A comparative study of experimental mouse models of central nervous system demyelination

Abstract

Several mouse models of multiple sclerosis (MS) are now available. We have established a mouse model, in which ocular infection with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2) causes CNS demyelination in different strains of mice. This model differs from most other models in that it represents a mixture of viral and immune triggers. In the present study, we directly compared MOG35–55, MBP35–47, and PLP190–209 models of EAE with our HSV-IL-2-induced MS model. Mice with HSV-IL-2-induced and MOG-induced demyelinating diseases demonstrated a similar pattern and distribution of demyelination in their brain, spinal cord, and optic nerves. In contrast, no demyelination was detected in the optic nerves of MBP- and PLP-injected mice. IFN-β injections significantly reduced demyelination in brains of all groups, in the spinal cords of the MOG and MBP groups, and completely blocked it in the spinal cords of the PLP and HSV-IL-2 groups as well as in optic nerves of MOG and HSV-IL-2 groups. In contrast to IFN-β treatment, IL-12p70 protected the HSV-IL-2 group from demyelination, while IL-4 was not effective at all in preventing demyelination. MOG-injected mice showed clinical signs of paralysis and disease-related mortality whereas mice in the other treatment groups did not. Collectively, the results indicate that the HSV-IL-2 model and the MOG model complement each other and, together, provide unique insights into the heterogeneity of human MS.

Type 2 Innate Lymphoid Cells Induce CNS Demyelination in an HSV-IL-2 Mouse Model of Multiple Sclerosis

“…(8) HSV-IL-2-induced CNS demyelination was blocked by co-infecting mice with a recombinant HSV-1 expressing IL-12p70 (HSV-IL-12p70) or injecting with IL-12p70 DNA ( Mott et al., 2011 ). Lastly, (9) a comparison of MOG 35–55 , MBP 35–47 , and PLP 190–209 models of EAE with our HSV-IL-2-induced MS model ( Dumitrascu et al., 2014 ) showed that our HSV-IL-2 model was similar to the MOG model and both differed from the MBP and PLP models.…”

“…HSV-IL-2 infection of WT mice causes CNS demyelination, whereas infection of mice with parental virus does not ( Dumitrascu et al., 2014 ; Mott et al., 2013 ; Zandian et al., 2009 , 2011a , 2011b ). Based on MS and experimental autoimmune encephalomyelitis (EAE) published studies, we investigated the roles of selected Pdcd1 (PD1), CSF2 (GM-CSF), IL-5, IL-6, IFNgr1, CCL5 (RANTES), CXCL10, Tnfrsf9 (4-1BB/CD137), HIF1α, CSF2rb, Havcr2 (Tim-3), and CTLA4 genes in CNS demyelination in vivo .…”

The mutated tegument protein UL7 attenuates the virulence of herpes simplex virus 1 by reducing the modulation of α-4 gene transcription

“…Given that the mutant HSV-1 UL7 gene led to decreased viral proliferation capacity, we further characterized this strain’s virulence in infected mice. Prior work has shown that mice can be used as an animal model for acute HSV-1 infection to effectively address pathologic injury induced by viral infection [ 29 – 31 ]. As evidenced by clinical observations of BALB/c mice infected with the WT, UL7-MU or MU- complemented P1 strains (infection dosage: 2.3x10 5 PFU/50 μl) via the nasal route, the UL7-MU strain exhibited reduced virulence, as evidenced by slight, abnormal changes in the mice, in contrast to the arched back and down hair, markedly lower activity levels and worse status in mice infected with WT or MU-complemented P1 virus.…”

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…In various inflammatory and non-inflammatory demyelination-induced rodent models, IFN-β reduced demyelination in the brain and spinal cord, as was evident from the increased levels of myelin-related proteins [207,220,248]. Furthermore, the serum of untreated MS patients and of patients treated with IFN-β for six months inhibited OPC proliferation in mixed rat glial cultures, while the serum of twelve-month IFN-β-treated patients did not show this effect [249].…”