Inhibition of Bruton’s tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease

Anti-CD20-mediated B-cell depletion effectively reduces acute multiple sclerosis (MS) flares. Recent data shows that antibody-mediated extinction of B cells as a lasting immune suppression, harbors the risk of developing humoral deficiencies over time. Accordingly, more selective, durable and revers...

Full description

Saved in:
Bibliographic Details
Published in:Acta neuropathologica 2020-10, Vol.140 (4), p.535-548
Main Authors: Torke, Sebastian, Pretzsch, Roxanne, Häusler, Darius, Haselmayer, Philipp, Grenningloh, Roland, Boschert, Ursula, Brück, Wolfgang, Weber, Martin S.
Format: Article
Language:English
Subjects:
Analysis
Animal models
Antibodies
Antigen-presenting cells
Antigens
B cells
B-cell receptor
Bruton's tyrosine kinase
CD20 antigen
Cell activation
Cytokines
Demyelinating diseases
Demyelination
Enzymes
Ethylenediaminetetraacetic acid
Lymphocytes B
Lymphocytes T
Medicine
Medicine & Public Health
Multiple sclerosis
Neurosciences
Original Paper
Pathology
Phenols
Protein-tyrosine kinase
T cells
Tyrosine
Viral antibodies
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Anti-CD20-mediated B-cell depletion effectively reduces acute multiple sclerosis (MS) flares. Recent data shows that antibody-mediated extinction of B cells as a lasting immune suppression, harbors the risk of developing humoral deficiencies over time. Accordingly, more selective, durable and reversible B-cell-directed MS therapies are needed. We here tested inhibition of Bruton’s tyrosine kinase (BTK), an enzyme centrally involved in B-cell receptor signaling, as the most promising approach in this direction. Using mouse models of MS, we determined that evobrutinib, the first BTK inhibiting molecule being developed, dose-dependently inhibited antigen-triggered activation and maturation of B cells as well as their release of pro-inflammatory cytokines. Most importantly, evobrutinib treatment functionally impaired the capacity of B cells to act as antigen-presenting cells for the development of encephalitogenic T cells, resulting in a significantly reduced disease severity in mice. In contrast to anti-CD20, BTK inhibition silenced this key property of B cells in MS without impairing their frequency or functional integrity. In conjunction with a recent phase II trial reporting that evobrutinib is safe and effective in MS, our mechanistic data highlight therapeutic BTK inhibition as a landmark towards selectively interfering with MS-driving B-cell properties.
ISSN:0001-6322
1432-0533
DOI:10.1007/s00401-020-02204-z