title: PD-L1 Monoclonal Antibody Treats Ischemic Stroke by Controlling Central Nervous System Inflammation.
abstract: OBJECTIVE
  Both pathogenic and regulatory immune processes are involved in the middle cerebral artery occlusion (MCAO) model of experimental stroke, including interactions involving the programmed death 1 (PD-1) receptor and its 2 ligands, PD-L1 and PD-L2. Although PD-1 reduced stroke severity, PD-L1 and PD-L2 appeared to play pathogenic roles, suggesting the use of anti-PD-L monoclonal antibody therapy for MCAO.
  
  
  METHODS
  Male C57BL/6 mice were treated with a single dose of anti-PD-L1 monoclonal antibody 4 hours after MCAO and evaluated for clinical, histological and immunologic changes after 96 hours of reperfusion.
  
  
  RESULTS
  Blockade of the PD-L1 checkpoint using a single injection of 200 μg anti-PD-L1 monoclonal antibody given intravenously 4 hours after occlusion significantly reduced MCAO infarct volumes and improved neurological outcomes after 96 hours of reperfusion. Treatment partially reversed splenic atrophy and decreased central nervous system infiltrating immune cells concomitant with enhanced appearance of CD8(+) regulatory T cells in the lesioned central nervous system hemisphere.
  
  
  CONCLUSIONS
  This study demonstrates for the first time the beneficial therapeutic effects of PD-L1 checkpoint blockade on MCAO, thus validating proposed mechanisms obtained in our previous studies using PD-1- and PD-L-deficient mice. These results provide strong support for the use of available humanized anti-PD-L1 antibodies for treatment of human stroke subjects.
authors: From the Neuroimmunology Research, VA Portland Health Care System, OR (S.B., A.L., A.L.D., A.A.V., H.O.); and Departments of Neurology (S.B., A.L., A.L.D., A.A.V., J.A.S., H.O.), Anesthesiology and Perioperative Medicine (Y.C., J.W., J.A.S., H.O.), Molecular Microbiology and Immunology (A.A.V.), and Medical and Molecular Genetics (J.A.S.), Oregon Health and Science University, Portland.
authors: Sheetal
authors: S
authors: Bodhankar
authors: From the Neuroimmunology Research, VA Portland Health Care System, OR (S.B., A.L., A.L.D., A.A.V., H.O.); and Departments of Neurology (S.B., A.L., A.L.D., A.A.V., J.A.S., H.O.), Anesthesiology and Perioperative Medicine (Y.C., J.W., J.A.S., H.O.), Molecular Microbiology and Immunology (A.A.V.), and Medical and Molecular Genetics (J.A.S.), Oregon Health and Science University, Portland.
authors: Yingxin
authors: Y
authors: Chen
authors: From the Neuroimmunology Research, VA Portland Health Care System, OR (S.B., A.L., A.L.D., A.A.V., H.O.); and Departments of Neurology (S.B., A.L., A.L.D., A.A.V., J.A.S., H.O.), Anesthesiology and Perioperative Medicine (Y.C., J.W., J.A.S., H.O.), Molecular Microbiology and Immunology (A.A.V.), and Medical and Molecular Genetics (J.A.S.), Oregon Health and Science University, Portland.
authors: Andrew
authors: A
authors: Lapato
authors: From the Neuroimmunology Research, VA Portland Health Care System, OR (S.B., A.L., A.L.D., A.A.V., H.O.); and Departments of Neurology (S.B., A.L., A.L.D., A.A.V., J.A.S., H.O.), Anesthesiology and Perioperative Medicine (Y.C., J.W., J.A.S., H.O.), Molecular Microbiology and Immunology (A.A.V.), and Medical and Molecular Genetics (J.A.S.), Oregon Health and Science University, Portland.
authors: Abby L
authors: AL
authors: Dotson
authors: From the Neuroimmunology Research, VA Portland Health Care System, OR (S.B., A.L., A.L.D., A.A.V., H.O.); and Departments of Neurology (S.B., A.L., A.L.D., A.A.V., J.A.S., H.O.), Anesthesiology and Perioperative Medicine (Y.C., J.W., J.A.S., H.O.), Molecular Microbiology and Immunology (A.A.V.), and Medical and Molecular Genetics (J.A.S.), Oregon Health and Science University, Portland.
authors: Jianming
authors: J
authors: Wang
authors: From the Neuroimmunology Research, VA Portland Health Care System, OR (S.B., A.L., A.L.D., A.A.V., H.O.); and Departments of Neurology (S.B., A.L., A.L.D., A.A.V., J.A.S., H.O.), Anesthesiology and Perioperative Medicine (Y.C., J.W., J.A.S., H.O.), Molecular Microbiology and Immunology (A.A.V.), and Medical and Molecular Genetics (J.A.S.), Oregon Health and Science University, Portland.
authors: Arthur A
authors: AA
authors: Vandenbark
authors: From the Neuroimmunology Research, VA Portland Health Care System, OR (S.B., A.L., A.L.D., A.A.V., H.O.); and Departments of Neurology (S.B., A.L., A.L.D., A.A.V., J.A.S., H.O.), Anesthesiology and Perioperative Medicine (Y.C., J.W., J.A.S., H.O.), Molecular Microbiology and Immunology (A.A.V.), and Medical and Molecular Genetics (J.A.S.), Oregon Health and Science University, Portland.
authors: Julie A
authors: JA
authors: Saugstad
authors: From the Neuroimmunology Research, VA Portland Health Care System, OR (S.B., A.L., A.L.D., A.A.V., H.O.); and Departments of Neurology (S.B., A.L., A.L.D., A.A.V., J.A.S., H.O.), Anesthesiology and Perioperative Medicine (Y.C., J.W., J.A.S., H.O.), Molecular Microbiology and Immunology (A.A.V.), and Medical and Molecular Genetics (J.A.S.), Oregon Health and Science University, Portland. offnerva@ohsu.edu.
authors: Halina
authors: H
authors: Offner
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D002490:Central Nervous System / Q000276:immunology; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse
keywords: anti-PD-L1 antibody therapy; interleukin-10; middle cerebral artery occlusion; reperfusion; stroke