Author Of 2 Presentations
P0404 - The Bruton’s tyrosine kinase inhibitor evobrutinib ameliorates meningeal inflammation in experimental autoimmune encephalomyelitis (ID 1354)
Abstract
Background
Leptomeningeal inflammation in multiple sclerosis (MS) is associated with worse clinical outcomes and greater cortical pathology. Both B cells and myeloid cells are found in areas of meningeal inflammation. We previously demonstrated that, in the relapsing–remitting encephalomyelitis (EAE) model in SJL mice, ultra-high field contrast-enhanced magnetic resonance imaging (MRI) could identify and track areas of meningeal inflammation. Bruton’s tyrosine kinase (BTK) mediates signaling through B cell receptor and Fc receptor pathways and leads to B cell and myeloid cell activation. We therefore hypothesized that a BTK inhibitor could target meningeal inflammation in EAE.
Objectives
To test the effect of evobrutinib, a highly selective BTK inhibitor, as a potential therapy targeting meningeal inflammation in a mouse model of MS.
Methods
We immunized 7- to 8-week-old female SJL/J mice with proteolipid protein 139–151 peptide and complete Freund’s adjuvant to induce EAE. Animals were weighed and disease severity was scored starting at 7 days post-immunization; at 6 weeks they underwent Gadolinium-enhanced MRI. Mice demonstrating the presence of meningeal contrast enhancement were randomized to receive daily oral doses by gavage of evobrutinib (10 mg/kg) or vehicle control between Weeks 6–10 post-immunization. MRI was repeated at Weeks 8 and 10 to assess meningeal inflammation, and brain tissues were collected for histopathological analysis.
Results
At baseline, both vehicle (n=16) and evobrutinib (n=19) groups had a similar number of areas of meningeal contrast enhancement (median: 10.5 vs 11; p=0.25). Following treatment, a greater reduction in the number of areas of meningeal contrast enhancement was identified in the evobrutinib group vs the vehicle group (median change: -3 vs 0.5; p=0.003). A significant decrease in B cells in areas of meningeal inflammation in the evobrutinib group compared to the vehicle group was noted. Also, astrocytosis in the adjacent cortex was reduced in the evobrutinib group compared with vehicle.
Conclusions
An amelioration of established meningeal inflammation, as assessed by imaging and pathological measures, in a relapsing–remitting EAE model was observed with evobrutinib treatment, suggesting the potential utility of this agent to target this phenomenon in MS patients.
P0962 - Expression of Bruton’s tyrosine kinase in B cell-rich meningeal infiltrates in two models of progressive MS (ID 1391)
Abstract
Background
The success of anti-CD20 therapies has emphasized the important contribution of B cells to the disease process in MS. Indeed, B cells sequestered in the central nervous system (CNS), including the ones forming organized leptomeningeal aggregates, are suspected to be a source of underlying progressive disease activity in MS. Their presence, when associated with adjacent subpial cortical pathology, is predictive of an aggressive disease course with rapid, unrelenting progression of disability. Yet CNS B cells are protected from the direct effects of anti-CD20 therapies. An alternative approach is to target the inflammatory process in the CNS by inhibiting Bruton’s tyrosine kinase (BTK), an enzyme critically involved in B cell activation and survival, but also expressed by macrophages and microglia. BTK inhibitors are small molecules potentially able to enter the CNS, that have the capacity to restrict peripheral and CNS-compartmentalized B cell responses.
Objectives
Here, we investigated the expression pattern of BTK in brain tissue from a spontaneous naturally-occurring canine neuroinflammatory disease (granulomatous meningoencephalomyelitis, GME), and from a murine experimental autoimmune encephalomyelitis (EAE) model, with both recapitulating determining aspects of progressive MS pathology.
Methods
To this end, we studied CNS samples from GME (n=9) and EAE (n=6) cases by immunofluorescent/confocal analysis of leptomeningeal and parenchymal areas affected by the neuroinflammatory process.
Results
Our analysis reveals both models are characterized by prominent B cell infiltrates in the leptomeninges that associate with submeningeal injury in the underlying parenchymal tissue. These injurious changes are reminiscent of the subpial neuropathology characteristic of MS. In both models, we found robust BTK expression within CD20+ B cell-rich leptomeningeal infiltrates. Meningeal B cell infiltration extended into the parenchymal tissue via the Virchow Robin spaces of penetrating vessels. BTK expression was also detected in B cells within these spaces and in cells moving from the perivascular space into the parenchymal tissue. In GME, BTK was also detected in microglia/macrophages in leptomeningeal infiltrates and in the neighboring parenchyma.
Conclusions
The prominent expression of BTK in leptomeningeal and perivascular B-cell rich infiltrates underscores its value as a potential candidate to target CNS compartmentalized immune responses thought to drive the progression of disability seen in MS.