Experimental autoimmune encephalomyelitis – achievements and prospective advances

Batoulis, Helena; Recks, Mascha S.; Addicks, Klaus; Küerten, Stefanie

doi:10.1111/j.1600-0463.2011.02794.x

Cited by 69 publications

(50 citation statements)

References 89 publications

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“…The most extensively used animal model of MS is experimental autoimmune encephalomyelitis (EAE), a T-cell-mediated autoimmune disease of the CNS in which inflammatory demyelination of the CNS induced by CD4 + T lymphocytes specific for CNS autoantigens such as myelin oligodendrocyte glycoprotein (MOG) occurs (3). EAE shares many histopathologic and immunologic characteristics with MS, and as such is considered a valuable model of the human disease (4).…”

mentioning

confidence: 99%

2-Methoxyestradiol inhibits experimental autoimmune encephalomyelitis through suppression of immune cell activation

Duncan

Brenner

Tusche

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The endogenous metabolite of estradiol, 2-Methoxyestradiol (2ME2), is an antimitotic and antiangiogenic cancer drug candidate that also exhibits disease-modifying activity in animal models of rheumatoid arthritis (RA). We found that 2ME2 dramatically suppresses development of mouse experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). 2ME2 inhibits in vitro lymphocyte activation, cytokine production, and proliferation in a dose-dependent fashion. 2ME2 treatment of lymphocytes specifically reduced the nuclear translocation and transcriptional activity of nuclear factor of activated T-cells (NFAT) c1, whereas NF-κB and activator protein 1 (AP-1) activation were not adversely affected. We therefore propose that 2ME2 attenuates EAE through disruption of the NFAT pathway and subsequent lymphocyte activation. By extension, our findings provide a molecular rationale for the use of 2ME2 as a tolerable oral immunomodulatory agent for the treatment of autoimmune disorders such as MS in humans.calcium signaling | autoimmunity

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mentioning

confidence: 99%

2-Methoxyestradiol inhibits experimental autoimmune encephalomyelitis through suppression of immune cell activation

Duncan

Brenner

Tusche

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…The MS-like disease animal model, experimental autoimmune encephalomyelitis (EAE), has provided invaluable information about the role of encephalitogenic T cells, antigen presentation, demyelination, and remyelination [4][5][6][7]. Although numerous T cell directed therapies significantly reduce disease severity in this model [8,9], T cell depletion with anti-CD3 and anti-CD4 monoclonal antibodies failed in clinical trials for MS [10,11].…”

Section: Introductionmentioning

confidence: 99%

B Cell Receptor Recognition of Glatiramer Acetate is Required for Efficacy through Antigen Presentation and Cytokine Production

Jackson

Selva²,

Niedzielko³

et al. 2014

J Clin Cell Immunol

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Multiple Sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) leading to neuronal demyelination, lack of remyelination, and axonal loss. If left untreated, patients inevitably suffer from severe cognitive, psychological and physical disabilities.Although not yet approved, B cell depletion achieved with anti-CD20 monoclonal antibodies is the most effective therapy to-date in MS patients. As this therapeutic depletes immune cells potentially important in pathogen immunity, an immense need remains for highly efficacious therapeutics maintaining a favorable safety profile. Even amongst the emergence of new therapeutic options for patients with MS, the myelin basic protein mimetic, Copaxone (glatiramer acetate, GA), remains the most commonly prescribed drug in the United States. As specific B cell depletion appears to be the most effective therapy for MS patients, the goal of this study was to further elucidate the mechanism of action of GA on B lymphocytes. Our studies show that GA directly interacts with human and murine B cell receptors (BCR) inducing the activation of B lymphocytes and BCR recognition of GA is required for efficacy in an animal model of MS. GA loaded B lymphocytes resulted in IL-2 production from CD4 + T cells suggesting B lymphocytes serve as an antigen presentation source for GA. In fifty-percent of the MS patients tested, GA stimulation reduced baseline levels of the pro-inflammatory cytokines IL-6 and TNFα in purified B lymphocytes, while other cytokines were not consistently altered. Taken together, this data suggests that the mechanism of action of GA on B lymphocytes includes the presentation of GA to T lymphocytes in the context of an anti-inflammatory cytokine milieu. The results from this study provide a strong foundation for future exploration of optimal Copaxone responders or synergistic combination therapies with an improved risk: benefit ratio compared to currently approved therapeutics for MS.

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“…It is characterized by myelin sheath loss and consequent axon and neuron injury [1] . Experimental autoimmune encephalomyelitis (EAE) shares many pathological and histological similarities with MS and is, therefore, widely used as a preclinical model of human disease [2,3] . Th1 cells have been considered as primary effector T cells that participate in the pathogenetic process of MS [4] .…”

Section: Introductionmentioning

confidence: 99%

Fasudil regulates T cell responses through polarization of BV-2 cells in mice experimental autoimmune encephalomyelitis

Chen

Zhang

et al. 2014

Acta Pharmacol Sin

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Aim: Fasudil, a selective Rho kinase (ROCK) inhibitor, has been shown to alleviate the severity of experimental autoimmune encephalomyelitis (EAE) via attenuating demyelination and neuroinflammation. The aim of this study was to investigate the effects of fasudil on interactions between macrophages/microglia and T cells in a mice EAE model. Methods: Mouse BV-2 microglia were treated with IFN-γ and fasudil. Cell viability was detected with MTT assay. BV-2 microglia polarization was analyzed using flow cytometry. Cytokines and other proteins were detected with ELISA and Western blotting, respectively. Mice were immunized with MOG 35-55 to induce EAE, and then treated with fasudil (40 mg/kg, ip) every other day from d 3 to d 27 pi. Encephalomyelitic T cells were prepared from the spleen of mice immunized with MOG 35-55 on d 9 pi. Results: Treatment of mouse BV-2 microglia with fasudil (15 μg/mL) induced significant phenotype polarization and functional plasticity, shifting M1 to M2 polarization. When co-cultured with the encephalomyelitic T cells, fasudil-treated BV-2 microglia significantly inhibited the proliferation of antigen-reactive T cells, and down-regulated IL-17-expressing CD4 + T cells and IL-17 production. Furthermore, fasudil-treated BV-2 microglia significantly up-regulated CD4 + CD25 high and CD4 + IL-10 + regulatory T cells (Tregs) and IL-10 production, suggesting that the encephalomyelitic T cells had converted to Tregs. In EAE mice, fasudil administration significantly decreased both CD11b + iNOS + and CD11b + TNF-α + M1 microglia, and increased CD11b + IL-10 + M2 microglia. Conclusion: Fasudil polarizes BV-2 microglia into M2 cells, which convert the encephalomyelitic T cells into Tregs in the mice EAE model.

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Experimental autoimmune encephalomyelitis – achievements and prospective advances

Cited by 69 publications

References 89 publications

2-Methoxyestradiol inhibits experimental autoimmune encephalomyelitis through suppression of immune cell activation

2-Methoxyestradiol inhibits experimental autoimmune encephalomyelitis through suppression of immune cell activation

B Cell Receptor Recognition of Glatiramer Acetate is Required for Efficacy through Antigen Presentation and Cytokine Production

Fasudil regulates T cell responses through polarization of BV-2 cells in mice experimental autoimmune encephalomyelitis

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