The relevance of animal models in multiple sclerosis research

Abstract

Multiple Sclerosis (MS) is a complex disease with an unknown etiology and no effective cure, despite decades of extensive research that led to the development of several partially effective treatments. Researchers have only limited access to early and immunologically active MS tissue samples, and the modification of experimental circumstances is much more restricted in human studies compared to studies in animal models. For these reasons, animal models are needed to clarify the underlying immune-pathological mechanisms and test novel therapeutic and reparative approaches. It is not possible for a single mouse model to capture and adequately incorporate all clinical, radiological, pathological and genetic features of MS. The three most commonly studied major categories of animal models of MS include: (1) the purely autoimmune experimental autoimmune/allergic encephalomyelitis (EAE); (2) the virally induced chronic demyelinating disease models, with the main model of Theiler's Murine Encephalomyelitis Virus (TMEV) infection and (3) toxin-induced models of demyelination, including the cuprizone model and focal demyelination induced by lyso-phosphatidyl choline (lyso-lecithine). EAE has been enormously helpful over the past several decades in our overall understanding of CNS inflammation, immune surveillance and immune-mediated tissue injury. Furthermore, EAE has directly led to the development of three approved medications for treatment in multiple sclerosis, glatiramer acetate, mitoxantrone and natalizumab. On the other hand, numerous therapeutical approaches that showed promising results in EAE turned out to be either ineffective or in some cases harmful in MS. The TMEV model features a chronic-progressive disease course that lasts for the entire lifespan in susceptible mice. Several features of MS, including the role and significance of axonal injury and repair, the partial independence of disability from demyelination, epitope spread from viral to myelin epitopes, the significance of remyelination has all been demonstrated in this model. TMEV based MS models also feature several MRI findings of the human disease. Toxin-induced demyelination models has been mainly used to study focal demyelination and remyelination. None of the three main animal models described in this review can be considered superior; rather, they are best viewed as complementary to one another. Despite their limitations, the rational utilization and application of these models to address specific research questions will remain one of the most useful tools in studies of human demyelinating diseases.

Introduction

Multiple Sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system [1]. It is the leading cause of non-traumatic disability among young adults and has great socioeconomic impact in developed countries. According to the National MS Society, approximately 400,000 people have been diagnosed with MS in the United States, with 200 new cases added every week. MS is a very heterogeneous disease from a variety of standpoints, including its clinical presentation, radiological features, immuno-pathological subtypes, response to therapy and genetic associations. A recent detailed analysis of a large series of active demyelinating lesions revealed four distinct patterns of immune-pathology [2]. The first two patterns feature well-demarcated perivascular demyelination and relative sparing of oligodendrocytes. Lesions in patterns I and II show close similarities to T cell-mediated and T cell- and antibody-mediated autoimmune demyelination. Lesions in patterns III and IV are suggestive of oligodendrogliopathy in an inflammatory background [3] (Fig. 1).

To date, there is still no definitive cause and no effective cure for MS, although several genetic and environmental risk factors have been identified, and a number of partially effective preventive treatment modalities are now available to modify the disease course. Therefore, animal models of MS are needed to further explore mechanisms of disease initiation and progression and test various therapeutical and restorative approaches. Given that MS is a complex disease with an unclear etiology; a single animal model is unlikely to accurately represent all aspects of pathology and clinical features of human MS. However, the availability of three major animal models of MS enables studies of several relevant features of the human disease.