An antibody to CD40 ligand prevents meningeal B cell aggregates and mitigates progressive disease in a spontaneous mouse model of chronic multiple sclerosis

Meningeal tertiary lymphoid structures (TLS) represent an immune niche associated with histological signs of immunopathology, including demyelination in the adjacent CNS parenchyma. Here, we show that the opticospinal encephalomyelitis (OSE) mouse model, in which meningeal TLS develop spontaneously based on the interaction of myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor (TCR) transgenic T cells with MOG B cell receptor (BCR) transgenic B cells, recapitulates the dynamics and the histological features of meningeal TLS observed in human MS.

Based on scRNAseq data sets of meningeal TLS from OSE mice, the CD40L-CD40 pathway is highly active in the T cell-B cell interaction in this niche. Accordingly, a monoclonal antibody to CD40L, applied systemically, abrogates the T-B interaction in the systemic compartment and even more so in the meningeal compartment. This leads to near-complete clearance of meningeal TLS, concomitant with clinical improvement of the progressive disease phase of OSE mice.