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B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets.

ABSTRACT: Increasing recognition of the role of B cells in the adaptive immune response makes B cells an important therapeutic target in autoimmunity. Numerous current and developmental immunotherapies target B cells for elimination through recognition of cell-surface proteins expressed specifically on B cells, in particular CD19 and CD20. Similarities and differences in the function and expression of these two molecules predict some shared, and some distinct, pharmacological effects of agents targeting CD19 versus CD20, potentially leading to differences in the clinical safety and efficacy of such agents. Here, we review current knowledge of CD19 and CD20 function and biology, survey current and developmental therapies that target these molecules, and discuss potential differences in elimination of B cells by drugs that target CD19 versus CD20, with particular focus on the central nervous system autoimmune diseases multiple sclerosis and neuromyelitis optica. The principles and mechanisms herein discussed might also be relevant to a variety of other nervous system autoimmune disorders, including NMDA (N-methyl-D-aspartate) receptor encephalitis, transverse myelitis and myasthenia gravis.

SUBMITTER: Forsthuber TG

PROVIDER: S-EPMC5865455 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets.

Forsthuber Thomas G TG Cimbora Daniel M DM Ratchford John Nolan JN Katz Eliezer E Stüve Olaf O

Therapeutic advances in neurological disorders 20180321

Increasing recognition of the role of B cells in the adaptive immune response makes B cells an important therapeutic target in autoimmunity. Numerous current and developmental immunotherapies target B cells for elimination through recognition of cell-surface proteins expressed specifically on B cells, in particular CD19 and CD20. Similarities and differences in the function and expression of these two molecules predict some shared, and some distinct, pharmacological effects of agents targeting C ...[more]

PMID: 29593838

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Project description:Leptomeningeal inflammation in multiple sclerosis is associated with worse clinical outcomes and greater cortical pathology. Despite progress in identifying this process in multiple sclerosis patients using post-contrast fluid-attenuated inversion recovery imaging, early trials attempting to target meningeal inflammation have been unsuccessful. There is a lack of appropriate model systems to screen potential therapeutic agents targeting meningeal inflammation. We utilized ultra-high field (11.7 T) MRI to perform post-contrast imaging in SJL/J mice with experimental autoimmune encephalomyelitis induced via immunization with proteolipid protein peptide (PLP139-151) and complete Freund's adjuvant. Imaging was performed in both a cross-sectional and longitudinal fashion at time points ranging from 2 to 14 weeks post-immunization. Following imaging, we euthanized animals and collected tissue for pathological evaluation, which revealed dense cellular infiltrates corresponding to areas of contrast enhancement involving the leptomeninges. These areas of meningeal inflammation contained B cells (B220+), T cells (CD3+) and myeloid cells (Mac2+). We also noted features consistent with tertiary lymphoid tissue within these areas, namely the presence of peripheral node addressin-positive structures, C-X-C motif chemokine ligand-13 (CXCL13)-producing cells and FDC-M1+ follicular dendritic cells. In the cortex adjacent to areas of meningeal inflammation we identified astrocytosis, microgliosis, demyelination and evidence of axonal stress/damage. Since areas of meningeal contrast enhancement persisted over several weeks in longitudinal experiments, we utilized this model to test the effects of a therapeutic intervention on established meningeal inflammation. We randomized mice with evidence of meningeal contrast enhancement on MRI scans performed at 6 weeks post-immunization, to treatment with either vehicle or evobrutinib [a Bruton tyrosine kinase (BTK) inhibitor] for a period of 4 weeks. These mice underwent serial imaging; we examined the effect of treatment on the areas of meningeal contrast enhancement and noted a significant reduction in the evobrutinib group compared to vehicle (30% reduction versus 5% increase; P = 0.003). We used ultra-high field MRI to identify areas of meningeal inflammation and to track them over time in SJL/J mice with experimental autoimmune encephalomyelitis, and then used this model to identify BTK inhibition as a novel therapeutic approach to target meningeal inflammation. The results of this study provide support for future studies in multiple sclerosis patients with imaging evidence of meningeal inflammation.

Dataset Information

B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets.

Publications

B cell-based therapies in CNS autoimmunity: differentiating CD19 and CD20 as therapeutic targets.

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