Assessment of Animal Models for MS and Demyelinating Disease in the Design of Rational Therapy

may represent initial attacks of MS that are self-conExperimental autoimmune encephalomyelitis (EAE) is a tained. useful model of acute demyelinating disease. Some There are three acute demyelinating diseases affectforms of EAE reflect chronic demyelination with exacering the CNS—acute optic neuritis (AON), acute transverse bations and remissions characteristic of multiple scleromyelopathy (ATM), and acute disemminated encephalosis (MS). The chronic models of MS reflect many of myelitis (ADE)—that appear identical both clinically and the pathophysiologic steps in MS, including the role of pathologically to MS during periods of exacerbation. certain adhesion molecules, the influence of T cells and Indeed, most relapses of chronic MS resemble these antibodies reactive to components of the myelin sheath, three acute conditions clinically and pathologically. the participation of metalloproteases in penetrating the There is no way to distinguish ADE, AON, and ATM from blood–brain barrier, and the cytotoxic role of certain a first episode of MS, and in about 25% of cases these cytokines. One of the three therapies, approved in the acute demyelinating syndromes culminate in recurrent United States, for treatment of multiple sclerosis was episodes of inflammation in brain, optic nerve, or spinal developed preclinically based on its success in treating cord. Once the syndromes return, the illness is then various models of EAE. However, the role of certain called MS. The acute demyelinating attacks last days cytokines in EAE is contradictory to what is seen when to weeks, often occurring following a viral infection. AON tried experimentally in MS. Recognition of the discrepis manifest by a transient disturbance of vision. ATM is ancies between MS and its experimental models is criticharacterized by transient paralysis and sensory disturcal in attempting to design rational therapies for demyebances in the extremities, often with bowel and bladder linating disease. dysfunction. ADE is distinguished by various motor and Pathologic Features of MS and Demyelinating sensory disturbances and occasionally by convulsions. Disease that Must Be Reflected One of the first known examples of ADE occurred in Animal Models when “paralytic accidents,” referring to spinal cord inMS is an inflammatory demyelinating disease of CNS flammation leading to clinical paralysis, were noted after white matter. It is the major chronic disease of white rabies immunization. This observation served as a basis matter, affecting z350,000 individuals in North America for the development of models of acute experimental and about twice that number in Europe. MS is much allergic encephalomyelitis (Stuart and Krikorian, 1928; less common in India and Asia, probably reflecting a Rivers et al., 1935; Kabat et al., 1947). The “paralytic genetic predisposition to a certain genotype encoded accidents” were due to immunization against brain tisby the major histocompatibility locus on chromosome sue, used for growing the attenuated rabies virus. 6, termed HLA (human leukocyte antigen). Genes in the Once it was recognized that immunization against HLA DRB region encode the highly polymorphic portion brain tissue could produce paralysis and demyelination of the molecule that presents peptides to thymic-derived in experimental animals, models of ADE were developed T lymphocytes in the immune system. Individuals with in monkeys at the Rockefeller Institute by Rivers. Injeca particular HLA type (HLA DRB1*1501, formerly known tion of a mixture of brain material with complete Freund’s as HLA DR2) are three to four times more susceptible adjuvant, an emulsion made from killed mycobacteria to MS than individuals who have a different HLA type tuberculosis, which is useful in initiating a vigorous imat this locus. The incidence of MS in northern Europe, mune response, permitted the development of highly where HLA DR2 is most common, is as high as 1 per reproducible models of acute paralysis and white matter 750 individuals. Females are affected twice as often as inflammation (Kabat et al., 1947). The efforts of Rivers, males (Steinman, 1996). Freund, and Kabat resulted in the establishment of aniApproximately 85% of MS cases begin as relapsing mal models of experimentally induced autoimmunity in remitting disease, with episodes of neurologic impairthe nervous system, termed experimental allergic enment involving major white matter tracts impairing vicephalomyelitis (later to be interchanged with experision, other sensory modalities, motor performance, or mental autoimmune encephalomyelitis), which is abbrecoordination. Episodes of relapse and remission often viated EAE. In the basic protocol for inducing EAE, evolve over many years to a more chronic form of disabilexperimental animals are immunized with either foreign ity without clear cut exacerbations. These clinical sceor self proteins from the white matter of the nervous narios become important in the development of animal system, most usually myelin basic protein (MBP), promodels of MS. The most useful animal models would teolipid protein (PLP), or myelin oligodendroglial glycodevelop acute attacks with specific neurologic deficits protein (MOG). The acute EAE models reflect many of