In Vitro Results May Show Promise for MS Patients
ST. PAUL, MN - A new strategy tested in cell cultures may offer hope for people with multiple sclerosis. A new drug can promote the growth of myelin, the protective layer surrounding nerve fibers that is damaged in MS, according to a study published in the current issue of Neurology, the scientific journal of the American Academy of Neurology.
French researchers added the drug eliprodil to cultures containing animal models of central nervous system myelin. The drug doubled the amount of myelination in the standard culture.
"These results have to be confirmed in animal tests, but this strategy is certainly very promising," said study author and neurologist Catherine Lubetzki, MD, PhD, of the unit of INSERM, the French national institute of health and medical research, at Salpetriere Hospital in Paris. "Although we obviously must discover how to stop the process that causes demyelination, it may be that this new strategy could limit the progression of the disease."
In the cultures, the myelin wraps around axons, the long extensions that send impulses away from the neurons. In an acute attack of multiple sclerosis, the most obvious abnormality is inflammation with a loss of myelin in the brain and spinal cord. However, studies have recently shown that long-term disability in MS may relate to damage to the axons.
Other research has demonstrated that in MS plaques, or areas of damage to the brain and spinal cord, cells attempt to replace lost myelin, but the repairs are not enough to prevent the progress of the disease. In addition, studies show that signals sent by axons are necessary in myelination, so they may also be required for remyelination, Lubetzki said.
Eliprodil was first developed as a drug to protect neurons, the cells that give off axons. "Other neuroprotective agents like eliprodil may be promising for MS, both to prevent damage to
neurons and to aid the cells' own efforts at remyelination by maintaining the axons' signals," Lubetzki said.
Lubetzki said other neuroprotective agents should be tested for their ability to promote the growth of myelin. Additional studies are also needed to investigate how eliprodil works within the brain to cause the growth of myelin, she said.
The study was supported in part by the French company Synthelabo Recherche, manufacturer of eliprodil. Eliprodil is not available commercially. The study was also supported by INSERM and ARSEP, the French MS society.
MS affects at least 300,000 Americans. Symptoms can include weakness, unsteady gait, double vision, fatigue and partial or complete paralysis.
Improving care for patients with multiple sclerosis and other neurological disorders is the goal of the American Academy of Neurology, an association of more than 15,000 neurologists and neuroscience professionals.
Antidepressant rolipram shown to decrease levels of inflammatory cytokines in MS in vitro
Researchers from the Huddinge University Hospital in Stockholm have discovered that the antidepressant rolipram can reduce production of proinflammatory cytokine by cells from patients with MS. According to the authors of the article published in the July-August issue of Clinical Neuropharmacology, rolipram "could have a potential role in the treatment of MS." The Swedish research group led by Dr. Vaidrius Navikas studied the effects of rolipram because "it was known to be capable of altering the cytokine balance in animal models of the disease." In fact, as the authors explain, "cytokines are thought to play a key role in modulating the autoimmune cell response to myelin. Autoimmune response to myelin is implicated in the pathogenesis of multiple sclerosis. During the in vitro experiments they carried out on blood cells isolated from 13 MS patients, they noted that "rolipram reduced the numbers of specific cells expressing the proinflammatory cytokines interferon-gamma and tumor necrosis factor alpha (TNF-alpha), but had no effect on the numbers of cells expressing anti-inflammatory or immunosuppressive cytokines." The cytokines interferon gamma and TNF-alpha are thought to be implicated in the autoimmune mechanisms that lead to myelin destruction in MS. Taking into account that rolipram has shown that it can induce "a selective reduction of the production of proinflammatory cytokines which may be sufficient to restore a relative cytokine imbalance in vitro," the Swedish group of researchers concludes that these experiments have demonstrated that rolipram could have a role in the treatment of MS.
Auto-Antibodies Contribute to Destruction of Myelin Sheath
CALIFORNIA, February 10 1999
Researchers have discovered that the body's own antibodies, culprits in the development of multiple sclerosis, actually play a direct role in the development of the disease.
The study, published in the February 1999 issue of Nature Medicine, was conducted by University of California at San Francisco (UCSF) scientists, in collaboration with investigators at the Albert Einstein College of Medicine in New York City.
The finding suggests that the suspicion of blame, currently resting on the immune systems T cells, which produce such chemical weapons as cytokines, should extend to B cells, which produce antibodies. It also suggests a possible new target for drug therapy for the intermittent, generally progressive neurologic disorder that remains elusive to wholly successful treatment.
The researchers conducted their study on brain tissue taken from patients with multiple sclerosis, as well as animals with a disease model called experimental allergic encephalomyelitis (EAE), which resembles multiple sclerosis.
In this investigation they determined that in active lesions, an antibody directly contributes to the destruction of myelin, a membranous sheath with highly organized structure that surrounds the communication wires, or axons, between nerve cells in the brain and whose destruction is characteristic of multiple sclerosis.
"We determined that these antibodies were bound to their target in myelin as the membrane was in the process of being disintegrated," said lead author of the study, Claude Genain, MD, UCSF. This is direct evidence that the antibody plays an integral role in the formation of the ruptured myelin sheath.
Researchers have long suspected that multiple sclerosis is an auto, or self, immune disease, in which the body's own immune system turns against specific targets, or antigens, in tissues of the body. Under normal conditions, the immune system targets foreign antigens, or invaders, such as bacteria or viruses, which are usually excluded from the brain compartment. But teasing out the role and relative contributions of the various, and often intertwined components of the immune system - T cells, B cells, and macrophages being the key players - has been daunting.
For the last decade, scientists have focused on the role played by auto- reactive T cells, as studies on EAE have demonstrated that T cells sensitized against myelin protein antigens in the sheath can trigger the immune attack on the brain.
But researchers have not been able to identify the antigen targets of T-cell attack in multiple sclerosis itself and the actual molecular mechanisms implicated in myelin damage have remained uncertain.
In recent work, the UCSF/Einstein team studied an EAE model in which the way myelin is destroyed is identical to the process that occurs in expanding lesions of multiple sclerosis. They determined that myelin destruction occurred only in the presence of both auto-reactive T cells and auto- reactive B-cell antibodies directed against a minor protein of myelin called myelin oligodendrocyte glycoprotein (MOG).
Thus, in the current study, the team was prompted to reconsider the role of B cells and the antibodies they produce, which were generally discounted years ago. A senior author of the study, Cedric Raine, PhD, DSc, Albert Einstein College of Medicine, was a pioneer in investigating the antibody theory during the late 1960s.
"Thirty years ago, we suspected antibodies played a role, but we lacked the technology to show it," said Raine. "The significance here is that for the first time we've been able to localize antibodies to the myelin sheath and to demonstrate their involvement in myelin breakdown."
The researchers detected MOG antibody, highlighted with a gold-labeled chemical tag for tracing purposes, in brain tissue obtained from patients during active phases of multiple sclerosis, where it appeared to be bound to the MOG antigen on the surface of myelin as the sheath was being destroyed.
These findings directly identified MOG-specific antibodies in actively demyelinating lesions of multiple sclerosis, indicating that these auto- antibodies play an integral part in the formation of vesiculated, disrupted myelin sheaths, said Raine.
"Such direct evidence for the role of antibodies in myelin damage has never been shown," said Genain. "We've identified one antibody in EAE. Our study also shows that there are probably others, too."
The finding does not suggest that the role of T cells should be discounted, said Genain. He suspects that they do initiate and play an integral role in the destruction of the myelin sheath, which acts as electrical insulator, allowing the conduction of nerve impulses along axons. Their principal role, he said, may be their ability to penetrate the blood-brain barrier thereby creating an opening that ushers in a cascade of immune system cells as well as the fluid known as serum, which contains antibodies. Alternatively, the antibodies could be generated within the brain.
What the study does suggest, said Genain, is that T cells and B-cells may play an integrated role in the destruction of the sheath.
"Clearly," he said, "the immune system of humans is much more complex than we had been led to believe on the basis of previous work, and much more difficult to manipulate than in rodents. There are many clinical and pathological presentations of multiple sclerosis. We have looked at what can be called hot lesions where there is intense destructive activity and found that these are invariably associated with antibody deposition. However, the respective part played by T- and B-cell-mediated mechanisms may well differ in individual cases."
One therapeutic answer for the disease surely lies in blocking autoimmune cells before they can attack the myelin sheath, said Genain. For it is in the progressive splitting and swelling of the myelin sheath that the disruption begins, causing inflammation in the surrounding area, destroying nerve-impulse conducting myelin and, ultimately, displacing the axons themselves causing sporadic, then progressive, neurological impairments, including paralysis of the limbs and eyes.
The study was funded by a grants from the U.S. National Institutes of Health (NIH), the National Multiple Sclerosis Society, and the Nancy Davis Center Without Walls.
Researchers have discovered that the body's own antibodies, in recent years considered minor, perhaps even inconsequential, culprits in the development of multiple sclerosis.
What induces the attack on MBP? Presumably infection with a virus -- most likely adenovirus or the measles virus -- containing a protein with an amino acid sequence that matches a stretch of amino acids in MBP.
A number of promising new therapies are under investigation for treating MS. Researchers at Kennedy Institute for Rheumatology in London and Chiron Corporation have produced a monoclonal antibody that binds tumor necrosis factor, an important element in demyelination. A single dose of their monoclonal antibody will suppress the autoimmune response for 5 to 10 weeks without reducing the general immune response to infection. The compound is under investigation for both rheumatoid arthritis and MS. Monoclonal antibodies have also been developed against the CD4 receptor on T-cells, which orchestrates the autoimmune attack. Another approach is to develop a monoclonal antibody that binds T cell proteins involved in attaching to the wall of blood vessels; the bound T cell is unable to breach the blood-brain barrier, the site of the autoimmune attack. Treating animals with this monoclonal antibody has been shown to protect against brain inflammation. Vaccinating a patient against the rogue T cells is also possible (using a peptide found in a T cell receptor that reacts to MBP). Finally, oral tolerance therapy is a promising technique. The body accepts most proteins ingested as food, and attacks most proteins that are presented directly to the tissues. In some cases feeding a patient the antigen targeted by the immune system results in tolerance. Bovine myelin fed to MS patients, for example, has been shown to reduce the number of relapses, although only in men, not in women.
Recently Steinman et al. at Stanford sequenced the gene that codes for the T cell receptor (TCR) involved in the autoimmune attack on MBP. The Stanford investigators examined the TCR gene arrangements in plaques taken at autopsy from the brains of 16 MS patients. They identified a specific gene sequence in 8 of the 16 patients and found that it is the identical gene sequence that causes the immune response in animal models of MS. Moreover, the TCR gene sequence matches the gene sequence known to code for MBP. (The 50% of patients who do not share the common TCR gene sequence will have to await the sequencing of other TCR genes and the development of specific drugs to block the products.) To develop the technology, Steinman cofounded Neurocrine Biosciences (San Diego, CA) in 1992 to design drugs to combat autoimmune diseases and aging. The first IND anticipated will be for a drug to treat MS, although Neurocrine Biosciences is also focused on neuropeptides and neuroimmunosteroids involved in immune mechanisms, and drugs to block cytokines involved in inflammatory diseases of the central nervous system (including Alzheimer's disease). (Steinman L. Sci Am. 1993; 269: 107-114. Additional information from Neurocrine Biosciences.)
Reprinted from the September 1994 issue of Medical Sciences Bulletin, published by Pharmaceutical Information Associates, Ltd. recently reported in The Wall Street Journal that a major pharmaceutical company, Eli Lilly, had invested $40 million in Autoimmune, Inc.'s, oral tolerance research. LaJolla recently announced that it had isolated several epitopes for the antiphospholipid disease, one of the causes of autoimmune stroke--and research into antiphospholipid disease is expected later this year.
AARDA recognizes the need for more collaboration in research involving autoimmune diseases and the need for more basic research into autoimmunity as the underlying cause of these diseases. This, along with helping to raise physician and public awareness of autoimmunity as a category of disease so that early screening and prevention programs will one day be commonplace, is the primary mission of AARDA
NICE, FRANCE -- June 9, 1998 -- Treatment with high doses of Rebif (interferon beta-1a) has for the first time significantly delayed disability progression in multiple sclerosis patients at high risk of disease progression, delegates to the European Neurological Society's annual meeting in Nice were told today.
The breakthrough was reported in an abstract from the PRISMS (Prevention of Relapses and Disability by Interferon beta-1a, Subcutaneously in Multiple Sclerosis) study presented by Lance Blumhardt, professor of clinical neurology at the University of Nottingham.
"Results of the PRISMS Study bring new hope to neurologists and people who suffer from MS," Blumhardt said. "Over time, most patients will experience some degree of disability, but the findings from the PRISMS study suggest that those at highest risk of becoming rapidly disabled require higher doses of interferon beta-1a than are currently used, in order to stabilise their disease and prevent further deterioration."
The PRISMS data indicate that those patients at greatest risk for progressing to secondary-progressive MS are characterised by: a clinical disability score of EDSS greater than 3.5 (moderately severe disability); greater burden of disease (BOD) levels according to MRI (magnetic resonance imaging); the occurrence of more frequent and severe exacerbations; and a disease duration of at least seven years. In addition, they have a generally more aggressive state of disease and are unlikely to respond to currently available therapies.
The PRISMS data suggest that these patients may require higher doses of interferon therapy to delay the more marked progression that is associated with SPMS.
Data from the cohort of 94 high EDSS patients showed interferon beta-1a at the higher dose (132 mcg/weekly) to be the first treatment to delay the progression of disability in MS patients with greater disability, tripling the time to progression of disability from seven to 21 months and more than halving the number of relapses (60 percent reduction) compared to placebo treatment. In addition, the high dose dramatically reduced the BOD and disease activity as revealed by MRI. In this cohort, relapses were more than 2.5 times more likely in the placebo group than in the higher dose group.
The PRISMS trial was first presented at the annual meeting of the American Neurological Association in September of 1997 and was the first MS trial to show efficacy on all major outcome measures using data from all treated patients at two doses of interferon beta-1a. In total, 560 patients were treated with interferon beta-1a or placebo, subcutaneously, three times a week for two years. The study involved 22 MS centres in nine countries across three continents, including North America. The PRISMS study, the largest randomised, placebo-controlled trial completed in relapsing-remitting MS, also clearly demonstrated that treatment with doses of interferon beta-1a as high as 132 mcg per week were safe and well tolerated.
More than two million people have MS. It is a chronic, debilitating disease of the central nervous system and is the most common cause of disability in young adults. Recent data from trials such as PRISMS suggest new therapies like interferon beta-1a may beneficially affect the long-term course of MS.