The development of new therapeutic strategies for treatment of multiple sclerosis (MS) including immunosuppressants, immunomodulators, and monoclonal antibodies require the use of appropriate animal models.
Experimental Autoimmune Encephalomyelitis
EAE is the model most commonly used to study efficacy of potential drugs for treatment of multiple sclerosis (MS).
Because of its many similarities to MS, EAE is used to study pathogenesis of autoimmunity, CNS inflammation, demyelination, cell trafficking and tolerance induction. EAE is characterized by paralysis (in some models the paralysis is remitting-relapsing), CNS inflammation and demyelination. EAE is mediated by myelin-specific CD4+ T cells, but CD8+ cells and B cells may also play a role in some models of EAE.
In principal, EAE can be induced in two ways:
By immunizing animals with myelin-derived proteins or peptides (active EAE) or by injecting animals with CD4+ T cells specific for myelin-derived peptides (adoptive or passive EAE).
MOG35-55/CFA-Induced EAE in C57BL/6 Mice
This model is recommended as a first pass for testing of potential drugs for treatment of MS, even if the exact mode of action of the drug is not fully understood. This is the shortest mouse model of EAE. It has a rather good predictive value for efficacy in MS. Mice develop EAE 8-14 days after immunization with the myelin peptide MOG35-55/CFA and stay chronically paralyzed for the duration of the experiment. Treatment of mice with a potential therapeutic usually starts on the day of immunization (preventive treatment), giving the drug the best chance of working, regardless of when it may be active during the disease induction process.
Treatment can also be initiated when a fraction of mice (10-20%) develop the first signs of EAE (semi-therapeutic treatment) or as each mouse develops first signs of EAE (therapeutic treatment). This model is approximately 25 to 30 days long. Test compound can be delivered either per os, intravenously, intraperitonealy, intraventricularily by stereotaxis, or by subcutaneous depot-injections.
PLP139-151/CFA-Induced, Remitting-Relapsing EAE in SJL Mice
This model most strongly resembles the remitting-relapsing form of MS (the most common form of MS). Mice develop the first episode of paralysis 11-14 days after immunization and, similar to most MS patients, they fully or almost fully recover from this first wave of paralysis. After a disease-free period of 1-2 weeks, 50 to 100% of the mice develop a second wave of paralysis (relapse).
ProMyelo recommends this model for testing the effect of compounds on the development of EAE relapses (therapeutic treatment). Treatment can be initiated at the onset of clinical signs of EAE, or at the start of recovery from the first wave of EAE. This model is typically run for 5 to 7 weeks, but mice are sometimes observed longer. Test compound can be delivered either per os, intravenously, intraperitonealy, intraventricularily by stereotaxis, or by subcutaneous depot-injections.
Experimental End Points
- Clinical scoring
- Detailed Histopathology – quantification of demyelination, lesion load and axonal changes
- Quantification of inflammatory gene expression levels
- FACS analysis of blood, spleen and thymus