Experimental Allergic Encephalomyelitis

As mentioned earlier, there is no spontaneous animal model that closely resembles MS. EAE is the most widely studied animal model of this disease. EAE is an antigen-specific, T-cell-mediated autoimmune disease that can be induced in many species, although rat and mice models predominate in the literature. Acute EAE is a monophasic illness that more closely resembles ADEM. Chronic-relapsing EAE closely mimics the clinical course of MS with repeated clinical relapses from which the animal makes an incomplete recovery; some animals develop a slow progressive course after several relapses. Although there is considerable variability in the various EAE models, several closely parallel the pathological picture of MS with perivascular inflammation and primary demyelination initially and subsequent gliosis and axonal loss.

Studies in EAE have advanced our understanding of the various stages of disease initiation that may underlie the MS disease process, including the initial immune activation of T cells by encephalitogenic antigens and factors that influence T cell recognition; TCR restriction; the genetic influences on disease resistance, susceptibility, and recovery; T cell/macrophage interactions; the various roles of soluble mediators of inflammation (including TH1 and TH2 cytokines); factors regulating blood-brain barrier permeability; T cell/adhesion molecule interactions; factors influencing oligodendrocyte function and survival; and possible ways to reduce astrocytic proliferation and induce remyelination.

For decades, investigators have used EAE to screen for potentially effective therapies. Recent work has focused on the chronic-relapsing EAE model, extending the multitude of previous studies of immunosuppressive drug therapies. Current work includes strategies to enhance TH2 cytokine production and block TH1 cytokine function; therapies that target T-cell subsets, class II molecules of the major histocompatibility complex, and TCRs used for the recognition of encephalitogenic antigens (using monoclonal antibodies, altered peptide analogues, and T-cell vaccination studies that target TCR variable regions). EAE has been used to enhance understanding of the many possible mechanisms whereby interferons may influence immunemediated CNS injury and to explore the possibility that antigen-specific immunotherapy may ultimately be applicable to patients through either oral tolerance ("bystander suppression," anergy or clonal deletion) or with peptide analogues to encephalitogenic antigens.

Another widely studied animal model is Theiler's murine encephalomyelitis virus model. Intracranial inoculation with Theiler's virus leads to chronic infection and chronic inflammatory demyelination. Studies have shown that immune suppression ameliorates the pathological damage in this model, verifying that it is the immune response and not the viral infection that is responsible for the chronic demyelination. TMEV has been particularly useful in exploring a number of possible mechanisms of inducing remyelination in the setting of chronic demyelination. As outlined earlier, both polyclonal antispinal cord immunoglobulins and monoclonal antibodies directed against several protein antigens and chemical haptens have been shown to promote extensive CNS remyelination in TMEV. This work has led to two phase II clinical trials of human immunoglobulin in patients with optic neuritis and multiple sclerosis.


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