title: DAB389IL-2 suppresses autoimmune inflammation in the CNS and inhibits T cell-mediated lysis of glial target cells.
abstract: In multiple sclerosis (MS) and its rodent model, experimental autoimmune encephalomyelitis (EAE), activated CD4(+) T cells with upregulated IL-2R mediate inflammation and demyelination in the central nervous system (CNS). DAB(389)IL-2, a chimeric fusion protein of IL-2 and diphtheria toxin, inhibits human and rodent IL-2 activated T cells that express the high affinity interleukin-2 receptor. In the present study, DAB(389)IL-2 was used to treat rats with EAE. We wanted to investigate the possibility that DAB(389)IL-2 could prevent tissue destruction within the CNS. We used a suboptimal dose of DAB(389)IL-2 that allowed substantial transmigration of inflammatory cells across the blood-brain barrier. DAB(389)IL-2 inhibited infiltration of CD4(+), CD8(+), CD25(+) and TCR αβ(+) associated mononuclear cells and inflammatory macrophages in the spinal cord on day 13 post-immunization, at the peak of disease. Gene expression study showed that DAB(389)IL-2 treatment suppressed TNF-α and IFN-γ as well as IL-10 cytokine gene expression in the spinal cord of rats with EAE on day 13. DAB(389)IL-2 in vitro treatment suppressed cytotoxicity of MBP-activated T cells from rats with EAE against oligodendrocytes in culture by 66%. Astrocytes were less targeted by MBP activated T cells in vitro. This study suggests that DAB(389)IL-2 directly targets CD4(+) and CD25(+) (IL-2R) T cells and effector T cell function and also indirectly suppresses the activation of macrophage CD169(+) (ED3(+)) and microglia CD11b/c (OX42(+)) populations in the CNS.
authors.affiliation: Department of Radiology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Mahendra K
authors.initials: MK
authors.lastname: Bhopale
authors.affiliation: Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Hilliard
authors.affiliation: Division of Clinical Neurology, University of Nottingham, England, UK.
authors.forename: Cris S
authors.initials: CS
authors.lastname: Constantinescu
authors.affiliation: Department of Neurology, Ohashi Hospital, Toho University, Tokyo, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Fujioka
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Elvira
authors.initials: E
authors.lastname: Ventura
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: S Michael
authors.initials: SM
authors.lastname: Phillips
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: a.m.rostami@jefferson.edu.
authors.forename: Abdolmohamad
authors.initials: A
authors.lastname: Rostami
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000276:immunology; D004167:Diphtheria Toxin / Q000627:therapeutic use*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D060888:Real-Time Polymerase Chain Reaction; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; D007376:Interleukin-2; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox; D007371:Interferon-gamma
keywords: Cytokine expression; DAB(389)IL-2; EAE; Oligodendrocyte; T cell cytotoxicity