Experimental autoimmune encephalomyelitis
The experimental autoimmune encephalomyelitis, sometimes experimental allergic encephalomyelitis (EAE) is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system (CNS). It is mostly used with rodents and is widely studied as an animal model of the human CNS demyelinating diseases, including multiple sclerosis and acute disseminated encephalomyelitis (ADEM). EAE is also the prototype for T-cell-mediated autoimmune disease in general.
EAE was motivated by observations during the convalescence from viral diseases by Thomas M. Rivers, D. H. Sprunt and G. P. Berry in 1933. Their findings upon a transfer of inflamed patient tissue to primates was published in the Journal of Experimental Medicine (Vol. 58, No. 1, pp. 39–56). An acute monophasic illness, it has been suggested that EAE is far more similar to ADEM than MS.
EAE can be induced in a number of species, including mice, rats, guinea pigs, rabbits and primates. The most commonly used antigens in rodents are spinal cord homogenate (SCH), purified myelin, myelin protein such as MBP, PLP and MOG, or peptides of these proteins, all resulting in distinct models with different disease characteristics regarding both immunology and pathology. It may also be induced by the passive transfer of T cells specifically reactive to these myelin antigens. Depending on the antigen used and the genetic make-up of the animal, rodents can display a monophasic bout of EAE, a relapsing-remitting form, or chronic EAE . The typical susceptible rodent will debut with clinical symptoms around two weeks after immunization and present with a relapsing-remitting disease. The archetypical first clinical symptom is weakness of tail tonus that progresses to paralysis of the tail, followed by a progression up the body to affect the hind limbs and finally the forelimbs. However, similar to MS, the disease symptoms reflect the anatomical location of the inflammatory lesions, and may also include emotional lability, sensory loss, optic neuritis, difficulties with coordination and balance (ataxia), and muscle weakness and spasms. Recovery from symptoms can be complete or partial and the time varies with symptoms and disease severity. Depending on the relapse-remission intervals, rats can have up to 3 bouts of disease within an experimental period.
EAE in mice
Demyelination is produced by injection of brain extracts, CNS proteins (such as myelin basic protein), or peptides from such protein emulsified in an adjuvant such as complete Freund's adjuvant. The presence of the adjuvant allows the generation of inflammatory responses to the protein/peptides. In many protocols, mice are coinjected with pertussis toxin to break down the blood-brain barrier and allow immune cells access to the CNS tissue. This immunisation leads to multiple small disseminated lesions of demyelination (as well as micro-necroses) in the brain and spinal cord and the onset of clinical symptoms.
Although sharing some features, mostly demyelination, this model, first introduced in 1930s, differs from human MS in several ways. EAE either kills animals or leaves them with permanent disabilities; animals with EAE also suffer severe nerve inflammation, and the time course of EAE is entirely different from MS, being the main antigen (MBP) in charge.
Notes and references
- Rivers TM, Spunt DH & Berry GP (1933). OBSERVATIONS ON ATTEMPTS TO PRODUCE ACUTE DISSEMINATED ENCEPHALOMYELITIS IN MONKEYS. Journal of Experimental Medicine 58:39-53.
- Rivers TM & Schwentker FF. (1935). Encephalomyelitis accompanied by myelin destruction experimentally produced in monkeys. Journal of Experimental Medicine 61:689 –701.
- Sriram S & Steiner I (2005) Experimental Allergic Encephalomyelitis: A misleading model of Multiple Sclerosis. Annals of Neurology 58:939 –945.
- MANNIE, M., R. H. SWANBORG and J. A. STEPANIAK, 2009 Experimental autoimmune encephalomyelitis in the rat. Curr Protoc Immunol Chapter 15: Unit 15 12
- MILLER, S. D., and W. J. KARPUS, 2007 Experimental autoimmune encephalomyelitis in the mouse. Curr Protoc Immunol Chapter 15: Unit 15 11
- Mult-sclerosis.org: information on EAE
- More than 100, freely available, published research articles on EAE and related topics such as multiple sclerosis by Professor Michael P. Pender, Neuroimmunology Research Unit, The University of Queensland