Experimental autoimmune encephalomyelitis (EAE) is a useful model of acute demyelinating disease. Some forms of EAE reflect chronic demyelination with exacerbations and remissions characteristic of ...multiple sclerosis (MS). The chronic models of MS reflect many of the pathophysiologic steps in MS, including the role of certain adhesion molecules, the influence of T cells and antibodies reactive to components of the myelin sheath, the participation of metalloproteases in penetrating the blood-brain barrier, and the cytotoxic role of certain cytokines. One of the three therapies, approved in the United States, for treatment of multiple sclerosis was developed preclinically based on its success in treating various models of EAE. However, the role of certain cytokines in EAE is contradictory to what is seen when tried experimentally in MS. Recognition of the discrepancies between MS and its experimental models is critical in attempting to design rational therapies for demyelinating disease.
Statins have been prescribed extensively for their cholesterol-lowering properties and efficacy in cardiovascular disease. However, compelling evidence now exists that statins also have extensive ...immunomodulatory properties that operate independently of lipid lowering. Consequently, much attention has been directed towards their potential as therapeutic agents for the treatment of autoimmune disease. Modulation of post-translational protein prenylation seems to be a key mechanism by which statins alter immune function. In this Review, the effect of statin therapy on immune function, and how this relates to the pathogenesis of autoimmune disease, is reviewed alongside current opinion of what the key biological targets of statins are.
A better understanding of the molecules involved in immune responses has identified many potential targets for the treatment of autoimmune diseases. But although successful therapies have been found ...for immune disorders in animal studies, few have passed the much harder test of treating human diseases. So far, non-antigen-specific approaches, such as the blocking of tumour-necrosis factor, are achieving some success but the same is not true for antigen-specific approaches. Future therapies will probably include both non-antigen-specific strategies that target cytokines (cell-cell signalling molecules) or block the molecules that stimulate immune responses, and antigen-specific therapies that induce tolerance to self antigens.
Immune Therapy for Autoimmune Diseases Steinman, Lawrence
Science (American Association for the Advancement of Science),
07/2004, Letnik:
305, Številka:
5681
Journal Article
Recenzirano
Our increasing understanding of the pathophysiology of autoimmune disease has revealed a number of checkpoints that can be targeted with immune therapy, including key mediators of lymphocyte adhesion ...and migration, destructive cytokines involved in tissue damage, and the complex of molecules critical in the presentation of self-antigen and the activation of autoaggressive T lymphocytes. In many organ-specific autoimmune diseases, the identity of the molecules attacked by T cells and autoantibodies is known and attempts are under way to tolerize the immune system with a high level of specificity to these targets.
Multiple sclerosis (MS) is the most common autoimmune disease involving the nervous system. In the United States similar to 250,000 individuals suffer from MS. The first clinical signs of MS ...typically begin in young adulthood, and women with the disease outnumber men 2:1. The cause of the disease is unknown, but genetic factors are important. The concordance rate among monozygotic twins is 30%, a 10-fold increase over dizygotic twins or first-degree relatives. The higher incidence rate among monozygotic twins emphasizes the importance of genetic factors, but the discordance rate of 70% among identical twins illuminates the role of nongenetic factors on disease penetrance. The fact that the prevalence of MS among nonbiological first-degree relatives of MS index cases is similar to that in the general population strongly supports a genetic basis for familial clustering. Among genetic factors, HLA class II genes exert an influence, with HLA DR2 carrying a 4-fold relative risk for northern European caucasoids. Geography plays an interesting role in determining susceptibility to MS. Among white populations, the prevalence of MS is highest in the temperate regions of the world. Migration from a location of high disease incidence to a location of low disease incidence after the age of 15 years carries with it the risk associated with the location where one dwelled during the first 15 years, while migration before the age of 15 years carries the risk associated with the immigrant's destination. A typical presentation of MS involves an initial course, running for several years to more than a decade, manifest by episodes of relapse followed by remission. Relapses often follow an episode of a viral infection of the upper respiratory system or gastrointestinal tract. In about one half of MS cases the disease progresses to a more chronic phase. The clinical symptoms of the disease are entirely attributable to pathology in the central nervous system. Clinical problems may include disturbances in visual acuity, sometimes culminating in blindness; double vision; motor disturbances affecting walking and use of the hands; incoordination; bowel and bladder incontinence; spasticity; and sensory disturbances including loss of touch, pain, and temperature and proprioception. Cognitive function is not impaired in MS. The pathology of the disease lies entirely in the central nervous system and is characterized by a classic picture of inflammation surrounding venules and extending into the myelin sheath. Understanding the pathogenesis of the disease allows for the rational design of therapeutic strategies.
Experimental autoimmune encephalomyelitis (EAE) is a useful model for aiding the development of new treatments for MS. All therapies approved for MS ameliorate EAE. Two approved medications, ...glatiramer acetate and Natalizumab, were developed directly from studies in EAE. Several trials are ongoing in MS after success in EAE, including altered peptide ligands of myelin, DNA vaccines and statins. However, EAE has failed to predict the outcome of certain approaches. The reasons underlying such failures are discussed here.
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