scholarly journals Comparison of Reported Spinal Cord Lesions in Progressive Multiple Sclerosis with Theiler’s Murine Encephalomyelitis Virus Induced Demyelinating Disease

2019 ◽  
Vol 20 (4) ◽  
pp. 989 ◽  
Author(s):  
Eva Leitzen ◽  
Wen Jin ◽  
Vanessa Herder ◽  
Andreas Beineke ◽  
Suliman Elmarabet ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Axonal Degeneration ◽  
Demyelinating Disease ◽  
Progressive Multiple Sclerosis ◽  
Axonal Damage ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Consistent Finding ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus

Background: Spinal cord (SC) lesions in Theiler’s murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) resemble important features of brain lesions in progressive multiple sclerosis (MS) including inflammation, demyelination, and axonal damage. The aim of the present study was a comparison of SC lesions in MS and TMEV-IDD focusing on spatial and temporal distribution of demyelination, inflammation, SC atrophy (SCA), and axonal degeneration/loss in major descending motor pathways. Methods: TMEV and mock-infected mice were investigated clinically once a week. SC tissue was collected at 42, 98, 147, and 196 days post infection, and investigated using hematoxylin and eosin (HE) staining, immunohistochemistry targeting myelin basic protein (demyelination), Mac3 (microglia/macrophages), phosphorylated neurofilaments (axonal damage) and transmission electron microscopy. Results: Demyelination prevailed in SC white matter in TMEV-IDD, contrasting a predominant gray matter involvement in MS. TMEV-infected mice revealed a significant loss of axons similar to MS. Ultrastructural analysis in TMEV-IDD revealed denuded axons, degenerative myelin changes, axonal degeneration, as well as remyelination. SCA is a consistent finding in the SC of MS patients and was also detected at a late time point in TMEV-IDD. Conclusion: This comparative study further indicates the suitability of TMEV-IDD as animal model also for the investigation of progressive SC lesions in MS.

scholarly journals Comparison of Theiler’s Murine Encephalomyelitis Virus Induced Spinal Cord and Peripheral Nerve Lesions Following Intracerebral and Intraspinal Infection

2019 ◽  
Vol 20 (20) ◽  
pp. 5134
Author(s):  
Jin ◽  
Leitzen ◽  
Goebbels ◽  
Nave ◽  
Baumgärtner ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Coordination ◽  
Demyelinating Disease ◽  
Clinical Signs ◽  
Axonal Damage ◽  
Infection Model ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Peripheral Nerve Lesions ◽  
Encephalomyelitis Virus

Hallmarks of Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) include spinal cord (SC) inflammation, demyelination and axonal damage occurring approximately 5–8 weeks after classical intracerebral (i.c.) infection. The aim of this study was to elucidate the consequences of intraspinal (i.s.) TMEV infection and a direct comparison of classical i.c. and intraspinal infection. Swiss Jim Lambert (SJL)-mice were i.s. infected with the BeAn strain of TMEV. Clinical investigations including a scoring system and rotarod analysis were performed on a regular basis. Necropsies were performed at 3, 7, 14, 28 and 63 days post infection (dpi) following i.s. and at 4, 7, 14, 28, 56, 98, 147 and 196 dpi following i.c. infection. Serial sections of formalin-fixed, paraffin-embedded SC and peripheral nerves (PN) were investigated using hematoxylin and eosin (HE) and immunohistochemistry. I.s. infected mice developed clinical signs and a deterioration of motor coordination approximately 12 weeks earlier than i.c. infected animals. SC inflammation, demyelination and axonal damage occurred approximately 6 weeks earlier in i.s. infected animals. Interestingly, i.s. infected mice developed PN lesions, characterized by vacuolation, inflammation, demyelination and axonal damage, which was not seen following i.c. infection. The i.s. infection model offers the advantage of a significantly earlier onset of clinical signs, inflammatory and demyelinating SC lesions and additionally enables the investigation of virus-mediated PN lesions.

A hybrid between a resistant and a susceptible strain of mouse alters the pattern of Theiler's murine encephalomyelitis virus-induced white matter disease and favors oligodendrocyte-mediated remyelination

1995 ◽  
Vol 1 (2) ◽  
pp. 95-103 ◽  
Author(s):  
MC Dal Canto ◽  
RW Melvold ◽  
BS Kim
Keyword(s):  
Spinal Cord ◽  
Demyelinating Disease ◽  
Phenotypic Expression ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Pathological Lesions ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus ◽  
Resistant Strains ◽  
The Relationship ◽  
Myelin Injury

Theiler's murine encephalomyelitis virus (TMEV) produces a chronic disease in its natural host, the mouse, characterised by primary inflammatory demyelination of the spinal cord. This viral infection is considered a very good model for human MS because the pathogenesis of myelin injury is mediated through the host immune response. Susceptibility and/or resistance to the demyelinating disease depend on multiple genes both in and outside the major histocompatibility complex (MHC). The pathological lesions in animals with different degrees of susceptibility vary in both their severity and in their ability to become remyelinated. In general, animals with intermediate levels of susceptibility show the best potential for remyelination. Most crosses of susceptible animals with resistant strains carrying the H-2b haplotype are resistant with only a couple of exceptions. One such exception is the (SJL/J × C57L/J)Fl hybrid, which is susceptible to the disease. To study whether the resistant genotype of C57L/J mice could modify the phenotypic expression of pathological lesions characteristic of the highly susceptible SJL/J mouse, we performed a light microscopical and ultrastructural study of the spinal cord of both parental strains and their Flprogeny. We focused particularly on the relationship between severity of inflammation, and especially macrophage infiltration, and the subsequent remyelinating potential of lesions. The results show a dramatic difference between the ability to remyelinate lesions by infected SJL/J mice vs similarly infected (SJL/L × C57L/J)Fl hybrids, and suggest an important influence by resistant genes in modulating the phenotypic expression of disease, including the ability to stimulate oligodendroglia-mediated remyelination.

scholarly journals Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis

2021 ◽  
Author(s):  
Fernando Cavalcanti ◽  
Elena Gonzalez-Rey ◽  
Mario Delgado ◽  
Leyre Mestre ◽  
Carmen Guaza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Gene Expression Signature ◽  
Autoimmune Encephalomyelitis ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus ◽  
Experimental Autoimmune

Abstract Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR. Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalomyelitis virus. The compound reduced lymphocyte egress and infiltration of immune cells in the spinal cord and prevented demyelination. ORY-2001 was more effective and/or faster acting than a sphingosine 1-phosphate receptor antagonist in the effector phase of the disease and reduced the induction of the inflammatory gene expression signature in the central nervous system more potently. Gene expression changes and axonal protection in animals, and protection against glutamate excitoxicity in spinal cord explants support that ORY-2001 has neuroprotective qualities. Conclusions ORY-2001 exerts therapeutic activity in two mouse models of multiple sclerosis. The anti-inflammatory properties of ORY-2001 are being tested in a Phase IIa clinical trial in patients with relapse remitting and secondary progressive multiple sclerosis, and in severely ill COVID-19 patients at risk for acute respiratory distress syndrome.

scholarly journals Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis

2020 ◽  
Author(s):  
Fernando Cavalcanti ◽  
Elena Gonzalez-Rey ◽  
Mario Delgado ◽  
Leyre Mestre ◽  
Carmen Guaza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Gene Expression Signature ◽  
Autoimmune Encephalomyelitis ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus ◽  
Experimental Autoimmune

Abstract Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR.Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalomyelitis virus. The compound reduced lymphocyte egress and infiltration of immune cells in the spinal cord and prevented demyelination. ORY-2001 was more effective and/or faster acting than a sphingosine 1-phosphate receptor antagonist in the effector phase of the disease and reduced the induction of the inflammatory gene expression signature in the central nervous system more potently. Gene expression changes and axonal protection in animals, and protection against glutamate excitoxicity in spinal cord explants support that ORY-2001 has neuroprotective qualities.Conclusions ORY-2001 exerts therapeutic activity in two mouse models of multiple sclerosis. The anti-inflammatory properties of ORY-2001 are being tested in a Phase IIa clinical trial in patients with relapse remitting and secondary progressive multiple sclerosis, and in severely ill COVID-19 patients at risk for acute respiratory distress syndrome.

scholarly journals Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis

2021 ◽  
Author(s):  
Fernando Cavalcanti ◽  
Elena Gonzalez-Rey ◽  
Mario Delgado ◽  
Leyre Mestre ◽  
Carmen Guaza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Gene Expression Signature ◽  
Autoimmune Encephalomyelitis ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus ◽  
Experimental Autoimmune

Abstract Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR. Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalomyelitis virus. The compound reduced lymphocyte egress and infiltration of immune cells in the spinal cord and prevented demyelination. ORY-2001 was more effective and/or faster acting than a sphingosine 1-phosphate receptor antagonist in the effector phase of the disease and reduced the induction of the inflammatory gene expression signature in the central nervous system more potently. Gene expression changes and axonal protection in animals, and protection against glutamate excitoxicity in spinal cord explants support that ORY-2001 has neuroprotective qualities. Conclusions ORY-2001 exerts therapeutic activity in two mouse models of multiple sclerosis. The anti-inflammatory properties of ORY-2001 are being tested in a Phase IIa clinical trial in patients with relapse remitting and secondary progressive multiple sclerosis, and in severely ill COVID-19 patients at risk for acute respiratory distress syndrome.

scholarly journals Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis

2020 ◽  
Author(s):  
Fernando Cavalcanti ◽  
Elena Gonzalez-Rey ◽  
Mario Delgado ◽  
Leyre Mestre ◽  
Carmen Guaza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Gene Expression Signature ◽  
Autoimmune Encephalomyelitis ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus ◽  
Experimental Autoimmune

Abstract Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR.Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalomyelitis virus. The compound reduced lymphocyte egress and infiltration of immune cells in the spinal cord and prevented demyelination. ORY-2001 was more effective and/or faster acting than a sphingosine 1-phosphate receptor antagonist in the effector phase of the disease and reduced the induction of the inflammatory gene expression signature in the central nervous system more potently. Gene expression changes and axonal protection in animals, and protection against glutamate excitoxicity in spinal cord explants support that ORY-2001 has neuroprotective qualities.Conclusions ORY-2001 exerts therapeutic activity in two mouse models of multiple sclerosis. The anti-inflammatory properties of ORY-2001 are being tested in a Phase IIa clinical trial in patients with relapse remitting and secondary progressive multiple sclerosis, and in severely ill COVID-19 patients at risk for acute respiratory distress syndrome.

scholarly journals Infection and Activation of B Cells by Theiler’s Murine Encephalomyelitis Virus (TMEV) Leads to Autoantibody Production in an Infectious Model of Multiple Sclerosis

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1787 ◽  
Author(s):  
Young-Hee Jin ◽  
Charles X. Kim ◽  
Jocelin Huang ◽  
Byung S. Kim
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Demyelinating Disease ◽  
Chronic Infections ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Autoantibody Production ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus ◽  
Anti Cd20 ◽  
Antigen Presenting

Theiler’s murine encephalomyelitis virus (TMEV) induces immune-mediated inflammatory demyelinating disease in susceptible mice that is similar to human multiple sclerosis (MS). In light of anti-CD20 therapies for MS, the susceptibility of B cells to TMEV infection is particularly important. In our study, direct viral exposure to macrophages and lymphocytes resulted in viral replication and cellular stimulation in the order of DCs, macrophages, B cells, and T cells. Notably, B cells produced viral proteins and expressed elevated levels of CD69, an activation marker. Similarly, the expression of major histocompatibility complex class II and costimulatory molecules in B cells was upregulated. Moreover, TMEV-infected B cells showed elevated levels of antigen-presenting function and antibody production. TMEV infection appeared to polyclonally activate B cells to produce autoantibodies and further T cell stimulation. Thus, the viral infection might potentially affect the outcome of autoimmune diseases, and/or the development of other chronic infections, including the protection and/or pathogenesis of TMEV-induced demyelinating disease.

scholarly journals Efficacy of vafidemstat in experimental autoimmune encephalomyelitis highlights the KDM1A/RCOR1/HDAC epigenetic axis in multiple sclerosis

2021 ◽  
Author(s):  
Fernando Cavalcanti ◽  
Elena Gonzalez-Rey ◽  
Mario Delgado ◽  
Leyre Mestre ◽  
Carmen Guaza ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Gene Expression Signature ◽  
Autoimmune Encephalomyelitis ◽  
Theiler's Murine Encephalomyelitis Virus ◽  
Theiler’S Murine Encephalomyelitis Virus ◽  
Encephalomyelitis Virus ◽  
Experimental Autoimmune

Abstract Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR. Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalomyelitis virus. The compound reduced lymphocyte egress and infiltration of immune cells in the spinal cord and prevented demyelination. ORY-2001 was more effective and/or faster acting than a sphingosine 1-phosphate receptor antagonist in the effector phase of the disease and reduced the induction of the inflammatory gene expression signature in the central nervous system more potently. Gene expression changes and axonal protection in animals, and protection against glutamate excitoxicity in spinal cord explants support that ORY-2001 has neuroprotective qualities. Conclusions ORY-2001 exerts therapeutic activity in two mouse models of multiple sclerosis. The anti-inflammatory properties of ORY-2001 are being tested in a Phase IIa clinical trial in patients with relapse remitting and secondary progressive multiple sclerosis, and in severely ill COVID-19 patients at risk for acute respiratory distress syndrome.

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