scholarly journals c-Jun N-Terminal Kinase as a Therapeutic Target in Experimental Autoimmune Encephalomyelitis

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2154
Author(s):  
Maud Bagnoud ◽  
Myriam Briner ◽  
Jana Remlinger ◽  
Ivo Meli ◽  
Sara Schuetz ◽  
...  
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cell ◽  
Disease Onset ◽  
Autoimmune Encephalomyelitis ◽  
Necrosis Factor Alpha ◽  
Experimental Autoimmune

c-Jun N-terminal kinase (JNK) is upregulated during multiple sclerosis relapses and at the peak of experimental autoimmune encephalomyelitis (EAE). We aim to investigate the effects of pharmacological pan-JNK inhibition on the course of myelin oligodendrocyte glycoprotein (MOG35-55) EAE disease using in vivo and in vitro experimental models. EAE was induced in female C57BL/6JRj wild type mice using MOG35-55. SP600125 (SP), a reversible adenosine triphosphate competitive pan-JNK inhibitor, was then given orally after disease onset. Positive correlation between SP plasma and brain concentration was observed. Nine, but not three, consecutive days of SP treatment led to a significant dose-dependent decrease of mean cumulative MOG35-55 EAE severity that was associated with increased mRNA expression of interferon gamma (INF-γ) and tumor necrosis factor alpha (TNF-α) in the spinal cord. On a histological level, reduced spinal cord immune cell-infiltration predominantly of CD3+ T cells as well as increased activity of Iba1+ cells were observed in treated animals. In addition, in vitro incubation of murine and human CD3+ T cells with SP resulted in reduced T cell apoptosis and proliferation. In conclusion, our study demonstrates that pharmacological pan-JNK inhibition might be a treatment strategy for autoimmune central nervous system demyelination.

scholarly journals Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice through inducing apoptosis of CD4+ T cells

2020 ◽  
Author(s):  
Ke An ◽  
Mengjiao Xue ◽  
Jiaying Zhong ◽  
Shengnan Yu ◽  
Zhongquan Qi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Arsenic Trioxide ◽  
Microglia Activation ◽  
Autoimmune Encephalomyelitis ◽  
Post Immunization ◽  
Experimental Autoimmune

Abstract Background: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by severe demyelination of white matter. There is no definite cure for MS owing to its complex pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an ideal animal model for the study of MS. Arsenic trioxide (ATO) is an ancient Chinese medicine used for its therapeutic properties for several autoimmune diseases. It is also used to inhibit acute immune rejection due to its anti-inflammatory and immunosuppressive properties. However, it is unclear whether ATO has a therapeutic effect on EAE, and the underlying mechanisms have not been clearly elucidated. In this study, we attempted to explore the possibility of using ATO to ameliorate EAE in mice.Methods: ATO (0.5 mg/kg/day) was administered intraperitoneally to EAE mice 10 days post-immunization for 8 days. On day 22 post-immunization, the spinal cord, spleen, and blood were collected to analyze demyelination, inflammation, microglia activation, and proportion of CD4+ T cells. In vitro, for mechanistic studies, CD4+ T cells were sorted from the spleen of naïve C57BL/6 mice and treated with ATO and then used for apoptosis assay, JC-1 staining, transmission electron microscope, and western blotting.Results: ATO delayed the onset of EAE and alleviated the severity of EAE in mice. Treatment with ATO also attenuated demyelination, alleviated inflammation, reduced microglia activation and decreased the expression of IL-2, IFN-γ, IL-1β, IL-6, and TNF-α in EAE mice. Moreover, the number and proportion of CD4+ T cells in the spinal cord, spleen, and peripheral blood were reduced in ATO-treated EAE mice. Finally, ATO induced CD4+ T cells apoptosis through the mitochondrial pathway both in vitro and in vivo. Additionally, the administration of ATO had no adverse effect on the heart, liver, and kidney function and did not induce apoptosis in the spinal cord.Conclusions: Overall, our findings indicated that ATO plays a protective role in the initiation and progression of EAE and has the potential to be a novel drug in the treatment of MS.

scholarly journals Modification of the Disease Progression in Mice with Experimental Autoimmune Encephalomyelitis Using Anti-Mitotic Compounds

2021 ◽  
Author(s):  
◽  
Kevin Patrick Crume
Keyword(s):  
Nitric Oxide ◽  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Onset ◽  
Autoimmune Response ◽  
Peloruside A ◽  
Proliferating Cells ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

<p>Multiple sclerosis (MS) is a multi-faceted disease, and is believed to be caused by an autoimmune response to myelin antigens in the central nervous system. Experimental autoimmune encephalomyelitis (EAE), an animal model for MS. manifests itself in various forms that parallel many aspects of MS, including the appearance of symptoms, initiation events, and pathophysiology. The hallmark of any immune response is the antigen-specific proliferation of immune cells, and during the initiation events of EAE, proliferating CD4+ T cells are the primary mediators of disease. This thesis explores if targeting these proliferating cells with the anti-mitotic compounds paclitaxel and peloruside A can delay or prevent the unset of EAE, thus providing a novel therapeutic avenue for MS research. The anti-cancer compound, paclitaxel, is an anti-mitotic drug that prevents microtubule depolymerisation. Although paclitaxel has been used in the clinical setting to treat cancer for over a decade, it has been determined that paclitaxel stimulates murine toll-like receptor 4 (TLR4) complex, which is the major LPS receptor. A novel microtubule-stabilising compound, peloruside, is currently subject to intensive investigations due to its functional similarity to paclitaxel. The results from this project found that peloruside and paclitaxel inhibited the proliferation of mitogen-stimulated splenocytes with IC50 values of 83 nM and 30 nM, respectively, but did not affect the viability of non-proliferating cells In contrast to paclitaxel, peloruside did not cause the TLR4-mediated production of the inflammatory mediators. TNF-epsilon, IL-12, and nitric oxide, when cultured with IFN-epsilon stimulated murine macrophages. Interestingly, when LPS was included with either paclitaxel or peloruside A, both drugs decreased the production of TNF-e and nitric oxide from macrophages, suggesting that microtubule-stabilising compounds may have anti-inflammatory effects. To identify any immunomodifying effects of paclitaxel in vivo, paclitaxel was administered to mice that were immunised with the myelin protein MOG in complete Freund's adjuvant (CFA) to induce EAE. When Taxol was administered to mice for 5 consecutive days immediately following CFA/MOG immunisation, the onset of EAE was delayed by approximately I week. Moreover, the administration of peloruside following the same treatment regime also resulted in a similar delay of disease onset. Taxol treatments, however, lead to significant mortality in immunised, but not unimmunised mice. Interestingly, although Taxol is an anti-mitotic drug, the proliferation of antigen-specific T cells was not inhibited in vivo by the Taxol treatment. The findings revealed in this thesis present an opportunity to pursue a new avenue of research for the therapeutic treatment of MS sufferers, and possibly other inflammatory autoimmune disorders.</p>

scholarly journals Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis

2005 ◽  
Vol 202 (3) ◽  
pp. 445-455 ◽  
Author(s):  
Niklas Beyersdorf ◽  
Stefanie Gaupp ◽  
Karen Balbach ◽  
Jens Schmidt ◽  
Klaus V. Toyka ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Cell Subset ◽  
High Dose ◽  
Autoimmune Encephalomyelitis ◽  
Lewis Rats ◽  
Experimental Autoimmune

CD4+CD25+ regulatory T cells (T reg cells) play a key role in controlling autoimmunity and inflammation. Therefore, therapeutic agents that are capable of elevating numbers or increasing effector functions of this T cell subset are highly desirable. In a previous report we showed that a superagonistic monoclonal antibody specific for rat CD28 (JJ316) expands and activates T reg cells in vivo and upon short-term in vitro culture. Here we demonstrate that application of very low dosages of the CD28 superagonist into normal Lewis rats is sufficient to induce T reg cell expansion in vivo without the generalized lymphocytosis observed with high dosages of JJ316. Single i.v. administration of a low dose of the CD28 superagonist into Dark Agouti (DA) rats or Lewis rats that suffered from experimental autoimmune encephalomyelitis (EAE) proved to be highly and equally efficacious as high-dose treatment. Finally, we show that T reg cells that were isolated from CD28-treated animals displayed enhanced suppressive activity toward myelin basic protein–specific T cells in vitro, and, upon adoptive transfer, protected recipients from EAE. Our data indicate that this class of CD28-specific monoclonal antibodies targets CD4+CD25+ T reg cells and provides a novel means for the effective treatment of multiple sclerosis and other autoimmune diseases.

scholarly journals Modification of the Disease Progression in Mice with Experimental Autoimmune Encephalomyelitis Using Anti-Mitotic Compounds

2021 ◽  
Author(s):  
◽  
Kevin Patrick Crume
Keyword(s):  
Nitric Oxide ◽  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Disease Onset ◽  
Autoimmune Response ◽  
Peloruside A ◽  
Proliferating Cells ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

<p>Multiple sclerosis (MS) is a multi-faceted disease, and is believed to be caused by an autoimmune response to myelin antigens in the central nervous system. Experimental autoimmune encephalomyelitis (EAE), an animal model for MS. manifests itself in various forms that parallel many aspects of MS, including the appearance of symptoms, initiation events, and pathophysiology. The hallmark of any immune response is the antigen-specific proliferation of immune cells, and during the initiation events of EAE, proliferating CD4+ T cells are the primary mediators of disease. This thesis explores if targeting these proliferating cells with the anti-mitotic compounds paclitaxel and peloruside A can delay or prevent the unset of EAE, thus providing a novel therapeutic avenue for MS research. The anti-cancer compound, paclitaxel, is an anti-mitotic drug that prevents microtubule depolymerisation. Although paclitaxel has been used in the clinical setting to treat cancer for over a decade, it has been determined that paclitaxel stimulates murine toll-like receptor 4 (TLR4) complex, which is the major LPS receptor. A novel microtubule-stabilising compound, peloruside, is currently subject to intensive investigations due to its functional similarity to paclitaxel. The results from this project found that peloruside and paclitaxel inhibited the proliferation of mitogen-stimulated splenocytes with IC50 values of 83 nM and 30 nM, respectively, but did not affect the viability of non-proliferating cells In contrast to paclitaxel, peloruside did not cause the TLR4-mediated production of the inflammatory mediators. TNF-epsilon, IL-12, and nitric oxide, when cultured with IFN-epsilon stimulated murine macrophages. Interestingly, when LPS was included with either paclitaxel or peloruside A, both drugs decreased the production of TNF-e and nitric oxide from macrophages, suggesting that microtubule-stabilising compounds may have anti-inflammatory effects. To identify any immunomodifying effects of paclitaxel in vivo, paclitaxel was administered to mice that were immunised with the myelin protein MOG in complete Freund's adjuvant (CFA) to induce EAE. When Taxol was administered to mice for 5 consecutive days immediately following CFA/MOG immunisation, the onset of EAE was delayed by approximately I week. Moreover, the administration of peloruside following the same treatment regime also resulted in a similar delay of disease onset. Taxol treatments, however, lead to significant mortality in immunised, but not unimmunised mice. Interestingly, although Taxol is an anti-mitotic drug, the proliferation of antigen-specific T cells was not inhibited in vivo by the Taxol treatment. The findings revealed in this thesis present an opportunity to pursue a new avenue of research for the therapeutic treatment of MS sufferers, and possibly other inflammatory autoimmune disorders.</p>

Interferon-β is a key regulator of proinflammatory events in experimental autoimmune encephalomyelitis

2010 ◽  
Vol 16 (12) ◽  
pp. 1458-1473 ◽  
Author(s):  
CL Galligan ◽  
LM Pennell ◽  
TT Murooka ◽  
E Baig ◽  
B Majchrzak-Kita ◽  
...  
Keyword(s):  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Lymph Nodes ◽  
Th17 Cells ◽  
Cell Activation ◽  
Immune Cell ◽  
Disease Onset ◽  
Rapid Progression ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Background: Interferon (IFN)-β is an effective therapy for relapsing-remitting multiple sclerosis, yet its mechanism of action remains ill-defined. Objectives: Our objective was to characterize the role of IFN-β in immune regulation in experimental autoimmune encephalomyelitis (EAE). Methods: IFN-β +/+ and IFN-β—/— mice were immunized with myelin oligodendrocyte glycoprotein peptide in the presence or absence of IFN-β, to induce EAE. Disease pathogenesis was monitored in the context of incidence, time of onset, clinical score, and immune cell activation in the brains, spleens and lymph nodes of affected mice. Results: Compared with IFN-β+/+ mice, IFN-β—/ — mice exhibited an earlier onset and a more rapid progression of EAE, increased numbers of CD11b+ leukocytes infiltrating affected brains and an increased percentage of Th17 cells in the central nervous system and draining lymph nodes. IFN-β treatment delayed disease onset and reduced disease severity. Ex vivo experiments revealed that the lack of IFN-β results in enhanced generation of autoreactive T cells, a likely consequence of the absence of IFN-β-regulated events in both the CD4+ T cells and antigen-presenting dendritic cells. Gene expression analysis of IFN-β-treated bone marrow macrophages (CD11b +) identified modulation of genes affecting T cell proliferation and Th17 differentiation. Conclusions: We conclude that IFN-β acts to suppress the generation of autoimmune-inducing Th17 cells during the development of disease as well as modulating pro-inflammatory mediators.

scholarly journals Attenuation in Nicotinic Acetylcholine Receptor α9 and α10 Subunit Double Knock-Out Mice of Experimental Autoimmune Encephalomyelitis

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 827 ◽  
Author(s):  
Qiang Liu ◽  
Minshu Li ◽  
Paul Whiteaker ◽  
Fu-Dong Shi ◽  
Barbara J. Morley ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Immune Cell ◽  
Autoimmune Encephalomyelitis ◽  
Nicotinic Acetylcholine ◽  
Knock Out ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is attenuated in nicotinic acetylcholine receptor (nAChR) α9 subunit knock-out (α9 KO) mice. However, protection is incomplete, raising questions about roles for related, nAChR α10 subunits in ionotropic or recently-revealed metabotropic contributions to effects. Here, we demonstrate reduced EAE severity and delayed onset of disease signs in nAChR α9/α10 subunit double knock-out (DKO) animals relative to effects in wild-type (WT) control mice. These effects are indistinguishable from contemporaneously-observed effects in nicotine-treated WT or in α9 KO mice. Immune cell infiltration into the spinal cord and brain, reactive oxygen species levels in vivo, and demyelination, mostly in the spinal cord, are reduced in DKO mice. Disease severity is not altered relative to WT controls in mice harboring a gain-of-function mutation in α9 subunits. These findings minimize the likelihood that additional deletion of nAChR α10 subunits impacts disease differently than α9 KO alone, whether through ionotropic, metabotropic, or alternative mechanisms. Moreover, our results provide further evidence of disease-exacerbating roles for nAChR containing α9 subunits (α9*-nAChR) in EAE inflammatory and autoimmune responses. This supports our hypothesis that α9*-nAChR or their downstream mediators are attractive targets for attenuation of inflammation and autoimmunity.

scholarly journals Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice by inducing CD4+ T cell apoptosis

2020 ◽  
Author(s):  
Ke An ◽  
Mengjiao Xue ◽  
Jiaying Zhong ◽  
Shengnan Yu ◽  
Tianshu Lan ◽  
...  
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Arsenic Trioxide ◽  
Cell Apoptosis ◽  
Autoimmune Encephalomyelitis ◽  
T Cell Apoptosis ◽  
Experimental Autoimmune

Abstract Background: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by severe white matter demyelination. Because of its complex pathogenesis, there is no definite cure for MS. Experimental autoimmune encephalomyelitis (EAE) is an ideal animal model for the study of MS. Arsenic trioxide (ATO) is an ancient Chinese medicine used for its therapeutic properties with several autoimmune diseases. It is also used to inhibit acute immune rejection due to its anti-inflammatory and immunosuppressive properties. However, it is unclear whether ATO has a therapeutic effect on EAE, and the underlying mechanisms have not yet been clearly elucidated. In this study, we attempted to assess whether ATO could be used to ameliorate EAE in mice.Methods: ATO (0.5 mg/kg/day) was administered intraperitoneally to EAE mice 10 days post-immunization for 8 days. On day 22 post-immunization, the spinal cord, spleen, and blood were collected to analyze demyelination, inflammation, microglia activation, and the proportion of CD4+ T cells. In vitro, for mechanistic studies, CD4+ T cells were sorted from the spleen of naïve C57BL/6 mice and treated with ATO and then used for an apoptosis assay, JC-1 staining, imaging under a transmission electron microscope, and western blotting.Results: ATO delayed the onset of EAE and alleviated the severity of EAE in mice. Treatment with ATO also attenuated demyelination, alleviated inflammation, reduced microglia activation and decreased the expression levels of IL-2, IFN-γ, IL-1β, IL-6, and TNF-α in EAE mice. Moreover, the number and proportion of CD4+ T cells in the spinal cord, spleen, and peripheral blood were reduced in ATO-treated EAE mice. Finally, ATO induced CD4+ T cell apoptosis via the mitochondrial pathway both in vitro and in vivo. Additionally, the administration of ATO had no adverse effect on the heart, liver, or kidney function, nor did it induce apoptosis in the spinal cord.Conclusions: Overall, our findings indicated that ATO plays a protective role in the initiation and progression of EAE and has the potential to be a novel drug in the treatment of MS.

scholarly journals Arsenic trioxide ameliorates experimental autoimmune encephalomyelitis in C57BL/6 mice through inducing apoptosis of CD4+ T cells

2020 ◽  
Author(s):  
Ke An ◽  
Mengjiao Xue ◽  
Jiaying Zhong ◽  
Shengnan Yu ◽  
Zhongquan Qi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Arsenic Trioxide ◽  
Cd4 T Cells ◽  
Microglia Activation ◽  
Autoimmune Encephalomyelitis ◽  
Post Immunization ◽  
Experimental Autoimmune

Abstract Background: Multiple sclerosis (MS) is an autoimmune disease of central nervous system characterized by severe demyelination of white matter. There is still no definite cure for MS because of its complex pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an ideal animal model for the study of MS. Arsenic trioxide (ATO) is an ancient Chinese medicine that is used as a therapeutic application for many autoimmune diseases. It is also used to inhibit acute immune rejection because of its anti-inflammatory and immunosuppressive properties. However, it is unclear if ATO has a curative effect on EAE, and the underlying mechanisms have not been clearly elucidated. In this study, we attempted to explore the possibility of using ATO to ameliorate EAE in mice. Methods: ATO (0.5 mg/kg/day) was administered intraperitoneally to EAE mice 10 days post-immunization for 8 days. On day 22 post-immunization, the spinal cord, spleen, and blood were collected to analyze demyelination, inflammation, microglia activation, and proportion of CD4 + T cells. In vitro , to further investigate the mechanism that underly the ameliorating effects of ATO in EAE mice, CD4 + T cells were traeted with ATO and then used for apoptosis assay, JC-1 staining, transmission electron microscope, and western bloting. Results: We found that ATO alleviated the severity of EAE in mice. Treatment with ATO also attenuated demyelination, alleviated inflammation, reduced microglia activation and decreased the expression of IL-2, IFN-γ, IL-1β, IL-6, and TNF-α in EAE mice. Moreover, the number and proportion of CD4 + T cells in the spinal cord, spleen, and peripheral blood were reduced in ATO-treated EAE mice. Finally, ATO induced CD4 + T cells apoptosis through the mitochondrial pathway both in vitro and in vivo . Additionally, the administration of ATO had no adverse effect on liver and kidney function and did not induce apoptosis in the spinal cord. Conclusions: Overall, our findings indicated that ATO plays a protective role in the initiation and progression of EAE and has the potential to be a novel drug in the treatment of MS.

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