Multiple Sclerosis (MS) is an inflammation-driven disease of the Central Nervous System (CNS). It is characterized by increased mononuclear cell infiltration of the CNS and autoimmune destruction of the myelin sheath of neurons resulting in distinct lesions/scarring and increased neural dysfunction. It is not known what causes this condition but there does seem to be a significant part played by the immune system. Supporting this is how MS mouse models develop lesions similar to those seen in MS patients after immunization with CNS-derived autoantigens or autoreactive T cells, broadly termed “immune theory”. This mouse model of MS is called experimental autoimmune (or allergic) encephalomyelitis (EAE) and it is currently the most commonly used mouse model of MS. “EAE mice” is a very broad term that describes a range of subsets of EAE with different pathologies and aetiologies. Each of these subtypes allows researchers to focus on different stages and subtypes of MS.
While much has been learnt about MS from murine models, there are some issues that researchers need to take into consideration. Here we’ll briefly examine some of the upsides and downsides of murine EAE models of MS as well as factors that make the whole issue very complicated indeed!
The Upside of Using EAE Mice
| Looks Similar: | There is much symptomatology overlap between the two disease including paralysis and incontinence. |
| Pathologic Similarities: | Demyelination (in some but not all EAE models) and inflammatory cell infiltration of the CNS (although the cell profile varies). |
| Affordable and Logistically Simple: | Mice are relatively inexpensive models and are easy to work with. Certainly the complexity and cost of mouse studies is nothing compared to human trials. |
| Lower Ethical Barrier: | Potentially harmful medications can be tested in animals rather than risking human lives so it is easier to justify murine studies and to take chances with new treatment ideas. |
| More Control: | Murine models can be controlled in ways not possible in humans, from their genetic makeup to their environment. This allows researchers more freedom with experimental design. It has its drawbacks however (see point two in the next section). |
| Lots of Help: | There are a wide variety of techniques that can be used to try out new treatments and there are a lot of tools available to assist in teasing out the details of the disease, e.g. flow cytometric antibody markers. |
| Source of New Ideas: | Studying mice with similar disorders to MS can provide new paths for exploration for example stem cell therapy looks promising in mice and may prove so in humans too. |
| Looking More Like Us: | Humanized mice (or “chimeras”) and genetically engineered (GE) mice allow us to more closely approximate the human version of the disease. Human progenitor cells or tissues are injected into immunodeficient mice from MS patients’ CSF in order to force their cells to appear more human-like. There are many more humanized mouse models available each year. |
The Downside of Using EAE Mice
| Different Chronic Features: | EAE is usually an acute, monophasic disease similar to acute demyelinating encephalomyelitis whereas MS is chronic and multiphasic with periods of relapse and remission. |
| Mice Live in Boarding Schools: | The conditions mice are kept in are very dissimilar to humans in that the lab mouse’s diet and environment are so controlled whereas humans are exposed to idiosyncratic environmental factors. |
| Infinity-Tuplets: | The mice are bred to be as genetically similar to each other as possible whereas humans are genetically diverse so the part played by this diversity isn’t usually accounted for in mouse studies. |
| Aetiological Differences: | EAE is induced whereas MS occurs spontaneously. While the aetiology of EAE is well understood, it is still a mystery in MS. |
| Here Today, Gone Tomorrow: | Longer term follow-up in mice isn’t feasible so the full impact of therapies isn’t known. |
| Dozens Not Hundreds: | Mouse studies are very small only involving a few dozen mice whereas human clinical trials past phase I usually involve hundreds of patients so any rare adverse events or even serious adverse events may not be seen with these low mouse study numbers. |
| Immune Profile Differences: | Different immunologic profiles to MS although this is true of some models more than others. The cytokine expression profile is also distinct. |
| Biomarker Differences: | Humans but not mice CD4+ T cells express class II on their surface and murine lymphocytes do not have CD52 protein on their surface. There are also differences in the molecular mechanisms behind the biochemistry of cells. |
| Different Pathology: | Extravasation of red blood cells, seen in some EAE models (SJL mice) is not a characteristic of MS. |
| Poor Track Record: | Many treatments for MS that were tested on EAE mice don’t translate into MS treatments in clinical studies, for example IFNγ, which showed benefit in EAE mice actually worsened MS in clinical trials and the natalizumab (Tysabri) disaster. |
| Brain and Spinal Cord: | Not all EAE models show signs of demyelination. Components of the CNS appear relatively intact and healthy in EAE but progressively degenerating in MS. |
| Gene Expression Profiles: | Greater changes in immunologically significant genes in EAE than of CNS genes in MS. |
And If It Wasn’t Complicated Enough
There are many factors which may make murine models seem better or worse than they are. These include inappropriate experimental design; using the wrong mouse model; picking the wrong dosages or injection sites; not choosing the best way to measure improvement; and not being able to follow the animals for long enough. It’s difficult to know how big a part these and other factors play in skewing results in favor or against murine EAE models.
Conclusion
MS is highly heterogeneous in its genetic basis, clinical course, and pathological mechanisms and for each patient the importance of various environmental factors is very hard to disentangle. EAE is a well-defined disease that is different in many ways to MS and mice are a different species to us living in very different conditions. There are clearly limiting factors at play and there is basis for scepticism on their relevance in human MS, however the role they’ve played thus far in helping us better understand MS and neurodegenerative disease is undeniable. Going forward, further improvements in humanized mice, validation of therapies in more than one EAE model, establishing spontaneous disease onset models, the inclusion of cell- and tissue-based models, and a healthy level of scepticism at miraculous findings in mice may serve to improve the rate of therapeutic developments that show efficacy in human studies.
