Targeting CD52 does not affect murine neuron and microglia function

Ellwardt, Erik; Vogelaar, Christina Francisca; Maldet, Carlos; Schmaul, Samantha; Bittner, Stefan; Luchtman, Dirk

doi:10.1016/j.ejphar.2020.172923

Cited by 6 publications

(8 citation statements)

References 23 publications

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“…The number of studies on the effects of AZ on CNS cells is limited. In hippocampal slice cultures of EAE mice, the blockade of CD52 with anti-mouse CD52 antibody triggered microglia morphology towards a less ramified, and thus possibly more activated M1 phenotype [301], while this antibody did not affect neuronal Ca 2+ levels or neuroprotection against excitotoxicity [301]. To our knowledge, there are at present no reports describing the effect of AZ on astrocytes and oligodendrocytes, in culture or in in vivo animal models.…”

Section: Microglia Astrocytes Neurons and Oligodendrocytesmentioning

confidence: 86%

“…To our knowledge, there are at present no reports describing the effect of AZ on astrocytes and oligodendrocytes, in culture or in in vivo animal models. AZ may have beneficial effects on CNS-resident glial populations, since CD52 expression is mainly found on microglia, and to a lesser extent on astrocytes, and is upregulated following the in vitro LPS treatment of primary mouse microglia cells [301].…”

Section: Microglia Astrocytes Neurons and Oligodendrocytesmentioning

confidence: 99%

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Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Kleijn

Martens

2020

IJMS

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Multiple sclerosis (MS) is characterized by peripheral and central inflammatory features, as well as demyelination and neurodegeneration. The available Food and Drug Administration (FDA)-approved drugs for MS have been designed to suppress the peripheral immune system. In addition, however, the effects of these drugs may be partially attributed to their influence on glial cells and neurons of the central nervous system (CNS). We here describe the molecular effects of the traditional and more recent FDA-approved MS drugs Fingolimod, Dimethyl Fumarate, Glatiramer Acetate, Interferon-β, Teriflunomide, Laquinimod, Natalizumab, Alemtuzumab and Ocrelizumab on microglia, astrocytes, neurons and oligodendrocytes. Furthermore, we point to a possible common molecular effect of these drugs, namely a key role for NFκB signaling, causing a switch from pro-inflammatory microglia and astrocytes to anti-inflammatory phenotypes of these CNS cell types that recently emerged as central players in MS pathogenesis. This notion argues for the need to further explore the molecular mechanisms underlying MS drug action.

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Section: Microglia Astrocytes Neurons and Oligodendrocytesmentioning

confidence: 86%

Section: Microglia Astrocytes Neurons and Oligodendrocytesmentioning

confidence: 99%

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Kleijn

Martens

2020

IJMS

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“…Recently, it has been shown that alemtuzumab treatment almost completely depleted CNS infiltrates and B cell aggregates in the CNS of mice with myelin basic protein (MBP)-proteolipid protein (PLP)-induced EAE [24]. While the neuroprotective effects of alemtuzumab have been suggested, anti-CD52 treatment does not appear to affect microglia functions in EAE [25]. Overall, data from murine studies suggested that the beneficial effects of alemtuzumab in MS appear to be mediated exclusively by peripheral immune mechanisms.…”

Section: Alemtuzumab For the Treatment Of Ms: Preclinical Studies In mentioning

confidence: 99%

The Meaning of Immune Reconstitution after Alemtuzumab Therapy in Multiple Sclerosis

Rolla

Maglione

Mercanti

et al. 2020

Cells

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Alemtuzumab is a monoclonal antibody that binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. It is currently used as an immune reconstitution therapy in patients with relapsing–remitting multiple sclerosis. Alemtuzumab treatment is an intermittent infusion that induces long-term remission of Multiple Sclerosis also in the treatment-free period. After the robust T and B cell depletion induced by alemtuzumab, the immune system undergoes radical changes during its reconstitution. In this review, we will discuss the current knowledge on the reconstitution of the lymphocyte repertoire after alemtuzumab treatment and how it could affect the development of side effects, which led to its temporary suspension by the European Medical Agency.

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“…38 Of note, a recent study defined that systemic anti-CD52 mAb affects microglia morphology in the EAE model without perturbing their function. 24 We did not observe visual alterations in microglia morphology in our experiments. This discrepancy may reflect differences in the experimental design and tissue analysis (e.g.…”

Section: Discussionmentioning

confidence: 45%

CNS delivery of anti-CD52 antibodies modestly reduces disease severity in an animal model for multiple sclerosis

Bogie

Grajchen

Wouters

et al. 2020

Therapeutic Advances in Chronic Disease

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Background and aims: Alemtuzumab is a humanized monoclonal antibody that depletes CD52-bearing B and T lymphocytes. Clinical trials defined that systemic administration of alemtuzumab reduces disease severity in the relapsing–remitting phase of multiple sclerosis (MS). However, its efficacy in progressive MS patients is limited, which may reflect the inability of alemtuzumab to cross the reconstituted BBB in these patients. Objective: to study whether central nervous system (CNS) delivery of anti-CD52 antibodies reduces disease severity and the neuroinflammatory burden in the experimental autoimmune encephalomyelitis (EAE) model. Methods: Anti-CD52 antibodies were administered intrathecally during the acute and chronic phases of EAE. Flow cytometry and immunohistochemistry were utilized to define immunological and pathological parameters. Results: We show that subcutaneously administrated anti-CD52 antibodies completely abolish EAE disease severity. CNS delivery of anti-CD52 antibodies during both the acute and chronic phases of EAE moderately reduces disease severity and the neuroinflammatory burden. Our findings further suggest that CNS delivery of anti-CD52 antibodies impacts both the peripheral and CNS immune cell compartments in the EAE model but not in healthy mice. Conclusion: Collectively, our findings highlight the therapeutic potential of CNS delivery of alemtuzumab for the treatment of progressive as well as early MS.

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Targeting CD52 does not affect murine neuron and microglia function

Cited by 6 publications

References 23 publications

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

The Meaning of Immune Reconstitution after Alemtuzumab Therapy in Multiple Sclerosis

CNS delivery of anti-CD52 antibodies modestly reduces disease severity in an animal model for multiple sclerosis

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