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Nat Immunol. 2018 Nov;19(11):1212-1223. doi: 10.1038/s41590-018-0232-x. Epub 2018 Oct 15.

Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.

Author information

1
Gladstone Institutes, San Francisco, CA, USA.
2
Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
3
Lundbeck Research USA, Paramus, NJ, USA.
4
H. Lundbeck A/S, Copenhagen, Denmark.
5
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
6
Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria.
7
Division of Neonatology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
8
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
9
National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA, USA.
10
Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA.
11
Neurology Service, San Francisco Veteran Affairs Medical Center, San Francisco, CA, USA.
12
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
13
Gladstone Institutes, San Francisco, CA, USA. kakassoglou@gladstone.ucsf.edu.
14
Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA. kakassoglou@gladstone.ucsf.edu.
15
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. kakassoglou@gladstone.ucsf.edu.

Abstract

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer's disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.

PMID:
30323343
PMCID:
PMC6317891
[Available on 2019-04-15]
DOI:
10.1038/s41590-018-0232-x

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