Experimental Autoimmune Encephalomyelitis (EAE) is an inflammatory demyelinating condition of the central nervous system induced in laboratory animals. It serves as the most common experimental model for multiple sclerosis (MS), replicating key features of the disease in a controlled setting. This allows researchers to investigate the complex interactions between the immune system and the nervous system, providing a platform for understanding autoimmune neuroinflammation.
Inducing the EAE Model in Mice
The EAE model is established in mice through active or passive induction. Active induction is more common and involves immunizing susceptible mouse strains with proteins derived from myelin, the protective sheath covering nerve fibers. Common myelin components include myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), or myelin basic protein (MBP). These antigens are mixed with an adjuvant, like Complete Freund’s Adjuvant (CFA), to stimulate a strong immune response.
To enhance disease development, pertussis toxin is often administered to the mice. The toxin increases the permeability of the blood-brain barrier, which normally protects the central nervous system. This allows activated T-cells that recognize myelin as a target to enter the brain and spinal cord and initiate an inflammatory attack.
A second method is passive or adoptive transfer EAE. This technique involves inducing EAE in a donor mouse through active immunization. The donor’s myelin-specific T-cells are then isolated and transferred into a healthy recipient mouse, which then develops EAE as the cells migrate to the central nervous system and attack the myelin sheath.
Clinical Manifestations and Pathology
Once EAE is induced, mice develop predictable and progressive neurological symptoms. Researchers track the disease severity using a standardized clinical scoring system, which allows for consistent assessment. This scale ranges from 0 to 5, where 0 indicates a healthy mouse. The first observable symptom is often a limp tail (score 1), followed by hind limb weakness (score 2), and progressing to complete hind limb paralysis (score 3).
The observable clinical signs result from the underlying pathology within the central nervous system. The pathology involves the infiltration of inflammatory immune cells, primarily T-cells and macrophages, into the brain and spinal cord. These cells attack the myelin sheath in a process known as demyelination, which disrupts the ability of nerves to transmit electrical signals efficiently.
This immune-mediated assault leads to inflammation and the destruction of oligodendrocytes, the cells responsible for producing and maintaining myelin. The resulting demyelination leaves nerve fibers, or axons, exposed and vulnerable to damage. Over time, this can lead to irreversible axonal loss, which is a contributor to permanent neurological disability in the model and mirrors the pathological processes in human MS.
Relevance to Multiple Sclerosis
The EAE model is used in MS research because it mimics the autoimmune process where the body’s immune system attacks the myelin of the central nervous system. This shared mechanism leads to corresponding pathologies, including inflammatory lesions and demyelination. The resulting clinical signs in mice, such as progressive paralysis, serve as a functional parallel to the motor disabilities experienced by individuals with MS.
However, the model has significant limitations. EAE is an induced disease with a known trigger, whereas MS in humans develops spontaneously from a complex and still not fully understood interplay of genetic and environmental factors. The disease course can also differ; many EAE models produce a single, acute disease course, whereas the most common form of human MS is characterized by relapses and remissions.
The location and characteristics of the central nervous system lesions can vary between the mouse model and the human condition. While EAE predominantly affects the spinal cord, leading to motor deficits, MS often involves lesion formation in the brain as well. This contributes to a wider range of symptoms including cognitive and sensory issues.
Role in Therapeutic Development
The EAE model has a practical function in the preclinical testing of new therapies for multiple sclerosis. Researchers use the model to evaluate the effectiveness of potential treatments by administering them at different stages of the disease. For instance, a compound can be given before immunization to see if it can prevent the disease, or administered after clinical signs have appeared to test its ability to treat active disease.
This system allows for screening therapeutic strategies aimed at modulating the immune response or protecting the nervous system. Scientists assess a drug’s impact on clinical scores and pathology by examining tissue for inflammation and demyelination. This provides data on a therapy’s potential effectiveness before human trials.
The model’s value is demonstrated by the fact that many medications currently approved for treating MS showed positive results in EAE studies first. Drugs like glatiramer acetate and natalizumab were validated in the EAE model before successfully progressing through human trials. This history underscores the model’s utility in identifying promising therapeutic candidates.