Multiple Sclerosis Research Yields Few Concrete Answers

Multiple sclerosis (MS) continues to baffle those who seek to understand it. The cause of the disease remains obscure, as does the mechanism of the drugs used to ameliorate its symptoms. Affecting 0.1 percent of the population, the neurodegenerative disease is marked by demyelination, or the destruction of the myelin sheath on neurons in the brain and spinal cord. Researchers have been scrutinizing the proteins and lipids composing myelin, studying genetics of patients, exploring links between similarity of microbial and myelin peptides, and attempting to incorporate this knowledge into effective treatments. "We've got a big pile of facts, but we don't have a lot of structure," says Jeffrey Latts, vice president for clinical research and development at Berlex Laboratories Inc. The Wayne, N.J.-based pharmaceutical firm has developed one of the drugs now available to treat MS. 'EPIPHENOMENA': Evidence for MS as an autoimmine disease is circumstantial, cautions Penn neurologist Donald Silberberg. Much research is based on the idea that MS is a disease in which immune system cells orchestrate an attack on myelin. Evidence for autoimmunity can be seen in the presence of immune globulin (IgG) in the spinal fluid of people with MS. High levels of IgG also surround MS lesions in the brain, notes Donald Silberberg, a professor of neurology at the University of Pennsylvania and editor for the Americas of Multiple Sclerosis Clinical and Laboratory Research. There are levels of immune-competent cells in the veins (see R. Martin, H. McFarland, "Immunology of Multiple Sclerosis and Experimental Allergic Encephalomyelitis" in C. Raine, H. McFarland, W. Tourtellotte, eds., Multiple Sclerosis: Clinical and Pathogenetic Basis, London, Chapman and Hall, 1997). But the evidence is circumstantial, cautions Silberberg: "Every bit of it could be . . . epiphenomena, following something else." Moreover, "no one knows what is truly the responsible antigen." One line of research has focused on myelin proteins as antigens. For example, Arthur A. Vandenbark, a neuroimmunologist at the Veterans Affairs Medical Center in Portland, Ore., and the Oregon Health Sciences University, has focused on myelin basic protein (MBP) to develop an altered T-cell receptor peptide vaccine against MS (A.A. Vandenbark et al., Nature Medicine, 2:1109-15, 1996). "We picked myelin basic protein because it is [essentially] the prototype antigen," he explains. "It makes up about 30 percent of myelin, and it's one of the few proteins in myelin that can be used to induce an animal model of MS called experimental allergic encephalomyelitis [EAE]." The vaccine showed some success in clinical trials. Proteolipid protein (PLP), which comprises 50 percent of central nervous system myelin, also has attracted much attention. John L. Trotter, a professor of neurology at Washington University in St. Louis, and his colleagues have found that activated T cells in MS patients recognize PLP peptides. This can have significant implications for therapies that focus on one antigen. "If multiple epitopes can be involved and multiple T cells can be involved, that discourages [the one antigen] approach." According to Henry F. McFarland, chief of the neuroimmunology branch of the National Institute of Neurological Disorders and Stroke, studies that have attempted to establish whether myelin antigens contribute to MS have been "unrewarding." He explains: "The only way we will probably ever prove or disprove that T-cell response to MBP or PLP or MOG [myelin oligodendrocyte glycoprotein] really has any causative role in the disease process is if we can go in safely, using some immunological technique, and eliminate a population of T cells, then establish if we have changed the disease." SHOT IN THE DARK? Neuroimmunologist Arthur Vandenbark is working on an altered T-cell receptor peptide vaccine against MS. Taking another approach to examining myelin is Cynthia A. Husted, an assistant research engineer at the University of California, Santa Barbara's Neuroscience Research Institute. "Myelin is 70 percent lipids. We're finding big changes in myelin lipids during multiple sclerosis," she notes. Using magnetic resonance imaging (MRI), she has detected changes in the lipids in areas that looked normal (C.A. Husted et al., Annals of Neurology, 36:157-65, 1994; C.A. Husted et al., Ann. Neurol., 36:239-41, 1994). "We're trying to characterize myelin [in MS] from normal-appearing white matter [myelinated nerves]," Husted explains. "We want to understand how the structure is altered that could potentially signal the immune system to attack." The approach involves solid-state nuclear MRI, used to characterize materials such as polymers and ceramics, to examine lipids. Using MRI, Husted has found damage to normal-appearing phospholipids, a finding whose significance is not completely understood. She plans to extend this work by analyzing autopsy tissue of MS patients and studying lipids in an EAE model in marmosets. Tolerization is the administration of soluble antigens that can induce specific immune tolerance. It has been examined as a way to treat MS in ways that actually down-regulate the immune response to it, explains Claude P. Genain, an assistant professor of neurology at the University of California, San Francisco School of Medicine. Giving the MOG antigen intravenously or intraperitoneally, as Genain did, is "known to suppress or even eradicate the lymphocyte responses to this particular antigen," he states. Using a marmoset model of EAE, which was induced by exposure to MOG in Freund's adjuvant, Genain found that tolerization to MOG protected the animals against the disorder. But once the tolerization injections were stopped, the animals developed a lethal form of EAE that was more severe than in the controls (C.P. Genain et al., Science, 274:2054-6, 1996). Giving the antigen by itself induces a Th2 response-the production of anti-inflammatory cytokines by T2 helper cells. "This clearly appears to suppress disease in mouse models [of EAE]," notes Genain. Th1 cells have been believed to provoke an inflammatory response, and Th2 cells have been regarded as producing a protective response. In the marmoset model, tolerization also resulted in the production of pathogenic autoantibodies. When tolerization was discontinued, the animals "were primed for demyelination the minute we stopped the treatment," he says. Th2 responses are known to promote antibodies. "So we clearly induced deviation toward Th2 with that therapy." Genain explains. The findings show the need for caution, he warns. "Let's say you have a therapy like this, which suppresses specific T-cell responses to an antigen but does prime for antibodies, and there is a viral infection or anything that can up-regulate the Th1 responses, there can be potential side effects such as the ones we describe," he says, referring to the demyelination that occurred when treatment stopped. In a commentary (Science, 274:2037-8, 1996), McFarland questioned if a Th2 response was induced in the animals in Genain's experiment. And he has a larger concern about EAE as a model for MS: It offers precision, but it may not accurately depict MS as it affects people. "In EAE, we know precisely what the antigen is, because we produced the disease. So if we produce the disease with MBP, then we go back in and give intravenous MBP [to modify the disease]. All of the T cells are in a relatively high level of activation, and we have an immunological process that is more or less in phase." In MS, researchers don't know the antigen that started the disease, and "the immunological parameters don't necessarily match what we have in EAE," notes McFarland. T cells in MS may be in different states of activation. Berlex Laboratories, Inc. 300 Fairfield Rd., Wayne, N.J. 07470 (800) 237-5391 - Fax: (201) 305-5388 15049 San Pablo Ave.,Richmond, Calif. 94804 (800) 888-4112 - Fax: (510) 262-7055 http://www.betaseron.com Biogen Inc. 14 Cambridge Center, Cambridge, Mass. 02142 (617) 679-2000 - Fax: (617) 679-2617 http://www.biogen.com Connetics Corp. 3400 W. Bayshore Rd., Palo Alto, Calif. 94303 (415) 843-2800 - Fax: (415) 843-2899 Food and Drug Administration 5600 Fishers Lane, Rockville, Md. 20857 (301) 443-1544 - Fax: (301) 594-2114 http://www.fda.gov National Multiple Sclerosis Society Sixth Floor, 733 Third Ave., New York, N.Y. 10017 (800) 344-4867 - Fax: (212) 986-7981 http://www.nmss.org Multiple Sclerosis Clinical and Laboratory Research Donald Silberberg, Editor for Americas Hospital of the University of Pennsylvania Department of Neurology 3 West Gates Bldg., 3400 Spruce St. Philadelphia, Pa. 19104-4823 (215) 662-3386 - Fax: (215) 662-3353 E-mail: silberbe@mail.med.upenn.edu A new technique called molecular mimicry has emerged from the lab of Kai W. Wucherpfennig, an assistant professor at the Dana-Farber Cancer Institute in Boston and Harvard Medical School (K.W. Wucherpfennig, Cell, 80:695-705, 1995). According to the concept, microbial peptides similar enough to a human peptide can trigger an autoimmune response. "The paradigm was that T cells are very specific. We have found that there is also a certain degree of degeneracy in T-cell recognition and that cross-reactive peptides can be identified that are potent activators of myelin specific T cells," Wucherpfennig says. "Among the T-cell clones that we have studied, some are quite specific and others are more degenerate," meaning they can recognize and attack more than one peptide. For example, in vitro experiments have demonstrated that four or more peptides from different pathogens can stimulate a myelin-specific T-cell clone. This suggests that a T cell so stimulated might also attack a myelin protein. MOLECULAR MIMICRY: Kai Wucherpfennig's lab is studying if certain microbial peptides can trigger an autoimmune response. Demonstrating such a phenomenon as a cause of MS can be difficult. Diagnosed MS patients already have lesions, so it's hard to show that a virus or other pathogen was responsible. "We plan to examine patients with postinfectious encephalomyelitis, which occurs after viral infections or vaccinations. There is evidence of T-cell reactivity to MBP. We're looking at cases where the viral agent is known to study this idea," says Wucherpfennig. Wucherpfennig sees the major histocompatibility complex (MHC), the chromosomal region controlling antigens, as closely connected to molecular mimicry. "A single MHC molecule can bind more than 1,000 different sequences. That sets the stage for cross-reactive T cells to come in and be activated by viral antigens and by MBP." Although MBP has been widely studied, he notes, it's not likely to be the only protein involved in MS. Research by the Multiple Sclerosis Genetics Group, a multiuniversity collaboration, also emphasizes the importance of the MHC to understanding MS. The MHC has "some sort of susceptibility, in which, when it comes into contact with the correct environmental or outside influences, you get the disease," observes Margaret Pericak-Vance, a professor and chief of medical genetics at Duke University (Multiple Sclerosis Genetics Group, Nature Genetics, 13:469-71,1996). The group's paper is one of four on the genetics of MS appearing in the same issue of Nature Genetics (S. Sawcer et al., 13:464-8, 1996; G.C. Ebers et al., 13:472-6, 1996; S. Kuokkanen et al., 13:477-80, 1996). As basic research moves forward, so have efforts to develop new treatments for the disorder. At the end of 1996, the Food and Drug Administration (FDA) approved Copaxone, a glatiramer acetate developed by Teva Pharmaceutical Industries, based in Israel. It reduces the rate of MS episodes by about 30 percent. "Nobody knows how it works for sure," says Sidney Gilman, a University of Michigan neurologist who serves as chairman of the FDA Peripheral and Central Nervous System Drug Advisory Committee that recommended approval. "It's a combination of amino acids that replicate the composition of myelin. The original theory is that it would replace the loss of myelin. But that may or may not be the basis of its effect." The vaccine developed by Vandenbark and his colleagues is undergoing early clinical trials sponsored by Connetics Corp., a Palo Alto, Calif.-based drug company. The vaccine, it is believed, stimulated the cytokine IL-10, which inhibited T cell (Th1) attack on MBP. The placebo double-blind trials found that six of 17 patients receiving a version of the vaccine showed some improvement (A.A. Vandenbark et al., Nature Medicine, 2:1109-15, 1996). Symptoms worsened in 11 patients who did not respond to the vaccine and in six patients who received placebo. Other drugs that recently became available include Betaseron, a modified version of beta-interferon made by Berlex Laboratories. Approved in 1993, Betaseron was designed to interfere with the replication of a latent virus that in the nervous system of MS patients. "It still is not proven whether that is the mechanism by which the interferons operate in MS," says Latts. And last spring, Cambridge, Mass.-based Biogen Inc. introduced Avonex, which is an identical version of the beta-interferon made in the body. While Avonex slows the relapse rate of MS, its mode of action similarly is uncertain. Molecular research clearly is spawning enormous amounts of data as researchers probe the complex and often confusing picture of MS. That growing mass of information makes Silberberg optimistic: "At some point the pieces are going to start fitting together in ways that make sense. To me what's hopeful is there are more and more pieces." Harvey Black is a freelance science writer in Madison, Wis.

Multiple Sclerosis Research Yields Few Concrete Answers

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