Mouse Models for Multiple Sclerosis

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Introduction: For complex diseases like multiple sclerosis (MS), animal models are highly important because they allow researchers to systematically study numerous factors which contribute to the disease in ways that are not possible in human patients. Animal models also serve as testing arenas for potential treatments. However, the disease complexity which makes animal models so necessary also means that animal models are only able to reflect some aspects of human MS.

Induced Models

Experimental autoimmune encephalomyelitis (EAE) is the oldest model of demyelinating diseases (1), and has led to the discovery of human therapies for MS, but EAE has shortcomings that make it difficult to connect findings from the animal model to the human disease, particularly with respect to drug testing (2). To induce EAE, researchers stimulate a T-cell-mediated immune response against myelin, which leads to an inflammatory response in the CNS, and demyelination. Not only is the pathophysiology of EAE potentially very different from MS, but since EAE is an induced model, the data is highly dependent on how the experiment is performed (3).

Viral Models

Epstein-Barr virus (EBV) infection has been identified as an environmental factor linked to MS susceptibility, and it is likely that other viruses can contribute as well (4,5). Many researchers have used Theiler’s murine encephalomyelitis virus (TMEV) intracerebral injections to cause demyelinating disease in mice. Despite being virally-induced, the pathology of these models is mediated by the immune system, not by direct viral effects. Also, the disease course is similar to that observed in chronic progressive MS, making these viral models valuable for studying MS (6).

Genetic Models

Transgenic mice have come to the forefront of MS research. Unlike previous animal models, some transgenic mouse models can spontaneously develop demyelinating disease, thereby mimicking a key aspect of MS. Two groups independently generated nearly identical double-transgenic mouse models that express both T-cell and B-cell receptors both recognizing myelin oligodendrocyte glycoprotein (MOG) (7-9). About half of these mice spontaneously develop an MS-like disease.

Humanized mouse models have also become powerful MS models in recent years. For example, mice expressing MS-associated versions of human leukocyte antigen (HLA) genes can be used in EAE induction experiments, and results can be translated more directly to MS in humans (10).

Reference

  1. Wolf A, Kabat EA, Bezer AE. (1947) The pathology of acute disseminated encephalomyelitis produced experimentally in the rhesus monkey and its resemblance to human demyelinating disease. J Neuropathol Exp Neurol. 6:333-57.
  2. Sriram S, Steiner I. (2005) Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis. Ann Neurol. 58:939-45.
  3. Amor S, Baker D. (2012) Checklist for reporting and reviewing studies of experimental animal models of multiple sclerosis and related disorders. Mult Scler Relat Disord. 1:111-5.
  4. De Jager PL, Simon KC, Munger KL, Rioux JD, Hafler DA, Ascherio A. (2008) Integrating risk factors: HLA-DRB1* 1501 and Epstein-Barr virus in multiple sclerosis. Neurology. 70:1113–1118.
  5. Ascherio A, Munger KL. (2007) Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 61:288–299.
  6. Denic A, Johnson AJ, Bieber AJ, Warrington AE, Rodriguez M, Pirko I. (2011) The relevance of animal models in multiple sclerosis research. Pathophysiology. 18:21-9.
  7. Ransohoff RM. (2006) A mighty mouse: building a better model of multiple sclerosis. J Clin Invest. 116:2313-6.
  8. Krishnamoorthy G, Lassmann H, Wekerle H, Holz A. (2006) Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation. J Clin Invest. 116:2385-92.

Original Source: Cyagen Biosciences (www.cyagen.com)

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