scholarly journals IC100: A Novel Anti-Asc Monoclonal Antibody Improves Functional Outcomes In An Animal Model Of Multiple Sclerosis

2020 ◽  
Author(s):  
Haritha L Desu ◽  
Melanie Plastini ◽  
Placido Illiano ◽  
Helen M Bramlett ◽  
W. Dalton Dietrich ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Therapeutic Strategy ◽  
Immune Cell ◽  
Neurological Diseases ◽  
Inflammasome Activation ◽  
Autoimmune Encephalomyelitis ◽  
Promising Target ◽  
Eae Model ◽  
Experimental Autoimmune

Abstract Background The inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is involved in immune signaling by bridging the interactions between inflammasome sensors and caspase-1. Strong experimental evidence has shown that ASC-/- mice are protected from disease progression in animal models of multiple sclerosis (MS), suggesting that targeting inflammasome activation via ASC inhibition may be a promising therapeutic strategy in MS. Thus, the goal of our study is to test the efficacy of IC100, a novel humanized antibody targeting ASC, in preventing and/or suppressing disease in the experimental autoimmune encephalomyelitis (EAE) model of MS. Methods We employed the EAE model of MS where disease was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55). Mice were treated with vehicle or increasing doses of IC100 (10, 30 and 45 mg/kg) and clinical disease course was evaluated up to 35 days post EAE induction. Immune cell infiltration into the spinal cord and microglia responses were assessed.Results We show that IC100 treatment reduced the severity of EAE when compared to vehicle-treated controls. At a dose of 30 mg/kg, IC100 significantly reduced the number of CD4+ and CD8+ T cells and CD11b+MHCII+ activated myeloid cells entering the spinal cord from the periphery, and reduced the number of total and activated microglia. Conclusions These data indicate that IC100 suppresses the immune-inflammatory response that drives EAE development and progression, thereby identifying ASC as a promising target for the treatment of MS as well as other neurological diseases with a neuroinflammatory component.

scholarly journals Ic100: A Novel Anti-ASC Monoclonal Antibody Improves Functional Outcomes In An Animal Model Of Multiple Sclerosis

2020 ◽  
Author(s):  
Haritha L Desu ◽  
Melanie Plastini ◽  
Placido Illiano ◽  
Helen M Bramlett ◽  
W. Dalton Dietrich ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Therapeutic Strategy ◽  
Immune Cell ◽  
Neurological Diseases ◽  
Inflammasome Activation ◽  
Autoimmune Encephalomyelitis ◽  
Promising Target ◽  
Eae Model ◽  
Experimental Autoimmune

Abstract Background The inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is involved in immune signaling by bridging the interactions between inflammasome sensors and caspase-1. Strong experimental evidence has shown that ASC -/- mice are protected from disease progression in animal models of multiple sclerosis (MS), suggesting that targeting inflammasome activation via ASC inhibition may be a promising therapeutic strategy in MS. Thus, the goal of our study is to test the efficacy of IC100, a novel humanized antibody targeting ASC, in preventing and/or suppressing disease in the experimental autoimmune encephalomyelitis (EAE) model of MS.Methods We employed the EAE model of MS where disease was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG 35-55 ). Mice were treated with vehicle or increasing doses of IC100 (10, 30 and 45 mg/kg) and clinical disease course was evaluated up to 35 days post EAE induction. Immune cell infiltration into the spinal cord and microglia responses were assessed.Results We show that IC100 treatment reduced the severity of EAE when compared to vehicle-treated controls. At a dose of 30 mg/kg, IC100 significantly reduced the number of CD4 + and CD8 + T cells and CD11b + MHCII + activated myeloid cells entering the spinal cord from the periphery, and reduced the number of total and activated microglia.Conclusions These data indicate that IC100 suppresses the immune-inflammatory response that drives EAE development and progression, thereby identifying ASC as a promising target for the treatment of MS as well as other neurological diseases with a neuroinflammatory component.

scholarly journals A Mushroom Extract Piwep fromPhellinus igniariusAmeliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Immune Cell Infiltration in the Spinal Cord

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Lan Li ◽  
Guang Wu ◽  
Bo Young Choi ◽  
Bong Geom Jang ◽  
Jin Hee Kim ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Lymph Node ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Immune Cell Infiltration ◽  
Autoimmune Encephalomyelitis ◽  
Phellinus Igniarius ◽  
Mushroom Extract ◽  
Experimental Autoimmune

The present study aimed to evaluate the therapeutic potential of a mushroom extract fromPhellinus igniariusin an animal model of multiple sclerosis. The medicinal mushroom,Phellinus igniarius, contains biologically active compounds that modulate the human immune system. Experimental autoimmune encephalomyelitis (EAE) was induced by immunization with myelin oligodendrocyte glycoprotein (MOG 35–55) in C57BL/6 female mice. A water-ethanol extract ofPhellinus igniarius(Piwep) was delivered intraperitoneally every other day for the entire experimental course. Three weeks after the initial immunization, demyelination and immune cell infiltration in the spinal cord were examined. Piwep injection profoundly decreased the daily incidence rate and clinical score of EAE. The Piwep-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination and infiltration of encephalitogenic immune cells including CD4+ T cells, CD8+ T cells, macrophages, and B cells in the spinal cord. Piwep reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in the spinal cord and integrin-α4in the lymph node of EAE mice. Piwep also inhibited proliferation of lymphocytes and secretion of interferon-γin the lymph node of EAE mice. The results suggest that a mushroom extract, Piwep, may have a high therapeutic potential for ameliorating multiple sclerosis progression.

AIM2 inflammasome activation in astrocytes occurs during the late phase of EAE

2021 ◽  
Author(s):  
William E. Barclay ◽  
M. Elizabeth Deerhake ◽  
Makoto Inoue ◽  
Toshiaki Nonaka ◽  
Kengo Nozaki ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Animal Model ◽  
Cell Death ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Inflammasome Activation ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Experimental Autoimmune

ABSTRACTInflammasomes are a class of innate immune signaling platforms that activate in response to an array of cellular damage and pathogens. Inflammasomes promote inflammation under many circumstances to enhance immunity against pathogens and inflammatory responses through their effector cytokines, IL-1β and IL-18. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), are such autoimmune conditions influenced by inflammasomes. Despite work investigating inflammasomes during EAE, little remains known concerning the role of inflammasomes in the central nervous system (CNS) during the disease. Here we use multiple genetically modified mouse models to monitor activated inflammasomes in situ based on ASC oligomerization in the spinal cord. Using inflammasome reporter mice, we found heightened inflammasome activation in astrocytes after the disease peak. In contrast, microglia and CNS-infiltrated myeloid cells had few activated inflammasomes in the CNS during EAE. Astrocyte inflammasome activation was dependent on AIM2, but low IL-1β expression and no significant signs of cell death were found in astrocytes during EAE. Thus, the AIM2 inflammasome activation in astrocytes may have a distinct role from traditional inflammasome-mediated inflammation.SIGNIFICANCE STATEMENTInflammasome activation in the peripheral immune system is pathogenic in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). However, inflammasome activity in the central nervous system (CNS) is largely unexplored. Here, we used genetically modified mice to determine inflammasome activation in the CNS during EAE. Our data indicated heightened AIM2 inflammasome activation in astrocytes after the disease peak. Unexpectedly, neither CNS-infiltrated myeloid cells nor microglia were the primary cells with activated inflammasomes in SC during EAE. Despite AIM2 inflammasome activation, astrocytes did not undergo apparent cell death and produced little of the proinflammatory cytokine, IL-1β, during EAE. This study showed that CNS inflammasome activation occurs during EAE without associating with IL-1β-mediated inflammation.

scholarly journals The spectrum of spinal cord lesions in a primate model of multiple sclerosis

2019 ◽  
Vol 26 (3) ◽  
pp. 284-293 ◽  
Author(s):  
Jennifer A Lefeuvre ◽  
Joseph R Guy ◽  
Nicholas J Luciano ◽  
Seung-Kwon Ha ◽  
Emily Leibovitch ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Nonhuman Primate ◽  
Ex Vivo ◽  
Inflammatory Cells ◽  
Common Marmoset ◽  
Autoimmune Encephalomyelitis ◽  
Primate Model ◽  
Magnetic Resonance Imaging Mri ◽  
Experimental Autoimmune

Background: Experimental autoimmune encephalomyelitis (EAE) in the common marmoset is a nonhuman primate model of multiple sclerosis (MS) that shares numerous clinical, radiological, and pathological features with MS. Among the clinical features are motor and sensory deficits that are highly suggestive of spinal cord (SC) damage. Objective: To characterize the extent and nature of SC damage in symptomatic marmosets with EAE using a combined magnetic resonance imaging (MRI) and histopathology approach. Materials and Methods: SC tissues from five animals were scanned using 7 T MRI to collect high-resolution ex vivo images. Lesions were segmented and classified based on shape, size, and distribution along the SC. Tissues were processed for histopathological characterization (myelin and microglia/macrophages). Statistical analysis, using linear mixed-effects models, evaluated the association between MRI and histopathology. Results: Marmosets with EAE displayed two types of SC lesions: focal and subpial lesions. Both lesion types were heterogeneous in size and configuration and corresponded to areas of marked demyelination with high density of inflammatory cells. Inside the lesions, the MRI signal was significantly correlated with myelin content ( p < 0.001). Conclusions: Our findings underscore the relevance of this nonhuman primate EAE model for better understanding mechanisms of MS lesion formation in the SC.

scholarly journals Elevated Expression of Fractalkine (CX3CL1) and Fractalkine Receptor (CX3CR1) in the Dorsal Root Ganglia and Spinal Cord in Experimental Autoimmune Encephalomyelitis: Implications in Multiple Sclerosis-Induced Neuropathic Pain

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Wenjun Zhu ◽  
Crystal Acosta ◽  
Brian MacNeil ◽  
Claudia Cortes ◽  
Howard Intrater ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Protein Expression ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Autoimmune Encephalomyelitis ◽  
Receptor Cx3cr1 ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a central nervous system (CNS) disease resulting from a targeted autoimmune-mediated attack on myelin proteins in the CNS. The release of Th1 inflammatory mediators in the CNS activates macrophages, antibodies, and microglia resulting in myelin damage and the induction of neuropathic pain (NPP). Molecular signaling through fractalkine (CX3CL1), a nociceptive chemokine, via its receptor (CX3CR1) is thought to be associated with MS-induced NPP. An experimental autoimmune encephalomyelitis (EAE) model of MS was utilized to assess time dependent gene and protein expression changes of CX3CL1 and CX3CR1. Results revealed significant increases in mRNA and the protein expression of CX3CL1 and CX3CR1 in the dorsal root ganglia (DRG) and spinal cord (SC) 12 days after EAE induction compared to controls. This increased expression correlated with behavioural thermal sensory abnormalities consistent with NPP. Furthermore, this increased expression correlated with the peak neurological disability caused by EAE induction. This is the first study to identify CX3CL1 signaling through CX3CR1 via the DRG /SC anatomical connection that represents a critical pathway involved in NPP induction in an EAE model of MS.

scholarly journals Early Postnatal Tobacco Smoke Exposure Aggravates Experimental Autoimmune Encephalomyelitis in Adult Rats

2020 ◽  
Author(s):  
Zhaowei Wang ◽  
Liping Wang ◽  
Fangfang Zhong ◽  
Chenglong Wu ◽  
Sheng-Tao Hou
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Risk Factor ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Tobacco Smoke ◽  
Early Life ◽  
Tobacco Smoke Exposure ◽  
Autoimmune Encephalomyelitis ◽  
Early Life Exposure ◽  
Experimental Autoimmune

AbstractAlthough substantial evidence supports smoking as a risk factor for the development of multiple sclerosis (MS) in adulthood, it remains controversial as to whether early-life exposure to environmental tobacco smoke (ETS) increases the risk of MS later in life. Here, using experimental autoimmune encephalomyelitis (EAE) as an animal model for MS, we show that exposing neonatal rats during the 1st week (ETS1-EAE), but not the 2nd week (ETS2-EAE) and the 3rd week (ETS3-EAE) after birth, increased the severity of EAE in adulthood in comparison to pups exposed to filtered compressed air (AIR-EAE). The EST1-EAE rats showed a worse neurological deficit score and a significant increase in CD4+ cell infiltration, demyelination, and axonal injury in the spinal cord compared to AIR-EAE, ETS2-EAE, and ETS3-EAE groups. Flow cytometry analysis showed that the ETS1 group had decreased numbers of regulatory T (Treg) cells and increased effector T (Teff) cells in the brain and spinal cord. The expressions of Treg upstream regulator Foxp3 and downstream cytokines such as IL-10 were also altered accordingly. Together, these findings demonstrate that neonatal ETS exposure suppresses Treg functions and aggravates the severity of EAE, confirming early-life exposure to EST as a potential risk factor for multiple sclerosis in adulthood.

scholarly journals Illumination of Molecular Pathways in Multiple Sclerosis Lesions and the Immune Mechanism of Matrine Treatment in EAE, a Mouse Model of MS

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengmeng Dou ◽  
Xueliang Zhou ◽  
Lifeng Li ◽  
Mingliang Zhang ◽  
Wenbin Wang ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Target Genes ◽  
Immune Cell ◽  
Gene Expression Omnibus ◽  
Network Pharmacology ◽  
Autoimmune Encephalomyelitis ◽  
Data Set ◽  
Tissue Samples ◽  
Gene Data ◽  
Experimental Autoimmune

The etiology of multiple sclerosis (MS) is not clear, and the treatment of MS presents a great challenge. This study aimed to investigate the pathogenesis and potential therapeutic targets of MS and to define target genes of matrine, a quinolizidine alkaloid component derived from the root of Sophorae flavescens that effectively suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To this end, the GSE108000 gene data set in the Gene Expression Omnibus Database, which included 7 chronic active MS lesions and 10 control samples of white matter, was analyzed for differentially expressed genes (DEGs). X cell was used to analyze the microenvironmental differences in brain tissue samples of MS patients, including 64 types of immune cells and stromal cells. The biological functions and enriched signaling pathways of DEGs were analyzed by multiple approaches, including GO, KEGG, GSEA, and GSVA. The results by X cell showed significantly increased numbers of immune cell populations in the MS lesions, with decreased erythrocytes, megakaryocytes, adipocytes, keratinocytes, endothelial cells, Th1 cells and Tregs. In GSE108000, there were 637 DEGs, including 428 up-regulated and 209 down-regulated genes. Potential target genes of matrine were then predicted by the network pharmacology method of Traditional Chinese medicine, and 12 key genes were obtained by cross analysis of the target genes of matrine and DEGs in MS lesions. Finally, we confirmed by RT-PCR the predicted expression of these genes in brain tissues of matrine-treated EAE mice. Among these genes, 2 were significantly downregulated and 6 upregulated by matrine treatment, and the significance of this gene regulation was further investigated. In conclusion, our study defined several possible matrine target genes, which can be further elucidated as mechanism(s) of matrine action, and novel targets in the treatment of MS.

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