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Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.


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 ?377-395, 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.

SUBMITTER: Ryu JK 

PROVIDER: S-EPMC6317891 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration.

Ryu Jae Kyu JK   Rafalski Victoria A VA   Meyer-Franke Anke A   Adams Ryan A RA   Poda Suresh B SB   Rios Coronado Pamela E PE   Pedersen Lars Østergaard LØ   Menon Veena V   Baeten Kim M KM   Sikorski Shoana L SL   Bedard Catherine C   Hanspers Kristina K   Bardehle Sophia S   Mendiola Andrew S AS   Davalos Dimitrios D   Machado Michael R MR   Chan Justin P JP   Plastira Ioanna I   Petersen Mark A MA   Pfaff Samuel J SJ   Ang Kenny K KK   Hallenbeck Kenneth K KK   Syme Catriona C   Hakozaki Hiroyuki H   Ellisman Mark H MH   Swanson Raymond A RA   Zamvil Scott S SS   Arkin Michelle R MR   Zorn Stevin H SH   Pico Alexander R AR   Mucke Lennart L   Freedman Stephen B SB   Stavenhagen Jeffrey B JB   Nelson Robert B RB   Akassoglou Katerina K  

Nature immunology 20181015 11


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  ...[more]

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