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ScienceWeek
MEDICAL BIOLOGY: ON MULTIPLE SCLEROSIS
The following points are made by E.M. Frohman et al (New Engl. J. Med. 2006 354:942):
1) Substantial advances have occurred in the understanding of some of the central mechanisms underlying the inflammation, demyelination, and neurodegeneration that occur in multiple sclerosis since what was known five years ago.[1] Accordingly, the available clinical strategies for the management of the disease have widened.[2] However, the treatment options for the disease are most effective during the relapsing-remitting phase (relapsing-remitting multiple sclerosis), which is characterized by clinical exacerbations, inflammation, and evidence of plaques within the brain and spinal cord on magnetic resonance imaging (MRI). Less understood are factors that promote the transition from relapsing-remitting multiple sclerosis to treatment-resistant secondary progressive multiple sclerosis. Evidence now suggests that neurodegenerative mechanisms within the disease plaques constitute the pathologic substrate for the latter disabling phase.[3-5] Effector mechanisms that underlie the relapsing inflammatory and the progressive neurodegenerative phases of multiple sclerosis appear to be distinctly different.
2) A central mission in multiple sclerosis research has been to determine the sequence of events underlying the development of the inflammatory plaque. It is generally held that this histopathological hallmark originates from a breach in the integrity of the blood-brain barrier in a person who is genetically predisposed to the disease. One hypothesis suggests that some forms of systemic infection may cause the up-regulation of adhesion molecules on the endothelium of the brain and spinal cord, allowing leukocytes to home to and traverse vessel walls to enter the normally immunologically privileged central nervous system. If lymphocytes programmed to recognize myelin antigen exist within the cell infiltrate, they may trigger a cascade of events resulting in the formation of an acute inflammatory, demyelinating lesion. These lesions typically develop in white matter, where the primary targets are the myelin sheath and the myelinating cell, the oligodendrocyte. However, gray-matter lesions, in which the primary target is also myelin, are known to occur.
3) Studies of animal models demonstrating that autoreactive T cells (CD4+ or CD8+) can result in inflammatory demyelination of the central nervous system support the theory that multiple sclerosis is an immune-mediated disorder involving one or more antigens located in the myelin of the central nervous system. Patients with multiple sclerosis and healthy persons appear to have similar numbers of T cells in peripheral blood that react to myelin. Nevertheless, these two groups have substantial qualitative differences in responses mediated by circulating mononuclear-cell populations (B cells, T cells, and macrophages). Myelin-reactive T cells from patients with multiple sclerosis exhibit a memory or activated phenotype, whereas these same antigen-specific cells in healthy persons appear to have a naive phenotype. Marked differences in the cytokines secreted and the specific chemokine receptors expressed suggest that myelin-reactive T cells from patients with multiple sclerosis are relatively more inflammatory. Further, myelin-specific CD8+ T cells appear to be more abundant in patients with relapsing multiple sclerosis than in healthy persons or in those with secondary progressive disease.
4) Perhaps the most convincing evidence that myelin-reactive T cells lead to inflammatory demyelination came from a clinical trial in which an altered peptide ligand was used as a putative disease-modifying treatment in patients with multiple sclerosis. In this study, either clinical exacerbations or an increase in disease activity, as measured by MRI, unexpectedly developed in several patients treated with the ligand (a peptide developed to stimulate autoreactive T cells and render them inactive). These changes coincided with marked increases in T cells responding to a specific component of myelin basic protein (signifying immune-cell activation rather than inactivation). In contrast, in another study, a lower dose of this peptide ligand actually reduced evidence of disease activity on MRI. This treatment strategy is currently being studied in a phase 2 clinical trial.
References (abridged):
1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000;343:938-952
2. Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis. Neurology 2002;58:169-178. [Erratum, Neurology 2002;59:480.]
3. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278-285
4. Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Brück W. Acute axonal injury in multiple sclerosis: correlation with demyelination and inflammation. Brain 2000;123:1174-1183
5. Kornek B, Storch MK, Weissert R, et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 2000;157:267-276. [Abstract/Full Text]
New Engl. J. Med. http://www.nejm.org
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Related Material:
MULTIPLE SCLEROSIS, STATINS, AND AUTOIMMUNE DISEASE.
The following points are made by Hartmut Wekerle (Nature 2002 420:39):
1) Multiple sclerosis owes its enormous socioeconomic importance to several factors. Worldwide, as many as one million people are affected by the disease. It tends to afflict sufferers for most of their lives, often taking a severe, disabling course. And there are no effective treatments that stop multiple sclerosis in its tracks (although there are some that slow its progression). New therapies are desperately needed, and one attractive candidate is atorvastatin, a drug that is already used to reduce blood cholesterol levels in people with atherosclerosis or heart disease(2).
2) Multiple sclerosis is generally believed to develop when the body's immune cells -- led by so-called helper T cells -- attack myelin, the insulating, fatty sheath around nerve cells. This damages the myelin and the underlying neurons in both the brain and the spinal cord, leading to impaired transmission of nerve impulses and progressive physical disability. Treatments available today include one that involves engineered interferon-beta proteins, which reduce the inflammation associated with nerve damage. Another is based on copaxone, a random composite of basic peptides, which probably activates brain-protein-detecting T cells that inhibit rather than support the autoimmune attack. Both drugs reduce the number of clinical relapses and the damage to the central nervous system. But both also come at a price --quite literally in one sense, as they are very expensive. Moreover, they must be administered frequently by injection, which is a severe bother and carries a risk of side-effects. New treatments are needed that can be given orally and that, hopefully, also have a greater effect on the disease.(1,3-5)
References (abridged):
1. Youssef, S. et al. Nature 420, 78-84 (2002).
2. Maron, D. J., Fazio, S. & Linton, M. F. Circulation 101, 207-213 (2000).
3. Stanislaus, R. Neurosci. Lett. 269, 71-74 (1999).
4. Ludewig, B. et al. J. Immunol. 166, 3369-3376 (2001).
5. Kwak, B., Mulhaupt, F., Myit, S. & Mach, F. Nature Med. 6, 1399-1402 (2000).
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MEDICAL BIOLOGY: INJECTION OF NEURAL PRECURSOR CELLS IN MULTIPLE SCLEROSIS
The following points are made by S. Pluchino et al (Nature 2003 422:688):
1) The permanent neurological impairment typical of chronic inflammatory demyelinating disorders of the central nervous system (CNS), such as multiple sclerosis, is due to the axonal loss resulting from recurrent episodes of immune-mediated demyelination. So far, experimental cell therapy for these disorders has been based mainly on the transplantation of myelin-forming cells, or their precursors, at the site of demyelination. Although such an approach can trigger functional recovery and restore axonal conduction, the limited migration of lineage-restricted, myelin-forming cells through the brain parenchyma highlights the beneficial effect of transplantation to the site of the injury. This raises critical issues regarding the therapeutic use of focal cell transplantation to treat diseases in which multifocal demyelination is the main pathological feature. Such issues are compounded by the poor expansion capacity of myelin-forming cells in culture, which greatly limits their availability and further hampers their prospective application in clinical settings.
2) Multipotent neural precursor cells -- with the capacity to generate neurons, astroglia and oligodendroglia -- are found in the adult brain and possess the critical features of somatic stem cells. They support neurogenesis within restricted areas throughout adulthood, can undergo extensive in vitro expansion and, therefore, have been proposed as a renewable source of neural precursors for regenerative transplantation in various CNS diseases.
3) In summary: Widespread demyelination and axonal loss are the pathological hallmarks of multiple sclerosis. The multifocal nature of this chronic inflammatory disease of the central nervous system complicates cellular therapy and puts emphasis on both the donor cell origin and the route of cell transplantation. The authors report they established syngenic adult neural stem cell cultures and injected them into an animal model of multiple sclerosis -- experimental autoimmune encephalomyelitis (EAE) in the mouse -- either intravenously or intracerebroventricularly. In both cases, significant numbers of donor cells entered into demyelinating areas of the central nervous system and differentiated into mature brain cells. Within these areas, oligodendrocyte progenitors markedly increased, with many of them being of donor origin and actively remyelinating axons. Furthermore, a significant reduction of astrogliosis and a marked decrease in the extent of demyelination and axonal loss were observed in transplanted animals. The functional impairment caused by EAE was almost abolished in transplanted mice, both clinically and neurophysiologically. Thus, adult neural precursor cells promote multifocal remyelination and functional recovery after intravenous or intrathecal injection in a chronic model of multiple sclerosis.
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