Author(s): Yukio Takeshita , MD, PhD, Birgit Obermeier , PhD, Anne C. Cotleur , MS, Simona F. Spampinato , MD, PhD, Fumitaka Shimizu , MD, PhD, Erin Yamamoto , BA, Yasuteru Sano , MD, PhD, Thomas J. Kryzer , AS, Vanda A. Lennon , MD, Takashi Kanda , MD, PhD, Richard M. Ransohoff , MD
Publication date (Electronic): 19 December 2016
Publisher: Lippincott Williams & Wilkins
To address the hypothesis that physiologic interactions between astrocytes and endothelial cells (EC) at the blood–brain barrier (BBB) are afflicted by pathogenic inflammatory signaling when astrocytes are exposed to aquaporin-4 (AQP4) antibodies present in the immunoglobulin G (IgG) fraction of serum from patients with neuromyelitis optica (NMO), referred to as NMO-IgG.
We established static and flow-based in vitro BBB models incorporating co-cultures of conditionally immortalized human brain microvascular endothelial cells and human astrocyte cell lines with or without AQP4 expression.
In astrocyte–EC co-cultures, exposure of astrocytes to NMO-IgG decreased barrier function, induced CCL2 and CXCL8 expression by EC, and promoted leukocyte migration under flow, contingent on astrocyte expression of AQP4. NMO-IgG selectively induced interleukin (IL)-6 production by AQP4-positive astrocytes. When EC were exposed to IL-6, we observed decreased barrier function, increased CCL2 and CXCL8 expression, and enhanced leukocyte transmigration under flow. These effects were reversed after application of IL–6 neutralizing antibody.
I am now employee of Biogen (Postdoctoral Scientist, for 2 years), but was affiliated with the Cleveland Clinic at the time the study was performed and I have no conflicts to declare.
Vanda Lennon receives royalties from RSR/Kronus for sale of aquaporin-4 autoantibody testing kits and for commercial aquaporin-4 autoantibody testing performed outside Mayo Clinic.
NIH R01-NS065829,?CNS Demyelinating Autoimmunity Targeting Water Channel Complexes?. Principal Investigator: S.J. Pittock Co-Investigator: V.A. Lennon Years: 2010-2015
1) RSR/Kronus for sale of aquaporin-4 autoantibody testing kits. 2) Non-Mayo sites performing “home brew” diagnostic testing for aquaporin-4 autoantibody.
Dr. Lennon has a potential financial interest in the technologies listed below: “Aquaporin-4 as an aid for cancer diagnosis”.
Clinical and Experimental Neuroimmunology Editor-in- Chief 2010- Neuropathology, Editorial Advisory Board Member 2009-
Contract Grant Sponsor: Japan Society for the Promotion of Science - Tokyo Contract Grant Number: 25293203, 26670443
BiogenIdec, speaker's honoraria Novartis, speaker's honoraria
Employed at present by Biogen. Work reported in this paper was completed before I joined Biogen.
Chemocentryx, sponsored research agreement Biogen, sponsored research agreement National MS Society
NIH: P50 NS38667 R01 NS32151 R01 NS74804 R21 NS74820 K24 NS51400
Travel support and/or honoraria were provided for each of the following: Special Guest & Speaker Max-Planck Institute Retreat Ringberg Germany, 2009 Invited Plenary Speaker 1st Keystone Symposium on MS, Santa Fe New Mexico, 2009 Grand Rounds in Neurology, Johns Hopkins University, Baltimore, 2009 Keynote Lecture, Opening of Neuropathology Institute, Freiburg Germany, 2009 Plenary Lecture, Kick-off meeting for Neurodegeneration Research Center, Bonn, 2009 Invited Seminar, Institute for Research in Biomedicine, Bellinzona, Switzerland, 2009 Invited Speaker, FDA/NYAS Conference: ?Cytokine Therapies?, New York, 2009 Invited External Speaker ?Annual Japanese MS Workshop? Kyushu Japan 2009 Visiting Professor, Dept of Neurology, Kyushu University, Fukuoka, Japan, 2009 Consultant, Nature ?Landscape? editorial meeting on Neuroimmunology, 2009 Invited Seminar, GSK Hammersmith Hospital, London, 2009 Invited Speaker 12th International Symposium “Signaling at the BBB”, London, England, 2009 Co-organizer/Speaker ?Chemokines and Chemokine Receptors in the CNS?, Rome, 2009 Grand Rounds in Neurology, Ottawa General Hospital, Ontario, Canada, 2009 Invited Speaker, Keystone Symposium ?Alzheimer?s Disease?, Colorado, 2010 NIH EUREKA Review IRGs, 2008-2010 Invited Speaker, ASN annual meeting, Santa Fe, 2010 Invited Speaker, Nikolas Histiocytosis-X Symposium, Athens, Greece, 2010 Invited speaker, FOCIS 2010 Symposium ?Interventional Immunology?, Boston, 2010 Keynote Speaker, Neuroimmunology Symposium, Kyoto, Japan, 2010 Workshop Chair, International Congress of Immunology, Kobe, Japan 2010 Plenary Lecture, PACTRIMS, Bali, Indonesia, 2010 Symposium Organizer and Chair ANA annual meeting, San Francisco, CA, 2010 Workshop Chair, Special Interest Groups, ANA, San Francisco, CA, 2010 Invited Speaker, Theodor Kocher Institute, Bern, Switzerland, 2010 Invited Speaker/Session Chair, Cell Press Symposium “Inflammation in Disease”, Lisbon, 2010 Invited Speaker, Brazilian Society of Pharmacology 42nd Annual Meeting, Brazil, 2010 External Reviewer, DFG ?Centers of Excellence? Applications, Frankfurt, Germany, 2011 Invited Speaker, AAAS/Abelson Symposium ?Defeating AD?, Washington DC, 2011
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