title: Murine experimental autoimmune encephalomyelitis is diminished by treatment with the angiogenesis inhibitors B20-4.1.1 and angiostatin (K1-3).
abstract: Angiogenesis is the formation of new blood vessels form pre-existing vasculature whose contribution to inflammatory conditions of the Central Nervous System is being studied in order to generate novel therapeutic targets. This study is the first to investigate the impact of two particular angiogenesis inhibitors on murine Experimental Autoimmune Encephalomyelitis (EAE), an inflammatory disease that mimics aspects of the human disease Multiple Sclerosis. The inhibitors were chosen to reduce angiogenesis by complimentary means. Extrinsic factors were targeted with B20-4.1.1 through its ability to bind to murine Vascular Endothelial Growth Factor (VEGF). Vascular processes connected to angiogenesis were targeted directly with K(1-3), the first three kringle domains of angiostatin. Mice treated with B20-4.1.1 and K(1-3) from onset of signs had reduced clinical scores 18-21 days after EAE induction. Both agents suppressed spinal cord angiogenesis without effect on local VEGF expression. B20-4.1.1 reduced spinal cord vascular permeability while K(1-3) had no effect. T cell infiltration into the spinal cord at day 21 was unaffected by either treatment. B20-4.1.1 reduced peripheral T cell proliferation while K(1-3) had no effect. Lymphoid cells from treated mice produced reduced levels of the T helper-17 (Th-17) cell cytokine interleukin (IL)-17 with no effect on the Th-1 cytokine interferon (IFN)-γ or Th-2 cytokine IL-4. However, when both drugs were added in vitro to naive T cells or to antigen stimulated T cells from mice with untreated EAE they had no effect on proliferation or levels of IL-17 or IFN-γ. We conclude that these angiogenesis inhibitors mitigate EAE by both suppressing spinal cord angiogenesis and reducing peripheral T cell activation.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: MacMillan
authors.affiliation: Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Doucette
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Jordan
authors.initials: J
authors.lastname: Warford
authors.affiliation: Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Furlong
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada ; Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Hoskin
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada ; Department of Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia, Canada ; Department of Surgery (Neurosurgery), Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Easton
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D043168:Angiostatins; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications / Q000188:drug therapy*; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000209:etiology; D013116:Spinal Cord / Q000098:blood supply / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D043168:Angiostatins