Experimental Autoimmune Encephalomyelitis in Mice

Terry, Rachael; Ifergan, Igal; Miller, Stephen D.

doi:10.1007/7651_2014_88

Cited by 62 publications

(55 citation statements)

References 58 publications

(17 reference statements)

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“…CNS-immune cells were isolated by Percoll gradient centrifugation from homogenized combined brain and spinal cords as previously described [20]. The numbers of cell subpopulations in the CNS were determined by multiplying the percentage of lineage marker—positive cells by the total number of mononuclear cells isolated from the CNS.…”

Section: Methodsmentioning

confidence: 99%

Targeting the GM-CSF receptor for the treatment of CNS autoimmunity

Ifergan

Davidson

Kébir

et al. 2017

Journal of Autoimmunity

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In multiple sclerosis (MS), there is a growing interest in inhibiting the pro-inflammatory effects of granulocyte-macrophage colony-stimulating factor (GM-CSF). We sought to evaluate the therapeutic potential and underlying mechanisms of GM-CSF receptor alpha (Rα) blockade in animal models of MS. We show that GM-CSF signaling inhibition at peak of chronic experimental autoimmune encephalomyelitis (EAE) results in amelioration of disease progression. Similarly, GM-CSF Rα blockade in relapsing-remitting (RR)-EAE model prevented disease relapses and inhibited T cell responses specific for both the inducing and spread myelin peptides, while reducing activation of mDCs and inflammatory monocytes. In situ immunostaining of lesions from human secondary progressive MS (SPMS), but not primary progressive MS patients shows extensive recruitment of GM-CSF Rα+ myeloid cells. Collectively, this study reveals a pivotal role of GM-CSF in disease relapses and the benefit of GM-CSF Rα blockade as a potential novel therapeutic approach for treatment of RRMS and SPMS.

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Section: Methodsmentioning

confidence: 99%

Targeting the GM-CSF receptor for the treatment of CNS autoimmunity

Ifergan

Davidson

Kébir

et al. 2017

Journal of Autoimmunity

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“…Spinal cords (SC) were harvested intact at disease peak and relapse by flushing the vertebral column with saline (37), then fixed in 4% paraformaldehyde overnight at 4°C. This method removes the meninges.…”

Section: Methodsmentioning

confidence: 99%

Cutting Edge: CD99 Is a Novel Therapeutic Target for Control of T Cell–Mediated Central Nervous System Autoimmune Disease

Winger

Harp

Chiang

et al. 2016

The Journal of Immunology

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Leukocyte trafficking into the central nervous system (CNS) is a prominent feature driving the immunopathogenesis of multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Blocking the recruitment of inflammatory leukocytes into the CNS represents an exploitable therapeutic target; however, the adhesion molecules that specifically regulate the step of leukocyte diapedesis into the CNS remain poorly understood. Here, we report that CD99 is critical for lymphocyte transmigration without affecting adhesion in a human blood-brain barrier model. CD99 blockade in vivo ameliorated EAE and decreased the accumulation of CNS inflammatory infiltrates, including dendritic cells, B-cells and CD4+ and CD8+ T-cells. Anti-CD99 therapy was effective when administered after onset of disease symptoms and blocked relapse when administered therapeutically after disease symptoms had recurred. These findings underscore an important role for CD99 in the pathogenesis of CNS autoimmunity and suggest it may serve as a novel therapeutic target for controlling neuroinflammation.

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“…Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory disease that leads to multifocal demyelination in the white matter of the human CNS with debilitating motor and sensory dysfunction (44, 45). Previous studies using EAE, a mouse model for MS, have shown that DCs play a critical role in initiation and development of CNS pathology through activation of effector T cells in the draining lymph nodes (DLN) and CNS (44, 45).…”

Section: Wnt/β-catenin Signaling In Dcs: a Potential Therapeutic Targmentioning

confidence: 99%

“…Previous studies using EAE, a mouse model for MS, have shown that DCs play a critical role in initiation and development of CNS pathology through activation of effector T cells in the draining lymph nodes (DLN) and CNS (44, 45). These studies have shown that DCs contribute to CNS pathology through differentiation and activation of naive CD4 + T cells to myelin-specific effector Th1 and Th17 cells (44, 46).…”

Section: Wnt/β-catenin Signaling In Dcs: a Potential Therapeutic Targmentioning

confidence: 99%

Modulation of Inflammatory Responses by Wnt/β-Catenin Signaling in Dendritic Cells: A Novel Immunotherapy Target for Autoimmunity and Cancer

et al. 2016

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The Wnt/β-catenin pathway is an evolutionarily conserved signaling pathway critical for several biological processes. An aberrant Wnt/β-catenin signaling is linked to several human diseases. Emerging studies have highlighted the regulatory role of the Wnt/β-catenin signaling pathway in normal physiological processes of parenchymal and hematopoietic cells. Recent studies have shown that the activation of Wnt/β-catenin pathway in dendritic cells (DCs) play a critical role in mucosal tolerance and suppression of chronic autoimmune pathologies. Alternatively, tumors activate Wnt/β-catenin pathway in DCs to induce immune tolerance and thereby evade antitumor immunity through suppression of effector T cell responses and promotion of regulatory T cell responses. Here, we review our work and current understanding of how Wnt/β-catenin signaling in DCs shapes the immune response in cancer and autoimmunity and discuss how Wnt/β-catenin pathway can be targeted for successful therapeutic interventions in various human diseases.

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Experimental Autoimmune Encephalomyelitis in Mice

Cited by 62 publications

References 58 publications

Targeting the GM-CSF receptor for the treatment of CNS autoimmunity

Targeting the GM-CSF receptor for the treatment of CNS autoimmunity

Cutting Edge: CD99 Is a Novel Therapeutic Target for Control of T Cell–Mediated Central Nervous System Autoimmune Disease

Modulation of Inflammatory Responses by Wnt/β-Catenin Signaling in Dendritic Cells: A Novel Immunotherapy Target for Autoimmunity and Cancer

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