title: Blocking of α4 integrin does not protect from acute ischemic stroke in mice.
abstract: OBJECTIVE
  T lymphocytes have recently been identified as key mediators of tissue damage in ischemic stroke. The interaction between very late antigen-4 (VLA-4) and vascular adhesion molecule-1 is crucial for the transvascular egress of T lymphocytes, and inhibition of this interaction by specific antibodies is a powerful strategy to combat autoimmune neuroinflammation. However, whether pharmacological blocking of T-lymphocyte trafficking is also protective during brain ischemia is still unclear. We investigated the efficacy of a monoclonal antibody directed against VLA-4 in mouse models of ischemic stroke.
  
  
  METHODS
  Transient and permanent middle cerebral artery occlusion was induced in male C57Bl/6 mice. Animals treated with a monoclonal anti-CD49d antibody (300 μg) 24 hours before or 3 hours after the onset of cerebral ischemia and stroke outcome, including infarct size, functional status, and mortality, were assessed between day 1 and day 7. The numbers of immune cells invading the ischemic brain were determined by immunocytochemistry and flow cytometry.
  
  
  RESULTS
  Blocking of VLA-4 significantly reduced the invasion of T lymphocytes and neutrophils on day 5 after middle cerebral artery occlusion and inhibited the upregulation of vascular adhesion molecule-1. However, the anti-CD49d antibody failed to influence stroke outcome positively irrespective of the model or the time point investigated.
  
  
  CONCLUSIONS
  Pharmacological inhibition of the VLA-4/vascular adhesion molecule-1 axis in experimental stroke was ineffective in our hands. Our results cast doubt on the effectiveness of anti-CD49d as a stroke treatment. Further translational studies should be performed before testing anti-VLA-4 antibodies in patients with stroke.
authors.affiliation: From the Department of Neurology, University Clinic of Würzburg, Würzburg, Germany (F.L., P.K., E.G., J.L., M.K.S., C.K.); the Institute of Clinical Epidemiology and Biometry, Comprehensive Heart Failure Center (P.K.) and Institute of Pharmacology and Toxicology (K.L.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (M.G., T.M.); and Department of Neurology (S.B., S.G.M., H.W.) and Institute of Physiology-Neuropathophysiology (S.G.M.), University of Münster, Münster, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Langhauser
authors.affiliation: From the Department of Neurology, University Clinic of Würzburg, Würzburg, Germany (F.L., P.K., E.G., J.L., M.K.S., C.K.); the Institute of Clinical Epidemiology and Biometry, Comprehensive Heart Failure Center (P.K.) and Institute of Pharmacology and Toxicology (K.L.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (M.G., T.M.); and Department of Neurology (S.B., S.G.M., H.W.) and Institute of Physiology-Neuropathophysiology (S.G.M.), University of Münster, Münster, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.affiliation: From the Department of Neurology, University Clinic of Würzburg, Würzburg, Germany (F.L., P.K., E.G., J.L., M.K.S., C.K.); the Institute of Clinical Epidemiology and Biometry, Comprehensive Heart Failure Center (P.K.) and Institute of Pharmacology and Toxicology (K.L.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (M.G., T.M.); and Department of Neurology (S.B., S.G.M., H.W.) and Institute of Physiology-Neuropathophysiology (S.G.M.), University of Münster, Münster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Göb
authors.affiliation: From the Department of Neurology, University Clinic of Würzburg, Würzburg, Germany (F.L., P.K., E.G., J.L., M.K.S., C.K.); the Institute of Clinical Epidemiology and Biometry, Comprehensive Heart Failure Center (P.K.) and Institute of Pharmacology and Toxicology (K.L.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (M.G., T.M.); and Department of Neurology (S.B., S.G.M., H.W.) and Institute of Physiology-Neuropathophysiology (S.G.M.), University of Münster, Münster, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Leinweber
authors.affiliation: From the Department of Neurology, University Clinic of Würzburg, Würzburg, Germany (F.L., P.K., E.G., J.L., M.K.S., C.K.); the Institute of Clinical Epidemiology and Biometry, Comprehensive Heart Failure Center (P.K.) and Institute of Pharmacology and Toxicology (K.L.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (M.G., T.M.); and Department of Neurology (S.B., S.G.M., H.W.) and Institute of Physiology-Neuropathophysiology (S.G.M.), University of Münster, Münster, Germany.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schuhmann
authors.affiliation: From the Department of Neurology, University Clinic of Würzburg, Würzburg, Germany (F.L., P.K., E.G., J.L., M.K.S., C.K.); the Institute of Clinical Epidemiology and Biometry, Comprehensive Heart Failure Center (P.K.) and Institute of Pharmacology and Toxicology (K.L.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (M.G., T.M.); and Department of Neurology (S.B., S.G.M., H.W.) and Institute of Physiology-Neuropathophysiology (S.G.M.), University of Münster, Münster, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lorenz
authors.affiliation: From the Department of Neurology, University Clinic of Würzburg, Würzburg, Germany (F.L., P.K., E.G., J.L., M.K.S., C.K.); the Institute of Clinical Epidemiology and Biometry, Comprehensive Heart Failure Center (P.K.) and Institute of Pharmacology and Toxicology (K.L.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (M.G., T.M.); and Department of Neurology (S.B., S.G.M., H.W.) and Institute of Physiology-Neuropathophysiology (S.G.M.), University of Münster, Münster, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Gelderblom
authors.affiliation: From the Department of Neurology, University Clinic of Würzburg, Würzburg, Germany (F.L., P.K., E.G., J.L., M.K.S., C.K.); the Institute of Clinical Epidemiology and Biometry, Comprehensive Heart Failure Center (P.K.) and Institute of Pharmacology and Toxicology (K.L.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (M.G., T.M.); and Department of Neurology (S.B., S.G.M., H.W.) and Institute of Physiology-Neuropathophysiology (S.G.M.), University of Münster, Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.affiliation: From the Department of Neurology, University Clinic of Würzburg, Würzburg, Germany (F.L., P.K., E.G., J.L., M.K.S., C.K.); the Institute of Clinical Epidemiology and Biometry, Comprehensive Heart Failure Center (P.K.) and Institute of Pharmacology and Toxicology (K.L.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (M.G., T.M.); and Department of Neurology (S.B., S.G.M., H.W.) and Institute of Physiology-Neuropathophysiology (S.G.M.), University of Münster, Münster, Germany.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.affiliation: From the Department of Neurology, University Clinic of Würzburg, Würzburg, Germany (F.L., P.K., E.G., J.L., M.K.S., C.K.); the Institute of Clinical Epidemiology and Biometry, Comprehensive Heart Failure Center (P.K.) and Institute of Pharmacology and Toxicology (K.L.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (M.G., T.M.); and Department of Neurology (S.B., S.G.M., H.W.) and Institute of Physiology-Neuropathophysiology (S.G.M.), University of Münster, Münster, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.affiliation: From the Department of Neurology, University Clinic of Würzburg, Würzburg, Germany (F.L., P.K., E.G., J.L., M.K.S., C.K.); the Institute of Clinical Epidemiology and Biometry, Comprehensive Heart Failure Center (P.K.) and Institute of Pharmacology and Toxicology (K.L.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (M.G., T.M.); and Department of Neurology (S.B., S.G.M., H.W.) and Institute of Physiology-Neuropathophysiology (S.G.M.), University of Münster, Münster, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
authors.affiliation: From the Department of Neurology, University Clinic of Würzburg, Würzburg, Germany (F.L., P.K., E.G., J.L., M.K.S., C.K.); the Institute of Clinical Epidemiology and Biometry, Comprehensive Heart Failure Center (P.K.) and Institute of Pharmacology and Toxicology (K.L.), University of Würzburg, Würzburg, Germany; Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (M.G., T.M.); and Department of Neurology (S.B., S.G.M., H.W.) and Institute of Physiology-Neuropathophysiology (S.G.M.), University of Münster, Münster, Germany. christoph.kleinschnitz@uni-wuerzburg.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology / Q000494:pharmacology*; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D004195:Disease Models, Animal; D039441:Integrin alpha4 / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D020521:Stroke / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D039441:Integrin alpha4
keywords: infarction, middle cerebral artery; inflammation; natalizumab; vascular cell adhesion molecule-1; very late antigen-4