title: Anti-IL-6 neutralizing antibody modulates blood-brain barrier function in the ovine fetus.
abstract: Impaired blood-brain barrier function represents an important component of hypoxic-ischemic brain injury in the perinatal period. Proinflammatory cytokines could contribute to ischemia-related blood-brain barrier dysfunction. IL-6 increases vascular endothelial cell monolayer permeability in vitro. However, contributions of IL-6 to blood-brain barrier abnormalities have not been examined in the immature brain in vivo. We generated pharmacologic quantities of ovine-specific neutralizing anti-IL-6 mAbs and systemically infused mAbs into fetal sheep at 126 days of gestation after exposure to brain ischemia. Anti-IL-6 mAbs were measured by ELISA in fetal plasma, cerebral cortex, and cerebrospinal fluid, blood-brain barrier permeability was quantified using the blood-to-brain transfer constant in brain regions, and IL-6, tight junction proteins, and plasmalemma vesicle protein (PLVAP) were detected by Western immunoblot. Anti-IL-6 mAb infusions resulted in increases in mAb (P < 0.05) in plasma, brain parenchyma, and cerebrospinal fluid and decreases in brain IL-6 protein. Twenty-four hours after ischemia, anti-IL-6 mAb infusions attenuated ischemia-related increases in blood-brain barrier permeability and modulated tight junction and PLVAP protein expression in fetal brain. We conclude that inhibiting the effects of IL-6 protein with systemic infusions of neutralizing antibodies attenuates ischemia-related increases in blood-brain barrier permeability by inhibiting IL-6 and modulates tight junction proteins after ischemia.
authors.affiliation: *Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA; ProThera Biologics, Incorporated, Providence, Rhode Island, USA; Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA; Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA; and Geriatric Research Educational, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: *Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA; ProThera Biologics, Incorporated, Providence, Rhode Island, USA; Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA; Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA; and Geriatric Research Educational, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Grazyna B
authors.initials: GB
authors.lastname: Sadowska
authors.affiliation: *Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA; ProThera Biologics, Incorporated, Providence, Rhode Island, USA; Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA; Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA; and Geriatric Research Educational, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Chen
authors.affiliation: *Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA; ProThera Biologics, Incorporated, Providence, Rhode Island, USA; Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA; Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA; and Geriatric Research Educational, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Seon Yeong
authors.initials: SY
authors.lastname: Park
authors.affiliation: *Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA; ProThera Biologics, Incorporated, Providence, Rhode Island, USA; Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA; Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA; and Geriatric Research Educational, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: *Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA; ProThera Biologics, Incorporated, Providence, Rhode Island, USA; Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA; Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA; and Geriatric Research Educational, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Bodge
authors.affiliation: *Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA; ProThera Biologics, Incorporated, Providence, Rhode Island, USA; Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA; Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA; and Geriatric Research Educational, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Cummings
authors.affiliation: *Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA; ProThera Biologics, Incorporated, Providence, Rhode Island, USA; Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA; Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA; and Geriatric Research Educational, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Yow-Pin
authors.initials: YP
authors.lastname: Lim
authors.affiliation: *Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA; ProThera Biologics, Incorporated, Providence, Rhode Island, USA; Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA; Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA; and Geriatric Research Educational, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Makeyev
authors.affiliation: *Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA; ProThera Biologics, Incorporated, Providence, Rhode Island, USA; Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA; Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA; and Geriatric Research Educational, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Walter G
authors.initials: WG
authors.lastname: Besio
authors.affiliation: *Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA; ProThera Biologics, Incorporated, Providence, Rhode Island, USA; Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA; Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA; and Geriatric Research Educational, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: John
authors.initials: J
authors.lastname: Gaitanis
authors.affiliation: *Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA; ProThera Biologics, Incorporated, Providence, Rhode Island, USA; Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA; Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA; and Geriatric Research Educational, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
authors.affiliation: *Department of Pediatrics, Alpert Medical School of Brown University, Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA; ProThera Biologics, Incorporated, Providence, Rhode Island, USA; Department of Electrical, Computer, and Biomedical Engineering, University of Rhode Island, Kingston, Rhode Island, USA; Department of Neurology, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, Rhode Island, USA; and Geriatric Research Educational, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington, USA bstonestreet@wihri.org.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Stonestreet
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D002352:Carrier Proteins / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000502:physiology*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D011247:Pregnancy; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D012756:Sheep; D062725:Tight Junction Proteins / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D002352:Carrier Proteins; D015850:Interleukin-6; D008565:Membrane Proteins; D062725:Tight Junction Proteins; D000093242:Interleukin-6 Inhibitors; C486772:Plvap protein, mouse
keywords: development; ischemia; monoclonal; permeability; tight junction proteins