All About Multiple Sclerosis

More MS news articles for March 2003

New Research: recently funded projects/spring 2003

http://www.nationalmssociety.org/pdf/research/NewResearch.pdf

Spring 2003

New Center Awards Launched
Targeted Research
Meet the Researcher
Pilot Projects

New MS Research Projects Begin April 1

The National Multiple Sclerosis Society has just committed $13.4 million to support 31 new MS research projects with terms running up to five years. These projects were found to be of the highest scientific merit and significance in the fight against MS, out of scores reviewed by our volunteer panel of scientific advisors. Two of these new projects are part of the Society’s targeted research initiative on gender differences in MS >>>

In addition, the Society has just committed $2.48 million to support three new Collaborative MS Research Centers, a new program launched to speed the search for the cause of, and cure for, MS. The new Center Awards are briefly described >>>.

Even when research commitments are made, the money is not in hand to meet them: The Society now has over $50 million in current- and future-year commitments to meet. Money must be raised each year to fulfill them. Contributions to the Society to help support committed projects are essential to helping us meet our financial obligations.

The new research projects are part of a research program that is slated to invest more than $30 million this year alone to advance MS research, including funding over 300 new and ongoing MS investigations in the U.S. and abroad. By the end of this year, the Society will have invested a total of $380 million since its founding to support basic and clinical research aimed at finding a cure for MS.

Following are brief summaries of the new research grants, grouped according to major avenues of MS investigation. In addition, 13 new “high-risk” projects aimed at testing innovative ideas were awarded over the last six months through the Pilot Research Program. These are listed >>>

THERAPY/REHABILITATION

Seeking Better MS Treatments

Ultimately, the goal of the biomedical research program of the National MS Society is to develop therapies that will combat MS. The Society supports clinical treatment trials in a number of ways: by providing full or partial financial support to investigators conducting trials on new therapies or FDAapproved medications; by funding parallel studies to understand how an experimental treatment may work; by participating on committees to monitor safety and ensure the quality of trials; and by training young physicians to excel in the meticulous process of MS clinical trials through our Sylvia Lawry Physician Fellowship Program. The Society also supports research into symptom management, care and rehabilitation strategies to improve the quality of life of those living with MS. The Society’s sponsorship of basic and clinical research lays the foundation upon which most clinical trials are based.

The Society is currently supporting 24 projects testing MS therapies and rehabilitation methods, for a total financial commitment of nearly $8 million, including this new study on a novel method of determining the effectiveness of current MS treatments.
 

Andrew Pachner, MD, is measuring interferon antibodies in people with MS. His studies may initiate major changes in how interferon therapy is monitored.

Effect of anti-interferon antibodies on interferon bioavailability in people with multiple sclerosis
Determining whether immune antibodies impede the effectiveness of treating MS with interferon beta.

Andrew R. Pachner, MD
University of Medicine & Dentistry of NJ New Jersey Medical School Newark, NJ
Region: Greater North Jersey Chapter 4/1/03-3/31/06;
$279,844

Injection of a “foreign” protein can cause antibodies to be produced to neutralize the protein. Treatment with interferon beta can result in such antibody formation, which could block the therapeutic benefit of this medication. There is debate on the impact of such antibodies, on their prevalence, and even on how to measure them, and physicians tend not do so because of the cost and complexity involved.

Andrew Pachner, MD, is measuring the presence of interferon antibodies using several methods with different degrees of reliability and cost, to evaluate which test is best and most practical to use. He is using these antibody assays to test 240 people with MS before and after initiation of interferon therapy. In addition to evaluating these methods, Dr. Pachner is seeking to determine to what extent the antibodies block the effects of interferon treatment, and if this leads to a poorer outcome for people with MS.

These findings may initiate major changes in how interferon therapy is monitored in people with MS, and may help to identify people in whom further treatment may be successful or unsuccessful.

NERVOUS SYSTEM REPAIR

Restoring Brain Tissues

How can the damage caused by MS be repaired? This question was explored in 2002 by some 120 researchers from around the world at an intensive scientific workshop organized by the National MS Society. While there is not yet an answer to this complex question, the take-home message was that a new age is dawning that will usher in vast potential for repairing brain and spinal cord tissues in MS.

Now that therapeutic agents are available that can at least reduce the ongoing immune assault against nervous-system tissue in some forms of MS, the idea of trying to repair the damage is no longer a mere dream. In particular, researchers are focusing on identifying and blocking natural processes that may actually inhibit the body’s ability to repair nervous system damage.

The Society is currently funding 15 investigations focusing on central nervous system repair, for a total commitment of $4.6 million. The following three new projects focus on identifying biological impediments that must be overcome if normal function is to be restored.

Understanding the molecular basis of remyelination failure
Identifying molecular mechanisms that may be responsible for incomplete myelin repair in MS.

Patrizia Casaccia-Bonnefil, MD, PhD
University of Medicine & Dentistry of NJ Robert Wood Johnson Medical School Piscataway, NJ
Region: Mid-Jersey Chapter 4/1/03-3/31/06;
$184,067

Multiple sclerosis is characterized by damage to the myelin sheath that insulates nerve fibers. Several studies have indicated that, early in the disease, immature myelinmaking cells – called, “oligodendrocyte progenitors” – are recruited to generate new myelin. A sufficient number of these cells is needed so that progenitors can migrate to the site of myelin damage and develop into myelin- making cells. Then, genes that instruct the formation of myelin components are activated and myelin is formed. In MS, this process fails.

Patrizia Casaccia-Bonnefil, MD, PhD, and colleagues are investigating factors that decrease the effectiveness of oligodendrocyte repair in MS. They believe that chromatins, proteins that exist within the nucleus of cells, may inhibit activation of the genes that promote myelin formation. Dr. Casaccia- Bonnefil is testing this theory by modifying the chromatins in rat tissue and observing how this affects myelin formation.

This study may provide important information on possible causes of the failure to renew myelin and possible strategies to prevent this failure.

Blocking the inhibition of axonal regeneration by MAG/myelin
Reversing the action of a protein that prohibits the regeneration of damaged nerve fibers, to find ways to re-grow nerve fibers that are lost in MS.

Marie Filbin, PhD
Hunter College New York, NY
Region: New York City Chapter 4/1/03-3/31/07;
$601,392

Abnormal immune activity in MS destroys myelin, the insulating sheath that surrounds nerve fibers, and can also damage nerve fibers themselves. Because nerve fibers do not regenerate spontaneously in adult brains, researchers must not only find a way to stop the destructive immune activity, but also find a way to encourage nerve fibers to regenerate.

Marie Filbin, PhD, and colleagues have been accumulating growing evidence that a myelin component called myelin-associated glycoprotein (MAG) actually inhibits nerve regeneration in MS. Now, Dr. Filbin’s team is examining this process more closely in nerve cells taken from mice, to understand the sequence of events that results in inhibition and to identify treatments that can overcome inhibition.

This study may eventually lead to a therapy that repairs damaged nerve fibers in people with MS.

Reactive astrocytes: a restrictive role in oligodendrocyte maturation” Determining the role of brain cells that may prevent myelin- making cells from maturing and repairing myelin in MS.

Gareth R. John, DVM, PhD
Albert Einstein College of Medicine Yeshiva University Bronx, NY
Region: New York City Chapter 4/1/03-3/31/06;
$437,389

Multiple sclerosis involves an immune attack that damages the myelin sheath that insulates nerve fibers, as well as nerve fibers and myelin- making cells called oligodendrocytes. Some lesions – areas of myelin damage in the brain tissue – show evidence of myelin repair, while others fail to repair. Recent studies indicate that lesions contain a large number of immature oligodendrocytes, which may mean that failure to repair myelin is not due to a lack of these cells, but some factor in the surrounding environment that limits their capabilities.

To determine this factor, Gareth John, DVM, PhD, is looking to astrocytes, brain cells that perform several support and “housekeeping” functions in the brain and spinal cord. When his team activated astrocytes with the immune messenger protein TGF-beta, they discovered that a protein called “Jagged1” was induced. Jagged1 is used in the early-stage developing brain and spinal cord to maintain oligodendrocytes in an immature state until they migrate to distant sites where the impact of Jagged1 is less, and the immature cells are released to mature and form myelin. The team is now testing the hypothesis that Jagged1 may inhibit the maturation of resident immature oligodendrocytes in the MS lesion as well, resulting in a failure to repair myelin. His team is attempting to identify the mechanisms by which TGF-beta induces Jagged1 in astrocytes and inhibits oligodendrocyte maturation in the laboratory, and is testing myelin-damaged brain tissue for a connection between this pathway and lack of myelin repair.

This study may identify new targets for treatment strategies that will allow myelin repair to proceed in people with MS.
 

$2.48 Million For 3 New MS Center Awards

Three new research centers have been established by the National MS Society to speed the search for the cause and cure of multiple sclerosis (MS), by teaming up investigators from diverse fields focusing on promising avenues of research. The new Collaborative MS Research Center Awards add $2.48 million to the Society’s long-term research commitments to over 300 research projects totaling some $50 million.

The individual five-year, $825,000 Center Awards are not meant to pay for “bricks and mortar” laboratory facilities, but rather to allow for flexible spending by collaborating teams based at the same or separate institutions.

The award-winning projects for 2003, and their principal investigators, are: David A. Hafler, MD (Harvard Medical School, Boston), whose team is speeding up the search for MS genes; Anne H. Cross, MD (Washington University in St. Louis) and colleagues, who are developing better diagnostic technologies for MS; and Charles D. Stiles, PhD (Dana- Farber Cancer Institute), who is leading an investigation into possible strategies for repairing the damage to nerve-insulating myelin that occurs in MS.

The National MS Society plans to create additional Collaborative MS Research Centers each year to foster cross-fertilization of ideas and techniques that will speed the search for a cure. For more information about the new Collaborative MS Research Center Awards, visit our Web site: http://www.nationalmssociety.org/Research-CenterAwards.asp.

EPIDEMIOLOGY

Who Gets MS?

Epidemiologists evaluate disease patterns among people with a certain disease, taking into account variations in geography, demographics, socioeconomic status, genetics, and exposure to infectious and toxic agents. They study the relationships between these factors, as well as patterns of migration, that may be related to areas with high or low rates of MS. Such efforts received federal attention in 2002, when the federal Agency for Toxic Substances and Disease Registries awarded research grants to five investigators to evaluate possible environmental risk factors for MS and amyotrophic lateral sclerosis in several communities in the U.S. located near hazardous waste sites.

By looking at who gets MS, we can begin to understand why this disease appears more frequently in certain populations, and why some people may be protected. Epidemiological studies ultimately seek to discover the cause of MS, and may also serve as the basis for developing future treatments.

The National MS Society is currently funding two research projects in epidemiology, including the following new project.

A case control study of past sun exposure and first demyelinating events
Investigating whether vitamin D, through sunlight exposure, reduces the risk of developing MS.

Anthony J. McMichael, MBBS, PhD
The Australian National University Canberra, Australia 4/1/03-3/31/08;
$617,717

Worldwide, MS occurs with much greater frequency in higher latitudes (above 40° latitude) away from the equator, than in lower latitudes, closer to the equator. One possibility is that an environmental factor in these areas may contribute to the development of MS, or protect against it. Anthony J. McMichael, MBBS, PhD, is investigating the possibility that this factor may be exposure to ultraviolet radiation (UVR) from the sun. MS is less common in tropical areas, which are exposed to greater UVR than temperate zones, and recent research indicates that UVR (or vitamin D synthesized via UVR exposure) can dampen the immune attack. This might provide a biological mechanism for reduced MS where UVR exposure is higher.

Dr. McMichael is enrolling 570 people who are at high risk for MS (individuals who have experienced a single, isolated neurologic event suggesting demyelination, loss of nerve-fiber insulation), and 876 people without MS. Participants live in various communities in Australia where the northsouth latitude impact on MS prevalence is marked and where a similar gradient in UVR exposure is seen. Dr. McMichael is comparing lifetime sun exposure in these two groups using advanced imaging technology to examine skin, measuring vitamin D status (produced by UVR), and administering a questionnaire about sun exposure.

This study may bring us new insight into non-genetic factors that may make people susceptible to the development of MS, and may suggest new avenues for treatment or prevention.
 

MS CLINICAL TRIALS

The latest information on 150 clinical trials in MS…

Studies in your area that are recruiting participants…

All on the Web site of the National MS Society:

http://www.nationalmssociety.org/Clinical%20Trials.asp

INFECTIOUS TRIGGERS

What Starts the MS Attack?

Our bodies’ immune systems are designed to fend off invading microbes, such as viruses and bacteria. Most of the time this complex system does its job successfully. In MS, something as yet unidentified causes this system to launch an attack against nervoussystem tissue.

For years, researchers have been searching for evidence that a virus or other microbe could be the culprit, not by directly causing MS – which is not an infectious disease – but possibly by fouling up immune responses such that the body’s brain and spinal cord tissue is mistaken for an outside invader.

The National MS Society is currently funding 10 research projects totaling $2.8 million which focus on infectious triggers in MS, including the following new grant, a researcher who is approaching this question by searching for evidence of a virus in blood samples from people with MS.

Herpes viruses as possible etiology of MS
Investigating a possible role of HHV-6 virus as a trigger for MS.

Christina G. Christodoulou, PhD
The Cyprus Inst. of Neurology and Genetics Nicosia, Cyprus 4/1/03-3/31/06;
$241,065

Partial evidence suggests that human herpesvirus (HHV) may be associated with MS. One strain, HHV-6, has been discovered in areas of the nervous system damaged by MS, and the genes that control the virus have been detected in nervous-system cells. But HHV-6 and other herpesviruses are commonly found even in people who do not have MS, and their connection to MS remains unclear.

To further elucidate the possible role of herpesviruses in MS, Christina Christodoulou, PhD, is investigating blood and spinal fluid samples taken from people with MS, looking for the presence of eight known herpesviruses. Her team is using a collection of samples that the Cyprus Institute of Neurology and Genetics takes from over 100 people with MS from the time of their first attack, and throughout the course of disease, during both relapses and remission. Of particular interest will be the relationship between disease activity and active viral infection with herpesvirus, versus dormant or “latent” infection, since it has been theorized that active infection might be more tied to disease relapses or attacks.

This study may shed light on a possible role for human herpesvirus in the development or relapses of MS.

TARGETED RESEARCH:

Gender Differences

The National MS Society’s targeted research initiative on gender differences in MS focuses on the question of why more women than men have multiple sclerosis, and what the biological differences between the sexes can tell us about the cause and course of MS. Answers to this question may also lead the way to better treatments for both men and women.

Society-funded researchers published exciting findings on such treatments in 2002: In a small-scale, earlyphase trial of the hormone estriol, a form of estrogen, women with relapsing- remitting MS showed decreases in brain lesion activity (detected by MRI – magnetic resonance imaging) and immune responses during treatment, suggesting that additional study of estriol is called for to determine longer-term efficacy and safety. One such trial is currently in the planning stages.

The Society is currently funding 11 projects in this targeted area, and is cofunding 6 additional projects as part of a collaborative effort with the National Institutes of Health, for a total of $5.4 million, including the following two new grants.

Mechanism of EAE suppression with non-steroidal estrogens
Exploring the use of a plant-derived hormone similar to estrogen to treat an MS-like disease in mice, for clues to its possible use in humans.

Bruce F. Bebo, PhD
Oregon Health & Science University Beaverton, OR
Region: Oregon Chapter 4/1/03-3/31/06;
$452,961

The clinical symptoms of MS are reduced during pregnancy, a time marked by a dramatic increase in sex hormones such as estrogen. This fact has spurred interest in investigating these hormones for treating MS. In a small-scale, earlyphase trial of estriol, a form of estrogen, women with relapsing-remitting MS showed decreases in disease activity.

Bruce Bebo Jr., PhD, is evaluating molecules that mimic estrogen, known as “phytoestrogens.” These compounds (found in isoflavones, an ingredient in soybeans) have an advantage over real estrogens because they are non-steroidal and thus lack some of the negative side effects of hormonal steroids. Steroidal forms of estrogen may affect the reproductive system adversely, possibly leading to breast and uterine cancers.

Dr. Bebo has found that phytoestrogens can suppress the MS-like disease EAE in mice, and is now attempting to determine which phytoestrogen has the most potent ability to suppress this disease. He also is investigating what signals are necessary to suppress disease, in a model of EAE that lacks the molecules that may be involved in this process.

This study may lead the way toward further clinical investigations of phytoestrogens for the treatment of MS.

Mammalian oligodendrocytes are sexually dimorphic
Examining biologic differences in myelin-making cells between male and female mice with an MS-like disease, and implications for human MS.

Robert P. Skoff, PhD
Wayne State University The School of Medicine Detroit, MI
Region: Michigan Chapter 4/1/03-3/31/06;
$469,087

Women are nearly twice as likely to develop MS than men, and this is commonly believed to be partly due to hormonal factors. One additional factor may be differences between men and women in myelin – nerve fiber insulation that is destroyed in MS – and cells that make myelin, oligodendrocytes.

With a pilot grant from the National MS Society, Robert P. Skoff, PhD, made the surprising finding that the number of oligodendrocytes is 20% to 40% higher in males, but that the death and growth of these cells is higher in females. Dr. Skoff and colleagues are now examining these differences further in different strains of mice with EAE, an MS-like disease. Among the questions they are asking: What is the life span of oligodendrocytes in male versus female mice at different ages of development? Does increased turnover of myelinmaking cells in females result in more disease-induced damage to myelin sheaths and proteins than in males? And, what is the impact of hormones on cell death and growth?

Answering these and other questions about gender differences in myelin may provide insight into the cause of MS.

GLIAL CELL/MYELIN BIOLOGY

Can Myelin Be Repaired?

Exploring glia, which include cells in the nervous system that make nerveinsulating myelin, is a cornerstone of MS research. Myelin, and the cells that make it, appear to be the main target of the immune attack in MS.

Immature myelin-making cells (“progenitors” or “precursors”) may have potential to repair myelin. Investigators are working on deciphering molecular signals that are sent out at sites of injury to recruit such cells, in hopes of finding ways to mimic these signals. In addition, a host of proteins known as “growth factors” are under investigation for their roles in turning on stages of myelin and nerve growth. Finally, researchers are investigating the “axoglial junction” where myelin and nerve fibers meet – this relationship may profoundly affect nerve impulse conduction.

The Society is funding 78 projects in glial cell/myelin biology, for a total commitment of some $21 million, including the following 10 new projects.

Control of oligodendrocyte proliferation & differentiation by notch signaling
Investigating the molecular mechanisms that regulate the development of myelin-making cells, for clues to repairing tissue damage caused by MS.

Bruce Appel, PhD
Vanderbilt University The School of Medicine Nashville, TN
Region: Mid-South Chapter 4/1/03-3/31/06;
$385,761

Proper nerve function requires that nerve fibers be ensheathed with the insulating substance myelin, which is produced by cells known as oligodendrocytes. Myelin repair is impaired in MS, leading to faulty transmission of nerve impulses.

Myelin-making oligodendrocytes are produced by “precursor” cells, immature cells in the central nervous system. Bruce Appel, PhD, is studying how these cells mature and develop into oligodendrocytes that can make myelin. His team is using zebrafish for these experiments, since embryos of these animals develop outside the mother and are transparent, and therefore can be observed during all stages of development. The developmental stages and molecular mechanisms underlying oligodendrocyte maturity in zebrafish are similar to other animal models, such as rodents. Dr. Appel is investigating the genes and signals that lead oligodendrocytes to become myelin-making cells.

This research will help clarify the steps needed to develop myelin-making oligodendrocytes and may lead to strategies for promoting myelin repair in MS.

Localization of mRNAs in oligodendrocytes
Studying genetic signals that control growth of proteins in nerve-insulating myelin, to find ways of stimulating myelin repair.

Elisa Barbarese, PhD
University of Connecticut Health Center School of Medicine Farmington, CT
Region: Greater Connecticut Chapter 4/1/03-3/31/06;
$343,451

Myelin is the insulation surrounding nerve cells, permitting cells to conduct nerve impulses rapidly and in a coordinated fashion. In MS, damage to myelin results in neurologic symptoms such as numbness, poor motor control or blurred vision. One factor required for proper myelin formation is the production of myelin basic protein (MBP, a major protein in myelin) and its proper location in the membrane of myelin. Not only is MBP a major player in proper myelin formation, but it is known that defects in MBP or its genes can cause MS-like disease.

Elisa Barbarese, PhD, is studying MBP production. Her team has found that myelinmaking cells “tag” the genes for MBP, allowing them to be rushed to the site of myelin assembly by other cells and proteins. One of these proteins, called “TOG,” has been identified and is involved in MBP transport. Now, Dr. Barbarese is investigating whether TOG is responsible for moving MBP to the right place at the right time for myelin formation, in samples of myelin-making cells taken from rodents.

Understanding how myelin is made can lead to ways to repair it in MS.

The development of nodes of Ranvier in the central nervous system
Understanding how myelin-making cells influence nerve fiber development, for clues to restoring nerve conduction in MS.

Ben A. Barres, MD, PhD
Stanford University Medical Center The School of Medicine Palo Alto, CA
Region: Silicon Valley Chapter 4/1/03-3/31/06;
$457,885

Normal nerve impulse transmission depends on an intact myelin sheath that insulates nerve fibers. Also instrumental are sodium channels – tiny pores – that cluster around unmyelinated spots called nodes, which are spaced out along the nerve fiber. When stimulated by a nerve impulse, the channels briefly open, admitting sodium and exciting the nerve fiber. The impulse then “jumps” to the next node. In this way, a nerve impulse is rapidly transmitted down a nerve fiber.

The clustering of sodium channels at these nodes is a direct consequence of the presence of myelin-making cells. After MS destroys myelin, however, sodium channels become disorganized, impairing impulse transmission. Ben Barres, MD, PhD, has found that chemical signals from myelinmaking cells, however, can trigger the clustering of sodium channels and enhance nerve conduction. He is further characterizing how these signals may trigger clustering in cell samples taken from rats. Using “gene chip” technology that can analyze thousands of genes at once, his team is determining which genes or proteins are activated by myelinmaking cells, and if any of these help to trigger sodium channel clustering.

This research may suggest new ways to enhance or restore nerve impulse transmission in MS by teaching us how to enhance reorganization of sodium channels that can help maintain nerve transmission even if myelin is lost.

Golli MBP gene expression in the nervous system
Studying the functions of a specific protein that may be involved in the growth, destruction and regeneration of nerve-insulating myelin.

Anthony T. Campagnoni, PhD
University of California at Los Angeles Neuropsychiatric Institute Los Angeles, CA
Region: Southern California Chapter 4/1/03-3/31/06;
$489,225
Funded in full by Research Honor Roll gifts from the NMSS Southern California Chapter

The protein known as “golli” is produced by both the immune system and by oligodendrocytes – cells that produce the nerveinsulating myelin which is destroyed in MS. One part of each golli protein is identical to a region of MBP, a myelin protein that is one target of the misdirected immune response in MS. Thus, golli may be involved in MSrelated immune mechanisms and may also be instrumental in manufacturing myelin, as it is produced in oligodendrocytes well before these cells even begin to make myelin.

In this study, Anthony T. Campagnoni, PhD, is seeking to unravel golli’s role in both myelin production and destruction. He has found evidence that it might be an important signaling molecule in the initiation of myelin formation by oligodendrocytes. Now, Dr. Campagnoni is trying to determine the exact molecular mechanisms by which golli proteins participate in myelin formation, in mice that are genetically engineered to produce too much or too few golli proteins.

Results of these studies should provide important insights into myelin destruction and repair.

Roles of ciliary neurotrophic factor in remyelination
Studying a molecule that may provide signals the promote myelin repair in an MS-like disease in mice.

Steven W. Levison, PhD
Pennsylvania State University The College of Medicine Hershey, PA
Region: Central Pennsylvania Chapter 4/1/03-3/31/06;
$386,681

In multiple sclerosis, nerve fiber-insulating myelin is damaged. Studies of brain tissue indicate that some repair of myelin does occur. Steven W. Levison, PhD, is investigating the factors that may promote this repair.

Dr. Levison and colleagues have shown that levels of a protein known as ciliary neurotrophic factor, or “CNTF,” are elevated in the spinal cords of mice with an MS-like disease, specifically during their recovery from disease. They found that CNTF induces brain cells to release molecules that promote the survival of myelin-making cells. CNTF also is elevated in the spinal fluid of people with MS, and the disease is worse in people who are genetically unable to make CNTF.

These findings led Dr. Levison to theorize that CNTF appears as a consequence of damage in the brain and spinal cord and that its appearance can trigger the production of factors that could enhance the possibility of repair. Now, Dr. Levison is analyzing the course of myelin damage and repair in mice that are genetically engineered to produce an excess of CNTF. His team is attempting to better understand how CNTF signals affect myelin-making cells and myelin repair.

This study may help to develop strategies that promote myelin repair in MS.

Axoglial communication through regulated release of neuregulin
Understanding the communication/mutual support between nerve fibers and myelin-making cells that maintain the function and structure of both.

Jeffrey A. Loeb, MD, PhD
Wayne State University School of Medicine Detroit, MI
Region: Michigan Chapter 4/1/03-3/31/06;
$385,367

Communication between nerve fibers and the myelin sheath that insulates them is key to maintaining the structure and function of both, and is key to nerve impulse transmission. In MS, myelin and nerve fibers are damaged and nerve impulse transmission falters, contributing to the debilitating symptoms of this disease.

Jeffrey A. Loeb, MD, PhD, is investigating a possible role for a molecule called “neuregulin” in maintaining communication between nerve fibers and myelin-making cells during development and how it might be manipulated to help restore damaged tissue. This molecule, released by nerve cells, has been shown to be essential to communication between nerve fibers and the cells that surround them.

Dr. Loeb is examining whether signals from myelin-making cells promote the release of neuregulin in nerve cells during the course of development and isolated in tissue cultures. Using genetic manipulation, he is analyzing each of the signaling steps involved in production and release of neuregulins, in order to track them as they are activated.

This research may unearth important clues to normal nervous system function, and how it may go awry in MS.
 

MEET THE RESEARCHER:

Michael K. Racke, MD

When Michael K. Racke, MD, was a resident in Neurology at Emory University in Atlanta, he approached a professor of microbiology, asking if he could “moonlight” in the professor’s lab. Many nights of work resulted in a publication on the immune response raised by Copaxone® (glatiramer acetate) in an MS-like disease in mice, before the drug was approved by the FDA to treat relapsing-remitting MS.

Since then, Dr. Racke has earned several grants from the Society, including the prestigious Harry Weaver Neuroscience Scholar Award, designed to help young scientists establish themselves as independent MS investigators. Now at the University of Texas Southwestern Medical Center, Dallas, he is combining clinical expertise and basic science to develop potential treatments for MS.

Dr. Racke and collaborators reported several exciting findings in 2002. He and a colleague tested Retinoic acid – a treatment derived from vitamin A and used to treat acne – on human immune cells. The treatment shifted the immune response from inflammatory to suppressive (Cellular Immunology, January 2002). Also, his team found that a compound that mimics PPAR-gamma, a molecule that modulates the immune system, improves MS-like disease in mice (The Journal of Immunology, March 1, 2002).

Now, with a new research grant from the National MS Society, Dr. Racke is investigating whether the same will hold for a compound that mimics a similar molecule, PPARalpha. “These compounds have been used to treat human diseases such as high cholesterol, and have been well tolerated,” explains Dr. Racke. “We hope these studies will provide the background information to test them in people with MS.” Read more about this new project >>>

Function of SHP-1 in oligodendroglia
Exploring interactions between a component of myelin-making cells and an immune chemical that may play a role in both inflammation and myelin repair in MS.

Paul T. Massa, PhD
SUNY Upstate Medical University The School of Medicine Syracuse, NY
Region: Upstate New York Chapter 4/1/03-3/31/06;
$509,562

In MS, the immune system initiates a destructive response against the myelin insulation of nerve fibers, slowing or interrupting nerve-signal conduction and causing a variety of neurologic symptoms. Cells that produce myelin, called oligodendrocytes, may also die in this immune attack, and myelin is only poorly repaired.

Paradoxically, a messenger chemical of the immune system, called interleukin-6 (IL-6), has been found to be involved in both stimulating the destructive inflammation in MS, as well as stimulating myelin development and repair. Paul T. Massa, PhD, has found that an enzyme called SHP-1 is critical for activating genes important in the development and maintenance of myelin. In mice with a genetic defect in SHP-1, IL-6 decreases the activation of myelin proteins, and these rodents do not recover from an MSlike disease. But in rodents without a defect in SHP-1, IL-6 causes an increase in myelin protein production. Now, Dr. Massa is attempting to block IL-6 activity in myelinmaking cells in test tubes, to determine the mechanism for the actions of this immune system chemical.

Because IL-6 regulates myelin proteins, and possibly myelin repair, and SHP-1 regulates IL-6 activity, both could be key to understanding myelin repair.

The role of NG2+ glial progenitor cells in remyelination
Exploring immature brain cells that may be capable of maturing into adult myelin-making cells, and their role in myelin repair in MS.

Akiko Nishiyama, MD, PhD
University of Connecticut College of Liberal Arts and Sciences Storrs Mansfield, CT
Region: Greater Connecticut Chapter 4/1/03-3/31/06;
$454,823

Oligodendrocytes are cells in the brain and spinal cord that manufacture nerve-insulating myelin. They develop from “progenitor” cells, immature cells incapable of making myelin. It was once thought that such progenitor cells were present only in the fetal brain, but recent research has uncovered large numbers of progenitor cells in the adult human brain. Finding ways to stimulate their growth into mature, myelin-making oligodendrocytes to replace those destroyed by MS could constitute a potential therapy.

Akiko Nishiyama, MD, PhD, is attempting to understand the role of one type of progenitor cell in myelin regeneration, called NG2+ cells. She has found that NG2+ cells form myelin-making cells, and now is investigating further to determine the molecular mechanisms that affect NG2+ cells as they grow and proliferate. Specifically, the team is investigating signaling from molecules known as “neuregulins” that might enhance cell development. Her team also is manipulating the genes that control these cells, to determine how they affect myelin repair.

Finding a way to exploit the potential of adult progenitor cells could lead to an MS therapy that enhances myelin repair.

Axonal-glial interactions at the paranodes
Exploring how nerve fibers and myelin interact to maintain proper nerve fiber function.

James L. Salzer, MD, PhD
New York University Medical Center The School of Medicine New York, NY
Region: New York City Chapter 4/1/03-3/31/07;
$516,063

The myelin sheath that insulates nerve fibers in the brain and spinal cord is produced by cells called oligodendrocytes. Each oligodendrocyte “arm” makes contact with a nerve fiber at a spot called the paranodal junction (PNJ). These junctions are thought to play a critical role in regulating the chemical signals that travel between oligodendrocytes and nerve fibers. Such signals are essential to maintaining the structure and function of the nervous system.

James Salzer, MD, PhD, has found that mice lacking “Caspr,” a protein in paranodal junctions on nerve fibers, experience progressive neurologic deterioration, suggesting that Caspr may be critical to nerve fiber health and function. His team is now examining these Caspr-deficient mice further to determine how signaling changes and defects in the paranodal junctions contribute to longterm damage to nerve fibers.

By increasing our understanding of the communication between nerve fibers and myelin at the paranodal junction, this study may lead to new therapeutic strategies to restore the function of myelin-damaged nerve fibers in MS.

Development of oligodendrocyte & microglia in the human brain: relevance for MS
The role of specific brain cells in the development of myelin-making cells and how they impact growth and repair of nerveinsulating myelin.

Nada R. Zecevic, MD, PhD
University of Connecticut Health Center School of Medicine Farmington, CT
Region: Greater Connecticut Chapter 4/1/03-3/31/06;
$354,635

Understanding the development of cells that make the myelin insulation of nerve fibers, called “oligodendrocytes,” is essential to learning how to harness their potential for repairing the damage caused to myelin in MS. Nada Zecevic, PhD, and colleagues are focusing on the differences between oligodendrocyte development in animals and in humans, and on the important role of “microglia” in oligodendrocyte development and myelin formation. Microglia are brain cells that both promote myelin growth and inhibit it.

Dr. Zecevic is categorizing various types of microglial cells in the developing brain and spinal cord, preparing samples of both animal and human developing oligodendrocytes, and is studying the impact of microglia on the course of oligodendrocyte and myelin development.

These data may contribute to our fundamental understanding of how myelin is formed and how myelin repair can be stimulated.

NEUROPHYSIOLOGY/NEUROPATHOLOGY

Nerve Conduction and Injury

Research in neuropathology suggests that the immune attack upon the central nervous system in MS not only causes damage to myelin, but also to nerve fibers. Investigators are working to determine how and when nerve fibers get damaged, and how to protect them.

In addition, researchers are investigating the physiologic processes of the nervous system. Nerve conduction occurs as a result of the opening and closing of specialized pores or channels, which allow sodium and potassium ions, among others, to flow in and out of the nerve fiber. Researchers are seeking to understand how normal nerve conduction occurs and is regulated, and the changes in this process seen in MS. Their goal is to find ways to return nerve conduction to its former, healthy state.

The National MS Society is currently funding 27 research projects in neuropathology and neurophysiology, including the following 4 new projects.

Selective targeting of sodium channel isoforms in neurons
Identifying mechanisms by which myelin-making cells may help to maintain healthy nerve impulse conduction.

S. Rock Levinson, PhD
Univ. of Colorado Health Science Center The School of Medicine Denver, CO
Region: Colorado Chapter 4/1/03-3/31/06;
$489,146

Myelin forms an insulating coating around axons (nerve fibers), the “wires” of the nerve cell that transmit nerve impulses. Clusters of sodium channels, tiny pores along axons, are essential for nerve conduction. After MS damage, these channel clusters become disorganized, contributing to the inability of axons to transmit signals, and causing the neurologic symptoms of MS.

S. Rock Levinson, PhD, has found that myelin-making cells known as oligodendrocytes may help to establish and maintain sodium channel clusters in nerve fibers through physical contact and exchange of “trophic factors.” His team believes that oligodendrocytes and nerve fibers send these factors to the nerve cell body that instructs the nerve to form sodium channels and to transport them to the point on the fiber where needed. Dr. Levinson and colleagues are investigating this possible “axoglial” interaction using a system for isolating nerve cells in the laboratory and forming myelin on them, as well as mouse models in which myelin formation is delayed or prevented.

The results of this study may help develop new strategies to recover nerve transmission and to improve neurologic symptoms of MS.
 

13 New Pilot Grants Test Innovative Ideas

Over the last six months, 13 Pilot Research grants were awarded. These projects help to quickly explore untested ideas and generate preliminary data needed to apply for a full grant.

Biology of Glia

Michael Glaser, Ph.D.Myelin formation in neural-glial co-cultures” University of Illinois, Urbana, IL, $44,000; 03/01/03-02/29/04

Charles Sanders, Ph.D.Biophysical characterization of the CNS proteolipid protein” Vanderbilt University, Nashville, TN, $44,000; 10/01/02-09/30/03

Central Nervous System Repair

Charles Howe, Ph.D.In vitro myelination of artifical axons” Mayo Clinic and Foundation, Rochester, MN, $44,000; 11/01/02-10/31/03

Human Genetics

Omar Khan, M.D. “ApoE frequency in African-American people with MS & association with disease severity” Wayne State University, Detroit, MI, $44,000; 10/01/02-09/30/03

Immunology

Wen-Zhe Ho, M.D. “Substance P, immune effector cells and multiple sclerosis” The Children’s Hospital of Philadelphia, Philadelphia, PA, $44,000; 10/01/02-09/30/03

Mark Mannie, Ph.D.Role of CD4 T cells in EAE” East Carolina University, Greenville, NC, $44,000; 10/01/02-09/30/03

Brian Martin, Ph.D.Cuprizone model of demyelination-remyelination: role of complement of C3a and C5a” The University of Iowa, Iowa City, IA, $44,000; 03/01/03-02/29/04

Fei Song, M.D., Ph.D. The thymus in induction of tolerance in EAE” Ohio State University, Columbus, OH, $44,000; 02/01/03-01/31/04

Chunhe Wang, Ph.D. Are alpha-B crystallin-specific T cells from gene knock-out mice encephalitogenic?” Oregon Health & Science University, Portland $44,000; 01/01/03-12/31/03

Neurophysiology

Scott Barnum, Ph.D. Complement anaphylatoxin modulation of calcium signalling and neuronal excitability” University of Alabama at Birmingham, $44,000; 11/01/02-10/31/03

Jyoti Dhar Malhotra, Ph.D. Interactions between voltage-gated sodium channel subunits and cadherins” University of Michigan, Ann Arbor, MI, $44,000; 11/01/02-10/31/03

Fletcher White, Ph.D. The study of peripheral nerve demyelination and neuropathic pain” Loyola University, Maywood, IL, $44,000; 03/01/2003-02/29/2004

Therapy/Management of MS

Andrea White, Ph.D. “Pilocarpine-induced sweat response to 15 weeks of exercise training in individuals with MS” University of Utah, Salt Lake City, UT, $44,000; 10/01/02-09/30/03

The role of cyclooxygenase in multiple sclerosis
Understanding how the immune attack in MS might also harm myelin-making cells and exploring ways to overcome this inhibition to repair.

John W. Rose, MD
University of Utah The School of Medicine Salt Lake City, UT
Region: Utah State Chapter 4/1/03-3/31/07;
$614,900

The immune attack in MS results in the death of cells that make the myelin insulation of nerve fibers. Recent results indicate that glutamate, a neurotransmitter (a substance released from nerve cells to transmit nerve impulses to another cell) may play a role in the death of myelin-making cells by overly exciting the central nervous system. Compounds that inhibit glutamate activity diminished myelin damage in EAE, an MSlike disease, in rats.

John W. Rose, MD, is investigating the steps that lead from the immune attack in MS to glutamate’s actions. He proposes that two inflammatory molecules, COX-2 and iNOS, may interact to enhance glutamate activity. Studies indicate that these agents release molecules that stimulate glutamate release.

Dr. Rose’s team is examining the extent of these molecules in myelin-damaged tissue in people with MS, and is analyzing spinal fluid to determine if increases of glutamate correlate with increases in COX-2 and iNOS. They also are evaluating inhibitors of COX-2 in mice with EAE; similar agents are FDA-approved to treat arthritis.

These studies may provide evidence for clinical trials of COX-2 inhibitors in MS.

MS Research Progress! Results!

Recently published results from Society grantees ...

“Research Highlights,” a newsletter of MS research progress…On our Web site:

http://www.nationalmssociety.org/Progress%20in%20Research.asp

In vivo characterization of white matter injury in the central nervous system
Evaluating the potential of a novel imaging technology to diagnose and evaluate demyelinating disease.

Sheng-Kwei Song, PhD
Washington University School of Medicine Saint Louis, MO
Region: Gateway Area Chapter 4/1/03-3/31/06;
$496,973

The primary feature of MS is damage to myelin, the sheath that insulates axons (nerve fibers) in the brain and spinal cord. Recent research indicates, however, that axons themselves may be damaged early in the course of MS, contributing to progressive disability. It is difficult to differentiate between damage to myelin and axons, both clinically and with imaging, which may have important treatment implications, since myelin damage may be more amenable to recovery than axonal damage.

Sheng-Kwei Song, PhD, is investigating the potential value of diffusion tensor imaging (DTI) – an advanced form of magnetic resonance imaging that measures the diffusion, or flow, of fluids through tissue – for understanding tissue damage in MS. Dr. Song used DTI in a rodent model similar to MS and determined differences in fluid flow, depending on whether just myelin was damaged, or both myelin and axons.

Now, Dr. Song is conducting a comprehensive DTI analysis in mice with MS-like diseases that primarily affect myelin, or primarily affect axons, or affect both. These models – which mimic both mild and progressive MS – are being compared with examinations of actual tissue damage. A better understanding of how DTI pictures correlate to actual tissue destruction in experimental models may help to obtain a more accurate picture of tissue damage in people with MS over time.

Intracellular calcium dynamics in myelinated axons
Understanding how calcium-activated enzymes in damaged nerve fibers contribute to nerve fiber dysfunction and death.

Peter K. Stys, MD, FRCP
Ottawa Civic Hospital Loeb Medical Research Inst. Ottawa Health Research Institute Ottawa, ON Canada 4/1/03-3/31/06;
$333,057

Recent evidence indicates that MS damages not only the myelin sheath insulating nerve fibers, but also the nerve fibers themselves. But how nerve fibers are damaged is not yet clear. There is evidence that enzymes within the fibers become overly activated and proceed to destroy the normal structure of the fibers. These enzymes are activated by calcium, which is normally stored in all nerve cells to help control growth and function.

Peter Stys, MD, FRCP, has found evidence that excessive release of stored calcium may result in nerve fiber injury. He believes that this may be a very early step in triggering a whole cascade of injury mechanisms in the nervous system. Now, in tissue samples in the laboratory, his team is investigating how nerve cells normally regulate stored calcium, and how regulation may fail after the immune attack in MS.

This study may provide a new target for early treatment that protects nerve cells and fibers from injury in MS.

IMMUNOLOGY

Why the Immune System Goes Awry

Better treatments and a cure are the ultimate goals of MS research, and perhaps no branch of investigation has borne more fruit toward these goals than the study of the immune system. All five FDA-approved therapies for MS emerged from the growing understanding of how the immune system works and how it can be manipulated to suppress or regulate immune attacks. In fact, some of the early studies on these drugs were funded by the National MS Society.

Researchers funded by the Society are investigating many cells and proteins in the immune system whose complex interactions can spur on or suppress the immune attack. By evaluating the importance of these components, we can find new and better ways to successfully treat MS.

The National MS Society has current, multi-year commitments of nearly $40 million to support 138 research projects focusing on the immunologic underpinnings of MS, including the following 9 new awards.

The role of complement C3 & C3 receptors in EAE
Exploring how the “complement” immune process contributes to brain and spinal cord inflammation in MS.

Scott R. Barnum, PhD
University of Alabama at Birmingham The School of Medicine Birmingham, AL
Region: Alabama Chapter 4/1/03-3/31/06;
$456,889

“Complement” is a product of an immune response in which proteins made by immune cells help neutralize foreign invaders. Unlike the T-cell immune response, in which T cells “recognize” specific molecules, complement does not have to recognize a specific foreign molecule to work. As such, it “complements” the T-cell response.

Recent research suggests that complement contributes to the destruction of nerve-insulating myelin that occurs in MS, mainly by initiating a powerful inflammatory response. Scott Barnum, PhD, has designed a mouse model that is genetically engineered to produce a protein that blocks activation of complement in the brain. The onset of an MS-like disease was prevented or delayed in this mouse. He is now studying in more detail the complement protein C3, to determine if deleting its docking sites in the immune system will affect the development of EAE in mice.

This study may provide the rationale for new MS treatment approaches that provide a different mechanism for blocking the complement immune.

Regulation and structural study of novel protease implicated in demyelination
Studying an enzyme in the nervous system that may play an important role in myelin loss in MS.

Michael Blaber, PhD
Florida State University Tallahassee, FL
Region: North Florida Chapter 4/1/03-3/31/06;
$342,021

Identifying each step in the process that leads to the loss of myelin (the substance that insulates nerve fibers) in MS is crucial to stopping this process. Michael Blaber, PhD, is investigating one novel possibility – the involvement of myelencephalon specific protease (MSP). MSP is an enzyme found in the brain, and like a digestive enzyme, it can destroy proteins.

Dr. Blaber has shown that MSP is active in the brain and spinal cord, and can destroy a wide variety of myelinassociated proteins. He is now analyzing the structure of MSP, as well as identifying the factors that both activate and inhibit this protein in the brain and spinal cord of rats.

Inhibiting such enzyme activity could be a key step in the control of MS damage.

Inhibiting demyelination by immunization using coxsackievirus vectors
Attempting to derail the immune attack in MS-like disease using a unique vaccination strategy.

Kristen M. Drescher, PhD
Creighton University School of Medicine Omaha, NE
Region: Nebraska Chapter 4/1/03-3/31/06;
$489,489

Kristen M. Drescher, PhD, is investigating a novel therapeutic strategy for MS by attempting to inhibit a similar disease in mice with a vaccine.

MS occurs when the immune system attacks the body’s own nerve-insulating myelin. Altering the immune response so that it might not do damage is an important goal of much MS research. Dr. Drescher is attempting to alter this “autoimmune response” by injecting mice with a virus that is modified to contain a piece of myelin protein and an immune messenger protein that can promote a suppressive immune response. A virus – which is inactivated from causing disease – can be used as a “vector” or vehicle, because it can release small quantities of its load of immune-altering proteins over a long period of time. Dr. Drescher is injecting the vaccine into mice with an MS-like disease before and after myelin damage has begun, to determine if disease progression can be prevented or reduced.

Pathophysiological significance of autoantibodies to myelin
Characterizing immune antibodies that play a role in the destruction of nerve-insulating myelin in MS-like disease.

Claude P. Genain, MD
University of California The School of Medicine San Francisco, CA
Region: Northern California Chapter 4/1/03-3/31/05;
$347,009

Antibodies are produced by immune cells that, under normal circumstances, attach to foreign intruders in the body and mark them for destruction. In MS, however, antibodies may be developed against a person’s own tissues – socalled “autoantibodies” and are involved in the destruction of nerveinsulating myelin in the brain and spinal cord.

Claude P. Genain, MD, and colleagues are investigating whether autoantibodies against myelin have a tendency to occur in families in which more than one person has MS, using blood samples collected by the MS DNA Bank at the University of California at San Francisco. They also are determining whether the presence of specific autoantibodies can be associated with different forms of MS, and whether certain patterns of autoantibodies might actually define new types of MS based on immunologic characteristics. Dr. Genain also is studying autoantibodies in people who are at high risk for developing MS (people who have had one neurologic episode suggesting myelin loss, and imaging-detected myelin damage), for a follow-up period of five years, and assessing the effects of disease- modifying therapy on autoantibodies in these patients.

This study may lead to a better understanding of the role of autoantibodies in MS, and to new diagnostic and treatment methods based on this role.
 

MEET THE RESEARCHER:

Gareth John, DVM, PhD

Gareth John, DVM, PhD, began his medical career as a veterinarian in the United Kingdom. After one year of clinical practice, he decided to pursue a doctoral degree in neuroscience with funding from the MS Society of Great Britain and Northern Ireland.

“I have always been fascinated by how disease develops in the central nervous system, particularly the mechanisms that control genes in this system,” says Dr. John, now at Albert Einstein College of Medicine, New York. “My ultimate goal is to open my own laboratory researching the pathways that regulate the repair of MS lesions [areas of myelin damage].”

To this end, he recently completed a highly successful postdoctoral fellowship funded by the National MS Society, reporting exciting findings in Nature Medicine (September 23, 2002).

“Our findings suggest that Jagged1 – a gene that helps to delay the timing of myelin formation in the normal developing brain – may be one of the factors determining the outcome of myelin repair in MS lesions,” he reports. “The data show that the Jagged1 gene is switched on by an inflammatory factor in MS lesions, and also suggest that Jagged1 signals to the cells that are capable of making new myelin.”

Dr. John is now exploring Jagged1 further with a Society research grant. “Our findings suggest a potential target for therapeutic intervention,” he says. “We are excited about exploring that possibility.” Read more about this new project >>>.

Role of T cells in the immunomodulation of MS
Understanding how treatment with glatiramir acetate affects the immune system in MS.

Nitin J. Karandikar, MD, PhD
Univ. of Texas Southwestern Med. Ctr. The School of Medicine Dallas, TX
Region: Lone Star Chapter 4/1/03-3/31/06;
$528,020

Multiple sclerosis occurs when the immune system mistakenly attacks the myelin substance that insulates nerve fibers. Copaxone® (glatiramer acetate), approved by the U.S. Food and Drug Administration to treat MS in 1996, is a synthetic protein which acts through immune regulatory mechanisms that are not completely understood.

Copaxone appears to work partly via regulation of CD4+ T cells, a type of immune cell that shifts immune responses from inflammatory to antiinflammatory. Using a new technology that measures responses in different subsets of T cells, Nitin J. Karandikar, MD, PhD, has now found the first direct evidence that CD8+ T cells – so-called suppressive T-cells – respond to Copaxone as well. His team is now investigating the diversity of T-cell responses to Copaxone by T cells taken from people with both mild and more progressive MS, in order to determine how these cells respond over the course of therapy.

Understanding the role of agents like Copaxone in modulating specific cells of the immune system is critical to improving treatment strategies with the agent. This study also may help to develop new technologies for monitoring the success of MS therapies.

Pathogenic & regulatory mechanisms in EAE
Identifying factors that control immune T cells that recognize and can attack myelin in MS-like disease.

Vijay Kuchroo, PhD, DVM
Brigham and Women’s Hospital Harvard Institutes of Medicine Boston, MA
Region: Central New England Chapter 4/1/03-3/31/06;
$414,048

Propteolipid protein (PLP) is one of several major protein components of myelin, the nerve-fiber insulation that comes under immune attack in the brain and spinal cord in multiple sclerosis.

The immune cells that launch this attack against myelin are called T cells. Each T cell is programmed to identify and react to a specific piece of protein, and some react to PLP, spurring on disease. Healthy individuals have circulating T cells that recognize parts of myelin, but which remain quiescent and do not attack it. Similarly, Vijay Kuchroo, DVM, PhD, has observed healthy mice from a strain that is very susceptible to developing the MS-like disease EAE but which are resistant to the disease. These animals have disproportionately high numbers of T cells that react to a particular portion of the PLP protein, but these cells seem to be held in check, and disease does not occur. He is now studying these mice for clues to possible regulatory controls that might prevent them from developing EAE.

Understanding how the immune system can regulate its own functions could help us understand immune factors that may be harnessed to control MS.

Peroxisome proliferator-activated receptor agonists as treatment for autoimmune demyelination
Testing whether anti-inflammatory molecules can improve an MS-like disease in mice, for clues to a new approach to treating MS in humans.

Michael K. Racke, MD
Univ. of Texas Southwestern Med. Ctr. School of Medicine Dallas, TX
Region: Lone Star Chapter 4/1/03-3/31/06;
$418,011

Michael K. Racke, MD, and colleagues are studying a group of molecules to determine whether they can be developed into a treatment for MS. Naturally occurring molecules called “peroxisome proliferator-activated receptors” (PPARs) appear to have important roles in modulating inflammation, and in the growth and proliferation of immune cells. Dr. Racke’s team has demonstrated that a molecule mimicking one type of PPAR, PPAR-gamma, can improve a number of animal model diseases similar to MS.

Now, Dr. Racke and colleagues are testing whether a molecule that mimics PPAR-alpha, another type of PPAR already used to treat cholesterol disorders, has a similar effect on EAE. They also are administering this agent to immune cells taken from people with MS, to determine whether changes to the human immune system can be induced.

These studies may provide the background information for testing oral PPAR drugs in people with MS. T cell and peptide vaccination is already underway in early treatment studies in MS.

Arthur Vandenbark, PhD, is studying how this treatment works and may lay the groundwork for a new generation of therapies for MS.

Manipulation of the B7-CD28/CTLA-4 costimulatory pathway & EAE
Attempting to block immune activity in MS-like disease in search of better treatment for human MS.

Arlene H. Sharpe, MD, PhD
Brigham and Women’s Hospital Harvard Medical School Boston, MA
Region: Central New England Chapter 4/1/03-3/31/07;
$431,024
Funded in part by the Estate of Norman Cohn

Multiple sclerosis involves an abnormal immune attack against nerve-insulating myelin. At least two steps are required before an immune T cell can initiate an attack against a myelin protein. First, special cells “present” a piece of the protein in a package to the potentially attacking T cell. Then, a second “costimulatory” signal, often provided by the presenting cell as well, must be received by the T cell before it will launch the attack against that protein.

Costimulatory molecules exert this “safeguard” effect by binding to certain docking proteins, or receptors, on the Tcell surface. But that binding can have multiple effects depending on the receptors: Binding to one receptor stimulates the T-cell response, leading to disease, while binding to another receptor suppresses the response, blocking disease.

Arlene H. Sharpe, MD, PhD, is dissecting the role of two recently discovered costimulatory molecules that block disease in mice with the MS-like disease, EAE. She has found that a costimulatory molecule, PD-L1, can inhibit activation of T cells and immune proteins in cells isolated in the laboratory and decrease disease. Now, Dr. Sharpe and colleagues are comparing how PD-L1 and another molecule, PDL2, affect T cell responses during the course of EAE. To do so, they have designed unique tools, such as mouse models that lack each of these molecules, and antibodies designed to block them.

These approaches may lead to new insights into how treatments can be developed to block harmful costimulatory signals, and stop MS.

T cell receptor-specific regulatory T cells in multiple sclerosis
Understanding the regulation of immune cells in MS, and the role of an experimental peptide therapy to control damage.

Arthur Vandenbark, PhD
Veterans Administration Medical Center Portland, OR
Region: Oregon Chapter 4/1/03-3/31/06;
$469,902

MS involves an immune attack launched by T cells against nervous system tissue. A natural system of regulatory T cells normally controls damaging T cells and inflammation by producing inhibitory factors that limit an immune attack. In people with MS, however, this protective system seems to be deficient or lacking.

Arthur A. Vandenbark, PhD, is studying the activity of potentially protective regulatory T cells and the mechanism by which they suppress immune activity in cell samples in the laboratory. In previous findings, Dr. Vandenbark and his team vaccinated people who have MS with protein fragments (called peptides) that make up a docking site, or TCR, on the surface of T cells by which they recognize immune targets. This vaccine stimulated the production of regulatory T cells that may inhibit the attack.

They are now examining whether the vaccine works by enhancing regulatory T cells, and further defining how regulatory T cells turn off attacks. T cell and peptide vaccination is already underway in early treatment studies in MS. This study will help expand our knowledge of how this treatment works and may lay the groundwork for a new generation of therapies for MS.

New Research” is produced twice a year by the Research Programs Department, National MS Society, 733 Third Avenue, NY, NY 10017-3288. For more info about MS, call: 1-800-FIGHT MS, or visit our Web site: http://www.nationalmssociety.org

TEAMING UP ON MS

The new Collaborative MS Research Center Awards funded by the National MS Society… Who are the investigators? What are they exploring? What does it mean to you? See p. 5, and our Web site, at:
http://www.nationalmssociety.org/Research-CenterAwards.asp
 

© Copyright 2003, National MS Society