Altered microglial polarization reduces demyelination in cerebellar slices treated with serum from CD20-depleted...

Ofatumumab (OFT) is a recently developed fully human anti-CD20 monoclonal antibody approved for treating relapsing multiple sclerosis (MS), targeting B-cells and thereby limiting antibody production. Admittedly, its impact on central nervous system (CNS) demyelination and glial cells remains underexplored.

Serum samples from MS patients before and after a 6-month OFT treatment were analyzed regarding cytokines and their impact on BV-2 microglia activation. These sera were then used in an acute demyelination model applying lysophosphatidylcholine (LPC)-induced murine cerebellar slice cultures to assess effects on myelination and glial modulation.

OFT treatment resulted in a decrease in proinflammatory cytokines and an increase in anti-inflammatory cytokines in patient sera, indicating a reduction in inflammation. Partially, inflammatory activation appears to be caused by serum-inherent TLR4 ligands which were absent in 6-month OFT sera, as evaluated by nitric oxide determination in BV-2 microglia. Serum from 6-month OFT treatment patients indirectly protected against myelin disintegration and supported oligodendrocyte survival during LPC-induced demyelination. This protection correlated with reduced astrogliosis and a shift in microglial polarization towards an anti-inflammatory phenotype, characterized by decreased nitric oxide and cytokine production, and increased arginase-1 and IL-10 levels.

Depletion of CD20 positive cells via OFT appears to indirectly prevent demyelination by modulating microglial polarization. This is linked to reduced serum cytokines and absence of serum-inherent TLR4 ligands post-treatment, suggesting a potential peripheral immunomodulation-mediated protective mechanism impacting CNS immune responses. These findings underscore the need to investigate how therapies targeting peripheral immune cells can also influence CNS immune mechanisms.