Blocking of α4 Integrin Does Not Protect From Acute Ischemic Stroke in Mice
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Blocking of α4 Integrin Does Not Protect From Acute Ischemic Stroke in Mice. / Langhauser, Friederike; Kraft, Peter; Göb, Eva; Leinweber, Jonas; Schuhmann, Michael K; Lorenz, Kristina; Gelderblom, Mathias; Bittner, Stefan; Meuth, Sven G; Wiendl, Heinz; Magnus, Tim; Kleinschnitz, Christoph.
in: STROKE, Jahrgang 45, Nr. 6, 2014, S. 1799-+.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Blocking of α4 Integrin Does Not Protect From Acute Ischemic Stroke in Mice
AU - Langhauser, Friederike
AU - Kraft, Peter
AU - Göb, Eva
AU - Leinweber, Jonas
AU - Schuhmann, Michael K
AU - Lorenz, Kristina
AU - Gelderblom, Mathias
AU - Bittner, Stefan
AU - Meuth, Sven G
AU - Wiendl, Heinz
AU - Magnus, Tim
AU - Kleinschnitz, Christoph
PY - 2014
Y1 - 2014
N2 - BACKGROUND AND PURPOSE: 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.
AB - BACKGROUND AND PURPOSE: 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.
U2 - 10.1161/STROKEAHA.114.005000
DO - 10.1161/STROKEAHA.114.005000
M3 - SCORING: Journal article
C2 - 24743435
VL - 45
SP - 1799-+
JO - STROKE
JF - STROKE
SN - 0039-2499
IS - 6
ER -