ReviewExperimental in vivo and in vitro models of multiple sclerosis: EAE and beyond
Introduction
Multiple sclerosis (MS), a common demyelinating disease of young adults can be classified in the group of inflammatory, demyelinating disease. That many inflammatory, demyelinating disorders in humans and animals, where the aetiological agent is known, are due to viral infection has lead to the development of several viral models to study MS. The autoimmune view of MS is strongly supported by the animal model experimental autoimmune encephalomyelitis (EAE), a group of disorders characterised by inflammation, myelin damage and neurodegeneration induced following immunisation with brain antigens. Remyelination, however, is better studied in toxin models such as the cuprizone model, where adaptive immune responses are not involved. Despite the extensive use of these models, the clinical course, immunology and neuropathology reflect only part of the pathological spectrum of MS, indicating that responses to therapies in animal models often cannot predict efficacy in humans. Thus, to understand the interactions between the human immune system and the human CNS, in vitro cultures of microglia, oligodendrocytes, astrocytes and neurons have been established. To study complex interactions of the blood–brain barrier (BBB) and cellular interactions, mouse brain spheroid cultures have been used to examine e.g. myelin damage. Of more relevance are human brain organotypic brain slice cultures in which the cells as well as the extracellular matrix are intact. While the latter models require further refinements to model demyelination and neurodegeneration, these new approaches highlight the importance and availability of novel yet relevant models to study the complexity of MS.
Several important issues surrounding the use of experimental animal models to study MS, or indeed other disorders, have recently been addressed (Baker et al., 2011, Vesterinen et al., 2010). Here, we also draw attention to the ‘Animals in Research: Reporting In Vivo Experiments’ (ARRIVE) guidelines recently released with the aim of improving the quality of research using animals (Kilkenny et al., 2010). Given the currently available 8400 papers on EAE it is appropriate to highlight and bring to attention this report. Examining and, where appropriate, adopting the ARRIVE guidelines will clearly improve experimental findings in MS research using experimental systems to model the disease.
Section snippets
Viral models
The similarities between MS pathology and viral demyelinating disorders of the CNS (Table 1) as well as epidemiological observations have made the infectious aetiology of MS an attractive hypothesis. Electron microscopical and virological studies have supported this by revealing the presence of viruses in MS brain tissues. In animals natural infections e.g. canine distemper virus in dogs, visna virus in sheep, and mink encephalitis, induce myelin damage in the CNS, and several of these were
Experimental autoimmune encephalomyelitis
Immunisation of susceptible animals with CNS antigens gives rise to a spectrum of inflammatory disorders collectively named EAE (Table 2). Although the experimental disease in animals was originally termed experimental disseminated encephalomyelitis, the idea that the ‘disease’ was allergic gave rise to the name experimental allergic encephalomyelitis. More recently, allergic has been replaced by autoimmune. Despite differences in disease course and pathology, EAE is still the most intensely
Transgenic mouse models
The generation of transgenic (tg) mice has greatly aided our understanding of the pathogenic mechanisms operating in EAE. Here we briefly review the major approaches using tg mice to examine the role of autoimmune responses to myelin, chemokines, cytokines and mechanisms of neuronal or oligodendrocyte damage. Transgenic mice expressing HLA haplotypes linked to susceptibility to MS have allowed dissection of human elements involved in EAE. While these animals offer unique approaches to
Toxin models
In principal, toxin demyelination can be induced by either focal application or systemic administration of the toxin. Agents for focal demyelination used so far are lysolecithin, also called lysophosphatidylcholine (LPC), ethidium bromide (EB) (Franklin et al., 1993, Mothe and Tator, 2008, Talbott et al., 2006), 6-aminonicotinamide (Blakemore, 1978), antibodies to oligodendrocyte-related proteins (Rosenbluth et al., 2003, Rosenbluth and Schiff, 2009), bacterial endotoxin (Felts et al., 2005)
In vitro models
Although animal studies have significantly contributed to the understanding of MS they only partially mimic the underlying pathogenic processes. In vitro approaches are thus crucial to study the role of CNS cells, allowing manipulations that cannot easily be performed in vivo. Many of the CNS culture systems commonly used are of animal origin. We would like to stress at this point that several essential differences exist between the rodent and human brain. Thus human in vitro models, such as
Perspectives and conclusions
The choice of the experimental model ultimately depends on the research question and the availability of technical equipment for e.g. stereotactic injections. The clinical episodes of neurological disease in EAE models provide excellent opportunities to uncover immune mechanisms leading to both myelin damage and neuronal and axonal degeneration and dysfunction. For therapeutic studies, the chronic-relapsing models better reflect the human situation in MS, allowing strategies to inhibit
Acknowledgments
The authors thank MS Research; the multiple sclerosis society of the Netherlands, the multiple sclerosis of Great Britain and Northern Ireland, the Deutsche Forschungsgemeinschaft (DFG), Hertie foundation and the DANA foundation for financial support for studies involved in this review. Dr. Hans van Noort is gratefully acknowledged for his critical and constructive views on this manuscript.
References (195)
- et al.
Neuronal damage in autoimmune neuroinflammation mediated by the death ligand TRAIL
Neuron
(2005) - et al.
Induction of chronic relapsing experimental allergic encephalomyelitis in Biozzi mice
Journal of Neuroimmunology
(1990) - et al.
Maedi-visna: the meningoencephalitis in naturally occurring cases
Journal of Comparative Pathology
(2009) Lesions in the cat spinal cord following local injections of 6-aminonicotinamide
Research in Veterinary Science
(1978)- et al.
Selective regulation of growth factor expression in cultured cortical astrocytes by neuro-pathological toxins
Neurochemistry International
(2009) - et al.
Culture and regeneration of human neurons after brain surgery
Journal of Neurosciences Methods
(2001) - et al.
New insights on culture and calcium signalling in neurons and astrocytes from epileptic patients
International Journal of Devlopmental Neuroscience
(2011) Spongiform encephalopathy induced in rats and guinea pigs by cuprizone
Experimental and Molecular Pathology
(1969)- et al.
Oxidative stress and reduced glutamine synthetase activity in the absence of inflammation in the cortex of mice with experimental allergic encephalomyelitis
Neuroscience
(2011) - et al.
Influence of rat substrain and growth conditions on the characteristics of primary cultures of adult rat spinal cord astrocytes
Journal of Neurosciences Methods
(2011)
Astrocytes as potential targets to suppress inflammatory demyelinating lesions in multiple sclerosis
Neurochemistry International
Minocycline promotes remyelination in aggregating rat brain cell cultures after interferon-gamma plus lipopolysaccharide-induced demyelination
Neuroscience
Tumor-necrosis-factor-related apoptosis-inducing-ligand (TRAIL)-mediated death of neurons in living human brain tissue is inhibited by flupirtine-maleate
Journal of Neuroimmunology
Cuprizone and piperonyl butoxide, proposed inhibitors of T-cell function, attenuate experimental allergic encephalomyelitis in SJL mice
Journal of Neuroimmunology
Neuronal in vitro models for the estimation of acute systemic toxicity
Toxicology In Vitro
Adult human brain cell culture for neuroscience research
International Journal for Biochemistry and Cell Biology
A technique for producing demyelination of the rat optic nerves
Journal of Clinical Neuroscience
An experimental model of secondary progressive multiple sclerosis that shows regional variation in gliosis, remyelination, axonal and neuronal loss
Journal of Neuroimmunology
Macrophage-like cells originate from neuroepithelium in culture: characterization and properties of the macrophage-like cells
International Journal of Devlopmental Neuroscience
Human rotation-mediated fetal mixed brain cell aggregate culture: characterization and N-methyl-D-aspartate toxicity
Neuroscience Letters
Encephalitogenic and tolerogenic potential of altered peptide ligands of MOG and PLP in Biozzi ABH mice
Journal of Neuroimmunology
Absence of perforin expression confers axonal protection despite demyelination
Neurobiology of Disease
Axonal loss and gray matter pathology as a direct result of autoimmunity to neurofilaments
Neurobiology of Disease
Differentiation of mouse embryonic stem cells into neurons using conditioned medium of dorsal root ganglia
Journal of Bioscience and Bioengineering
Microglia: a sensor for pathological events in the CNS
Trends in Neuroscience
Tamoxifen-inducible glia-specific Cre mice for somatic mutagenesis in oligodendrocytes and Schwann cells
Molecular and Cellular Neuroscience
An in vitro model for neuroscience: differentiation of SH-SY5Y cells into cells with morphological and biochemical characteristics of mature neurons
Journal of Alzheimer's Disease
Practical guide to the induction of relapsing progressive experimental autoimmune encephalomyelitis in the Biozzi ABH mouse
Multiple Sclerosis and Related Disorders
Identification of a major encephalitogenic epitope of proteolipid protein (residues 56–70) for the induction of experimental allergic encephalomyelitis in Biozzi AB/H and nonobese diabetic mice
Journal of Immunology
Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice
Journal of Immunology
Role of immune responses in protection and pathogenesis during Semliki Forest virus encephalitis
Journal of General Virology
Encephalitogenic epitopes of myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein for experimental allergic encephalomyelitis induction in Biozzi ABH (H-2Ag7) mice share an amino acid motif
Journal of Immunology
Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation
Nature Medicine
Oligodendrocyte-specific protein is encephalitogenic in rhesus macaques and induces specific demyelination of the optic nerve
European Journal of Immunology
Critical appraisal of animal models of multiple sclerosis
Multiple Sclerosis
The origin and application of experimental autoimmune encephalomyelitis
Nature Reviews Immunology
Endogenous amyloidogenesis in long-term rat hippocampal cell cultures
BMC Neuroscience
Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis
Journal of Experimental Medicine
Lysolecithin induces demyelination in vitro in a cerebellar slice culture system
Journal of Neuroscience Research
Modelling large areas of demyelination in the rat reveals the potential and possible limitations of transplanted glial cells for remyelination in the CNS
Glia
Remyelination in experimental models of toxin-induced demyelination
Current Topics in Microbiology and Immunology
Demyelination in cultures of rat cerebellum produced by experimental allergic encephalomyelitic serum
Transactions of the American Neurological Association
Characterization of three human oligodendroglial cell lines as a model to study oligodendrocyte injury: morphology and oligodendrocyte-specific gene expression
Journal of Neurocytology
Experimental demyelinating optic neuropathy: a model for combined morphological and electrophysiological studies
Clinical and Experimental Neurology
Neural progenitor cells derived from the adult rat subventricular zone: characterization and transplantation
Cell Transplant
Production of neurons, astrocytes and oligodendrocytes from mammalian CNS stem cells
Nature Protocols
Olig2 overexpression induces the in vitro differentiation of neural stem cells into mature oligodendrocytes
Stem Cells
A dynamic in vitro BBB model for the study of immune cell trafficking into the central nervous system
Journal of Cerebral Blood Flow and Metabolism
S. Differentiation of induced pluripotent stem cells into functional oligodendrocytes
Glia
Axonal damage is T cell mediated and occurs concomitantly with demyelination in mice infected with a neurotropic coronavirus
Journal of Virology
Cited by (79)
The innovative animal monitoring device for experimental autoimmune encephalomyelitis (“I AM D EAE”): A more detailed evaluation for improved results
2022, Multiple Sclerosis and Related DisordersMultiple sclerosis and neuromyelitis optica spectrum disorders
2022, Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders, Second Edition