title: Autoantigen-specific immunosuppression with tolerogenic peripheral blood cells prevents relapses in a mouse model of relapsing-remitting multiple sclerosis.
abstract: Dendritic cells (DCs) rendered suppressive by treatment with mitomycin C and loaded with the autoantigen myelin basic protein demonstrated earlier their ability to prevent experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis (MS). This provides an approach for prophylactic vaccination against autoimmune diseases. For clinical application such DCs are difficult to generate and autoantigens hold the risk of exacerbating the disease.
  
  
  
  We replaced DCs by peripheral mononuclear cells and myelin autoantigens by glatiramer acetate (Copaxone(®)), a drug approved for the treatment of MS. Spleen cells were loaded with Copaxone(®), incubated with mitomycin C (MICCop) and injected into mice after the first bout of relapsing-remitting EAE. Immunosuppression mediated by MICCop was investigated in vivo by daily assessment of clinical signs of paralysis and in in vitro restimulation assays of peripheral immune cells. Cytokine profiling was performed by enzyme-linked immunosorbent assay (ELISA). Migration of MICCop cells after injection was examined by biodistribution analysis of (111)Indium-labelled MICCop. The number and inhibitory activity of CD4(+)CD25(+)FoxP3(+) regulatory T cells were analysed by histology, flow cytometry and in vitro mixed lymphocyte cultures. In order to assess the specificity of MICCop-induced suppression, treated EAE mice were challenged with the control protein ovalbumin. Humoral and cellular immune responses were then determined by ELISA and in vitro antigen restimulation assay.
  
  
  
  MICCop cells were able to inhibit the harmful autoreactive T-cell response and prevented mice from further relapses without affecting general immune responses. Administered MICCop migrated to various organs leading to an increased infiltration of the spleen and the central nervous system with CD4(+)CD25(+)FoxP3(+) cells displaying a suppressive cytokine profile and inhibiting T-cell responses.
  
  
  
  We describe a clinically applicable cell therapeutic approach for controlling relapses in autoimmune encephalomyelitis by specifically silencing the deleterious autoimmune response.
authors.affiliation: Department of Transplantation Immunology, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany. christian.kleist@med.uni-heidelberg.de.|Department of Radiology, Division of Nuclear Medicine, University of Heidelberg, 69120, Heidelberg, Germany. christian.kleist@med.uni-heidelberg.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Kleist
authors.affiliation: Department of Transplantation Immunology, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.|Hexal AG, 83607, Holzkirchen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mohr
authors.affiliation: Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.|Quintiles GmbH, 63263, Neu-Isenburg, Germany.
authors.forename: Sadanand
authors.initials: S
authors.lastname: Gaikwad
authors.affiliation: Department of Transplantation Immunology, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.|Becton Dickinson GmbH, BD Life Sciences, 69120, Heidelberg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Dittmar
authors.affiliation: Department of Anatomy I, University of Cologne, Joseph-Stelzmann-Str. 9, 50931, Cologne, Germany.|Department of Anatomy and Cell Biology, University of Wuerzburg, 97070, Würzburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kuerten
authors.affiliation: Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.|Department of Neurooncology, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.affiliation: Department of Radiology, Division of Nuclear Medicine, University of Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Mier
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: Department of Transplantation Immunology, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Opelz
authors.affiliation: Department of Transplantation Immunology, Institute for Immunology, University of Heidelberg, Im Neuenheimer Feld 305, 69120, Heidelberg, Germany. esa.germany@gmx.org.
authors.forename: Peter
authors.initials: P
authors.lastname: Terness
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001324:Autoantigens / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D005260:Female; D000068717:Glatiramer Acetate / Q000494:pharmacology / Q000627:therapeutic use; D007108:Immune Tolerance / Q000187:drug effects; D007165:Immunosuppression Therapy; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D009928:Organ Specificity / Q000187:drug effects; D000072916:Peripheral Blood Stem Cells / Q000187:drug effects / Q000378:metabolism*; D012008:Recurrence; D013154:Spleen / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D014466:Ultraviolet Rays
chemical_list: D001324:Autoantigens; D016685:Mitomycin; D000068717:Glatiramer Acetate
keywords: Autoimmunity; Cell therapy; Copaxone®; Immune tolerance; Mitomycin C; Regulatory T cells; Relapsing-remitting MS