title: Mannan-conjugated myelin peptides prime non-pathogenic Th1 and Th17 cells and ameliorate experimental autoimmune encephalomyelitis.
abstract: Antigen presenting cells (APC) are critical for regulating immune responses. We tested mannan-peptide conjugates for targeting myelin peptides to APC to induce T cell tolerance and resistance to experimental autoimmune encephalomyelitis (EAE). Myelin peptides conjugated to mannan in oxidized (OM) or reduced (RM) forms protected mice against EAE in prophylactic and therapeutic protocols, with OM-conjugated peptides giving best results. Protection was peptide-specific and associated with reduced antigen-specific T cell proliferation, but not alterations in Th1, Th17 and Treg cell differentiation or T cell apoptosis compared to EAE controls. Bone marrow-derived dendritic cells (DC) loaded with OM-MOG showed up-regulated expression of co-stimulatory molecules, reduced PD-L1 expression and enhanced CD40-inducible IL-12 and IL-23 production compared to MOG DC, features consistent with immunogenic DC. OM-MOG induced active T cell tolerance because i.d. administration or passive transfer of OM-MOG DC suppressed ongoing EAE, while OM-MOG-vaccinated mice did not reduce the proliferation of transferred MOG-specific T cells. As in vivo, MOG-specific T cells cultured with OM-MOG DC showed reduced proliferation and equal Th1 and Th17 cell differentiation compared to those with MOG DC, but surprisingly cytokine production was unresponsive to CD40 engagement. Impaired effector T cell function was further evidenced in spinal cord sections from OM-MOG-vaccinated EAE mice, where markedly reduced numbers of CD3(+) T cells were present, restricted to leptomeninges and exceptional parenchymal lesions. Our results show that mannan-conjugated myelin peptides protect mice against EAE through the expansion of antigen-specific Th1 and Th17 cells with impaired proliferation responses and APC-induced co-stimulatory signals that are required for licensing them to become fully pathogenic T cells.
authors.affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Vivian
authors.initials: V
authors.lastname: Tseveleki
authors.affiliation: Department of Chemistry, University of Patras, Rio Patras, Greece. Electronic address: ttselios@chemistry.upatras.gr.
authors.forename: Theodore
authors.initials: T
authors.lastname: Tselios
authors.affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kanistras
authors.affiliation: Laboratory of Cellular Immunology, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Olga
authors.initials: O
authors.lastname: Koutsoni
authors.affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Karamita
authors.affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Sotiris-Spyros
authors.initials: SS
authors.lastname: Vamvakas
authors.affiliation: Centre for Chronic Disease Prevention & Management, Victoria University, Melbourne, Australia.
authors.forename: Vasso
authors.initials: V
authors.lastname: Apostolopoulos
authors.affiliation: Laboratory of Cellular Immunology, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Dotsika
authors.affiliation: Department of Chemistry, University of Patras, Rio Patras, Greece.
authors.forename: John
authors.initials: J
authors.lastname: Matsoukas
authors.affiliation: Division of Neuroimmunology, Centre for Brain Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece. Electronic address: lesley@pasteur.gr.
authors.forename: Lesley
authors.initials: L
authors.lastname: Probert
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology / Q000628:therapy*; D019394:Ki-67 Antigen / Q000378:metabolism; D008213:Lymphocyte Activation; D008351:Mannans / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000627:therapeutic use*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology / Q000633:toxicity; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D010455:Peptides / Q000627:therapeutic use; D018417:Th1 Cells / Q000502:physiology*; D058504:Th17 Cells / Q000502:physiology*; D013997:Time Factors
chemical_list: D016207:Cytokines; D019394:Ki-67 Antigen; D008351:Mannans; D004676:Myelin Basic Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D010455:Peptides; C445081:myelin oligodendrocyte glycoprotein (35-55)
keywords: Anergy/suppression/tolerance; CNS; Dendritic cells; EAE/MS; T cells