title: Neutralizing anti-interleukin-1β antibodies reduce ischemia-related interleukin-1β transport across the blood-brain barrier in fetal sheep.
abstract: Hypoxic ischemic insults predispose to perinatal brain injury. Pro-inflammatory cytokines are important in the evolution of this injury. Interleukin-1β (IL-1β) is a key mediator of inflammatory responses and elevated IL-1β levels in brain correlate with adverse neurodevelopmental outcomes after brain injury. Impaired blood-brain barrier (BBB) function represents an important component of hypoxic-ischemic brain injury in the fetus. In addition, ischemia-reperfusion increases cytokine transport across the BBB of the ovine fetus. Reducing pro-inflammatory cytokine entry into brain could represent a novel approach to attenuate ischemia-related brain injury. We hypothesized that infusions of neutralizing IL-1β monoclonal antibody (mAb) reduce IL-1β transport across the BBB after ischemia in the fetus. Fetal sheep were studied 24-h after 30-min of carotid artery occlusion. Fetuses were treated with placebo- or anti-IL-1β mAb intravenously 15-min and 4-h after ischemia. Ovine IL-1β protein expressed from IL-1β pGEX-2T vectors in Escherichia coli (E. coli) BL-21 cells was produced, purified, and radiolabeled with125I. BBB permeability was quantified using the blood-to-brain transfer constant (Ki) with125I-radiolabeled-IL-1β. Increases in anti-IL-1β mAb were observed in the brain of the mAb-treated group (P<0.001). Blood-to-brain transport of125I-IL-1β was lower (P<0.04) across brain regions in the anti-IL-1β mAb-treated than placebo-treated ischemic fetuses. Plasma125I-IL-1β counts were higher (P<0.001) in the anti-IL-1β mAb- than placebo-treated ischemic fetuses. Systemic infusions of anti-IL-1β mAb reduce IL-1β transport across the BBB after ischemia in the ovine fetus. Our findings suggest that conditions associated with increases in systemic pro-inflammatory cytokines and neurodevelopmental impairment could benefit from an anti-cytokine therapeutic strategy.
authors.affiliation: Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, United States. Electronic address: aparna.patra@uky.edu.
authors.forename: Aparna
authors.initials: A
authors.lastname: Patra
authors.affiliation: Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, United States.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, United States.
authors.forename: Grazyna B
authors.initials: GB
authors.lastname: Sadowska
authors.affiliation: Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, United States.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: ProThera Biologics, Providence, RI 02903, United States.
authors.forename: Yow-Pin
authors.initials: YP
authors.lastname: Lim
authors.affiliation: Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, United States.
authors.forename: James F
authors.initials: JF
authors.lastname: Padbury
authors.affiliation: Veterans Affairs Puget Sound Health Care System, Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA 98104, United States.
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
authors.affiliation: Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, United States. Electronic address: bstonestreet@wihri.org.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Stonestreet
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000008:administration & dosage* / Q000627:therapeutic use; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D005260:Female; D005311:Fetal Hypoxia / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D005865:Gestational Age; D020925:Hypoxia-Ischemia, Brain / Q000276:immunology* / Q000378:metabolism* / Q000517:prevention & control; D053583:Interleukin-1beta / Q000276:immunology* / Q000378:metabolism; D011247:Pregnancy; D012756:Sheep
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D053583:Interleukin-1beta
keywords: blood–brain barrier; cytokines; fetus; hypoxia-ischemia; interleukin-1β; sheep