Siponimod Inhibits the Formation of Meningeal Ectopic Lymphoid Tissue in Experimental Autoimmune Encephalomyelitis

Brand, Rosa Margareta; Diddens, Jolien; Friedrich, Verena; Pfaller, Monika; Radbruch, Helena; Hemmer, Bernhard; Steiger, Katja; Lehmann‐Horn, Klaus

doi:10.1212/nxi.0000000000001117

Cited by 17 publications

(9 citation statements)

References 30 publications

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“…Numerous studies using anti-CD20 antibodies and other drugs [ 52 , 58 , 59 , 60 ] have shown that early treatment (before EAE onset or at the time point of EAE onset) typically prevents or significantly diminishes EAE development onset. This is not surprising because early interference with the immune response induced by immunization also affects the later development of CNS pathology.…”

Section: Discussionmentioning

confidence: 99%

Effects of a Fully Humanized Type II Anti-CD20 Monoclonal Antibody on Peripheral and CNS B Cells in a Transgenic Mouse Model of Multiple Sclerosis

Tacke

Chunder

Schropp

et al. 2022

IJMS

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Successful therapy with anti-CD20 monoclonal antibodies (mAbs) has reinforced the key role of B cells in the immunopathology of multiple sclerosis (MS). This study aimed to determine the effects of a novel class of anti-CD20 mAbs on vascular and extravascular central nervous system (CNS)-infiltrating B cells in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Male hCD20xhIgR3 mice and wild-type C57BL/6 (B6) mice were immunized with human myelin oligodendrocyte glycoprotein (MOG)1–125 to induce EAE. While hCD20xhIgR3 mice were injected intravenously with an anti-human CD20 mAb (5 mg/kg) (rituximab (a type I anti-CD20 mAb) or obinutuzumab (a type II anti-CD20 mAb), B6 mice received the anti-mouse CD20 antibody 18B12. Neither mAb affected clinical disease or serum antibody levels. Obinutuzumab and rituximab had an impact on splenic and CNS-infiltrated B cells with slightly differential depletion efficacy. Additionally, obinutuzumab had beneficial effects on spinal cord myelination. B cell depletion rates in the 18B12/B6 model were comparable with those observed in obinutuzumab-treated hCD20xhIgR3 mice. Our results demonstrate the usefulness of anti-CD20 mAbs for the modulation of B cell-driven peripheral immune response and CNS pathology, with type II antibodies potentially being superior to type I in the depletion of tissue-infiltrating B cells.

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Section: Discussionmentioning

confidence: 99%

Effects of a Fully Humanized Type II Anti-CD20 Monoclonal Antibody on Peripheral and CNS B Cells in a Transgenic Mouse Model of Multiple Sclerosis

Tacke

Chunder

Schropp

et al. 2022

IJMS

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“…This small molecule can also cross the BBB and reach the CNS parenchyma as well as the meninges, thereby it could block lymphocyte migration to the meningeal compartment. Siponimod reduced EAE severity and halted the formation of meningeal ectopic lymphoid follicles [ 146 ]. It is still under debate if the reduction of this meningeal compartmentalized inflammation is enough to reduce the clinical symptoms of progressive MS, or if in the case of siponimod, other secondary effects have roles.…”

Section: Effects Of Ms Therapies On B Cell Migrationmentioning

confidence: 99%

Breaching Brain Barriers: B Cell Migration in Multiple Sclerosis

et al. 2022

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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) known for the manifestation of demyelinated lesions throughout the CNS, leading to neurodegeneration. To date, not all pathological mechanisms that drive disease progression are known, but the clinical benefits of anti-CD20 therapies have put B cells in the spotlight of MS research. Besides their pathological effects in the periphery in MS, B cells gain access to the CNS where they can contribute to disease pathogenesis. Specifically, B cells accumulate in perivascular infiltrates in the brain parenchyma and the subarachnoid spaces of the meninges, but are virtually absent from the choroid plexus. Hence, the possible migration of B cells over the blood–brain-, blood–meningeal-, and blood–cerebrospinal fluid (CSF) barriers appears to be a crucial step to understanding B cell-mediated pathology. To gain more insight into the molecular mechanisms that regulate B cell trafficking into the brain, we here provide a comprehensive overview of the different CNS barriers in health and in MS and how they translate into different routes for B cell migration. In addition, we review the mechanisms of action of diverse therapies that deplete peripheral B cells and/or block B cell migration into the CNS. Importantly, this review shows that studying the different routes of how B cells enter the inflamed CNS should be the next step to understanding this disease.

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“…Interestingly the DMT siponimod, which is licenced for SPMS, was found to reduce the formation of meningeal lymphoid structures in a mouse model of EAE [ 138 ]. It was observed that when siponimod was administered prior to EAE onset, formation of TLS was reduced.…”

Section: Therapeutic Strategies Targeting Meningeal Inflammation and Tlsmentioning

confidence: 99%

A Review of Compartmentalised Inflammation and Tertiary Lymphoid Structures in the Pathophysiology of Multiple Sclerosis

et al. 2022

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Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease of the central nervous system (CNS). The most common form of MS is a relapsing–remitting disease characterised by acute episodes of demyelination associated with the breakdown of the blood–brain barrier (BBB). In the relapsing–remitting phase there is often relative recovery (remission) from relapses characterised clinically by complete or partial resolution of neurological symptoms. In the later and progressive stages of the disease process, accrual of neurological disability occurs in a pathological process independent of acute episodes of demyelination and is accompanied by a trapped or compartmentalised inflammatory response, most notable in the connective tissue spaces of the vasculature and leptomeninges occurring behind an intact BBB. This review focuses on compartmentalised inflammation in MS and in particular, what we know about meningeal tertiary lymphoid structures (TLS; also called B cell follicles) which are organised clusters of immune cells, associated with more severe and progressive forms of MS. Meningeal inflammation and TLS could represent an important fluid or imaging marker of disease activity, whose therapeutic abrogation might be necessary to stop the most severe outcomes of disease.

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Siponimod Inhibits the Formation of Meningeal Ectopic Lymphoid Tissue in Experimental Autoimmune Encephalomyelitis

Cited by 17 publications

References 30 publications

Effects of a Fully Humanized Type II Anti-CD20 Monoclonal Antibody on Peripheral and CNS B Cells in a Transgenic Mouse Model of Multiple Sclerosis

Effects of a Fully Humanized Type II Anti-CD20 Monoclonal Antibody on Peripheral and CNS B Cells in a Transgenic Mouse Model of Multiple Sclerosis

Breaching Brain Barriers: B Cell Migration in Multiple Sclerosis

A Review of Compartmentalised Inflammation and Tertiary Lymphoid Structures in the Pathophysiology of Multiple Sclerosis

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