Progress in Neurobiology 92 (2010) 386–404

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Progress in Neurobiology
journal homepage: www.elsevier.com/locate/pneurobio

Animal models of multiple sclerosis—Potentials and limitations

Eilhard Mix a, Hans Meyer-Rienecker a, Hans-Peter Hartung b,*, Uwe K. Zettl a
a
Department of Neurology, University of Rostock, Germany
b
Department of Neurology, Heinrich-Heine-University, Moorenstr. 5, 40225 Duesseldorf, Germany

A R T I C L E I N F O A B S T R A C T

Article history: Experimental autoimmune encephalomyelitis (EAE) is still the most widely accepted animal model of
Received 8 March 2010 multiple sclerosis (MS). Different types of EAE have been developed in order to investigate pathogenetic,
Received in revised form 1 June 2010 clinical and therapeutic aspects of the heterogenic human disease. Generally, investigations in EAE are
Accepted 7 June 2010
more suitable for the analysis of immunogenetic elements (major histocompatibility complex restriction
and candidate risk genes) and for the study of histopathological features (inflammation, demyelination
Keywords: and degeneration) of the disease than for screening of new treatments. Recent studies in new EAE
Animal model
models, especially in transgenic ones, have in connection with new analytical techniques such as
Autoimmunity
microarray assays provided a deeper insight into the pathogenic cellular and molecular mechanisms of
Experimental autoimmune
encephalomyelitis EAE and potentially of MS. For example, it was possible to better delineate the role of soluble pro-
Immunogenetics inflammatory (tumor necrosis factor-a, interferon-g and interleukins 1, 12 and 23), anti-inflammatory
Immunomodulatory therapy (transforming growth factor-b and interleukins 4, 10, 27 and 35) and neurotrophic factors (ciliary
Multiple sclerosis neurotrophic factor and brain-derived neurotrophic factor). Also, the regulatory and effector functions of
distinct immune cell subpopulations such as CD4+ Th1, Th2, Th3 and Th17 cells, CD4+FoxP3+ Treg cells,
CD8+ Tc1 and Tc2, B cells and gd+ T cells have been disclosed in more detail. The new insights may help to
identify novel targets for the treatment of MS. However, translation of the experimental results into the
clinical practice requires prudence and great caution.
ß 2010 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
1.1. Origins of EAE: from primates to rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
1.2. Different types of EAE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
1.3. Current EAE models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
2. Investigation of immunogenetic and pathogenetic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
2.1. Immunogenetics of EAE and MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
2.2. Gene expression studies by microarray analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
2.3. Immunopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392
3. Development and validation of novel therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
3.1. Therapies developed primarily in EAE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
3.2. Therapies investigated secondarily in EAE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
3.3. Therapy failures in MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
4. Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398

Abbreviations: APC, antigen-presenting cell; AT-EAE, adoptive transfer EAE; BBB, blood–brain barrier; BDNF, brain-derived neurotrophic factor; CD, cluster of differentiation;
CNS, central nervous system; CNTF, ciliary neurotrophic factor; EAE, experimental autoimmune encephalomyelitis; HLA, human leukocyte antigen; Ig, immunoglobulin; IL,
interleukin; IFN, interferon; IVIg, intravenous immunoglobulin; mAb, monoclonal antibody; MBP, myelin basic protein; MHC, major histocompatibility complex; MOG,
myelin oligodendrocyte glycoprotein; MP, methylprednisolone; MRI, magnetic resonance imaging; MS, multiple sclerosis; NK, natural killer; ODC, oligodendrocyte; QTL,
quantitative trait locus; PLP, proteolipid protein; Tc, cytotoxic T cell; TCR, T cell receptor; TGF, transforming growth factor; Th cell, helper T cell; TNF, tumor necrosis factor.
* Corresponding author. Tel.: +49 211 8117880; fax: +49 211 8118469.
E-mail address: Hans-Peter.Hartung@uni-duesseldorf.de (H.-P. Hartung).

0301-0082/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.pneurobio.2010.06.005
 E. Mix et al. / Progress in Neurobiology 92 (2010) 386–404 387

1. Introduction 1.2. Different types of EAE

1.1. Origins of EAE: from primates to rodents Importantly, by stepwise reduction of the complexity of the
antigenic material from crude brain tissue and protein extracts
Trials to investigate pathogenetic, diagnostic and therapeutic through various central myelin proteins such as
aspects of multiple sclerosis (MS) in animal models date back to
the first half of the 20th century (Lindsey, 2005) (Fig. 1). Before, (i) myelin basic protein (MBP) (Einstein et al., 1962; Laatsch et al.,
Louis Pasteur’s rabies vaccination (Pasteur and Illo, 1996) gave first 1962),
hints to the possibility that immunization of humans with (ii) myelin oligodendrocyte (ODC) glycoprotein (MOG) (Lebar
xenogenic nervous tissue induces ascending paralysis. Specifically, et al., 1986),
inoculation of rabies patients with desiccated spinal cord of rabies- (iii) proteolipid protein (PLP) (Tuohy et al., 1988),
infected rabbits caused pareses of limb, neck and facial muscles (iv) myelin-associated oligodendrocytic basic protein and 20 ,30 -
resulting in gait, swallowing and breathing problems (Baxter, cyclic nucleotide 30 -phosphodiesterase (Määttä et al., 1998)
2007). Conversely, it was shown by Koritschoner and Schweinburg
(1925) and Stuart and Krikorian (1928) that injection of human to small encephalitogenic peptides (Eylar et al., 1970; Lennon
spinal cord or sheep brain into rabbits leads to limb paralysis et al., 1970) such as MBP1–37, MBP1–11, MBP1–9, MBP83–99, MOG55–
(clumsy gait and muscle weakness). Rivers et al. (1933) first 75 and PLP139–151, more reproducible EAE models became available
demonstrated in monkeys immunized with rabbit brain or brain that mirror different features of MS (Wekerle et al., 1994). More
extracts that paralysis was associated with perivascular infiltrates recently a variety of additional antigens have been supposed to be
and demyelination in the brain and spinal cord. He called the involved in autoimmune reaction in MS and EAE (Table 1). Some of
disease acute disseminated encephalomyelitis, a term that was them are myelin constituents such as neurofascin NF 155 (Mathey
later changed to experimental allergic or autoimmune encephalo- et al., 2007), others are expressed on myelin and axons such as
myelitis (EAE). Since the frequency and severity of paralyses was contactin-2/transient axonal glycoprotein-1 (TAG-1) (Derfuss
correlated to the titer of anti-brain antibodies, researchers in et al., 2009) and some are entirely non-myelin antigens such as
subsequent trials boosted the humoral immune response with the neuronal membrane protein neurofascin NF 186 (Mathey et al.,
Freund’s adjuvant (CFA) (Freund and McDermott, 1942), later 2007), the neuronal cytoskeletal protein neurofilament-M (Krish-
complemented by pertussis toxin (Munoz et al., 1984). Thereby namoorthy et al., 2009) and the astrocyte-typical Ca2+-binding
they could induce oscillatory symptoms and relapsing–remitting protein S100b (Kojima et al., 1997). The neurofascins NF 155 and
courses of the disease accompanied by perivascular leukocyte NF 186 and the adhesion molecule contactin-2/TAG-1have been
infiltration in acute lesions and gliosis in chronic lesions both identified as putative MS auto-antigens by a proteomics-based
reminiscent of MS pathology (Wolf et al., 1947). Experiments were screening approach of MS sera and were subsequently shown to
performed first in guinea pigs (Freund et al., 1947) and monkeys promote the autoimmune pathogenesis of EAE in rat models
(Kabat et al., 1947; Morgan, 1947; Wolf et al., 1947) and later in (Derfuss et al., 2009, 2010; Mathey et al., 2007). Antibodies to
various other species including mice (Olitzky and Yager, 1949) and neurofascins, in particular to NF 186, caused axonal injury without
rats (Lipton and Freund, 1952) enabling more extensive immuno- enhancing inflammation and demyelination in MOG–EAE (Mathey
genetic, histopathological and therapeutic studies. It turned out et al., 2007). In contrast to MOG–EAE, contactin-2/TAG-1-specific T
that the histopathology and the clinical course of the disease varied cells induced inflammatory lesions preferentially in the cerebral
significantly reflecting in part the heterogeneity of its human cortex and the spinal cord white and gray matter (Derfuss et al.,
counterpart dependent on the genetic background of the animals, 2009). However, while these cells were unable to cause
the source of the antigenic material and the mode of application of demyelination by themselves they opened the blood–brain barrier
the antigen (Hartung et al., 2005; Olsson et al., 2000; Wekerle et al., (BBB) thereby allowing access of anti-MOG antibodies to the
1994). central nervous system (CNS) where they could trigger demyelin-
[(Fig._1)TD$IG]

Fig. 1. Timeline of milestones in the history of animal models of MS. Abbreviations: AT-EAE, adoptive transfer EAE; CD, cluster of differentiation; CNS, central nervous system;
MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; TCR, T cell receptor; Th17 cell, interleukin-17 producing T helper cell.
388 E. Mix et al. / Progress in Neurobiology 92 (2010) 386–404

Table 1
Putative protein and lipid auto-antigens in EAE and/or MS.

Antigens Results in MS and/or EAE References

Myelin basic protein T and B cell response in EAE and MS Einstein et al. (1962), Laatsch et al. (1962)
MOG T and B cell response in EAE and MS Lebar et al. (1986)
PLP T and B cell response in EAE and MS Tuohy et al. (1988)
20 ,30 -CNP T and B cell response in EAE and MS Määttä et al. (1998)
NF 155 Antibodies recognize the extracellular domain in MS Charles et al. (2002), Derfuss et al. (2010),
and cause axonal injury in EAE, but only in preexisting Mathey et al. (2007)
demyelinated lesions
NF 186 Antibodies recognize the extracellular domain in MS, Derfuss et al. (2010), Hedstrom et al. (2007),
inhibit axonal conduction in a complement-dependent Mathey et al. (2007)
manner and cause axonal injury in EAE
Neurofilament-M Neurofilament-M-specific T cells induce severe clinical Krishnamoorthy et al. (2009)
EAE with confluent demyelination and massive axonal loss
Contactin-2/TAG-1 Contactin-2/TAG-1-specific T cells induce inflammatory Derfuss et al. (2009, 2010), Mörtl et al. (2007),
lesions in the cortex and white and gray matter thereby Shimoda and Watanabe (2009)
opening locally the BBB and causing occasionally clinical EAE
S100b Strong T cell response in EAE Kojima et al. (1997)
Phosphatidylserine Promotion of demyelination in marmoset EAE Ohler et al. (2004)
Sulfatides T and B cell response in EAE Kanter et al. (2006)
Oxidized phosphatidylcholine Strong antibody reactivity in MS brain and EAE spinal cord Qin et al. (2007)
Ganglioside GM1, sulfatide Increased reactivity of pro-inflammatory cytokine secreting Shamshiev et al. (1999)
and galactosylceramide CD8+ T cells in MS patients
Gangliosides GM3 and GQ1b Increased T cell response in primary progressive MS patients Pender et al. (2003)
Ganglioside GD1a Increased antibodies in serum and cerebrospinal fluid of Matà et al. (1999)
patients with MS and optic neuritis
Lactosylceramide and Strong antibody reactivity in serum and cerebrospinal Kanter et al. (2006), Quintana et al. (2008b)
L-a-lysophosphatidylserine fluid of MS patients

ation. The EAE variants induced by axonal antigens may reflect as primary neuronal degeneration, shift of CD4+ T helper cells to
special features of MS subtypes, e.g. those characterized by cortical CD8+ cytotoxic T cells and lesions in cortical areas are rarely
lesions or by histological patterns II and IV according to the reproduced by actively induced EAE models (Aktas et al., 2007;
classification of Lucchinetti et al. (2000). The schematic drawing in Gold et al., 2006; Herrero-Herranz et al., 2008; Linker et al., 2005;
Fig. 2 indicates the molecular localisation of currently known Pomeroy et al., 2005). Hitherto it is not clear to which extent
putative auto-antigens in EAE. Proteins, glycoproteins and cortical lesions account for the brain atrophy in MS. Merkler et al.
lipoproteins possessing encephalitogenic epitopes may be exposed (2006) could induce focal demyelinating lesions in the cortex of
to the outer surface of ODCs (1) or myelin (2) or they may reside in MOG–EAE rats by stereotactical injection of the pro-inflammatory
the compact myelin zone (3), at the myelin–axon interface (4) or cytokines tumor necrosis factor-a (TNF-a) and interferon-g (IFN-
the node of Ranvier (5). As to the last localisation the three g). Corresponding to findings in MS the focal cortical lesions were
adhesion molecules NF 155 and NF 186 contactin-2/TAG-1 are rapidly remyelinated. Accordingly, in marmoset MOG–EAE focal
differentially expressed. Whereas NF 155 is localised at the cortical lesions were not the major cause of diffuse cortical atrophy
paranodal myelin loop and interact with contactin-1/F3 and the (Pomeroy et al., 2008). The potential pathomechanisms of CNS
contactin-associated protein 2 (caspr 2) on the axoplasm in a atrophy in MS are complex and may include several mechanisms of
ternary complex (Charles et al., 2002), NF 186 is exposed in the neuronal damage such as anterograde Wallerian degeneration,
non-myelinated part of the node of Ranvier and interacts with the neuronal dying-back and neuronal soma and dendritic shrinkage
neuron-glia-related cell adhesion molecule (NrCAM) and voltage- (Dziedzic et al., 2010; Siffrin et al., 2010). Currently, disclosure of
gated Na+ channels (Hedstrom et al., 2007). Contactin-2/TAG-1 is the exact mechanisms of axon damage is a major challenge of MS
also expressed juxtaparanodal by both the myelin and axonal research, since it appears to be the main cause of clinical disability
membrane forming dimers or molecular zippers (Mörtl et al., 2007; and may be the result of immune and/or non-immune attacks on
Shimoda and Watanabe, 2009). Whether lipids, glycolipids and neurons rather than a consequence of immune-mediated demye-
phospholipids play also a role as auto-antigens in EAE and MS is lination (Siffrin et al., 2010).
not clear, although several evidences from experimental and Concerning the aetiopathogenesis of MS the role of infections is
clinical studies support such a role (Podbielska and Hogan, 2009). still a matter of controversy. In mice lymphocytic choriomenigitis
Candiate myelin lipid auto-antigens in MS and/or EAE are shown in virus protein expression could elicit chronic autoimmune inflam-
Table 1. In a lipid microarray study of Kanter et al. (2006) co- mation and demyelination in the CNS (Evans et al., 1996). A
immunization with sulfatides and co-application of sulfatide- Chlamydia pneumonia-specific peptide sharing an immunodomi-
specific antibodies worsened the clinical course of PLP139–151–EAE nant epitope with MBP-induced severe clinical and histological
in SJL/J mice, and Quintana et al. (2008b) found auto-antibodies to EAE (Lenz et al., 2001), whereas intestinal parasites conveyed
lipids such as oxidized cholesterol derivatives in the serum of MS resistance to EAE in EAE-susceptible Lewis rats (Zorzella et al.,
patients with the immunopathologic pattern II according to 2007). Also, human herpes virus type 6, Epstein–Barr virus,
Lucchinetti et al. (2000). However, the oxidized cholesterol measles virus and retroviruses have been implicated in the
derivatives did not affect the specific humoral and T cell response aetiopathogenesis of MS, but currently available experimental
in MOG55–75–EAE. and clinical data are not convincing enough to justify anti-viral or
Several studies have shown that actively induced EAE models antibiotic therapy in MS. However, experimental demyelinating
can reproduce the typical temporal maturation of MS lesions from diseases induced by Theiler’s virus (Theiler, 1934; Ure and
inflammation with or without deposition of immunoglobulin Rodriguez, 2005), coronavirus (Lavi, 2005) or canine distemper
through demyelination and axonal damage to gliosis and partial virus (Seehusen and Baumgärtner, 2010) are suitable models for
remyelination. However, special phenotypes of MS pathology such the investigation of some aspects of MS pathology.
[(Fig._2)TD$IG] E. Mix et al. / Progress in Neurobiology 92 (2010) 386–404 389

Fig. 2. Putative auto-antigens in EAE with indication of their preferential localisation. Insets refer to the ODC membrane (inset 1), myelin surface zone (inset 2), compact
myelin zone (inset 3), myelin/axon interface zone (inset 4), and nodal and paranodal zone of node of Ranvier (inset 5). Abbreviations: CNP, 20 ,30 -cyclic nucleotide-30 -
phosphodiesterase; cyt, cytoplasm; ext, extracellular space; MAG, myelin-associated glycoprotein; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein;
NF, neurofascin; PLP, proteolipid protein; TAG, transient axonal glycoprotein.

Milestones of the development of increasingly specific EAE inducible spatially and temporally restricted gene targeting,
models were (Fig. 1): which has been only recently introduced for studies directed to
the CNS (Gavériaux-Ruff and Kieffer, 2007; Hövelmeyer et al.,
(i) Induction of EAE by transfer of total lymph node cells (Paterson, 2005).
1960), isolated MBP-specific T cell-line cells (Ben-Nun et al., Despite the obvious importance of autoimmune processes in
1981) or interleukin-23 (IL-23)-dependent PLP-specific CD4+ T the pathogenesis of MS, there is evidence for a non-immune origin
helper IL-17 (Th17) cells (Langrish et al., 2005) into naive rats of at least some subtypes of MS. For example, even aggressive
or mice, respectively, establishing distinct forms of adoptive immunosuppression is not sufficient to treat progressive MS.
transfer EAE (AT-EAE) and Therefore, additional experimental models are needed, especially
(ii) generation of transgenic mice with deletion (knock-out leading for the study of non-immune-mediated demyelination and axonal
to loss-of-function) or over-expression (knock-in leading to loss via ODC degeneration. For this purpose a toxic model of
gain of function) of pathogenetically relevant genes (reviewed demyelination has been developed that is based on the selective
in Krishnamoorthy et al., 2007). Examples of such genes are toxicity for ODCs of the copper chelator biscyclohexanone
those encoding T cell receptors (TCRs) (Bettelli et al., 2006; oxaldihydrazone (cuprizone) (Blakemore, 1972; Carlton, 1966).
Goverman et al., 1993; Lafaille et al., 1994; Mendel et al., 2004), If young mice are fed with cuprizone, focal demyelination occurs
major histocompatibility complex (MHC) molecules (Friese predominantly in the cerebellar cortex and peduncle. After
et al., 2008; Khare et al., 2005; Linker et al., 2005; Mangalam withdrawal of the toxin spontaneous remyelination can be seen
et al., 2008), cytokines (reviewed in Campbell et al., 1998; predominantly in the rostral regions (Skripuletz et al., 2010;
Owens et al., 2001) as well as neurotrophic factors (Linker et al., Torkildsen et al., 2008). Thereby the cuprizone-model correlates
2005, 2008a, 2009b; Mirowska-Guzel, 2009) and their recep- well with histopathological features of MS, especially in the
tors (Dallenga et al., 2009; Linker et al., 2009b). subtype or variant classified as histological pattern III according to
Lucchinetti et al. (2000), which renders it a useful tool for MS
The constitutive knock-out or knock-in of cytokine genes research (Einstein et al., 2009; Kipp et al., 2009). Paradoxically,
throughout the whole development and adulthood of an animal according to a recent report of Herder et al. (2009) cuprizone
implies serious drawbacks due to redundancy and feed-back ameliorates Theiler’s murine encephalomyelitis suggesting that it
loops of cytokine signal pathways (Owens et al., 2001; Steinman, might have immunomodulatory and/or anti-viral properties in
1997). This constraint can been overcome by approaches with addition to its toxic effects.
390 E. Mix et al. / Progress in Neurobiology 92 (2010) 386–404

1.3. Current EAE models control the susceptibility to the disease and to compare these QTL
with the susceptibility loci in the animal model EAE (Serrano-
Currently, the most common mode of EAE induction is based on Fernández et al., 2004). The high frequency of intergenomic EAE/MS
the injection of an encephalitogenic peptide, mostly MOG35–55 or consensus genes supports the value of EAE for studying of MS
PLP139–151, which is emulsified in CFA containing mineral oil and features. Backcross (offspring-parent mating) and intercross (sibling
Mycobacterium tuberculosis strain H37RA, followed by intraperito- mating) experiments with EAE susceptible and resistant animal
neal injections of pertussis toxin (Fig. 3). The resulting phenotype strains of mice, rats, guinea pigs and hamsters revealed mainly MHC-
depends mainly on the antigen source and the genetic background linked QTL (Encinas et al., 1996; Olsson et al., 2000). Combined-cross
of the animal species and strains used. For example, PLP139–151 analysis could enhance the detection of QTL with moderate effects in
induces a relapsing–remitting EAE in SJL mice, whereas MOG35–55 rats (Jagodic and Olsson, 2006). Genotyping of 150 microsatellite
triggers chronic-progressive EAE in C57BL mice that are the most markers in F2 intercross populations of EAE-susceptible SJL/L mice
favored mice for transgenic experiments (Gold et al., 2006). and EAE-resistant C57BL/10.S mice identified QTL linked to
Crossing of C57BL mice, which over-express MOG-TCR and MOG- increased latency of cortical motor evoked potentials in non-
specific B cells, resulted in a severe form of EAE that closely immunized animals, which correlated with earlier onset of the
replicated Devic’s variant of MS with inflammatory lesions of optic disease (Mazón Peláez et al., 2005). This finding points to a role of
nerves and spinal cord (Bettelli et al., 2006). MOG-TCR transgenic myelin composition and synaptic transmission in susceptibility to
mice backcrossed to SJL/J background develop a relapsing– EAE and provides a chance to detect individuals with high risk for
remitting form of EAE with episodes altering between optic nerve, autoimmune demyelination by QTL analysis before the disease is
cerebellum and spinal cord. Evolution of this model depends on an manifested. In MS, some immune response-related genes have been
intact B cell compartment. Apparently, MOG-TCR transgenic T cells identified by genome-wide association studies using single nucleo-
expand endogenous auto-reactive B cells that manufacture tide polymorphism analysis with microarray technique as being
pathogenic demyelinating auto-antibodies to a conformational heritable risk factors of the disease, although their individual
epitope on native MOG protein whilst not recognizing the T cell contribution is clearly modest with odds ratios for most not
target MOG peptide (Pöllinger et al., 2009). The authors claim to exceeding 1.2 (IMSGC, 2007). These genes include the interleukin
have generated the first spontaneous animal model for relapsing– (IL)-2a and IL-7a receptor genes on chromosomes 10 and 5,
remitting MS. Current types of AT-EAE include those induced by respectively, and some human leukocyte antigens (HLA) belonging
Th17 cells suggesting that these newly detected effector cells may to MHC class II molecules on chromosome 6 (Table 2) (Gregory et al.,
in part be responsible for the pathological heterogeneity of MS 2007; IMSGC, 2007). More recently, the genes encoding the
lesions (Afzali et al., 2007; Gold and Lühder, 2008; Hofstetter et al., following proteins have been confirmed as novel MS risk genes
2007, 2009; Jäger et al., 2009; Korn et al., 2007; Quintana et al., (explanation of abbreviations in Table 2) (Aulchenko et al., 2008;
2008a; Reboldi et al., 2009). All EAE models are directly accessible Dabbeekeh et al., 2007; De Jager et al., 2009a,b; Hafler et al., 2009;
to investigation of the immune and nervous system (Fig. 3), which Hoppenbrouwers et al., 2008, 2009; IMSGC, 2007; Johnson et al.,
interact during the pathogenesis of the disease and which are both 2010; Mero et al., 2010; Rubio et al., 2008; Sarrias et al., 2007):
targeted by established and experimental therapies.
- EV15, CD58, KIF1B, RGS1 and RPL5 (on chromosome 1),
2. Investigation of immunogenetic and pathogenetic features - IL-12A (on chromosome 3),
- PTGER4 (on chromosome 5),
2.1. Immunogenetics of EAE and MS - OLIG3-TNFAIP3 (on chromosome 6),
- CD6 (on chromosome 11),
Since MS appears to be a polygenetically determined disease, - TNFRSF1A (on chromosome 12),
efforts have been undertaken by linkage and association studies to - IRF8 and CLEC16A (on chromosome 16),
define chromosomal regions, quantitative trait loci (QTL), that - CD226 (on chromosome 18), and
[(Fig._3)TD$IG] - TYK2 (on chromosome 19).

The strongest association to MS susceptibility, although not to

the age of onset and severity of the disease, was found for the HLA-
DRB1*1501 allel (Barcellos et al., 2006; Chao et al., 2008), whereas
transgenic mice over-expressing the human HLA-DRB1*1502 allel
developed a severe MOG–EAE (Khare et al., 2005). In contrast, genes
related to antigen processing can also slow down disease progres-
sion as reflected by a milder course of the disease in MOG35–55–EAE
of congenic NOR/LtJ mice compared to the wild-type NOD mice
(Mayo and Quinn, 2007). Similarly, congenic mapping of the rat
genome confirmed that a chromosomal region homologous to a
human MS susceptibility region confers protection against MOG–
EAE (Jagodic et al., 2001). Also, transgenic MOG35–55–EAE mice over-
expressing the TCR for MOG35–55 showed protective rather than
pathogenic effects (Mendel et al., 2004). In contrast, transgenic mice
Fig. 3. Most common animal models of MS with indication of the compartments
over-expressing MBP-specific TCR developed high frequency
investigated for analysis of systemic and local disease processes. For active
immunization antigens are preferentially applied to the flank or toe pad of the spontaneous EAE (Goverman et al., 1993; Lafaille et al., 1994).
animal, since draining lymph nodes of these areas mediate a highly effective The relevance of these findings for the human disease remains to be
systemic immune response to the putative auto-antigens as a first step for elucidated. Research in EAE also yielded hints for the existence of
induction of autoimmune processes in the CNS. Abbreviations: AT-EAE, adoptive
chromosomal loci that control disease susceptibility in dependence
transfer EAE; CFA, complete Freund’s adjuvant; i.p., intraperitoneal; i.v.,
intravenous; LN, lymph node; MOG, myelin oligodendrocyte glycoprotein; PB,
of age and season pointing to a role of chronobiology in
peripheral blood; PLP, proteolipid protein; s.c., subcutaneous; SP, spleen, Th1 cells, autoimmunity (Teuscher et al., 2006). Moreover, EAE susceptibility
T helper type 1 cells. can vary even between different colonies of the same animal strain
 E. Mix et al. / Progress in Neurobiology 92 (2010) 386–404 391

Table 2
Susceptibility genes of MS.

Gene Function References

HLA-DRB1*1501 Antigen presentation Barcellos et al. (2006), Chao et al. (2008),

IMSGC (2007), Khare et al. (2005)
IL-2a receptor T and B cell activation IMSGC (2007)
IL-7a receptor T cell survival, differentiation and homeostasis, Gregory et al. (2007), IMSGC (2007)
B cell development
EV15 GTPase activation Dabbeekeh et al. (2007), Hoppenbrouwers et al. (2008)
CD58 (lymphocyte-associated antigen Ligand of CD2, costimulatory molecule for T De Jager et al. (2009a), Hoppenbrouwers et al. (2009)
3, LFA-3) cells enhancing FoxP3 expression in Treg cells
CLEC16A (C-type lectin domain Unknown function, but highly expressed in Hoppenbrouwers et al. (2009), Johnson et al. (2010),
family 16, member A) dendritic cells, B cells and NK cells. . . Rubio et al. (2008)
CD6
Bacterial molecular pattern recognition and De Jager et al. (2009b), Sarrias et al. (2007)
suppressing TNF-a, IL-6 and IL-1b
IRF8 (IFN regulatory factor 8) Activation or repressing of IFN type I transcription De Jager et al. (2009b), Johnson et al. (2010)
TNFRSF1A (tumor necrosis factor Pro-inflammatory and proapoptotic activity De Jager et al. (2009b)
receptor superfamily, member 1A)
OLIG3-TNFAIP3 (oligodendrocyte Development of neuronal cells, tumor suppression De Jager et al. (2009b)
transcription factor 3—NF-a-induced and anti-inflammation
protein 3)
IL-12A (IL-12p35) Growth factor for activated T and NK cells, Rubio et al. (2008)
enhancing the lytic activity of NK/lymphokine-
activated killer cells
PTGER4 (prostaglandin E receptor 4) Activation of T cell factor signaling De Jager et al. (2009b)
RGS1 (regulator of G-protein signaling 1) B cell activation Johnson et al. (2010)
TYK-2 (tyrosine kinase 2) Intracellular signal transduction of type I IFNs Johnson et al. (2010), Mero et al. (2010)
CD226 Intercellular adhesion, lymphocyte signaling, Hafler et al. (2009)
cytotoxicity and lymphokine secretion mediated
by cytotoxic T cells and NK cells
KIF1B (kinesin family member 1B) Motor protein transporting mitochondria and Aulchenko et al. (2008)
synaptic vesicle precursors
RPL5 (ribosomal protein L5) Transport of nonribosome-associated cytoplasmic Rubio et al. (2008)
5S rRNA to the nucleolus for assembly into ribosomes.

as demonstrated for Lewis rats purchased from different animal with the EAE-susceptible strain C57BL/6 in the MOG35–55–EAE
facilities (Gould et al., 1994). Since the genetic background of these model strongly supported EAE-resistance to be an active process
animals is almost identical, other mechanisms, preferentially those revealing new target genes for therapeutic intervention (Mix et al.,
involving gene regulating, may be responsible for differences in 2004). Moreover, data of Baranzini et al. (2005) derived from the
disease susceptibility and progression. Transcriptome and proteome MOG35–55–EAE model led to new conclusions such as
analyses are powerful new tools for the elucidation of those
mechanisms (Elkabes and Li, 2007; Fernald et al., 2005; Goertsches (i) early non-specific BBB impairment (mainly neutrophil-relat-
and Zettl, 2007; Ibrahim et al., 2001; Ibrahim and Gold, 2005). ed) secondary to immunization with CFA,
(ii) transition from innate to adaptive immune responses before
2.2. Gene expression studies by microarray analysis onset of EAE,
(iii) identification of at least 3 discrete EAE phases (early EAE, peak
An integrated analysis of available data from genome-wide EAE and early recovery) with characteristic gene expression
genetic screens and high-throughput gene expression studies in patterns, and
MS and EAE revealed that differentially expressed genes appear (iv) early neuronal damage.
mainly in clusters rather than in uniform distribution throughout
the genome (Fernald et al., 2005). The hereby included hypothesis- Therefore, gene expression studies can provide new insights into
neutral gene expression studies are mainly performed with the dynamics of discrete early and progressive phases of EAE on the
microarray technique (RNA profiling) and applied in MS patients transcriptional level, which are consistent with the histological and
to peripheral blood mononuclear cells or brain tissue and in EAE clinical phenotype. They can serve as a tool for fingerprinting of
animals to lymphatic and nervous tissue (Goertsches and Zettl, individual disease processes in man. As a practical consequence new
2007; Tajouri et al., 2007). They deliver an increasing wealth of therapeutic targets surface. RNA profiling has also enabled
data, which implies a great challenge for bioinformatic analysis researchers to identify genes which support maintenance of the
that may include pathway analyses using background information hematopoietic stem cell niche synapse as a source for therapeutic
from the Gene Ontology project and other data bases as well as mesenchymal stem cells that can ameliorate EAE (Pedemonte et al.,
data mining approaches. Results of gene expression studies are 2007). On the other hand, EAE can also serve as a tool to validate new
generally hampered by methodical problems such as the targets derived from gene-microarray analysis (Lock et al., 2002).
heterogeneity of the material from different individuals and the Despite the clear benefit of the transcriptome approach there are
difficulties in defining a reasonable threshold for differentially voices advising caution concerning overinterpretation of results of
expressed genes. Nevertheless, meaningful data have already been global gene expression analysis. In any case, due to its obvious
obtained from expression studies in EAE that point to new EAE-QTL limitations transcriptomics should be employed only with a clear
and susceptibility genes, dissect new pathogenic and protective and specific question in mind and carefully in view of the regulatory
pathways and identify new therapeutic targets (Comabella and settings and potential pitfalls of the technique (Casciano and
Martin, 2007; Jelinsky et al., 2005; Matejuk et al., 2003; Mazón Woodcock, 2006; Fathallah-Shaykh, 2005). The same is true for the
Peláez et al., 2005; Mix et al., 2002, 2006; Paintlia et al., 2004). As proteome approach (reviewed in Elkabes and Li, 2007; Linker et al.,
an example, the comparison of the EAE-resistant strain C57BL/10.S 2009a). In EAE, it has served to generate differential protein
392 [(Fig._4)TD$IG]
E. Mix et al. / Progress in Neurobiology 92 (2010) 386–404

expression profiles (Duzhak et al., 2003; Liu et al., 2007), to monitor

the diversity of autoantibody responses (Robinson et al., 2003) and
to validate new therapeutic targets derived from laser-capture
micro-dissections of MS lesions (Han et al., 2008). Also putative lipid
auto-antigens could be identified by the microarray approach in MS
and EAE (Kanter et al., 2006; Quintana et al., 2008b).

2.3. Immunopathogenesis

There is still consensus amongst most researchers that

immunological processes play a pivotal role in the pathogenesis
and progression of MS (Gold et al., 2006; Linker et al., 2008c;
Steinman and Zamvil, 2006; Weiner, 2009), although the
aetiological factors may vary between different subtypes of MS
and may not primarily affect the immune system, especially in
cases with the histopathologic patterns III and IV according to
Lucchinetti et al. (2000). Moreover, in early MS with histologic
patterns I–III Wallerian degeneration seems to contribute signifi-
cantly to axonal loss in the plaques and periplaque white matter
(Dziedzic et al., 2010). The current concept of pathogenetic
processes in MS is schematically depicted in Fig. 4, which indicates
also therapeutic interventions and their putative targets. Recent
paradigm shifts relate to the recognition of new roles for CD8+ T
cells (Friese and Fugger, 2009), B cells (Franciotta et al., 2008),
innate immunity (Weiner, 2009) and emerging pathogenic path-
ways causing neuronal damage (Aktas et al., 2010; Centonze et al.,
2010; Dziedzic et al., 2010; Herz et al., 2009).
EAE models have considerably contributed to our understand-
ing of immune regulatory processes in the pathogenesis of MS
(Gold et al., 2006; Wekerle et al., 1994). While traditionally
regulatory (suppressive) activity in autoimmune processes was
primarily attributed to CD8+ T cells (Zozulya and Wiendl, 2008),
more recently CD4+CD25+FoxP3+ regulatory T cells (Yi et al., 2006)
have attracted interest in this respect (Ephrem et al., 2008; Paintlia
et al., 2008; Tischner et al., 2006). They seem to be important as
antagonists of CD4+ Th17 cells (Afzali et al., 2007; Littman and
Rudensky, 2010; Quintana et al., 2008a) that are supposed to be
effector cells in EAE (Hofstetter et al., 2007; Huppert et al., 2010;
Liu et al., 2010; Steinman, 2007) and MS (Gold and Lühder, 2008).
However, the pathogenic role of Th17 cells and of IL-17 in EAE is
controversial. According to findings of Haak et al. (2009) in
transgenic mice the in vivo function of IL-17 in the CNS may be
redundant and the members of the IL-17 family IL-17A and IL-17F
may contribute only marginally to the autoimmune pathogenesis
of MOG35–55–EAE. On the other hand, Huppert et al. (2010) found
that IL-17A promotes breakdown of the BBB, a crucial step in the
development of EAE. Moreover, findings of Nowak et al. (2009)
point to a pro-inflammatory role of the Th17-derived IL-9 in
MOG35–55–EAE. Th17 cells are driven by IL-21 (Korn et al., 2007) Fig. 4. Putative pathogenic mechanisms of MS. Auto-reactive lymphocytes may be
recruited from peripheral lymphoid organs and after migration through the BBB
and IL-23 (Langrish et al., 2005; McKenzie et al., 2006) and
reactivated in the CNS, where an inflammatory cascade is initiated leading to
suppressed by IL-27 (Fitzgerald et al., 2007; Wang et al., 2008). subsequent damage of myelin and axons. Alternatively, primary oligodendroglial
Recently, the IL-7-IL-7R pathway has been implicated in the and axonal degeneration may be followed by an inflammatory autoimmune
survival and expansion of effector/memory Th17 cells. Blockade of process. The adjacent table depicts the putative pathogenic processes that are
IL-7R rendered differentiated Th17 cells susceptible to apoptosis targeted by established and experimental therapies. Treatments are grouped
according to the contribution made by EAE to their development, i.e. they are either
which led to attenuation of MOG–EAE (Liu et al., 2010).
successfully translated into the clinic (green), only successful in EAE (red) or
Corresponding IL-17+ CD8+ Tc cells show impaired cytotoxicity currently tested in EAE and/or MS (yellow). Abbreviations: AICAR, 5-
and IFN-g production, but may through their excessive IL-17 aminoimidazole-4-carboxamide-1-b-D-ribofuranoside; APC, antigen-presenting
production contribute to inflammatory processes in EAE and MS cell; APL, altered peptide ligand; BBB, blood–brain barrier; BDNF, brain-derived
neurotrophic factor; CD, cluster of differentiation; CNS, central nervous system;
(Huber et al., 2009). Recently, Sobottka et al. (2009) could
CNTF, ciliary neurotrophic factor; CRYAB, aB-crystallin; CYLA, Calpain inhibitor;
demonstrate in brain slices of transgenic mice that myelin- 3,4-DAA, N-(3,4,-dimethoxycinnamoyl) anthranilic acid; DRD1, dopamine receptor
directed CD8+ Tc cells cause extensive damage not only of the type 1; EGCG, ()-epigallocatechin-3-gallate; IL, interleukin; IFN-g, interferon-g;
myelin sheath, but also of the axons. Consequently, these cells may major histocompatibility complex; MOG, myelin oligodendrocyte glycoprotein;
contribute to axonal loss in EAE and probably also in MS with the MP, methylprednisolone; MRI, magnetic resonance imaging; NK, natural killer;
ODC; oligodendrocyte; PLP, proteolipid protein; PPAR-a, peroxisome proliferator-
immunopathologic pattern I according to Lucchinetti et al. (2000).
activated receptor-a; SSRI, selective serotonin reuptake inhibitor; Tc, cytotoxic T
B cells are involved in the immunopathogenesis of MS and EAE cell; TCR, T cell receptor; TGF-b, transforming growth factor-b; Th cell, helper T
at least by two functional activities, i.e. as antigen-presenting cells cell; TNF-a, tumor necrosis factor-a.
 E. Mix et al. / Progress in Neurobiology 92 (2010) 386–404 393

(APCs) and as antibody producers (Franciotta et al., 2008; 2008). Disclosure of the complex mechanisms of neuro-immune
Goverman, 2009; Hohlfeld et al., 2008; Martin Mdel and Monson, interactions requires further investigations in the EAE model.
2007; Weiner, 2009; Ziemssen and Ziemssen, 2005). In addition Many other aspects of MS research are investigated in the
they may co-stimulate T cells, facilitate recruitment of inflamma- animal model. Among them monitoring of disease activity by
tory cells to the CNS and myelin opsonization, but also promote traditional magnetic resonance imaging (MRI) (Morrissey et al.,
remyelination, and take part in immunoregulatory processes. Anti- 1996) and new bioluminescence techniques (Luo et al., 2008)
myelin antibodies are supposed to be major components of the deserve special attention. Identification of reliable surrogate
histopathologic MS pattern II according to Lucchinetti et al. (2000). markers for diagnostic and prognostic purposes (responder
A special role as targets for antibodies in distinct types of EAE and detection for specific therapies, disease follow-up) will be a
MS is ascribed to the myelin molecules MOG (Haase et al., 2001) prominent task of the future. However, a consistent limitation for
and the axonal molecule neurofascin (Hohlfeld et al., 2008). the translation of experimental results into the clinic is the
Another distinct lymphocyte subpopulation that has been different situation in EAE and MS concerning the timeline of
implicated in CNS autoimmunity is the gd+ T cell subset bearing detection of clinical signs and of therapeutic interventions (Fig. 5).
TCRgd. These fetal-type T cells are increased in number in MS Whereas in EAE pathological processes can be observed from the
cerebrospinal fluid (Mix et al., 1990) and may exert pathogenic and beginning and treatment approaches can be started at the early
regulatory functions (reviewed in Blink and Miller, 2009 and pre-clinical phase, in MS diagnostic measures will commonly not
Goverman, 2009). Interestingly, the majority of IL-17 producing be initiated before first clinical signs are present and the intensity
host cells in a Th1-mediated AT-EAE belonged to the gd+ T cell type of treatment increases usually until late progression of the disease.
(Lees et al., 2008).
Adding to the complexity, there is an obvious pathogenic role 3. Development and validation of novel therapies
for EAE and MS of innate immunity mediated by dendritic cells,
monocytes and microglia (Furtado et al., 2006). Whereas the 3.1. Therapies developed primarily in EAE
adaptive immune system seems to drive mainly relapses of MS,
abnormalities of the innate immune system may prevail in the Despite extensive screening for new targets of MS therapy in
progressive stage of the disease (Weiner, 2009). EAE so far only a few of the established MS therapies have been
An important aspect of MS pathogenesis is the apoptotic developed in the animal model. Examples are glatiramer acetate,
activity in the lymphatic and nervous system. Therefore, apoptotic mitoxantrone and natalizumab (Kieseier and Hartung, 2003;
processes have been analysed in EAE. While apoptosis plays Steinman and Zamvil, 2006).
obviously a pivotal pathogenic role when affecting ODCs (Hövel- The glatiramer acetate preparation is a random polymer
meyer et al., 2005), it appears to be protective when eliminating consisting of repeated sequences of the four amino acids glutamic
myelin-reactive and bystander T cells (Zettl et al., 1997). This acid, lysine, alanine and tyrosine that occur in MBP in a specific
process is augmented by therapeutic drugs such as methylpred- molar ratio. It was primarily called copolymer 1 and tested first for
nisolone (MP) (Schmidt et al., 2000) and resveratrol (Singh et al., its encephalitogenic potency and subsequently for its influence on
2007). guinea pig EAE (Teitelbaum et al., 1971). Surprisingly, it turned out
The role of cytokines and neurotrophic factors for the that copolymer 1 suppressed rather than induced EAE, most
pathogenesis of MS and EAE has been investigated in a plethora probably via stimulation of Th2/Th3-mediated anti-MBP immune
of studies and the results have been reviewed elsewhere (Gover- response (Aharoni et al., 1997, 2008). Recent studies utilising
man, 2009; Imitola et al., 2005; Link, 1998; Linker et al., 2009b; sophisticated immunologic techniques point to a more complex
Mirowska-Guzel, 2009; Owens et al., 2001; Ozenci et al., 2002). For mechanism of action of glatiramer acetate, including modification
details the reader is referred to these reviews. and killing of APCs, generation of regulatory T cells and turning the
In addition to the mentioned immunopathogenic pathways a polyclonal CD8+ T cell response into an oligoclonal one (Racke
direct crosstalk between the immune and nervous system may et al., 2010).
influence the pathogenesis of MS and EAE (Kerschensteiner et al., Mitoxantrone has first been proven to be a powerful
2009; Mix et al., 2007). This involves direct effects of cytokines and immunosuppressive drug in EAE (Ridge et al., 1985) and it is
chemokines on nerve cells and modulation of immune cell activity now a second-line component of escalating MS therapy (Hartung
by neurotrophins and neurotransmitters implicating new treat- et al., 2002; Krapf et al., 2005; Neuhaus et al., 2006a,b; Rieckmann
ment approaches, e.g. by associative conditioning (Jones et al., et al., 2004). Its mechanism of action relies most probably on
[(Fig._5)TD$IG]

Fig. 5. Timeline of the pathophysiological and clinical course of EAE and MS. In EAE, the complete pathological course including the pre-clinical phase is detected and immune
therapeutic interventions start early and decrease usually with the proceeding time. In MS, there is an opposite situation. First radiological signs remain usually undetected
and immunomodulatory treatment starts only with first clinical signs and is usually intensified until late progression of the disease. Abbreviations: CIS, clinical isolated
syndrome; CNS, central nervous system; RIS, radiologic isolated syndrome; RRMS, relapsing–remitting MS; SPMS, secondary progressive MS.
394 E. Mix et al. / Progress in Neurobiology 92 (2010) 386–404

cytotoxic effects on lymphocytes and induction of apoptosis of APC ganglion cells and optic nerve of rats with MOG-induced EAE from
such as monocytes and dendritic cells (Neuhaus et al., 2005; morphological and functional impairment, whereas monotherapy
Vollmer et al., 2010). caused only isolated neuronal or axonal protection without clinical
Natalizumab is a monoclonal antibody (mAb) that inhibits the benefit (Diem et al., 2005). In a MBP-induced active rat EAE model,
transmigration of immune cells into the inflamed parenchyma of the anti-inflammatory, anti-demyelinating and neuroprotective
lymphatic organs and the CNS. It binds to a4b1-integrin effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase
(CD49dCD29, very late activation antigen-4) on lymphocytes inhibitory statins could be improved by combination with the
and blocks the interaction with the integrin ligand CD106 (vascular selective phosphodiesterase-4 inhibitor rolipram (Paintlia et al.,
cell adhesion molecule-1) on endothelia cells thereby being 2008; Paintlia et al., 2009) or the protein kinase A activating
effective in preventing EAE (Rice et al., 2005; Yednock et al., substance 5-aminoimidazole-4-carboxamide-1-b-D-ribofurano-
1992). It is the first mAb approved for therapeutic trials in MS side (Paintlia et al., 2006), even when the statin was applied in
(Polman et al., 2006) now belonging to second-line MS therapeu- suboptimal doses. For rolipram alone, beneficial effects in the
tics, although it carries the risk to activate the polyoma virus JC animal model could previously not be reproduced in the human
leading to progressive multifocal leukoencephalopathy, especially system (Zhu et al., 2001). In actively induced chronic murine EAE a
if applied in combination with IFN-b (Clifford et al., 2010; synergistic therapeutic effect of IFN-b and the immunomodulatory
Kleinschmidt-DeMasters and Tyler, 2005; Langer-Gould et al., drug laquinimod was observed (Runström et al., 2006). In a patient
2005; Stüve and Bennett, 2007; Yousry et al., 2006). Recently, even study, the IFN-b-mediated up-regulation of the anti-inflammatory
cases of progressive multifocal leukoencephalopathy on natalizu- cytokine IL-10 was enhanced by additive administration of the
mab monotherapy have been reported (Clifford et al., 2010; non-selective phosphodiesterase inhibitor pentoxiphylline (Weber
Hartung, 2009; Hartung et al., 2009; Lindå et al., 2009; Wenning et al., 1998). Pentoxiphylline also reduced side-effects of IFN-b
et al., 2009). therapy such as myalgia, fever and injection site reactions
(Rieckmann et al., 1996). IVIg decreased T cell apoptosis and liver
3.2. Therapies investigated secondarily in EAE damage, but increased ODC apoptosis in high-dose MBP-treated
rats with AT-EAE induced by MBP-specific T cells (Weishaupt et al.,
A number of established MS therapies have subsequently been 2002). But there are also perilous combination effects, which
investigated in the EAE model. The aims are: cannot always be foreseen and thereby prevented in the animal
model as illustrated by the hazardous combination of IFN-b with
(i) to get a deeper insight into the mechanisms of action including natalizumab (Hartung et al., 2009; Kleinschmidt-DeMasters and
disclosure of the specific targets of the therapies and Tyler, 2005; Langer-Gould et al., 2005; Stüve and Bennett, 2007) or
(ii) to improve regimens of old therapies and to develop new statin (Birnbaum et al., 2008).
therapies targeting the same pathogenic mechanisms, but While disease-modifying agents act largely through modula-
being more convenient for clinical practice (low frequency of tion of peripheral immune mechanisms, some of them appear to
application, oral application) and avoiding adverse side-effects. act additionally or even predominantly locally within the CNS, e.g.
at the BBB like IFN-b (Dhib-Jalbut and Marks, 2010) and
For example, with respect to methylprednisolone therapy for natalizumab (Rice et al., 2005), on resident auto-reactive T cells
MS relapses Schmidt et al. (2000) could unravel a switch from and ODC like fingolimod (Miron et al., 2008, 2010; Papadopoulos
cytoplasmic to nuclear effects accompanied by enhanced T cell et al., 2010). When entering the CNS via a locally disrupted BBB at
apoptosis with increasing steroid dosage. Moreover, liposome lesion site, IFN-b may also directly act on astrocytes (Boutros et al.,
encapsulated MP revealed a dose-dependently increased thera- 1997) and microglia (Prinz et al., 2008) and even exert direct
peutic efficiency compared to free MP in EAE (Linker et al., 2008b). protective effects on neurons (Plioplys and Massimini, 1995).
In IFN-b treated EAE, interruption of therapy caused disease
exacerbation (van der Meide et al., 1998). In an attempt to explore 3.3. Therapy failures in MS
the influence of intravenous immunoglobulin (IVIg) therapy on the
local immune response in the CNS, Jørgensen et al. (2007) found On the other hand, there are several examples of compounds
accumulation of IVIg only in active CNS lesions with BBB which were quite effective in curtailing disease activity in the
breakdown limiting its prospects for repair processes. However, animal model but turned out to lack therapeutic utility or proved
natural CD4+CD25+FoxP3+ regulatory T cells were enhanced by to generate inacceptable adverse effect in MS patients. These
prophylactic application of IVIg in an EAE study of Ephrem et al. inconsistencies prompted Sriram and Steiner (2005) to consider
(2008) suggesting a potential benefit of this therapy in early onset EAE a ‘‘misleading model of MS’’. Examples for therapy failures in
MS. MS are given in Table 3. Reasons for the discrepant result obtained
In other therapeutic trials, two treatments have been combined in the animal and human systems could be manifold. Their nature
in order to achieve synergistic effects and/or to reduce adverse may be genetic (species differences, peculiarities of inbred animal
side-effects of single agents. For example, combined application of strains), pathogenetic (individual variability between MS patients)
MP and erythropoietin protected neurons and axons of retinal or kinetic (different ontogeny and biorhythms, temporal differences

Table 3
Failure of translation of experimental therapies from the animal model to the clinical practice (selected examples).

Therapy Results in MS patients References

Anti-TNF-a mAb infliximab Increased MRI activity van Oosten et al. (1996)
Anti-CD3 and anti-CD4 antibodies No significant clinical effect Wiendl and Hohlfeld (2002)
Anti-CD28 mAb TGN-1412 Cytokine storm causing multiple organ failure Hünig (2007)
Altered peptide ligands Anaphylactic reactions and exacerbation of MS Bielekova et al. (2000), Kappos et al. (2000)
Oral tolerogens No significant clinical effect Faria and Weiner (2006)
Sulfasalazine Only transient clinical effect Noseworthy et al. (1998)
Linomide Cardiopulmonary toxicity Noseworthy et al. (2000)
The table is reproduced from Mix et al. (2008) with permission of the publisher (Springer).
 E. Mix et al. / Progress in Neurobiology 92 (2010) 386–404 395

of immune reactivity and response to therapy). Additionally, in MS 4. Perspectives

the BBB may be insufficiently disrupted as compared to EAE thereby
preventing therapeutic molecules to reach their target within the As outlined before, several therapeutic interventions have been
CNS. This seems to be relevant especially when targeting cytokines successful exclusively in EAE, but not in MS. Other therapeutic
in MS. For example, the mAb to IL-12 p40 ustekinumab failed to agents have shown proven benefit in both EAE and MS. A survey of
improve relapsing–remitting MS despite promising results in rodent these agents is given in Table 4. There are also few instances where
and marmoset EAE (Segal et al., 2008; reviewed in Steinman, 2010). therapeutic agents for the treatment of MS have been clinically
Other promising therapeutic principles revealed already in the developed without prior evaluation in the animal model. Examples
animal model limited benefit or adverse effects precluding their use of such drugs including their proposed mechanism of action are
as MS therapeutics. Examples are: listed in Table 5.
Nonetheless, an increasing number of emerging therapies for MS
(i) the neuroprotective polypeptide hormone ciliary neuro- are currently being tested in pre-clinical phases by making use of the
trophic factor (CNTF), which elicited an acute-phase response EAE model (Cohen and Rieckmann, 2007; Linker et al., 2008c;
in rat liver (Dittrich et al., 1994), Weiner, 2009). The most promising experimental therapies rely on
(ii) the anti-adhesion molecule mAb anti-CD54, which revealed gene transfer, stem cell transplantation, oral administration of small
no MRI effect in AT-EAE (Morrissey et al., 1996), molecular weight disease-modifying drugs and intravenous or
(iii) the Na+-channel blocker phenytoin, which potentially protects subcutaneous application of mAb targeting cells or molecules crucial
demyelinated axons, but resulted in exacerbation of MOG–EAE in the pathogenesis of the disease (Aktas et al., 2010; Bielekova and
after withdrawal (Black et al., 2007), Becker, 2010; Butti et al., 2008; Einstein et al., 2009; Hauser et al.,
(iv) the phosphodiesterase-4 inhibitor rolipram, while very effec- 2008; Hawker et al., 2009; Hemmer and Hartung, 2007; Kieseier
tive in suppressing EAE, failed to suppress inflammatory and Wiendl, 2007; Pluchino and Martino, 2008; Wynn et al., 2010).
activity as gleaned through magnetic resonance imaging in a Table 6 provides a survey of experimental therapeutic approaches
pilot trial in patients with relapsing–remitting MS (Bielekova that are currently being investigated, some of which being already
et al., 2009), approved for phase I-III clinical trials. Table 6 also includes proposed
(v) the immunosuppressive drug cyclosporin A prevented BBB mechanisms of action of the new therapies. Putative targets of
disruption and suppressed the development of EAE, but established and experimental MS therapies with and without prior
was classified as unacceptable for treatment of MS based on testing in EAE are indicated in Fig. 4. Other experimental approaches
risk/benefit consideration due to low efficacy and frequent for MS are based on vaccination, e.g. with pathogenic T cells, TCRs,
adverse reactions (Goodin et al., 2002; Kappos et al., 1988; dendritic cells pulsed with antigen, DNA vaccine encoding MBP,
Kieseier and Hartung, 2003; McCombe et al., 1999; Paul and axonal growth inhibitors associated with myelin or pro-inflamma-
Bolton, 1995). tory cytokines. These approaches are extensively reviewed else-
where (Correale et al., 2008). Recently, a new therapeutic target for a
If one therefore considers only the therapeutic trials conducted in more selective treatment of EAE and MS compared to available
EAE and their translation into the clinic, it may well be regarded as a therapies has been proposed, i.e. the IL-7-IL-7R pathway that affects
misleading model of MS. However, several aspects of the pathogenic Th17 cells, but spares regulatory T cells and unrelated
aetiopathogenesis of MS such as susceptibility genes, immunoregu- immune cells (Liu et al., 2010).
latory circuits, mechanisms of immune cell activation, migration An important field of therapeutic approaches in EAE and MS
and elimination as well as of nervous tissue destruction and repair that will deserve more attention in the future is the enhancement
have been successfully studied in EAE rendering it a useful model of of remyelination. So far experimental trials have involved
MS (Hemmer and Hartung, 2007; Schreiner et al., 2009). EAE will be transplantation of neural stem cells, ODC precursor cells, Schwann
of continued utility in the future if one capitalizes on the availability cells and olfactory ensheathing cells and application of growth
of distinct types of EAE, including those induced in transgenic and factors such as platelet derived growth factor and epidermal
knockout animals, to explore pathogenic pathways and strategies of growth factor (Franklin and Ffrench-Constant, 2008). However,
intervention in different subtypes or variants of MS. these trials are hampered by the fact that the demyelinating

Table 4
Therapeutic agents effective in both MS and EAE.

Agent Clinically isolated syndrome (CIS) MS EAE

Azathioprine Yudkin et al. (1991) Błaszczyk et al. (1978), Rosenthale and

Gluckman (1968)
Cyclophosphamide Gauthier and Weiner (2007), Neuhaus et al. (2007), Mangano et al. (2010)
Vollmer et al. (2010)
Fingolimod Cohen et al. (2010), Kappos et al. (2006b) Balatoni et al. (2007), Foster et al. (2009),
Miron et al. (2008, 2010), Papadopoulos et al. (2010)
Fumarate Kappos et al. (2008) Schilling et al. (2006), Kappos et al. (2008)
Glatiramer acetate Comi et al. (2009) Comi et al. (2001b), Kieseier and Hartung (2003) Aharoni et al. (1997, 2008), Racke et al. (2010),
Teitelbaum et al. (1971)
IFN-b Comi et al. (2001a, 2009), Kappos and Lindberg (2007), Kieseier and Dhib-Jalbut and Marks (2010), Ruuls et al. (1996)
Jacobs et al. (2000), Hartung (2003), Marrie and Cohen (2007)
Kappos et al. (2006a, 2007)
Laquinimod Comi et al. (2008) Brunmark et al. (2002), Runström et al. (2006),
Wegner et al. (2009), Yang et al. (2004)
Methotrexate Goodkin et al. (1995), Neuhaus et al. (2007), Lange et al. (2005)
Vollmer et al. (2010)
Methylprednisolone Fox and Kinkel (2007) Lühder and Reichardt (2009)
Mitoxantrone Edan et al. (2007), Hartung et al. (2002), Ridge et al. (1985), Neuhaus et al. (2006a)
Krapf et al. (2005), Neuhaus et al. (2006a,b),
Rieckmann et al. (2004), Vollmer et al. (2010)
Natalizumab Polman et al. (2006); Rice et al. (2005) Rice et al. (2005), Yednock et al. (1992)
396 E. Mix et al. / Progress in Neurobiology 92 (2010) 386–404

Table 5
Experimental therapies for MS evaluated in clinical trials without prior investigation in the animal model (selected examples).

Therapy Proposed mechanism of action References

Monoclonal antibodies Bielekova and Becker (2010), McLaughlin and

Wucherpfennig (2008), Linker et al. (2008c)
- Rituximab,ocrelizumab, Anti-CD20 inhibits B cells. Hauser et al. (2008), Hawker et al. (2009)
ofatumumab
- Daclizumab Anti-CD25 inhibits lymphocyte activation and expands subpopulation Rose et al. (2007), Wynn et al. (2010)
of regulatory T cells.
- Alemtuzumab Anti-CD52 depletes lymphocytes. CAMMS 223 Trial Investigators (2008),
Jones and Coles (2008)
Teriflunomide Dihydro-orotate dehydrogenase inhibitor disrupts the immunologic synapse. O’Connor et al. (2006), Zeyda et al. (2005)
Temsirolimus Antifungal antibiotic rapamycin acts immunosuppressive. Carlson et al. (1993), Keever-Taylor
et al. (2007)
Cladribine 2-Chloro-20 -deoxyadenosine alters binding of transcription factors to the Foley et al. (2004), Giovannoni et al. (2010),
gene regulatory AT-rich sequences; accumulated cladribine nucleotides Hartung et al. (2010), Sipe et al. (1996)
disrupt DNA synthesis and repair and suppress CD4+ and CD8+ T cells.
The table is reproduced from Mix et al. (2008) with slight modification with permission of the publisher (Springer).

Table 6
Experimental therapies for MS as tested in EAE.

Therapeutic approach Proposed mechanism of action References

Gene therapy Furlan et al. (2003)

- IL-4 Inhibits Th1 cell activation. Broberg et al. (2004),
Butti et al. (2008)
- IFN-b Inhibits local autoimmune reaction in the CNS. Makar et al. (2008a)
Stem cell transplantation Scolding (2006)
- Mesenchymal stem cells Modulate T cell function, decrease IL-17 via IL-23 secretion. Pedemonte et al. (2007),
Wang et al. (2008)
- Neural stem cells Down-regulate inflammation, stimulate the endogenous brain repair system. Aharonowiz et al. (2008),
Einstein et al. (2006, 2009),
Martino and Pluchino (2007),
Pluchino and Martino (2008)
Neurotrophic factors Mirowska-Guzel (2009)
- BDNF Reduces inflammation and apoptosis. Makar et al. (2008b)
- Erythropoietin Activates the neuroprotective phosphatidylinositol 3-kinase/Akt pathway, Agnello et al. (2002),
down-regulates glial MHC class II. Sättler et al. (2004),
Yuan et al. (2008)
Monoclonal antibodies Buttmann and Rieckmann (2008),
Lutterotti and Martin (2008),
Rose et al. (2008)
Natalizumab Anti-CD49d inhibits lymphocyte adhesion. Rice et al. (2005),
Stüve and Bennett (2007)
Anti-cytokines Small molecular weight drug suppresses pro-inflammatory cytokines. Karpus et al. (2008)
CRYAB Stress protein aB-crystallin has an anti-inflammatory effect. Ousman et al. (2007)
Beta-lactam antibiotic Ceftriaxone modulates myelin antigen presentation and impairs Melzer et al. (2008)
antigen-specific T cell migration into the CNS.
Steroids Estradiol and progesterone increase BDNF and myelination. Garay et al. (2008)
Statins 3-Hydroxy-3-methylglutaryl-coenzymeA-reductase inhibitors Aktas et al. (2003),
prevent geranyl-geranylation of RhoA GTPase and its tethering to the Mix et al. (2006),
membrane and thereby inhibit T cell activation and infiltration into the CNS. Stanislaus et al. (1999),
Waiczies et al. (2008),
Youssef et al. (2002)
Fingolimod (FTY720) Sphingosine-1-phosphate agonist reduces systemic T and B cell response Balatoni et al. (2007),
as well as auto-reactive T cells in the CNS and it promotes remyelination Foster et al. (2009),
by stimulation of ODC function. Kappos et al. (2006b),
Miron et al. (2008, 2010),
Papadopoulos et al. (2010)
Fumarate (BG-12) Fumaric acid esters increase the anti-inflammatory cytokine IL-10. Schilling et al. (2006)
Minocycline Inhibits matrix metalloproteinases and thereby T cell transmigration. Brundula et al. (2002)
Gemfibrozile, fenofibrate, Peroxisome proliferator-activated receptor (PPAR)-a agonists increase the Lovett-Racke et al. (2004)
ciprofibra anti-inflammatory cytokine IL-4.
Laquinimod Linomide-derivative ABR-215062 changes the cytokine balance towards Brunmark et al. (2002),
the anti-inflammatory cytokines IL-4, IL-10 and TGF-b Comi et al. (2008),
Runström et al. (2006),
Wegner et al. (2009),
Yang et al. (2004)
AICAR Protein kinase A activating 5-aminoimidazole-4-carboxamide-1- Nath et al. (2005)
b-D-ribofuranoside inhibits the pro-inflammatory cytokines IFN-g
and TNF-a and induces the anti-inflammatory cytokines IL-4 and IL-10.
CYLA Calpain inhibitor reduces inflammatory infiltration, demyelination Hassen et al. (2008)
and axonal injury.
3,4-DAA Derivative of tryptophan metabolite N-(3,4,-Dimethoxycinnamoyl) Platten et al. (2005)
anthranilic acid inhibits pro-inflammatory cytokines.
EGCG Green tea constituent ()-epigallocatechin-3-gallate blocks proteasome Aktas et al. (2004)
complex, proliferation and TNF-a production of encephalitogenic T
cells and formation of neurotoxic reactive oxygen species.
 E. Mix et al. / Progress in Neurobiology 92 (2010) 386–404 397

Table 6 (Continued )

Therapeutic approach Proposed mechanism of action References

Flavonoids Luteoline scavenges oxygen radicals, inhibits RhoA GTPase and Hendriks et al. (2004)
prevents monocyte infiltration into the CNS.
Metallothionein I and II Antioxidant proteins act anti-inflammatory and neuroprotective. Espejo et al. (2005)
Vitamin D 1,25-Dihydroxyvitamin D3 declines inducible nitric oxide synthase, Pedersen et al. (2007)
chemokines and monocyte recruitment into the CNS and stimulates
activated CD4+ T cell apoptosis in the CNS.
K+-channel blocker Alkoxypsoralens, kaliotoxin, charybdotoxin, psora-4, bupivacaine, Beeton et al. (2001),
anandamide, spermine and ruthenium red inhibit T cell activation. Meuth et al. (2008),
Strauss et al. (2000),
Wulff et al. (2009)
Na+-channel blocker Phenytoin, flecainide and lamotrigine prevent axonal degeneration. Bechtold et al. (2004),
Bechtold et al. (2006),
Lo et al. (2003)
Dopamine receptor antagonists DRD1 antagonist SCH23390 blocks dopamine receptors on Th17 cells. Nakano et al. (2008)
Glutamate receptor antagonists AMPA/kainate antagonists NBQX and MPQX prevent glutamate-mediated Smith et al. (2000)
demyelination and neuronal death.
Histamine receptor antagonists Histamine-1 receptor antagonist hydroxyzine blocks mast cell degranulation. Dimitriadou et al. (2000)
Serotonin reuptake inhibitors Venlafaxine suppresses pro-inflammatory cytokines. Vollmar et al. (2008)
Bifunctional hybrid molecules
Bifunctional peptide inhibitor (BPI) Hybrid peptides made of integrin CD11a237–246 and antigenic Kobayashi et al. (2008)
epitopes PLP139–151 or glutamic acid decarboxylase GAD208–217
block the immunologic synapse.
Fulleren hybrid molecule (ABS-75) Hybrid molecules made of an antioxidant carboxy-fullerene Basso et al. (2008)
moiety and NMDA receptor-targeting adamantyl groups inhibit
oxidative injury, chemokine expression, CD11b+ cell infiltration,
demyelination and axonal loss.
The table is reproduced from Mix et al. (2008) with slight modification with permission of the publisher (Springer).

Table 7
Comparison of immunopathological, clinical and therapeutic features of EAE and MS.

EAE MS

Genetics Susceptible and resistant animal strains and colonies, e.g. C57BL/6 Weak evidence of association (confirmed only
vs C57BL/10.S mice and different colonies of Lewis rat for HLA-DRB1*15), risk alleles: IL-2RA, IL-7RA
and EV15
Pathology
- Inflammation Dominant (CD4+ T cells and macrophages) Rare (type I/II, CD4+/CD8+ T cells, CD20+ B cells,
macrophages)
- Demyelination Rare (anti-MOG–EAE) Strong
- Degeneration Late (murine EAE) Early (type III/IV)
- Cortical lesions Rare (MOG–EAE in marmosets) Rare
Clinical course
- Acute Frequent (active EAE) Rare (Marburg type)
- Primary chronic-progrssive Rare (MOG–EAE, AT-EAE) Rare (<10%)
- Relapsing–remitting Rare (PLP139–151–EAE, pertussis toxin-EAE) Frequent (>90%)
- Immunotherapy
- Immunosuppression/ Azathioprine, IFN-b, glatiramer acetate, gene therapy, stem cell Azathioprine, IFN-b, glatiramer acetate, plasma
immunomodulation transplantation, mitoxantrone, mAb, small molecular weight exchange, immunoadsorption, mitoxantrone, mAb, IVIg
disease-modifying drugs
- Anti-inflammatory Methylprednisolone Methylprednisolone
- Antigen specific Altered peptide ligands, bifunctional peptide inhibitors, oral and
nasal tolerance, DNA vaccines
- Neuroprotective CNTF, BDNF, erythropoietin

lesions are regularly wide-spread and dispersed within the CNS ation. Further information on advantages and disadvantages of EAE
and that they, additionally, lack stimulating factors of ODC and additionally of virus-mediated demyelinating diseases can be
precursor cell recruitment and differentiation, or even contain derived from the excellent monograph ‘‘Experimental models of
inhibitory factors of remyelination like the neurite outgrowth multiple sclerosis’’ edited by Lavi and Constantinescu (2005).
inhibitor-A (Nogo-A) and its receptor component leucin-rich In summary, specific questions of MS genetics, pathogenesis
repeat and Ig domain containing-1 (Lingo-1) (Pernet et al., and therapy require investigations in different available and
2008). Therefore, current efforts to enhance remyelination in forthcoming EAE models. A comparison of the most important
EAE and MS rely mainly on established therapies with remyelinat- immunopathological, clinical and therapeutic features of EAE and
ing potency such as IVIg, especially polyclonal IgM (Bieber et al., MS is given in Table 7. Thereby it becomes obvious that great
2000; Trebst and Stangel, 2006; Wright et al., 2009), glatiramer precaution is advisable when translating the results of experimen-
acetate (Aharoni et al., 2008; Arnon and Aharoni, 2009; Racke et al., tal therapeutic trials into clinical practice.
2010) and fingolimod (Miron et al., 2008, 2010) or on the
application of antagonists of the remyelination inhibitors Nogo- Conflict of interest
A and Lingo-1 (Bourquin et al., 2008; Mi et al., 2007, 2009; Rudick
et al., 2008; Yang et al., 2010). Eilhard Mix, Hans Meyer-Rienecker, Hans-Peter Hartung and
This review is restricted to the EAE model of MS and a short Uwe K. Zettl have no conflict of interest related to this review to
reference to the toxic cuprizone-mediated model of demyelin- declare.
398 E. Mix et al. / Progress in Neurobiology 92 (2010) 386–404

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