Journal of Pediatric Biochemistry 2016; 06(03): 121-135
DOI: 10.1055/s-0036-1597698
Review Article
Georg Thieme Verlag KG Stuttgart · New York

The Role of Dendritic Cells in Central Nervous System Autoimmunity: Focusing on Multiple Sclerosis and Emerging Therapeutics Targeting Dendritic Cells

Nassim Matin
1   Tehran University of Medical Science, Tehran, Iran
Raffaele Falsaperla
2   General and Acute Pediatrics Operative Unit, Policlinico-Vittorio-Emanuele University Hospital, University of Catania, Catania, Italy
Omidreza Tabatabaie
1   Tehran University of Medical Science, Tehran, Iran
Piero Pavone
2   General and Acute Pediatrics Operative Unit, Policlinico-Vittorio-Emanuele University Hospital, University of Catania, Catania, Italy
Riccardo Lubrano
3   Pediatric Nephrology Operative Unit, La Sapienza University of Rome, Rome, Italy
Giovanna Vitaliti
2   General and Acute Pediatrics Operative Unit, Policlinico-Vittorio-Emanuele University Hospital, University of Catania, Catania, Italy
› Author Affiliations
Further Information

Publication History

19 February 2016

24 November 2016

Publication Date:
26 December 2016 (online)


Dendritic cells (DCs) are the sentinel innate immune cells that initiate antigen-specific adaptive immune responses. On the one hand, DCs have been extensively analyzed because of their roles in immune response against pathogens, and on the other hand, there are numerous other studies that have investigated their role in immune tolerance of autoimmune disorders such as type 1 diabetes, systemic lupus erythematosus, multiple sclerosis (MS), and psoriasis. The presence, recruitment, and activation of DCs in the cerebral spinal fluids of experimental allergic encephalomyelitis and MP models, initiated the long array of studies of pathogenic and the potential therapeutic role of DCs in MS. Many classic disease-modifying therapies that are employed have used strategies to alter the maturation and function of DCs; several other novel therapeutic strategies are currently under investigations, which we aim to briefly review in this article. We have focused on reviewing the role of DCs in the central nervous system (CNS), underlying their pathogenesis involvement, and proposing targeting therapies for autoimmune CNS disorders.

  • References

  • 1 Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. J Exp Med 1973; 137 (5) 1142-1162
  • 2 Inaba K, Steinman RM. Protein-specific helper T-lymphocyte formation initiated by dendritic cells. Science 1985; 229 (4712) 475-479
  • 3 Steinman RM. Lasker Basic Medical Research Award. Dendritic cells: versatile controllers of the immune system. Nat Med 2007; 13 (10) 1155-1159
  • 4 Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature 2007; 449 (7161): 419-426
  • 5 Kadowaki N, Ho S, Antonenko S , et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 2001; 194 (6) 863-869
  • 6 Coombes JL, Siddiqui KR, Arancibia-Cárcamo CV , et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J Exp Med 2007; 204 (8) 1757-1764
  • 7 Bar-On L, Birnberg T, Kim KW, Jung S. Dendritic cell-restricted CD80/86 deficiency results in peripheral regulatory T-cell reduction but is not associated with lymphocyte hyperactivation. Eur J Immunol 2011; 41 (2) 291-298
  • 8 Sánchez-Sánchez N, Riol-Blanco L, Rodríguez-Fernández JL. The multiple personalities of the chemokine receptor CCR7 in dendritic cells. J Immunol 2006; 176 (9) 5153-5159
  • 9 Miga AJ, Masters SR, Durell BG , et al. Dendritic cell longevity and T cell persistence is controlled by CD154-CD40 interactions. Eur J Immunol 2001; 31 (3) 959-965
  • 10 Kelleher M, Beverley PC. Lipopolysaccharide modulation of dendritic cells is insufficient to mature dendritic cells to generate CTLs from naive polyclonal CD8+ T cells in vitro, whereas CD40 ligation is essential. J Immunol 2001; 167 (11) 6247-6255
  • 11 Hermans IF, Silk JD, Gileadi U , et al. NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J Immunol 2003; 171 (10) 5140-5147
  • 12 Nishimura T, Kitamura H, Iwakabe K , et al. The interface between innate and acquired immunity: glycolipid antigen presentation by CD1d-expressing dendritic cells to NKT cells induces the differentiation of antigen-specific cytotoxic T lymphocytes. Int Immunol 2000; 12 (7) 987-994
  • 13 Fujii S, Liu K, Smith C, Bonito AJ, Steinman RM. The linkage of innate to adaptive immunity via maturing dendritic cells in vivo requires CD40 ligation in addition to antigen presentation and CD80/86 costimulation. J Exp Med 2004; 199 (12) 1607-1618
  • 14 Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol 2003; 21: 685-711
  • 15 Ohnmacht C, Pullner A, King SB , et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J Exp Med 2009; 206 (3) 549-559
  • 16 Birnberg T, Bar-On L, Sapoznikov A , et al. Lack of conventional dendritic cells is compatible with normal development and T cell homeostasis, but causes myeloid proliferative syndrome. Immunity 2008; 29 (6) 986-997
  • 17 Mahnke K, Guo M, Lee S , et al. The dendritic cell receptor for endocytosis, DEC-205, can recycle and enhance antigen presentation via major histocompatibility complex class II-positive lysosomal compartments. J Cell Biol 2000; 151 (3) 673-684
  • 18 Mahnke K, Qian Y, Knop J, Enk AH. Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells. Blood 2003; 101 (12) 4862-4869
  • 19 Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J Exp Med 2002; 196 (12) 1627-1638
  • 20 Hawiger D, Inaba K, Dorsett Y , et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J Exp Med 2001; 194 (6) 769-779
  • 21 Torres-Aguilar H, Aguilar-Ruiz SR, González-Pérez G , et al. Tolerogenic dendritic cells generated with different immunosuppressive cytokines induce antigen-specific anergy and regulatory properties in memory CD4+ T cells. J Immunol 2010; 184 (4) 1765-1775
  • 22 Yamazaki S, Iyoda T, Tarbell K , et al. Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J Exp Med 2003; 198 (2) 235-247
  • 23 Maldonado RA, von Andrian UH. How tolerogenic dendritic cells induce regulatory T cells. Adv Immunol 2010; 108: 111-165
  • 24 D'Ambrosio A, Colucci M, Pugliese O, Quintieri F, Boirivant M. Cholera toxin B subunit promotes the induction of regulatory T cells by preventing human dendritic cell maturation. J Leukoc Biol 2008; 84 (3) 661-668
  • 25 Matin N, Tabatabaie O, Falsaperla R , et al. Epilepsy and innate immune system: a possible immunogenic predisposition and related therapeutic implications. Hum Vaccin Immunother 2015; 11 (8) 2021-2029
  • 26 Tsuji NM, Kosaka A. Oral tolerance: intestinal homeostasis and antigen-specific regulatory T cells. Trends Immunol 2008; 29 (11) 532-540
  • 27 Coombes JL, Powrie F. Dendritic cells in intestinal immune regulation. Nat Rev Immunol 2008; 8 (6) 435-446
  • 28 Nikolic T, Roep BO. Regulatory multitasking of tolerogenic dendritic cells - lessons taken from vitamin D3-treated tolerogenic dendritic cells. Front Immunol 2013; 4: 113 DOI: 10.3389/fimmu.2013.00113.
  • 29 Spicuzza L, Salafia S, Capizzi A , et al. Granuloma annulare as first clinical manifestation of diabetes mellitus in children: a case report. Diabetes Res Clin Pract 2012; 95 (3) e55-e57
  • 30 Bosma BM, Metselaar HJ, Nagtzaam NM , et al. Dexamethasone transforms lipopolysaccharide-stimulated human blood myeloid dendritic cells into myeloid dendritic cells that prime interleukin-10 production in T cells. Immunology 2008; 125 (1) 91-100
  • 31 Cederbom L, Hall H, Ivars F. CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur J Immunol 2000; 30 (6) 1538-1543
  • 32 Oderup C, Cederbom L, Makowska A, Cilio CM, Ivars F. Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory T-cell-mediated suppression. Immunology 2006; 118 (2) 240-249
  • 33 Mahnke K, Johnson TS, Ring S, Enk AH. Tolerogenic dendritic cells and regulatory T cells: a two-way relationship. J Dermatol Sci 2007; 46 (3) 159-167
  • 34 Kryczek I, Wei S, Zou L , et al. Cutting edge: induction of B7-H4 on APCs through IL-10: novel suppressive mode for regulatory T cells. J Immunol 2006; 177 (1) 40-44
  • 35 Awasthi A, Carrier Y, Peron JP , et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol 2007; 8 (12) 1380-1389
  • 36 Ganguly D, Haak S, Sisirak V, Reizis B. The role of dendritic cells in autoimmunity. Nat Rev Immunol 2013; 13 (8) 566-577
  • 37 Price JD, Tarbell KV. The role of dendritic cell subsets and innate immunity in the pathogenesis of type 1 diabetes and other autoimmune diseases. Front Immunol 2015; 6: 288 DOI: 10.3389/fimmu.2015.00288.
  • 38 Prodinger C, Bunse J, Krüger M , et al. CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system. Acta Neuropathol 2011; 121 (4) 445-458
  • 39 Pashenkov M, Huang Y-M, Kostulas V, Haglund M, Söderström M, Link H. Two subsets of dendritic cells are present in human cerebrospinal fluid. Brain 2001; 124 (Pt 3) 480-492
  • 40 McMenamin PG. Distribution and phenotype of dendritic cells and resident tissue macrophages in the dura mater, leptomeninges, and choroid plexus of the rat brain as demonstrated in wholemount preparations. J Comp Neurol 1999; 405 (4) 553-562
  • 41 Fischer H-G, Reichmann G. Brain dendritic cells and macrophages/microglia in central nervous system inflammation. J Immunol 2001; 166 (4) 2717-2726
  • 42 Fischer H-G, Bielinsky AK. Antigen presentation function of brain-derived dendriform cells depends on astrocyte help. Int Immunol 1999; 11 (8) 1265-1274
  • 43 Vitaliti G, Pavone P, Guglielmo F, Spataro G, Falsaperla R. The immunomodulatory effect of probiotics beyond atopy: an update. J Asthma 2014; 51 (3) 320-332
  • 44 Pashenkov M, Teleshova N, Kouwenhoven M , et al. Recruitment of dendritic cells to the cerebrospinal fluid in bacterial neuroinfections. J Neuroimmunol 2002; 122 (1-2): 106-116
  • 45 Curtin JF, King GD, Barcia C , et al. Fms-like tyrosine kinase 3 ligand recruits plasmacytoid dendritic cells to the brain. J Immunol 2006; 176 (6) 3566-3577
  • 46 Carson MJ, Reilly CR, Sutcliffe JG, Lo D. Disproportionate recruitment of CD8+ T cells into the central nervous system by professional antigen-presenting cells. Am J Pathol 1999; 154 (2) 481-494
  • 47 Hatterer E, Davoust N, Didier-Bazes M , et al. How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes. Blood 2006; 107 (2) 806-812
  • 48 Fisher Y, Nemirovsky A, Baron R, Monsonego A. Dendritic cells regulate amyloid-β-specific T-cell entry into the brain: the role of perivascular amyloid-β. J Alzheimers Dis 2011; 27 (1) 99-111
  • 49 Vitaliti G, Pavone P, Mahmood F, Nunnari G, Falsaperla R. Targeting inflammation as a therapeutic strategy for drug-resistant epilepsies: an update of new immune-modulating approaches. Hum Vaccin Immunother 2014; 10 (4) 868-875
  • 50 Reichmann G, Schroeter M, Jander S, Fischer H-G. Dendritic cells and dendritic-like microglia in focal cortical ischemia of the mouse brain. J Neuroimmunol 2002; 129 (1-2): 125-132
  • 51 Vitaliti G, Tabatabaie O, Matin N , et al. The usefulness of immunotherapy in pediatric neurodegenerative disorders: a systematic review of literature data. Hum Vaccin Immunother 2015; 11 (12) 2749-2763
  • 52 Matyszak MK, Perry VH. The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system. Neuroscience 1996; 74 (2) 599-608
  • 53 Matsumoto Y, Hara N, Tanaka R, Fujiwara M. Immunohistochemical analysis of the rat central nervous system during experimental allergic encephalomyelitis, with special reference to Ia-positive cells with dendritic morphology. J Immunol 1986; 136 (10) 3668-3676
  • 54 Suter T, Malipiero U, Otten L , et al. Dendritic cells and differential usage of the MHC class II transactivator promoters in the central nervous system in experimental autoimmune encephalitis. Eur J Immunol 2000; 30 (3) 794-802
  • 55 Dittel BN, Visintin I, Merchant RM, Janeway Jr CA. Presentation of the self antigen myelin basic protein by dendritic cells leads to experimental autoimmune encephalomyelitis. J Immunol 1999; 163 (1) 32-39
  • 56 Weir CR, Nicolson K, Bäckström BT. Experimental autoimmune encephalomyelitis induction in naive mice by dendritic cells presenting a self-peptide. Immunol Cell Biol 2002; 80 (1) 14-20
  • 57 Huang YM, Yang JS, Xu LY, Link H, Xiao BG. Autoantigen-pulsed dendritic cells induce tolerance to experimental allergic encephalomyelitis (EAE) in Lewis rats. Clin Exp Immunol 2000; 122 (3) 437-444
  • 58 Xiao BG, Huang YM, Yang JS, Xu LY, Link H. Bone marrow-derived dendritic cells from experimental allergic encephalomyelitis induce immune tolerance to EAE in Lewis rats. Clin Exp Immunol 2001; 125 (2) 300-309
  • 59 Yang JS, Xu LY, Huang YM, Van Der Meide PH, Link H, Xiao BG. Adherent dendritic cells expressing high levels of interleukin-10 and low levels of interleukin-12 induce antigen-specific tolerance to experimental autoimmune encephalomyelitis. Immunology 2000; 101 (3) 397-403
  • 60 Xiao B-G, Huang Y-M, Xu L-Y, Ishikawa M, Link H. Mechanisms of recovery from experimental allergic encephalomyelitis induced with myelin basic protein peptide 68-86 in Lewis rats: a role for dendritic cells in inducing apoptosis of CD4+ T cells. J Neuroimmunol 1999; 97 (1-2): 25-36
  • 61 Okura Y, Jee Y, Matsumoto Y. Acquired thymic tolerance to autoimmune encephalomyelitis is associated with activation of peripheral IL-10-producing macrophages/dendritic cells. Int Immunol 2003; 15 (3) 437-446
  • 62 Khoury SJ, Sayegh MH, Hancock WW, Gallon L, Carpenter CB, Weiner HL. Acquired tolerance to experimental autoimmune encephalomyelitis by intrathymic injection of myelin basic protein or its major encephalitogenic peptide. J Exp Med 1993; 178 (2) 559-566
  • 63 Zhang GX, Kishi M, Xu H, Rostami A. Mature bone marrow-derived dendritic cells polarize Th2 response and suppress experimental autoimmune encephalomyelitis. Mult Scler 2002; 8 (6) 463-468
  • 64 Li H, Zhang G-X, Chen Y , et al. CD11c+CD11b+ dendritic cells play an important role in intravenous tolerance and the suppression of experimental autoimmune encephalomyelitis. J Immunol 2008; 181 (4) 2483-2493
  • 65 Bailey SL, Schreiner B, McMahon EJ, Miller SD. CNS myeloid DCs presenting endogenous myelin peptides ‘preferentially’ polarize CD4+ T(H)-17 cells in relapsing EAE. Nat Immunol 2007; 8 (2) 172-180
  • 66 Yogev N, Frommer F, Lukas D , et al. Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells. Immunity 2012; 37 (2) 264-275
  • 67 Deshpande P, King IL, Segal BM. Cutting edge: CNS CD11c+ cells from mice with encephalomyelitis polarize Th17 cells and support CD25+CD4+ T cell-mediated immunosuppression, suggesting dual roles in the disease process. J Immunol 2007; 178 (11) 6695-6699
  • 68 Pettersson A, Wu XC, Ciumas C , et al. CD8α dendritic cells and immune protection from experimental allergic encephalomyelitis. Clin Exp Immunol 2004; 137 (3) 486-495
  • 69 Bailey-Bucktrout SL, Caulkins SC, Goings G, Fischer JA, Dzionek A, Miller SD. CNS plasmacytoid dendritic cells regulate the severity of relapsing experimental autoimmune encephalomyelitis. J Immunol 2008 180 (10) 6457-6461
  • 70 Isaksson M, Ardesjö B, Rönnblom L , et al. Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE. Eur J Immunol 2009; 39 (10) 2925-2935
  • 71 Bailey-Bucktrout SL, Caulkins SC, Goings G, Fischer JA, Dzionek A, Miller SD. Cutting edge: central nervous system plasmacytoid dendritic cells regulate the severity of relapsing experimental autoimmune encephalomyelitis. J Immunol 2008; 180 (10) 6457-6461
  • 72 Zozulya AL, Ortler S, Lee J , et al. Intracerebral dendritic cells critically modulate encephalitogenic versus regulatory immune responses in the CNS. J Neurosci 2009; 29 (1) 140-152
  • 73 Menges M, Rössner S, Voigtländer C , et al. Repetitive injections of dendritic cells matured with tumor necrosis factor α induce antigen-specific protection of mice from autoimmunity. J Exp Med 2002; 195 (1) 15-21
  • 74 Ring S, Maas M, Nettelbeck DM, Enk AH, Mahnke K. Targeting of autoantigens to DEC205+ dendritic cells in vivo suppresses experimental allergic encephalomyelitis in mice. J Immunol 2013; 191 (6) 2938-2947
  • 75 Jain P, Coisne C, Enzmann G, Rottapel R, Engelhardt B. α4β1 integrin mediates the recruitment of immature dendritic cells across the blood-brain barrier during experimental autoimmune encephalomyelitis. J Immunol 2010; 184 (12) 7196-7206
  • 76 Lande R, Gafa V, Serafini B , et al. Plasmacytoid dendritic cells in multiple sclerosis: intracerebral recruitment and impaired maturation in response to interferon-β. J Neuropathol Exp Neurol 2008; 67 (5) 388-401
  • 77 Longhini AL, von Glehn F, Brandão CO , et al. Plasmacytoid dendritic cells are increased in cerebrospinal fluid of untreated patients during multiple sclerosis relapse. J Neuroinflammation 2011; 8 (1) 2 DOI: 10.1186/1742-2094-8-2.
  • 78 Zozulya AL, Clarkson BD, Ortler S, Fabry Z, Wiendl H. The role of dendritic cells in CNS autoimmunity. J Mol Med (Berl) 2010; 88 (6) 535-544
  • 79 Huang Y-M, Xiao B-G, Özenci V , et al. Multiple sclerosis is associated with high levels of circulating dendritic cells secreting pro-inflammatory cytokines. J Neuroimmunol 1999; 99 (1) 82-90
  • 80 Huang YM, Stoyanova N, Jin YP , et al. Altered phenotype and function of blood dendritic cells in multiple sclerosis are modulated by IFN-β and IL-10. Clin Exp Immunol 2001; 124 (2) 306-314
  • 81 Huang Y-M, Kouwenhoven M, Jin Y-P, Press R, Huang W-X, Link H. Dendritic cells derived from patients with multiple sclerosis show high CD1a and low CD86 expression. Mult Scler 2001; 7 (2) 95-99
  • 82 Stasiolek M, Bayas A, Kruse N , et al. Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis. Brain 2006; 129 (Pt 5): 1293-1305
  • 83 Mycko MP, Cwiklinska H, Cichalewska M , et al. Plasmocytoid dendritic cell deficit of early response to toll-like receptor 7 agonist stimulation in multiple sclerosis patients. Clin Immunol 2014; 153 (1) 211-219
  • 84 Schwab N, Zozulya AL, Kieseier BC, Toyka KV, Wiendl H. An imbalance of two functionally and phenotypically different subsets of plasmacytoid dendritic cells characterizes the dysfunctional immune regulation in multiple sclerosis. J Immunol 2010; 184 (9) 5368-5374
  • 85 Aung LL, Fitzgerald-Bocarsly P, Dhib-Jalbut S, Balashov K. Plasmacytoid dendritic cells in multiple sclerosis: chemokine and chemokine receptor modulation by interferon-beta. J Neuroimmunol 2010; 226 (1-2): 158-164
  • 86 Nuyts AH, Ponsaerts P, Van Tendeloo VF , et al. Except for C-C chemokine receptor 7 expression, monocyte-derived dendritic cells from patients with multiple sclerosis are functionally comparable to those of healthy controls. Cytotherapy 2014; 16 (7) 1024-1030
  • 87 Vitaliti G, Matin N, Tabatabaie O , et al. Natalizumab in multiple sclerosis: discontinuation, progressive multifocal leukoencephalopathy and possible use in children. Expert Rev Neurother 2015; 15 (11) 1321-1341
  • 88 Lee B, Sharron M, Montaner LJ, Weissman D, Doms RW. Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages. Proc Natl Acad Sci U S A 1999; 96 (9) 5215-5220
  • 89 Pashenkov M, Teleshova N, Kouwenhoven M , et al. Elevated expression of CCR5 by myeloid (CD11c+) blood dendritic cells in multiple sclerosis and acute optic neuritis. Clin Exp Immunol 2002; 127 (3) 519-526
  • 90 Teleshova N, Pashenkov M, Huang Y-M , et al. Multiple sclerosis and optic neuritis: CCR5 and CXCR3 expressing T cells are augmented in blood and cerebrospinal fluid. J Neurol 2002; 249 (6) 723-729
  • 91 Karni A, Abraham M, Monsonego A , et al. Innate immunity in multiple sclerosis: myeloid dendritic cells in secondary progressive multiple sclerosis are activated and drive a proinflammatory immune response. J Immunol 2006; 177 (6) 4196-4202
  • 92 López C, Comabella M, Al-zayat H, Tintoré M, Montalban X. Altered maturation of circulating dendritic cells in primary progressive MS patients. J Neuroimmunol 2006; 175 (1-2): 183-191
  • 93 Navarro J, Aristimuño C, Sánchez-Ramón S , et al. Circulating dendritic cells subsets and regulatory T-cells at multiple sclerosis relapse: differential short-term changes on corticosteroids therapy. J Neuroimmunol 2006; 176 (1-2): 153-161
  • 94 Krystyna M-S, Jacek T, Sebastian R , et al. Changes in circulating dendritic cells and B-cells in patients with multiple sclerosis relapse during corticosteroid therapy. J Neuroimmunol 2009; 207 (1-2): 107-110
  • 95 Bartholomé EJ, Willems F, Crusiaux A, Thielemans K, Schandené L, Goldman M. Interferon-beta inhibits Th1 responses at the dendritic cell level. Relevance to multiple sclerosis. Acta Neurol Belg 1999; 99 (1) 44-52
  • 96 Schreiner B, Mitsdoerffer M, Kieseier BC , et al. Interferon-β enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J Neuroimmunol 2004; 155 (1-2): 172-182
  • 97 Bartholomé EJ, Willems F, Crusiaux A, Thielemans K, Schandene L, Goldman M. IFN-beta interferes with the differentiation of dendritic cells from peripheral blood mononuclear cells: selective inhibition of CD40-dependent interleukin-12 secretion. J Interferon Cytokine Res 1999; 19 (5) 471-478
  • 98 Hirotani M, Niino M, Fukazawa T , et al. Decreased interferon-α production in response to CpG DNA dysregulates cytokine responses in patients with multiple sclerosis. Clin Immunol 2012; 143 (2) 145-151
  • 99 Sweeney CM, Lonergan R, Basdeo SA , et al. IL-27 mediates the response to IFN-β therapy in multiple sclerosis patients by inhibiting Th17 cells. Brain Behav Immun 2011; 25 (6) 1170-1181
  • 100 Nagai T, Devergne O, Mueller TF, Perkins DL, van Seventer JM, van Seventer GA. Timing of IFN-β exposure during human dendritic cell maturation and naive Th cell stimulation has contrasting effects on Th1 subset generation: a role for IFN-β-mediated regulation of IL-12 family cytokines and IL-18 in naive Th cell differentiation. J Immunol 2003; 171 (10) 5233-5243
  • 101 Ramgolam VS, Sha Y, Jin J, Zhang X, Markovic-Plese S. IFN-β inhibits human Th17 cell differentiation. J Immunol 2009; 183 (8) 5418-5427
  • 102 Zhang X, Jin J, Tang Y, Speer D, Sujkowska D, Markovic-Plese S. IFN-β1a inhibits the secretion of Th17-polarizing cytokines in human dendritic cells via TLR7 up-regulation. J Immunol 2009; 182 (6) 3928-3936
  • 103 Derkow K, Bauer JM, Hecker M , et al. Multiple sclerosis: modulation of toll-like receptor (TLR) expression by interferon-β includes upregulation of TLR7 in plasmacytoid dendritic cells. PLoS One 2013; 8 (8) e70626 DOI: 10.1371/journal.pone.0070626.
  • 104 Severa M, Rizzo F, Giacomini E , et al. IFN-β therapy regulates tlr7-mediated response in plasmacytoid dendritic cells of multiple sclerosis patients influencing an anti-inflammatory status. J Interferon Cytokine Res 2015; 35 (9) 668-681
  • 105 Chen M, Chen G, Deng S, Liu X, Hutton GJ, Hong J. IFN-β induces the proliferation of CD4+CD25+Foxp3+ regulatory T cells through upregulation of GITRL on dendritic cells in the treatment of multiple sclerosis. J Neuroimmunol 2012; 242 (1-2): 39-46
  • 106 Vieira PL, Heystek HC, Wormmeester J, Wierenga EA, Kapsenberg ML. Glatiramer acetate (copolymer-1, copaxone) promotes Th2 cell development and increased IL-10 production through modulation of dendritic cells. J Immunol 2003; 170 (9) 4483-4488
  • 107 Hussien Y, Sanna A, Söderström M, Link H, Huang Y-M. Glatiramer acetate and IFN-β act on dendritic cells in multiple sclerosis. J Neuroimmunol 2001; 121 (1-2): 102-110
  • 108 Hussien Y, Sanna A, Söderström M, Link H, Huang Y-M. Multiple sclerosis: expression of CD1a and production of IL-12p70 and IFN-γ by blood mononuclear cells in patients on combination therapy with IFN-β and glatiramer acetate compared to monotherapy with IFN-β. Mult Scler 2004; 10 (1) 16-25
  • 109 Sellebjerg F, Hesse D, Limborg S , et al. Dendritic cell, monocyte and T cell activation and response to glatiramer acetate in multiple sclerosis. Mult Scler 2013; 19 (2) 179-187
  • 110 del Pilar Martin M, Cravens PD, Winger R , et al. Decrease in the numbers of dendritic cells and CD4+ T cells in cerebral perivascular spaces due to natalizumab. Arch Neurol 2008; 65 (12) 1596-1603
  • 111 de Andrés C, Teijeiro R, Alonso B , et al. Long-term decrease in VLA-4 expression and functional impairment of dendritic cells during natalizumab therapy in patients with multiple sclerosis. PLoS One 2012; 7 (4) e34103 DOI: 10.1371/journal.pone.0034103.
  • 112 Kivisäkk P, Francois K, Mbianda J, Gandhi R, Weiner HL, Khoury SJ. Effect of natalizumab treatment on circulating plasmacytoid dendritic cells: a cross-sectional observational study in patients with multiple sclerosis. PLoS One 2014; 9 (7) e103716 DOI: 10.1371/journal.pone.0103716.
  • 113 Schaper K, Kietzmann M, Bäumer W. Sphingosine-1-phosphate differently regulates the cytokine production of IL-12, IL-23 and IL-27 in activated murine bone marrow derived dendritic cells. Mol Immunol 2014; 59 (1) 10-18
  • 114 Zeng X, Wang T, Zhu C , et al. Topographical and biological evidence revealed FTY720-mediated anergy-polarization of mouse bone marrow-derived dendritic cells in vitro. PLoS One 2012; 7 (5) e34830 DOI: 10.1371/journal.pone.0034830.
  • 115 Durafourt BA, Lambert C, Johnson TA, Blain M, Bar-Or A, Antel JP. Differential responses of human microglia and blood-derived myeloid cells to FTY720. J Neuroimmunol 2011; 230 (1-2): 10-16
  • 116 Luessi F, Kraus S, Trinschek B , et al. FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis. Mult Scler 2015; 21 (14) 1811-1822
  • 117 Aldinucci A, Biagioli T, Manuelli C, Repice AM, Massacesi L, Ballerini C. Modulating dendritic cells (DC) from immunogenic to tolerogenic responses: a novel mechanism of AZA/6-MP. J Neuroimmunol 2010; 218 (1-2): 28-35
  • 118 Jolivel V, Luessi F, Masri J , et al. Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis. Brain 2013; 136 (Pt 4): 1048-1066
  • 119 Gross CC, Jonuleit H, Wiendl H. Fulfilling the dream: tolerogenic dendritic cells to treat multiple sclerosis. Eur J Immunol 2012; 42 (3) 569-572
  • 120 Lee D-H, Linker RA. The role of myelin oligodendrocyte glycoprotein in autoimmune demyelination: a target for multiple sclerosis therapy?. Expert Opin Ther Targets 2012; 16 (5) 451-462
  • 121 Liu HY, Buenafe AC, Matejuk A , et al. Estrogen inhibition of EAE involves effects on dendritic cell function. J Neurosci Res 2002; 70 (2) 238-248
  • 122 Zhang Q-H, Hu Y-Z, Cao J, Zhong Y-Q, Zhao Y-F, Mei Q-B. Estrogen influences the differentiation, maturation and function of dendritic cells in rats with experimental autoimmune encephalomyelitis. Acta Pharmacol Sin 2004; 25 (4) 508-513
  • 123 Pettersson A, Ciumas C, Chirsky V, Link H, Huang Y-M, Xiao B-G. Dendritic cells exposed to estrogen in vitro exhibit therapeutic effects in ongoing experimental allergic encephalomyelitis. J Neuroimmunol 2004; 156 (1-2): 58-65
  • 124 Papenfuss TL, Powell ND, McClain MA , et al. Estriol generates tolerogenic dendritic cells in vivo that protect against autoimmunity. J Immunol 2011; 186 (6) 3346-3355
  • 125 Piemonti L, Monti P, Sironi M , et al. Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol 2000; 164 (9) 4443-4451
  • 126 Falsaperla R, Pavone P, Miceli Sopo S , et al. Epileptic seizures as a manifestation of cow's milk allergy: a studied relationship and description of our pediatric experience. Expert Rev Clin Immunol 2014; 10 (12) 1597-1609
  • 127 Besusso D, Saul L, Leech MD , et al. 1,25-Dihydroxyvitamin D3-conditioned CD11c+ dendritic cells are effective initiators of CNS autoimmune disease. Front Immunol 2015; 6: 575 DOI: 10.3389/fimmu.2015.00575.
  • 128 Bartosik-Psujek H, Tabarkiewicz J, Pocinska K, Stelmasiak Z, Rolinski J. Immunomodulatory effects of vitamin D on monocyte-derived dendritic cells in multiple sclerosis. Mult Scler 2010; 16 (12) 1513-1516
  • 129 Raϊch-Regué D, Grau-López L, Naranjo-Gómez M , et al. Stable antigen-specific T-cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients. Eur J Immunol 2012; 42 (3) 771-782
  • 130 Zhan XX, Liu Y, Yang JF , et al. All-trans-retinoic acid ameliorates experimental allergic encephalomyelitis by affecting dendritic cell and monocyte development. Immunology 2013; 138 (4) 333-345
  • 131 Perona-Wright G, Anderton SM, Howie SE, Gray D. IL-10 permits transient activation of dendritic cells to tolerize T cells and protect from central nervous system autoimmune disease. Int Immunol 2007; 19 (9) 1123-1134
  • 132 Delgado M, Chorny A, Ganea D, Gonzalez-Rey E. Vasoactive intestinal polypeptide induces regulatory dendritic cells that prevent acute graft versus host disease and leukemia relapse after bone marrow transplantation. Ann N Y Acad Sci 2006; 1070: 226-232
  • 133 Chorny A, Gonzalez-Rey E, Fernandez-Martin A, Ganea D, Delgado M. Vasoactive intestinal peptide induces regulatory dendritic cells that prevent acute graft-versus-host disease while maintaining the graft-versus-tumor response. Blood 2006; 107 (9) 3787-3794
  • 134 Chorny A, Gonzalez-Rey G, Delgado M. Regulation of dendritic cell differentiation by vasoactive intestinal peptide. Ann N Y Acad Sci 2006; 1088: 187-194
  • 135 Chorny A, Gonzalez-Rey E, Ganea D, Delgado M. Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo: therapeutic applications in autoimmunity and transplantation. Ann N Y Acad Sci 2006; 1070: 190-195
  • 136 Gonzalez-Rey E, Varela N, Chorny A, Delgado M. Therapeutical approaches of vasoactive intestinal peptide as a pleiotropic immunomodulator. Curr Pharm Des 2007; 13 (11) 1113-1139
  • 137 Tan Y-V, Abad C, Lopez R , et al. Pituitary adenylyl cyclase-activating polypeptide is an intrinsic regulator of Treg abundance and protects against experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2009; 106 (6) 2012-2017
  • 138 Tan Y-V, Waschek JA. Targeting VIP and PACAP receptor signalling: new therapeutic strategies in multiple sclerosis. ASN Neuro 2011; 3 (4) e00065 DOI: 10.1042/AN20110024.
  • 139 Morell M, Souza-Moreira L, González-Rey E. VIP in neurological diseases: more than a neuropeptide. Endocr Metab Immune Disord Drug Targets 2012; 12 (4) 323-332
  • 140 Fernandez-Martin A, Gonzalez-Rey E, Chorny A, Ganea D, Delgado M. Vasoactive intestinal peptide induces regulatory T cells during experimental autoimmune encephalomyelitis. Eur J Immunol 2006; 36 (2) 318-326
  • 141 Gonzalez-Rey E, Fernandez-Martin A, Chorny A , et al. Therapeutic effect of vasoactive intestinal peptide on experimental autoimmune encephalomyelitis: down-regulation of inflammatory and autoimmune responses. Am J Pathol 2006; 168 (4) 1179-1188
  • 142 Fernandez-Martin A, Gonzalez-Rey E, Chorny A , et al. VIP prevents experimental multiple sclerosis by downregulating both inflammatory and autoimmune components of the disease. Ann N Y Acad Sci 2006; 1070: 276-281
  • 143 Kato H, Ito A, Kawanokuchi J , et al. Pituitary adenylate cyclase-activating polypeptide (PACAP) ameliorates experimental autoimmune encephalomyelitis by suppressing the functions of antigen presenting cells. Mult Scler 2004; 10 (6) 651-659
  • 144 Toscano MG, Delgado M, Kong W, Martin F, Skarica M, Ganea D. Dendritic cells transduced with lentiviral vectors expressing VIP differentiate into VIP-secreting tolerogenic-like DCs. Mol Ther 2010; 18 (5) 1035-1045
  • 145 Cobo M, Anderson P, Benabdellah K , et al. Mesenchymal stem cells expressing vasoactive intestinal peptide ameliorate symptoms in a model of chronic multiple sclerosis. Cell Transplant 2013; 22 (5) 839-854
  • 146 Abad C, Tan Y-V, Lopez R , et al. Vasoactive intestinal peptide loss leads to impaired CNS parenchymal T-cell infiltration and resistance to experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2010; 107 (45) 19555-19560
  • 147 Tan PH, Beutelspacher SC, Xue S-A , et al. Modulation of human dendritic-cell function following transduction with viral vectors: implications for gene therapy. Blood 2005; 105 (10) 3824-3832
  • 148 Vitaliti G, Pavone P, Guglielmo F, Falsaperla R. Sublingual immunotherapy in preschool children: an update. Expert Rev Clin Immunol 2013; 9 (4) 385-390
  • 149 Xiao B-G, Zhu W-H, Lu C-Z. The presence of GM-CSF and IL-4 interferes with effect of TGF-β1 on antigen presenting cells in patients with multiple sclerosis and in rats with experimental autoimmune encephalomyelitis. Cell Immunol 2007; 249 (1) 30-36
  • 150 Ishikawa M, Jin Y, Guo H, Link H, Xiao B-G. Nasal administration of transforming growth factor-β1 induces dendritic cells and inhibits protracted-relapsing experimental allergic encephalomyelitis. Mult Scler 1999; 5 (3) 184-191
  • 151 Ge Z, Da Y, Xue Z , et al. Vorinostat, a histone deacetylase inhibitor, suppresses dendritic cell function and ameliorates experimental autoimmune encephalomyelitis. Exp Neurol 2013; 241: 56-66
  • 152 Zhang K, Ge Z, Da Y , et al. Plumbagin suppresses dendritic cell functions and alleviates experimental autoimmune encephalomyelitis. J Neuroimmunol 2014; 273 (1-2): 42-52
  • 153 Jia Y, Jing J, Bai Y , et al. Amelioration of experimental autoimmune encephalomyelitis by plumbagin through down-regulation of JAK-STAT and NF-κB signaling pathways. PLoS One 2011; 6 (10) e27006 DOI: 10.1371/journal.pone.0027006.
  • 154 Xue Z, Li W, Wang H , et al. ZSTK474, a novel PI3K inhibitor, modulates human CD14+ monocyte-derived dendritic cell functions and suppresses experimental autoimmune encephalomyelitis. J Mol Med (Berl) 2014; 92 (10) 1057-1068
  • 155 Xue Z, Ge Z, Zhang K , et al. Embelin suppresses dendritic cell functions and limits autoimmune encephalomyelitis through the TGF-β/β-catenin and STAT3 signaling pathways. Mol Neurobiol 2014; 49 (2) 1087-1101
  • 156 Zhou F, Ciric B, Zhang G-X, Rostami A. Immune tolerance induced by intravenous transfer of immature dendritic cells via up-regulating numbers of suppressive IL-10(+) IFN-γ(+)-producing CD4(+) T cells. Immunol Res 2013; 56 (1) 1-8
  • 157 Zhou F, Lauretti E, di Meco A , et al. Intravenous transfer of apoptotic cell-treated dendritic cells leads to immune tolerance by blocking Th17 cell activity. Immunobiology 2013; 218 (8) 1069-1076
  • 158 Mansilla MJ, Sellès-Moreno C, Fàbregas-Puig S , et al. Beneficial effect of tolerogenic dendritic cells pulsed with MOG autoantigen in experimental autoimmune encephalomyelitis. CNS Neurosci Ther 2015; 21 (3) 222-230
  • 159 Villoslada P, Zubizarreta I. Treatment of Multiple Sclerosis and Neuromyelitis Optica with Regulatory Dendritic Cell: Clinical Trial Phase 1 B. Institut d'Investigacions Biomèdiques August Pi i Sunyer.:; 2000
  • 160 Massimo Trucco P. Autologous Immunoregulatory Dendritic Cells for Type 1 Diabetes Therapy. Pittsburgh, PA: Institute of Cellular Therapeutics, Allegheny General Hospital; 2000-2016
  • 161 Ramo C. Neurology Service. Multiple Sclerosis Department. Tolerogenic Dendritic Cells as a Therapeutic Strategy for the Treatment of Multiple Sclerosis Patients (TOLERVIT-MS) (TOLERVIT-MS). Badalona Hospital Germans Trias i Pujol 2000–2016
  • 162 Nathalie Cools P. A “Negative” Dendritic Cell-based Vaccine for the Treatment of Multiple Sclerosis: A First-in-Human Clinical Trial (MS tolDC). Universiteit Antwerpen 2000–2016
  • 163 Giannoukakis N, Phillips B, Finegold D, Harnaha J, Trucco M. Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Diabetes Care 2011; 34 (9) 2026-2032
  • 164 Benham H, Nel HJ, Law SC , et al. Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Sci Transl Med 2015; 7 (290) 290ra87 DOI: 10.1126/scitranslmed.aaa9301.
  • 165 Bell GM, Anderson AE, Diboll J , et al. Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. Ann Rheum Dis 2016; DOI: 10.1136/annrheumdis-2015-208456.
  • 166 Jauregui-Amezaga A, Cabezón R, Ramírez-Morros A , et al. Intraperitoneal administration of autologous tolerogenic dendritic cells for refractory Crohn's disease: a phase I study. J Crohn's Colitis 2015; 9 (12) 1071-1078
  • 167 Ten Brinke A, Hilkens CM, Cools N , et al. Clinical use of tolerogenic dendritic cells-harmonization approach in European collaborative effort. Mediators Inflamm 2015; 2015: 471719 DOI: 10.1155/2015/471719.