Animal models for multiple sclerosis

To study myelin disorders, several animal models have been developed. Models used to study the pathogenesis of MS involve virus- and toxin-induced demyelination (Oleszak et al., 2004; Rodriguez, 2007), as well as experimentally induced autoimmune reactions and gene mutations (Dal Canto et al., 1995; Table 1-4).

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Table 1-4. Animal models of multiple sclerosis.

Animals models of multiple sclerosis

Disease Reference

Viral Naturally occurring

Canine distemper (Beineke et al, 2009)

Visna of sheep (Sigurdsson et al., 1957)

Experimentally induced

Murine coronavirus (JHM strain)-infection (Herndon et al., 1975) Semliki forest virus-infection (Fazakerley et al., 1983)

Theiler’s murine encephalomyelitis (Theiler, 1934)

Immune-mediated

Ethidium bromide-induced demyelination (Woodruff and Franklin, 1999) Lysolecithin-induced demyelination (Woodruff and Franklin, 1999)

Genetic

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1.2.2.1 Viral-induced demyelination

Some demyelinating diseases of the CNS in humans and animals are induced by viruses. Here, demyelination is caused by the lysis of virus-infected glial cells or by delayed-type hypersensitivity due to viral persistence. The fact that viruses induce myelin disorders further supports the idea of a viral involvement in MS. Therefore, different viral infections of animals, including canine distemper, visna, murine coronavirus (JHM strain)-infection, Semliki forest virus-infection and Theiler’s murine encephalomyelitis represent models for human demyelinating diseases (Baumgärtner and Alldinger, 2005; Herndon et al., 1975; Sigurdsson et al., 1957; Sospedra and Martin, 2005; Theiler, 1934; Waksman, 1999; Table 1-4).

1.2.2.1.1 Theiler’s murine encephalomyelitis

The causative agent of the Theiler’s murine encephalomyelitis (TME) is the Theiler’s murine encephalomyelitis virus (TMEV). In mice, natural TMEV infection usually affects the digestive tract without the development of clinical signs (asymptomatic infection). Only occasionally the CNS is involved following enteral infection. However, experimental intracerebral TMEV-infection is commonly used to study the mechanisms of viral persistence and demyelination. Therefore, it serves as a model for the chronic-progressive form of MS (Dal Canto et al., 1995; Monteyne et al., 1997; Ure and Rodriguez, 2005). TMEV is an icosahedral, positive-sense, double-stranded virus, which belongs to the Picornaviridae family (Oleszak et al., 2004; Theiler, 1934;

Figure 1-2). Two subgroups of TMEV are recognized on the basis of neurovirulence after intracerebral inoculation. The GDVII and FA strains are highly neurovirulent, causing severe apoptosis of infected neurons and an acute fatal polioencephalitis (Tsunoda and Fujinami, 1996). The other subgroup consists of Theiler’s original (TO) virus strains which cause persistent infection and chronic demyelination of the CNS.

Examples of TO strains are the Daniel’s strain (DA) and BeAn-strain (Oleszak et al., 2004; Tsunoda et al., 2009; Lipton, 1975; Figure 1-3).

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Intracerebral infection with the low virulent BeAn-strain of TMEV causes an acute virus-induced polioencephalitis in mice (Lipton, 1975), characterized by an infiltration of virus-specific CD4⁺ and CD8⁺ T-cells, as well as B-cells and macrophages in the brain (Gerhauser et al., 2007a; Oleszak et al., 1995).

Figure 1-2. Theiler’s murine encephalomyelitis virus taxonomy.

Information obtained from the International Committee on Taxonomy of Viruses (www.ictvonline.org/virusTaxonomy.asp)

(+)ss: positive-sense double-stranded, RNA: ribonucleic acid, GDVII: Gard’s type VII strain, TO:

Theiler’s original strains, DA: Daniel’s strain. GDVII and FA: high-neurovirulent strains. DA and BeAn: low-neurovirulent strains.

Figure 1-3. Image of the Theiler’s murine encephalomyelitis virus (BeAn-strain).

The Theiler’s murine encephalomyelitis virus of the BeAn-strain consists of a spherical protein shell that encapsulates a single-stranded RNA genome of positive polarity and 8098 nucleotides. There are four polypeptides in the capsid: VP1, VP2, VP3 and VP4. The capsid presents an icosahedral symmetry and contains 60 copies of each of the four polypeptides (Luo et al., 1992; Sayle and Milner-White, 1995).

Rasmol image courtesy of Dr. J.-Y. Sgro, University of Wisconsin-Madison, USA © 2004

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While resistant C57/BL6-mice eliminate the virus from the cerebral gray matter after the acute phase by specific cellular immunity (Monteyne, 1999), inadequate viral clearance in SJL-mice leads to viral persistence predominately in macrophages and/or glial cells (Hou et al., 2009; Tsunoda and Fujinami, 1996). Subsequently, delayed-type hypersensitivity and myelin-specific autoimmunity are supposed to induce demyelination in the spinal cord white matter during the chronic phase (Lipton, 1975;

Monteyne, 1999; Tsunoda and Fujinami, 1996; Tsunoda, 2008). Clinical signs of TME include spastic paresis, progressive ataxia and depressed behavior (Ulrich et al., 2006;

Monteyne et al., 1997; Theiler, 1934; Tsunoda and Fujinami, 1996; Gerhauser et al., 2007a).

Initially, neurons are the predominately infected cell type and viral dissemination occurs through the axons (Oleszak et al., 2004). Axonal degeneration is supposed to be a mechanism of viral elimination and probably stops the virus spread throughout the CNS (Tsunoda et al., 2007). Inflammation during the acute disease phase is located in the cortex and subcortical grey matter, including the thalamus, hypothalamus and subthalamus. In addition, the hippocampus and basal ganglia are affected. Inflammation can be observed also in the anterior horns of the spinal cord gray matter (Oleszak et al., 2004). Infiltrates of inflammatory cells consist predominantly of T-lymphocytes and macrophages. The following period is characterized by a chronic demyelinating phase (Lipton, 1975; Monteyne, 1999;

Tsunoda and Fujinami, 1996) as a result of viral persistence in glial cells and macrophages of the spinal cord white matter (Luo et al., 1992; Rodriguez et al., 1996;

Oleszak et al., 2004).

1.2.2.2 Immune-mediated myelin loss disorders 1.2.2.2.1 Experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE; Roboz-Einstein, 1959) is the most commonly used model for MS. It is produced by experimentally immunizing animals with myelin components in Freund’s adjuvant, inducing a CD4⁺ T-cell mediated

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immune disease in susceptible animals (Sospedra and Martin, 2005; Tsunoda and Fujinami, 1996). Susceptibility to EAE depends on various factors like species, gender and age of the animals. The signs vary depending on the animal model in which the disease is induced, ranging from an acute monophasic disease to a more chronic relapsing-remitting form (Tsunoda and Fujinami, 1996). Lesions are the result of a cell-mediated response induced by active priming with whole myelin proteins, myelin proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) or myelin basic protein (MBP), respectively. Additionally, the disease can be induced in naïve animals by the adoptive transfer of myelin-specific CD4⁺ T-cells. The CNS lesions are characterized by mononuclear infiltration, focal vasculitis, demyelination and axonal damage. Due to epitope spreading different myelin-specific antibodies can be detected in the serum of affected animals (Dal Canto et al., 1995; Martin et al., 1992).

1.3 Immune cells involved in demyelinating diseases