. DCs differentiated in the presence of HGF adopt a protolerogenic phenotype with increased ability to generate regulatory T cells, a property that might be exploited therapeutically in T cell-mediated immune disorders such as MS. © 2013 Elsevier B.V. All rights reserved.

1. Introduction The recognition of multiple sclerosis (MS) as an immune-mediated inflammatory demyelinating neurodegenerative disorder (Sospedra and Martin, 2005) imparts the need to develop novel therapeutic strategies that could cripple the three hallmarks of MS simultaneously (Hemmer and Hartung, 2007). This can be accomplished with the power of combinatorial or single-agent therapy eliciting multiple protective and reparative processes simultaneously. In the search for single new therapeutics combining these requirements, recent findings indicate that hepatocyte growth factor (HGF) is one such candidate (Benkhoucha et al., 2010, Bai et al., 2012). HGF is a factor with strong neuroprotective properties (Ebens et al., 1996) reported to enhance the migration and differentiation of myelin producing oligodendrocyte precursor cells (Lalive et al., 2005, Kitamura et al., 2007). In animal models of MS, treatment with HGF results in functional improvement that reflects both modulation of the immune response and myelin repair (Benkhoucha et al., 2010, Bai et al., 2012). Data from MS patients further suggest that HGF may

contribute to both stimulation for remyelination (Muller et al., 2012) and immune modulation (Molnarfi et al., 2012). While DCs play a major role in the initiation of T cell-mediated CNS autoimmunity (Steinman and Banchereau, 2007), DCs alternatively may favor the induction of tolerance, and thus make the induction of immunological tolerance by DCs an attractive strategy in MS (Raiotach-Regue et al., 2012, Nuyts et al., 2013). The administration of tolerogenic immature antigen-pulsed monocyte-derived DCs (MoDCs) in healthy volunteers has shown great potential (Dhodapkar et al., 2001) and augur well the future use of these cells for clinical application. Here we report that immature human MoDCs differentiated in the presence of HGF exhibited lower expression of HLA-DR and costimulatory molecules and an enhanced capacity to generate responding T cells with a regulatory phenotype, compared with conventional immature MoDCs. Our findings further provide a proof of concept for future application of HGF in MS therapy.

2. Materials and methods 2.1. Standard protocol approvals

⁎ Corresponding author at: Department of Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology and Multiple Sclerosis, Geneva University Hospital, and Department of Pathology and Immunology, Geneva Faculty of Medicine, Gabrielle-Perret-Gentil 4, 1211 Geneva 14, Switzerland. Tel.: +41 22 372 83 18; fax: +41 22 372 83 32. E-mail address: [email protected] (P.H. Lalive). 1 The authors contributed equally to this study. 0165-5728/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jneuroim.2013.12.004

Peripheral blood monocytes were isolated from buffy coats of blood of healthy volunteers (eleven male and four female, median age 45 years, range 19–67 years) provided by the Geneva Hospital Blood Transfusion Center. In accordance with the ethical committee of the Geneva Hospital, the blood bank obtained informed consent from the

106

N. Molnarfi et al. / Journal of Neuroimmunology 267 (2014) 105–110

2.4. T-cell isolation, mixed lymphocyte reaction (MLR)

Table 1 HGF supplementation does not interfere with MoDC development.

Monocytes Ctr-MoDCs HGF-MoDCs

CD1a

CD1c

CD14

CD11c

CD209

1.6 (0.2–2.4) 90.2 (86.9–92.2) 91.9 (87.7–92.3)

8.6 (2.2–14.4) 98.3 (97.2–99.3) 97.5 (95.4–99.5)

74.0 (69.7–80.5) 3.4 (0.5–8.6) 1.7 (0.4–4.0)

5.7 (0.0–16.4) 97.7 (97.4–98.0) 97.6 (97.1–98.1)

0.6 (0.0–2.1) 95.9 (94.7–97.0) 96.2 (95.3–96.6)

MLR was performed using purified allogeneic T cells as responder cells and MoDCs as stimulator cells. Highly purified CD4+ T cells were isolated from PBMCs by negative selection (Human CD4+ T Cell Enrichment Kit; EasySep, STEMCELL Technologies). MoDCs (10 × 103) were cultured for 7 days with allogeneic responder CD4+ T cells (10 × 104) in 96-well flat-bottom microtest plates (Costar, Integra Biosciences).

The data indicate the median (min–max) % of three independent experiments.

2.5. Immunologic markers and flow cytometry donors, who are thus informed that part of their blood will be used for research purposes. 2.2. Cytokines and reagents Human recombinant GM-CSF and IL-4 were obtained from Miltenyi Biotec. Human recombinant HGF was obtained from eBioscience. LPS was obtained from Sigma (Escherichia coli 055:B5).

MoDC staining was performed using fluorochrome-conjugated antibodies or with the appropriate fluorochrome-conjugated, isotypematched irrelevant mAbs from the same provider to establish background fluorescence. Expression of FoxP3 was detected in fixed/ permeabilized CD3+CD4+CD25+ (BioLegend) T cells using the AntiHuman FoxP3 Staining Kit (eBioscience). Samples were run through a FACSCanto flow cytometer (Becton Dickinson) with standard equipment.

2.3. Generation of DCs from peripheral blood monocytes 2.6. Analysis of cytokine production Highly purified CD14+ monocytes were isolated from the mononuclear fraction using negative selection microbeads (Human Monocyte Enrichment Kit; EasySep, STEMCELL Technologies). Monocytes were cultured for 6 days at 2.0 × 106 per ml in 6-well tissue culture plates (Falcon, Becton-Dickinson) in standard culture medium consisting of RPMI 1640 medium with 10% fetal bovine serum (Thermo Fisher Scientific) supplemented every second day with 20 ng/ml GM-CSF and 20 ng/ml IL-4 (Ctr-MoDCs); 20 ng/ml GM-CSF and 20 ng/ml IL-4 and 30 ng/ml HGF (HGF-MoDCs). After six days in culture, the nonadherent cells were recovered for use as immature MoDCs in subsequent assays. Day 6 immature MoDCs were matured by using 5 ng/ml of LPS for 24 h.

Cell-free supernatants were analyzed (Bioplex, Biorad) for cytokine content using a multiplex bead-based assay (Luminex Performance assay; R&D Systems) according to the manufacturer's instructions. The results are expressed as an average of triplicate wells ± standard error of the mean (SEM).

2.7. Statistical analysis Comparisons were performed by Student's t test. Values of p b 0.05 were considered statistically significant.

Fig. 1. HGF decreases HLA-DR, CD80, CD83 and CD86 expression by immature MoDCs. MoDCs were generated from monocytes cultured with GM-CSF and IL-4 for 6 days. Expression of HLA-DR, CD40, CD80, CD83, CD86, PD-L1, and IL-T3 by control MoDCs and MoDCs differentiated in the presence of 30 ng/ml HGF was determined by FACS analysis. HGF decreased the expression of HLA-DR molecules. Overlapping histogram profiles of the expression of each marker. Data are representative of three independent experiments. Ctr-MoDCs are represented by a thick solid line, and HGF-MoDCs are represented by a thick dotted line. MoDCs stained with isotype matched mAb are represented by a gray profile.

N. Molnarfi et al. / Journal of Neuroimmunology 267 (2014) 105–110

107

Table 2 HGF supplementation generates protolerogenic immature MoDCs.

Ctr-MoDCs HGF-MoDCs

CD40

CD80

CD83

CD86

HLA-DR

PD-L1

IL-T3

98.7 (98.5–99.2) 98.7 (98.2–99.4)

29.0 (26.2–30.6) 21.6 ⁎ (16.7–26.1)

26.3 (25.8–27.4) 17.0 ⁎ (16.2–19.2)

46.8 (42.0–51.9) 38.8 ⁎ (36.7–42.8)

31.5 (28.3–33.2) 24.0 ⁎ (23.4–24.8)

90.7 (87.4–93.8) 90.6 (82.4–98.6)

44.7 (16.4–77.4) 44.5 (12.0–84.3)

The data indicate the median (min–max) % of three independent experiments. ⁎ p b 0.05 (comparison between the two groups).

3. Results 3.1. HGF reduces the expression of HLA-DR and co-stimulatory molecules by immature MoDCs In order to investigate the effect of HGF on DC differentiation, monocytes were cultured in the presence of GM-CSF/IL-4 (medium control) or GM-CSF/IL-4 supplemented with 30 ng/ml of HGF. After 6 days of culture, CD14hi monocytes were differentiated into typical CD1ahi CD1chi CD11chi, CD14low, CD209hi and HLA-DR+ immature MoDCs (Table 1). The viability of MoDCs was greater than 90%, and treatment of cells with HGF did not alter viability of MoDCs as determined by Trypan blue exclusion (data not shown). As shown in Fig. 1 and Table 2, treatment of monocytes with HGF constantly decreased the expression of HLA-DR, CD80, CD83 and CD86 molecules by immature MoDCs. HGF did not modulate the expression of CD40 or the inhibitory molecules PD-L1 and IL-T3 (Cella et al., 1997, Wang et al., 2008) on immature MoDCs (Fig. 1 and Table 2). Taken together, these data indicate that HGF had a suppressive impact on the differentiation of MoDCs.

and Tedder, 1996) (Fig. 2 and Table 3). In these settings, HGF-MoDCs failed to up-regulate HLA-DR expression following exposure to LPS. The expression of CD80, CD83 and CD86 was not affected by the addition of HGF during the DC differentiation process. The expression of the inhibitory receptor PD-L1 and IL-T3 molecules was similarly not affected (Fig. 2 and Table 3). 3.3. HGF does not modulate the secretion of inflammatory cytokines by MoDCs We evaluated cytokine secretion by MoDCs following their differentiation in the presence or absence of HGF. Culture supernatants from immature MoDCs did not contain measurable levels of inflammatory cytokines. Secretion of inflammatory mediators by MoDCs was however detected following stimulation with LPS. When added into MoDC cultures, HGF did not enhance the production of the immunoregulatory cytokines IL-10 and IL-27 nor inhibit the secretion of the proinflammatory cytokines IL-23, IL-6, IFN-γ, and TNF in response to LPS (Fig. 3).

3.2. HGF restrains HLA-DR expression by mature MoDCs

3.4. HGF does not directly impact the phonotypical maturation of MoDCs

Immature MoDCs could further differentiate into fully mature MoDCs by exposure to LPS. Stimulation with LPS resulted in 90% to 95% of MoDCs expressing surface CD83, a marker of mature DCs (Zhou

We next investigated whether the exposure of immature MoDCs to HGF could promote the acquisition of a protolerogenic phenotype by mature MoDCs. On day 6, HGF was added to immature MoDCs, 1 day

Fig. 2. HGF reduces HLA-DR expression by mature MoDCs. Immature MoDCs obtained by a 6-day culture with GM-CSF and IL-4 in the presence or not of 30 ng/ml HGF were matured by stimulation with 5 ng/ml LPS for 24 h. Expression of HLA-DR, CD40, CD80, CD83, CD86, PD-L1 and IL-T3 molecules by MoDCs was determined by FACS analysis. HGF decreased, although not consistently, the expression of HLA-DR molecules. Overlapping histogram profiles of the expression of each marker in a representative experiment from three are shown. Ctr-MoDCs are represented by a thick solid line, and HGF-MoDCs are represented by a thick dotted line. MoDCs stained with isotype matched mAb are represented by a gray profile.

108

N. Molnarfi et al. / Journal of Neuroimmunology 267 (2014) 105–110

Table 3 HGF supplementation reduces HLA-DR expression by mature MoDCs.

Ctr-MoDCs HGF-MoDCs

CD40

CD80

CD83

CD86

HLA-DR

PD-L1

IL-T3

98.4 (97.5–99.0) 98.3 (97.5–98.8)

71.3 (40.7–86.8) 70.0 (40.2–80.8)

93.9 (87.6–96.5) 94.5 (92.1–96.1)

96.8 (92.8–99.0) 97.4 (97.4–98.7)

73.6 (53.2–89.8) 64.7 ⁎ (40.7–81.8)

95.1 (89.1–99.1) 98.3 (97.4–98.7)

56.7 (41.1–70.8) 57.9 (30.6–83.4)

The data indicate the median (min–max) % of three independent experiments. ⁎ p b 0.05 (comparison between the two groups).

prior to stimulation with LPS for an additional 24 h. Interestingly, conditioning of immature MoDCs with HGF did not inhibit their maturation as they upregulated CD80, CD83 and CD86 and maintained high surface expression of HLA-DR molecules (Table 4). Altogether, these data indicate that HGF primarily affects the differentiation of DCs from monocytes but not the maturation of MoDCs. 3.5. HGF potentiates the capacity of human MoDCs to induce Treg cells Given the acquisition of a protolerogenic phenotype by immature HGF-MoDCs, we next investigated whether their co-culture with allogeneic CD4+ T cells in MLR assays might favor the induction of Treg cells, defined as CD4+CD25+ cells with elevated expression of Foxp3. Co-culture of naïve allogeneic T cells with HGF-MoDCs promoted an increase (up to 20%) appearance of CD25+FoxP3+ Tregs (27.1% [22.7– 35.4] vs 32.1% [28.3–38.3]; Ctr-MoDCs vs HGF-MoDCs) (Fig. 4). These data suggest that HGF substantially augments the ability of MoDCs to convert CD4+ naïve T cells to CD4+CD25+FoxP3+ Tregs. 4. Discussion Recent findings indicate that HGF ameliorates neuroinflammation in animal models of MS (Benkhoucha et al., 2010, Bai et al., 2012). Using myelin oligodendrocyte-induced EAE, a well-established preclinical MS model, we demonstrated that administration of HGF-treated DCs, pulsed with a source of myelin antigen, secured the recovery of recipients with ongoing paralysis. If such a conditioning regime could be applied to human DC differentiated from monocytes, it might prove feasible to establish operational tolerance to myelin antigens in MS. While different types of DCs can be used for immunotherapy studies, MoDCs were suggested to be the preferential source for clinical use of inducible DC-type cells (Herbst et al., 1997). The studies showed herein demonstrate that HGF promotes the acquisition of a protolerogenic phenotype to human immature MoDCs, associated with reduced

expression of HLA-DR and co-stimulatory molecules, and endows them with an increased capacity of inducing Tregs. Consistent with our observations, human blood CD14+ monocytes cultured with HGF alone were shown to differentiate into regulatory accessory cells with DC features that favor the differentiation of Tregs (Rutella et al., 2006). These findings therefore suggest that HGF may have the desirable properties of promoting tolerance to myelin autoantigens through induction of Tregs, a strategy that could be exploited therapeutically in MS. DCs isolated from patients with MS were shown to produce large amounts of pro-inflammatory cytokines, which suggests that DCs contribute to disease pathogenesis (Huang et al., 1999, Karni et al., 2006, Vaknin-Dembinsky et al., 2006, Comabella et al., 2010). Similar results were obtained using MoDCs generated in vitro from the monocytes of patients with MS (Vaknin-Dembinsky et al., 2008), hence putting the use of MoDCs from MS patients as a new approach for therapeutic intervention at risk. Data, however, indicate that altered phenotype and function of MoDCs from MS patients were no longer apparent when MoDCs were generated in the presence of potent immunoregulatory agents (Huang et al., 2001, Bartosik-Psujek et al., 2010) and that MoDCs generated in this manner induce myelin-specific tolerance similar to those of healthy controls (Raiotach-Regue et al., 2012). These data support the therapeutic potential of tolerogenic MoDCs derived from MS patients and warrant further evaluation of HGF for future cellular immunotherapy of MS. In the current study we demonstrated that the capacity of human MoDCs to induce Tregs was enhanced when differentiated in the presence of HGF. These cells showed reduced expression of HLA-DR and CD80/CD86 co-stimulatory molecules when compared to control MoDCs. No effect on cytokine production was seen. Similar to these data, HGF treatment of mouse DCs increased their potential to generate Tregs. HGF-treated mouse DCs were associated with a hypoactive phenotype with low CD40 expression, and reduced IL-12 secretion, but normal MHC class II and CD80/CD86 expression (Benkhoucha et al., 2010). While different molecular mechanisms may account for the suppressive activities of HGF on both DC populations, our data altogether support a key role for HGF in regulating the balance between tolerogenic and immunogenic activity of DCs. In addition to its immunoregulatory properties, HGF was reported to be a potent neuroprotective and neuroregenerative factor (Lalive et al., 2005, Nakamura et al., 2011). In humans, high cerebrospinal fluid HGF levels were suggested to be positively implicated in the repair of white matter damage in demyelinating diseases (Tsuboi et al., 2002) and in particular in MS (Muller et al., 2012). Moreover, HGF was shown to mediate human mesenchymal stem cell-induced recovery in animal MS models by promoting neural cell development and immunoregulation (Bai et al., 2012). As suggested by our current studies, HGF may be thus one combined neuroprotective, neuroregenerative and immunoregulatory factor for the clinical treatment of RRMS. Author contributions

Fig. 3. Effect of HGF on the secretion of IL-23, IL-6, IFN-γ, TNF, IL-10, and IL-27 by mature MoDCs. Measurement of cytokines was performed on supernatants of MoDCs obtained after maturation with LPS. Average of three independent experiments is shown as bar graphs (mean ± SEM).

N.M. and M.B. contributed equally to this work. N.M., M.B., C.J., and P.H.L. conceived and designed the experiments. N.M. C.J. and K.B. performed the experiments. N.M., M.B., C.J. and P.H.L. analyzed the data. N.M. and P.H.L. wrote the paper.

N. Molnarfi et al. / Journal of Neuroimmunology 267 (2014) 105–110

109

Table 4 HGF supplementation does not directly impact MoDC maturation.

MoDCs Ctr-MoDCs + LPS HGF-MoDCs + LPS

CD40

CD80

CD83

CD86

HLA-DR

84.1 (81.3–87.0) 87.2 (76.7–98.8) 86.1 (76.9–97.3)

28.1 (16.6–50.4) 46.9 (37.0–54.2) 47.6 (42.5–52.7)

43.6 (26.2–54.6) 66.4 (63.7–78.6) 65.9 (58.9–77.1)

33.4 (28.9–38.2) 68.0 (56.3–81.2) 67.0 (58.0–78.7)

54.2 (51.3–60.6) 81.1 (80.2–82.3) 80.1 (79.3–80.6)

The data indicate the median (min–max) % of three independent experiments.

Fig. 4. Phenotypic characterization of CD25+Foxp3+ Treg cells from co-cultures of MoDCs and naïve CD4+ T cells. The percentage of the CD25+Foxp3+ population induced in the presence of HGF-MoDCs is increased in comparison with conventional Ctr-MoDCs. Intracellular staining shows the percentage of CD4+CD25+FoxP3+ T cells after 7 days in culture. Data are representative of three separate experiments. Average of three independent experiments is shown as bar graphs (mean ± SEM) (*p ≤ 0.05).

Study funding This study was supported by the Swiss National Foundation (#310030-132705 to P.H.L.) and the Swiss Multiple Sclerosis Society (to P.H.L. and N.M.). N.M. is a recipient of an ECTRIMS fellowship exchange program.

Disclosure The authors report no disclosures.

References Bai, L., Lennon, D.P., Caplan, A.I., DeChant, A., Hecker, J., Kranso, J., et al., 2012. Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models. Nat. Neurosci. 15, 862–879. Bartosik-Psujek, H., Tabarkiewicz, J., Pocinska, K., Stelmasiak, Z., Rolinski, J., 2010. Immunomodulatory effects of vitamin D on monocyte-derived dendritic cells in multiple sclerosis. Mult. Scler. 16, 1513–1516. Benkhoucha, M., Santiago-Raber, M.L., Schneiter, G., Chofflon, M., Funakoshi, H., Nakamura, T., et al., 2010. Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3 + regulatory T cells. Proc. Natl. Acad. Sci. U. S. A. 107, 6424–6429. Cella, M., Dohring, C., Samaridis, J., Dessing, M., Brockhaus, M., Lanzavecchia, A., et al., 1997. A novel inhibitory receptor (ILT3) expressed on monocytes, macrophages, and dendritic cells involved in antigen processing. J. Exp. Med. 185, 1743–1751. Comabella, M., Montalban, X., Munz, C., Lunemann, J.D., 2010. Targeting dendritic cells to treat multiple sclerosis. Nat. Rev. Neurol. 6, 499–507. Dhodapkar, M.V., Steinman, R.M., Krasovsky, J., Munz, C., Bhardwaj, N., 2001. Antigenspecific inhibition of effector T cell function in humans after injection of immature dendritic cells. J. Exp. Med. 193, 233–238. Ebens, A., Brose, K., Leonardo, E.D., Hanson Jr., M.G., Bladt, F., Birchmeier, C., et al., 1996. Hepatocyte growth factor/scatter factor is an axonal chemoattractant and a neurotrophic factor for spinal motor neurons. Neuron 17, 1157–1172. Hemmer, B., Hartung, H.P., 2007. Toward the development of rational therapies in multiple sclerosis: what is on the horizon? Ann. Neurol. 62, 314–326.

Herbst, B., Kohler, G., Mackensen, A., Veelken, H., Mertelsmann, R., Lindemann, A., 1997. CD34+ peripheral blood progenitor cell and monocyte derived dendritic cells: a comparative analysis. Br. J. Haematol. 99, 490–499. Huang, Y.M., Stoyanova, N., Jin, Y.P., Teleshova, N., Hussien, Y., Xiao, B.G., et al., 2001. Altered phenotype and function of blood dendritic cells in multiple sclerosis are modulated by IFN-beta and IL-10. Clin. Exp. Immunol. 124, 306–314. Huang, Y.M., Xiao, B.G., Ozenci, V., Kouwenhoven, M., Teleshova, N., Fredrikson, S., et al., 1999. Multiple sclerosis is associated with high levels of circulating dendritic cells secreting pro-inflammatory cytokines. J. Neuroimmunol. 99, 82–90. Karni, A., Abraham, M., Monsonego, A., Cai, G., Freeman, G.J., Hafler, D., et al., 2006. Innate immunity in multiple sclerosis: myeloid dendritic cells in secondary progressive multiple sclerosis are activated and drive a proinflammatory immune response. J. Immunol. 177, 4196–4202. Kitamura, K., Iwanami, A., Nakamura, M., Yamane, J., Watanabe, K., Suzuki, Y., et al., 2007. Hepatocyte growth factor promotes endogenous repair and functional recovery after spinal cord injury. J. Neurosci. Res. 85, 2332–2342. Lalive, P.H., Paglinawan, R., Biollaz, G., Kappos, E.A., Leone, D.P., Malipiero, U., et al., 2005. TGF-beta-treated microglia induce oligodendrocyte precursor cell chemotaxis through the HGF–c-Met pathway. Eur. J. Immunol. 35, 727–737. Molnarfi, N., Benkhoucha, M., Bjarnadottir, K., Juillard, C., Lalive, P.H., 2012. Interferon-beta induces hepatocyte growth factor in monocytes of multiple sclerosis patients. PLoS One 7, e49882. Muller, A.M., Jun, E., Conlon, H., Sadiq, S.A., 2012. Cerebrospinal hepatocyte growth factor levels correlate negatively with disease activity in multiple sclerosis. J. Neuroimmunol. 251 (1-2), 80–86. Nakamura, T., Sakai, K., Nakamura, T., Matsumoto, K., 2011. Hepatocyte growth factor twenty years on: much more than a growth factor. J. Gastroenterol. Hepatol. 26 (Suppl. 1), 188–202. Nuyts, A., Lee, W., Bashir-Dar, R., Berneman, Z., Cools, N., 2013. Dendritic cells in multiple sclerosis: key players in the immunopathogenesis, key players for new cellular immunotherapies? Mult. Scler. 19, 995–1002. Raiotach-Regue, D., Grau-Lopez, L., Naranjo-Gomez, M., Ramo-Tello, C., Pujol-Borrell, R., Martinez-Caceres, E., et al., 2012. Stable antigen-specific T-cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients. Eur. J. Immunol. 42, 771–782. Rutella, S., Bonanno, G., Procoli, A., Mariotti, A., de Ritis, D.G., Curti, A., et al., 2006. Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)10++IL-12low/neg accessory cells with dendritic-cell features. Blood 108, 218–227. Sospedra, M., Martin, R., 2005. Immunology of multiple sclerosis. Annu. Rev. Immunol. 23, 683–747. Steinman, R.M., Banchereau, J., 2007. Taking dendritic cells into medicine. Nature 449, 419–426.

110

N. Molnarfi et al. / Journal of Neuroimmunology 267 (2014) 105–110

Tsuboi, Y., Kakimoto, K., Akatsu, H., Daikuhara, Y., Yamada, T., 2002. Hepatocyte growth factor in cerebrospinal fluid in neurologic disease. Acta Neurol. Scand. 106, 99–103. Vaknin-Dembinsky, A., Balashov, K., Weiner, H.L., 2006. IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J. Immunol. 176, 7768–7774. Vaknin-Dembinsky, A., Murugaiyan, G., Hafler, D.A., Astier, A.L., Weiner, H.L., 2008. Increased IL-23 secretion and altered chemokine production by dendritic cells

upon CD46 activation in patients with multiple sclerosis. J. Neuroimmunol. 195, 140–145. Wang, L., Pino-Lagos, K., de Vries, V.C., Guleria, I., Sayegh, M.H., Noelle, R.J., 2008. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc. Natl. Acad. Sci. U. S. A. 105, 9331–9336. Zhou, L.J., Tedder, T.F., 1996. CD14+ blood monocytes can differentiate into functionally mature CD83+ dendritic cells. Proc. Natl. Acad. Sci. U. S. A. 93, 2588–2592.

The neurotrophic hepatocyte growth factor induces protolerogenic human dendritic cells.

Hepatocyte growth factor (HGF) limits mouse autoimmune neuroinflammation by promoting the development of tolerogenic dendritic cells (DCs). Given the ...
624KB Sizes 0 Downloads 0 Views