More MS news articles for March 2001

Summaries of 26 New Research Projects

Recently funded projects/ spring 2001

http://www.nationalmssociety.org/pdf/research/spring_01.pdf

Wednesday March 14  2:40pm
Source: BusinessWire

The National Multiple Sclerosis Society has just committed $10.7 million to support 26 new MS research projects over the next two to four years. These projects were found to have the highest scientific merit and significance in the fight against MS, out of 77 proposals reviewed by our volunteer scientific advisors.

When the Society makes a commitment to a research project, it is actually making a commitment to find the funds to support that project. When research commitments are made, the money is not in hand to meet them. We now have over $40 million in currentand future-year commitments. Money must be raised each year to fulfill those commitments.

The 26 new projects are part of a research program that will spend about $30 million this year alone to advance MS research, including funding over 300 new and ongoing MS investigations in the U.S. and abroad.

Following are brief summaries of the new projects, grouped according to avenues of investigation. In addition, 11 new one-year pilot projects were awarded over the last six months to swiftly test innovative ideas in MS research. These are listed on page 12.

EPIDEMIOLOGY
Who Gets MS?

Epidemiologists evaluate disease patterns among people with a certain disease, taking into account variations in geography, demo-graphics, 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.

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 six research projects in epidemiology, including the following new project.
 

Milton Alter, MD, PhD
Lankenau Institute for Medical Research
Wynnewood, PA
Area: Greater Delaware Valley Chapter
Term: 4/1/01 - 3/31/03
Funding Required: $230,700

“Multiple sclerosis frequency in the Arab & Jewish populations in Israel” Comparing rates and characteristics of MS in two populations in Israel, to ascertain factors that may lead to the development of MS.

Multiple sclerosis occurs with uneven geographic distribution around the world, and it can also appear with different incidence rates in peoples of different ethnic origins living in the same region. Over the years, researchers have worked to tease out factors that may account for these differences – genetic and environmental – but there is still much work to be done.

Milton Alter, MD, PhD, and colleagues are approaching this question by focusing on the risk factors that may determine whether Israeli-born Arabs and Jews face different risks of developing MS. First they are doing a population study in attempts to confirm previous findings that Arabs born in Israel have a lower risk of developing MS than Jews born in Israel. To do this they are conducting a country-wide study to expand an existing database of people with MS so that it includes medical information on all native-born individuals who have the disease.

The team will then be in a position to calculate incidence and prevalence rates of MS in native-born Jewish and Arab populations, and to analyze and compare other characteristics such as age at onset, clinical course and sex ratios. If this study is successful, the team would like to investigate aspects of these populations that may explain any differences in incidence, including age of childhood infections, genetic factors, sociocultural differences and economic factors.

This study could lay the groundwork for additional epidemiological investigations aimed at finding the cause of MS.
 

MEASURING DISEASE ACTIVITY
Tracking the Course of MS

Although we know a great deal about the damage wrought by MS in the brain and spinal cord, we know little about how this damage relates to the variety of symptoms and courses experienced by people with MS. This category of Society-funded research seeks to fulfill this need. Tools that can measure disease activity in MS are key to detecting changes quickly, and to evaluating the usefulness of new treatments in clinical trials. The following grantee is investigating an exciting new imaging technology and its applicability to MS.

The National MS Society is currently funding 10 research projects that are measuring disease activity in MS, including the following new project.
 

Heather A. Wishart, PhD
Dartmouth Medical School
Lebanon, NH
Area: Central New England Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $279,454

“Brain activation in MS: an fMRI study of working memory and motor functions” Using a novel brain imaging method to observe brain activity during memory and movement tasks in MS.

Cognitive impairments such as memory deficits and slowed information processing often occur in individuals who have multiple sclerosis, along with motor, or movement, problems. Heather Wishart, PhD, and colleagues are applying a new magnetic resonance imaging technique called functional MRI (fMRI) to study these problems in people with MS.

Functional MRI tracks patterns of brain activity by detecting changes in blood flow in brain tissues during certain activities. Forty people with mild relapsing-remitting MS, along with 20 control participants who do not have MS, are undergoing fMRI scans while performing tests of fine motor skills and working memory.

Patterns and sites of brain activity during these tests will be compared with the sites of MS brain lesions (damaged areas), and the fMRIs of patients will be compared with those of controls. The investigators are seeking information about the physiological basis of fine motor and cognitive deficits, and are also seeking evidence that the brain may compensate for deficits by shifting activity to areas of the brain unaffected by the disease.

In addition to providing a window on how the brain works in MS, this study may help establish functional MRI as a tool for objectively monitoring the effects of drug or rehabilitation therapies.
 

New Targeted Research Awards Exploring Genetics and Gender Differences in MS

GENETICS
Understanding Susceptibility

While MS is not directly inherited in a strict sense, we know that several genes may work in concert with some unidentified environmental trigger to influence whether a person develops the disease. So far, researchers have clues to the locations of several MS genes (segments of hereditary material on chromosomes that direct all activities of a cell), but none have been identified. Knowing their identity will bring us a giant step closer to understanding the cause of MS and ways to treat or even prevent it. For this reason, genetics has been targeted by the Society as a crucial area of research.

The National MS Society is currently funding seven major research projects in the targeted area of genetic susceptibility, including the following new project.
 

John R. Richert, MD
Georgetown University Medical Center
Washington, DC
Area: National Capital Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $484,935

“Deficient sp3 gene expression in MS” Investigating why the gene responsible for a certain molecule that stimulates immune cells does not appear to be active in many people with MS.

In MS, a misdirected immune response against nerve-insulating myelin and nerve fibers themselves ultimately leads to debilitating neurological symptoms. It is still not known, however, what causes the immune system to go awry in this disease. John R. Richert, MD, is researching a possible genetic basis for this immune malfunction.

Previously, Dr. Richert and colleagues compared the genetic makeup of identical twins in which only one of the twins had MS. They found that a key gene called Sp3 was not activated in most of those with MS. Sp3 is the gene for a “transcription factor” which turns on and off genes in immune cells. It is possible that inactivation of Sp3 underlies the immune malfunction in MS. Now Dr. Richert is examining what causes normal Sp3 activation in people who do not have MS, and how this gene becomes deactivated in MS.

This research could help to explain why the immune system malfunctions in MS, and may lead to a therapy that “turns on” the Sp3 gene to treat and possibility prevent MS.
 

GENDER DIFFERENCES
Clues to the Cause of MS?

Can disparities between how men and women experience MS offer clues to its treatment and cure?

The influence of gender on MS may be a powerful one, and research indicates that gender strongly influences many autoimmune diseases. It is vital that we understand how the biology of gender exerts its influence, and for this reason, the Society has targeted this as an important area of exploration.

Researchers are investigating the intricate mechanisms that may be involved when sex hormones interact with the immune system. This frontier is one of the most exciting in MS research, given the implications for developing therapies involving these hormones, if indeed they can influence the course of MS.

Since targeting this area of research, the National MS Society has funded 10 large research grants on gender differences (including the following two new ones), four smaller pilot projects and 22 financial supplements to researchers adding explorations of gender differences to existing research projects.

Society and NIH Join Forces to Fund Gender and Immunity Research

The National MS Society has extended the reach of its targeted research initiative on gender differences in MS by collaborating with the National Institute of Allergy and Infectious Disease on a first-ever, multi-million dollar initiative to fund research on “Sex-based Differences in the Immune Response.” NIAID is one of the federal government’s National Institutes of Health, NIH.

The objectives of the initiative are to identify and define differences in immune responses between males and females to increase understanding and treatment of immune-based diseases such as MS. The Society, NIAID and several other institutions will co-fund grants relevant to MS. A Request for Applications has been released (http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-01-005.html), and the deadline for applications is August 2001.

The Society has leveraged its first-year support of $1 million such that NIAID and other NIH agencies will provide nearly $3.5 million. Over the course of this agreement, up to $20 million could be spent, of which the Society plans to contribute up to $4 million.

This collaboration extends the reach of the Society’s targeted research initiative on gender differences in MS by increasing support for high quality research, forging new collaborations to address existing gaps, and providing wider visibility of the problem.

By promoting and funding innovative research programs aimed at understanding the mechanisms of gender differences in immune function, significant progress will be made toward developing new therapeutic strategies for MS.
 

Paul D. Drew, PhD
University of Arkansas for Med. Sciences
Little Rock, AR
Area: Arkansas Division
Term: 4/1/01 - 3/31/04
Funding Required: $330,000

“Female sex steroids: effects on glia” Determining mechanisms by which certain sex hormones may protect myelin-making cells.

Several lines of research point to a “protective” role in MS of female sex hormones such as estrogen and progesterone, including the fact that estrogen can suppress EAE, an MS-like disease in mice. Such hormones might suppress disease by changing the actions of T cells, immune cells that orchestrate the attack in MS, as well as microglia, brain cells that are capable of furthering the immune attack in the brain.

Dr. Drew’s experiments focus on the influence of female sex hormones on the participation of microglia in the immune attack. Using T cells and microglia in laboratory tissue cultures, he is studying whether female hormones can prevent microglia from producing toxic molecules. Dr. Drew is also exploring whether, by preventing the release of toxic molecules, the hormones can increase the survival of oligodendrocytes, brain cells that make myelin and which are targeted in MS.

If these studies can identify the mechanisms through which female sex hormones may suppress the immune attack in MS and protect oligodendrocytes from destruction, they may open the door to devising therapies that can mimic the protective nature of these hormones.
 

Clara M. Pelfrey, PhD
Cleveland Clinic Foundation
Cleveland, OH
Area: Northeast Ohio Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $418,301

“Gender differences in immune responses in MS” Determining in what ways the immune attack that leads to MS is different in men and women who have the disease.

Almost three-quarters of people with autoimmune diseases are women: this “gender gap” is poorly understood. MS is one such disease in which the immune system attacks the body, in this case, the myelin coating that insulates nerve fibers, and nerve fibers themselves. Clara M. Pelfrey, PhD, believes that differences in the immune responses of men and women contribute to the gender gap in MS.

Dr. Pelfrey previously found significant differences in male and female immune responses to proteins in the brain that may be important in MS. Now she is collecting blood samples from men and women with MS to determine if the immune response in women involves immune cells, proteins and signaling molecules that are more inflammatory than those in men, and what role sex hormones play in regulating responses.

The studies will help define the role of sex hormones in promoting or suppressing the immune response in MS, and may allow for the development of therapies that capitalize on these findings.
 

NEUROPATHOLOGY/NEUROPHYSIOLOGY
Nerve Tissue and Conduction

Nerve signals are transmitted through the wire-like arm of nerve cells, called the nerve fiber. Any disruption to the myelin that insulates the nerve fiber, or to the nerve fiber itself, can weaken or block these vital signals. Recent 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 nine research projects in neuropathology and six projects in neurophysiology, including the following two new projects.
 

Shing-yan Chiu, PhD
University of Wisconsin-Madison
Madison, WI
Area: Wisconsin Chapter
Term: 4/1/01 - 3/31/04
Funding: $396,380
Paid in full by the Estate of Norman Cohn

“Axonal calcium and its role in axonal degeneration in dysmyelination” Determining whether an influx of calcium contributes to nerve fiber damage and loss in MS.

Our nerve cells have a wire-like arm, called the nerve fiber or axon, that reaches out to other nerve cells or muscles and through which nerve signals are conducted. When myelin, the insulating coating on axons, is attacked during the course of the immune response in MS, the axons are stripped (“demyelinated”). This can block nerve signals, but it can also compromise the integrity of the axon’s outer membrane and the axons can even die.

Shing-yan Chiu, PhD, is investigating the possible role of calcium flooding in the death of axons. Calcium is important in conducting nerve signals but too much of it in the axon may trigger destructive enzymes into action.

Using a unique system to tag calcium molecules with fluorescent dye, Dr. Chiu is tracking the ways in which calcium may enter and flood demyelinated axons. He is also exploring what types of nerve activity increase calcium flooding, and how much calcium it takes to trigger destructive enzymes.

This research will provide important information about a mechanism that may cause the death of axons in MS, and may also help determine safety limits of drugs such as 4AP, which may enhance nerve conduction but increase influx of possibly harmful calcium.
 

Peter Shrager, PhD
University of Rochester Medical Center
Rochester, NY
Area: Upstate New York Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $318,754

“Sodium channels in myelinated axons” Learning factors controlling the position of nerve fiber “pores” that facilitate nerve conduction, for clues to restoring nerve function in MS.

In MS, nerve signals are impaired due to a loss of myelin, the coating that insulates the wire-like nerve fibers, and damage to the nerve fibers themselves. Ordinarily, myelin is broken at regular intervals, leaving gaps where the nerve fiber is exposed. These gaps have a high concentration of pores, called sodium channels, that are vital to the nerve signaling process. To restore signal conduction after myelin is damaged, new myelin must replace it and sodium channels must be clustered in the newly formed gaps.

Peter Shrager, PhD, is investigating mechanisms controlling the movement and placement of sodium channels in the nerve fiber. It appears that oligodendrocytes, the cells that make myelin and wrap it around the nerve fiber, as well as nerve fibers themselves, play roles in this process. He is focusing on a little-understood protein called contactin, which seems capable of increasing the density of sodium channels, and conducting experiments in tissue cultures to explore how contactin regulates them.

By identifying mechanisms that regulate the placement of sodium channels, this research may ultimately lead to new therapies aimed at increasing electrical signals to compensate for MS-mediated damage.
 

INFECTIOUS TRIGGERS
What Starts the MS Attack?

Our immune systems are designed to fight off invading microbes, such as viruses or bacteria: In MS, this defense is misguided and ends up attacking nervous system tissue. Although no microbe has been shown to cause MS, it is possible that one or more such organisms may alter the immune response and trick the brain into thinking that brain and spinal cord tissue is similarly an “outside invader” to be fended off. Mouse models in which viruses trigger diseases similar to MS are invaluable to this research.

The National MS Society is currently funding 19 research projects in the area of infectious triggers, including the following new project.
 

Susan Weiss, PhD
University of Pennsylvania
Philadelphia, PA
Area: Greater Delaware Valley Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $439,511

“Role of the immune response in murine coronavirus-induced demyelination” Understanding the role of immune cells in a virus-induced model of MS in mice.

In recent years, scientists interested in in-fectious
triggers for MS have tried to under-stand
how viral or bacterial infections may
contribute to MS by affecting immune re-
sponses. Susan Weiss, PhD, is studying the
development of an MS-like disease in mice
infected with mouse hepatitis virus (MHV).

These mice develop a condition in which myelin – the substance that insulates nerve fibers and is damaged in MS – is destroyed. Although the exact mechanism that causes this disease is not known, it is believed that the response of immune cells to MHV plays a major role. Dr. Weiss is investigating how a certain type of immune cell, the CD8+ T cell, affects the spread of MHV and whether and how this leads to the destruction of myelin.

Understanding how a virus may trigger MS-like disease in mice will provide significant clues to how a similar process could trigger multiple sclerosis in humans, and how to combat it.
 

GLIAL CELL/MYELIN BIOLOGY
Can Myelin Be Repaired?

Recent discoveries are making the biology of glial cells an increasingly exciting area. Exploring glia, which include cells in the nervous system that make myelin, the coating that insulates nerve fibers, has always been a cornerstone of MS research. Myelin, and cells that make it, appear to be the main target of the immune attack in MS.

Researchers are finding, however, that certain cells resident in our bodies may have the potential to play a role in myelin repair. Several Society-funded grantees described here are investigating this potential. They are looking at immature myelin-making cells, known as “progenitors.” If these cells can be compelled to repair myelin, this may present exciting opportunities for treatments in which cells are transplanted into the nervous systems of people with MS.

The National MS Society is currently funding 65 research projects in glial cell/myelin biology, including the following five new projects.
 

Charissa A. Dyer, PhD
Children’s Hospital of Phildelphia
Philadelphia, PA
Area: Greater Delaware Valley Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $404,316

“The role of mixed phenotype glia in the CNS” Evaluating biological switch that may turn on or off the ability of cells to produce myelin.

After the immune attack against myelin, the substance that insulates nerve fibers, in MS, a certain amount of myelin repair takes place, but it is not capable of keeping ahead of the damage. It is not certain what happens to myelin-making cells, called oligodendrocytes, that survive the immune attack. Within certain MS brain lesions (areas of myelin damage), oligodendrocytes have been observed that can switch on or off their ability to make myelin, depending on conditions.

Charissa A. Dyer, PhD, is conducting a series of studies to test the idea that during periods of disease, the oligodendrocytes are inhibited from making myelin and produce an excess of a protein called “GFAP”; later, they may revert to making myelin and GFAP decreases. She is using a unique rodent model in which such cells are present to explore the mechanisms that underlie this ability to turn on and off myelin formation.

Understanding how oligodendrocytes switch on their ability to repair myelin could lead to therapies that stimulate myelin restoration in people with MS.
 

Nancy Ratner, PhD
University of Cincinnati
Cincinnati, OH
Area: SW Ohio/N. Kentucky Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $329,170

“NF1 signaling in progenitor cells” Understanding how signals from a specific molecule regulate the growth of immature myelin-making cells.

Recently, Society-supported investigators and others have reported the discovery of a population of immature cells that are resident in the brain. Mature oligodencrocytes are responsible for making myelin, the substance that insulates nerve fibers and which is damaged in MS. These immature cells, which are called “progenitor” oligodendrocytes, may have the potential to repair myelin that has been destroyed by MS, and possibly to aid in the recovery of function.

Nancy Ratner, PhD, is investigating the role of “NF1” – a molecule that may regulate the growth of oligodendrocytes by signaling them as they grow. She is exploring whether and how NF1 influences the formation of oligodendrocyte progenitors. Dr. Ratner is also using mice that lack the gene that makes NF1 to explore the abnormalities that result in the progenitors, seeking clues to NF1’s significance in the process of maturation and myelin formation.

Understanding the signals that control the availability of oligodendrocyte progenitors will help scientists exploit these reserve cells to stimulate myelin repair in people with MS.
 

Marilyn D. Resh, PhD
Memorial Sloan Kettering
Cancer Institute
New York, NY
Area: New York City Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $377,768

“Identification of activated Fyn substrates in differentiating oligodendrocytes” Identifying proteins involved in the maturation of myelin-making cells, for clues to ways to stimulate myelin repair in MS.

In MS, the immune system attacks the insulating coating, called myelin, that covers nerve fibers in the brain and spinal cord, as well as nerve fibers themselves. Oligodendrocytes are the brain cells responsible for maintaining myelin. Researchers including Marilyn Resh, PhD, are focusing on the steps involved when immature oligodendrocytes, called progenitors, mature and begin to make myelin, with an aim to understanding how to foster myelin repair.

Previous work by Dr. Resh and colleagues identified “Fyn,” a protein whose activity appears essential for progenitors to mature into oligodendrocytes. During a pilot research grant from the National MS Society, Dr. Resh screened oligodendrocyte proteins that interact with Fyn to further elucidate this process. One that she identified, “p190RhoGAP,” is a promising candidate for being a key regulator of the early myelin-making process.

In this project, Dr. Resh’s team is studying how p190RhoGAP interacts with Fyn during the early steps of myelin development. Understanding these steps will shed light on ways to stimulate myelin repair in people with MS.
 

James L. Salzer, MD, PhD
New York University Medical Center
New York, NY
Area: New York City Chapter
Term: 4/1/01 - 3/31/05
Funding Required: $549,521

“Axonal regulation of myelinating glia: roles of neuregulin and signaling pathways” Determining whether growth molecules on nerve fibers play a critical role in the formation of the myelin sheathes that envelope them.

In MS, the myelin coating that insulates nerve fibers is broken down, resulting in abnormal nerve impulse conduction and neurologic disability. The nerve fibers themselves may also be damaged. Research indicates that the formation of myelin in early development may depend on signals from nerve fibers to the oligodendrocytes, the cells that make myelin. These signals may also play a role in stimulating myelin repair once it has been damaged.

James L. Salzer, PhD, is investigating how nerve fibers may signal and regulate oligodendrocytes. In particular, his team is looking at a family of growth factors, known as “neuregulins,” that are found on the surface of nerve fibers and may be critical to myelin formation. Recent studies indicate that neuregulins may be effective as therapies in rodent models of MS-like disease.

If Dr. Salzer’s research confirms that neuregulins are pivotal in myelin formation, and they prove to have a role in myelin repair, these molecules may have potential as a new therapy to stimulate myelin repair in people with MS.
 

Gihan I. Tennekoon, MD
Children’s Hospital of Philadelphia
Philadelphia, PA
Area: Greater Delaware Valley Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $400,181

“Can mesenchymal stromal cells differentiate into oligodendroglia?” Investigating the potential of bone marrow cells to develop into myelin-making cells and possibly repair myelin lost in MS.

In MS, the damage done to myelin, the insulating coating on nerve fibers, by the immune-system attack is repaired to a certain extent, but the body’s natural repair mechanisms cannot keep up with the damage. One reason is that oligodendrocytes, which manufacture myelin, can also be damaged by the disease. Gihan I. Tennekoon, MD, is investigating the possibility of stimulating myelin repair by replenishing oligodendrocytes from another source within the body: the bone marrow.

Researchers have found that immature cells in bone marrow can grow into many different mature cells including bone cells and even nerve cells. Through innovative experiments, Dr. Tennekoon is attempting to determine what growth factors and conditions allow bone marrow cells in laboratory dishes to develop into mature oligodendrocytes capable of making myelin.

If he succeeds, these and further preclinical experiments could lead to the possibility of transplanting such immature bone marrow cells into the nervous systems of people with MS to restore lost myelin.
 

BIOCHEMISTRY/BIOPHYSICS
Chemical and Physical Processes

A major goal of Society-sponsored research is to understand the disease process of MS. This involves understanding chemical and physical processes that occur in the healthy brain, and revealing how these may go awry in people with MS. Evidence is growing in particular about the damage that is caused by oxidants, toxic molecules that may contribute to tissue damage. Understanding how this process may increase the potency of the immune attack in MS may enable scientists to devise ways to prevent greater damage from occurring.

The National MS Society is currently funding 11 research projects in the area of biochemistry/biophysics, including the following new project.
 

Steven M. LeVine, PhD
University of Kansas Medical Center
Kansas City, KS
Area: Mid-America Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $378,206

“Protective mechanisms in CNS demyelinating diseases” Understanding natural defense mechanisms of cells that may be exploited to limit tissue damage in MS.

In response to injury or trauma, the body’s cells attempt to limit the damage by producing “stress response” chemicals that can neutralize potentially harmful oxidants that are released when tissues are broken down. Such oxidants are likely released during the immune attack against myelin and nerve tissue during the course of MS, adding insult to the damage more directly caused by the immune system. Controlling oxidant damage, then, is an important goal in MS research.

Steven LeVine, PhD, is conducting experiments in mice with the MS-like disease EAE to explore protective mechanisms such as the stress response in cells. He has identified several stress-response proteins that brain cells produce during the course of EAE, and is determining which cells produce these protective proteins and under what circumstances. He is also testing the ability of molecules that inhibit oxidants to limit disease damage in mice with EAE.

This project will help find ways to tip the balance toward the production of anti-oxidants that can protect brain cells from destruction 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 born more fruit toward these goals than the study of the immune system. All four of the FDA-approved treatments for this disease emerged from the growing understanding of how the immune system works and how it can be manipulated to suppress or regulate immune attacks.

Researchers funded by the Society are investigating many cells and proteins in the immune system that may be key to instigating the immune attack, spurring it on, or suppressing it. By evaluating the importance of these components, we can find new and better ways to successfully treat MS.

The National MS Society is currently funding 116 research projects in immunology, including the following 12 new projects.
 

Avraham Ben-Nun, PhD
Weizmann Institute of Science
Rehovot, Israel
Term: 4/1/01 - 3/31/04
Funding Required: $366,660

“Synthetic gene products for multi-target-directed immunomodulation of EAE” Designing a therapy that attempts to target all known myelin components that may stimulate the immune attack in MS.

Although MS is believed to result from an immune attack against myelin (the substance that insulates nerve fibers) and against nerve fibers themselves, it is unclear exactly what component of myelin or other nervous tissue is the target. Several major proteins in myelin have been identified – such as myelin basic protein (MBP) and proteolipid protein (PLP). Considering the variable nature of MS, it is probable that these and several others are involved, and that different protein targets are present in different people.

Avraham Ben-Nun, PhD, is attempting to develop a therapy that neutralizes all potential protein targets in myelin concurrently, including MBP and PLP. Dr. Ben-Nun is determining which proteins are most often “recognized” by the immune cells of people with MS, and which proteins can cause the immune reaction that leads to EAE (an MS-like disease) in mice. He is designing protein- and gene-based products that contain portions of these different myelin proteins. Dr. Ben-Nun will then develop treatments based on his findings, and test their ability to prevent or treat existing EAE in mice.

If successful, this research could lead to the development of a new therapy for people with MS.
 

Brian D. Evavold, PhD
Emory University
Atlanta, GA
Area: Georgia Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $388,559

“Control of EAE-specific T cells through modified peptide interaction with MHC” Developing a potential therapy that targets molecules that may stimulate the im-mune attack in MS-like disease.

T cells – cells of the immune system – are responsible for marshalling the immune attack against myelin (the substance that insulates nerve fibers) and nerve fibers in MS. Brian D. Evavold, PhD, is testing a novel method of controlling these T cells.

Normally, a T cell “recognizes” its myelin target when a piece of myelin protein (“peptide”) is presented to its receptor (the docking site that is crucial to the launch of an immune attack). The peptide is presented in a sandwich-like pairing with another molecule, called MHC, or “class II major histocompatibility complex.” Previously, Dr. Evavold and others had some success in dampening the T cell response by altering molecules on T cell receptors. This approach is known as an “altered peptide ligand” (APL). However, while APL may suppress one type of T cell, there is more than one type of T cell involved in MS.

Now, Dr. Evavold is approaching T cell suppression from the other side of the pairing. His team is attempting to weaken the MHC/peptide pairing to alter how it binds to T cell receptors. This approach may disarm the many types of T cells involved in MS. The team will then determine whether these alterations affect the onset and severity of EAE, an MS-like disease in mice.

This innovative approach could provide groundwork for a future therapy that limits or stops the immune attack in MS.
 

Arthur A. Hurwitz, PhD
SUNY Upstate Medical University
Syracuse, NY
Area: Upstate New York Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $302,010

“CTLA-4 mediated modulation of T cell tolerance in autoimmune demyelinating disease” Examining how blocking a certain molecule prevents an MS-like disease in mice, to determine its applicability to treating MS in people.

The immune system usually differentiates between substances that are part of the body, or “self,” and foreign proteins, and only attacks foreign proteins, such as those from bacteria and viruses. However, certain immune cells may become activated that do attack self, and these are known as “self-reactive T cells.” This may result in autoimmune diseases such as MS, in which the immune response damages the central nervous system.

Arthur A. Hurwitz, PhD, is examining a component of T cells that might explain why the abnormal immune attack against self doesn’t turn off in MS. He is studying the role of “CTLA-4,” a receptor (a molecule that serves as a docking site) on T cells for self and foreign proteins. Blocking this receptor in mice with EAE, an MS-like disease, worsens their condition. This suggests that CTLA-4 may help ensure appropriate T cell responses and turn off inappropriate self-responses.

Preliminary evidence suggests that some people who are susceptible to MS may have abnormal CTLA-4 receptors. Dr. Hurwitz is studying how CTLA-4 normally regulates immune attacks in search of a new avenue for treating MS.
 

J. William Lindsey, MD
University of Texas Health Science Center
Houston, TX
Area: Lone Star Chapter
Term: 4/1/01 - 3/31/03
Funding Required: $279,610

“Isolation of an immune regulatory CNS glycoprotein” Studying a protein that may turn on or off immune attacks in the brain, and whether it shows promise for stopping MS.

MS involves an inappropriate immune-system
attack against tissues in the brain and
spinal cord. J. William Lindsey, MD, is ex-ploring
how this sort of attack is normally
suppressed in people who do not have MS.

Dr. Lindsey believes that there are signal-ing
proteins in brain tissue that usually “turn
off” immune cells that enter the brain, and
that these signals may go awry in MS. He
has already shown that a “glycoprotein,” a
protein component of brain cells, can suppress
immune responses in tissue cultures.
Dr. Lindsey is now doing the painstaking
work of isolating this glycoprotein, and determining
whether it can suppress EAE, an
MS-like disease, in mice.

If scientists can identity and understand a
natural weapon that prevents or turns off immune
attacks to the brain, such as this glycoprotein,
this novel project could lead to the
development of a therapy for MS.
 

Joseph A. Madri, MD, PhD
Yale University
New Haven, CT
Area: Greater Connecticut Chapter
Term: 4/1/01 - 3/31/05
Funding Required: $575,362

“Proteinase modulation during T-cell endothelial adhesion” Investigating an en-zyme involved in allowing immune cells to invade the brain and spinal cord in MS.

In order for immune T cells to move into the brain and spinal cord to launch their attack against nervous system tissue in multiple sclerosis, they have to make their way from the bloodstream, through the blood-brain barrier and into the central nervous system. The attractive possibility of stopping the destructive immune attack at this point of entry makes it vital to learn about how T cells and the blood-brain barrier interact.

The blood-brain barrier is composed of tightly packed cells in the walls of blood vessels. Joseph A. Madri, MD, PhD, is focusing on what happens when proteins on the surface of T cells “stick” to other proteins on the surface of blood vessels and begin the process of squeezing through to the brain. He is testing the idea that specific enzymes, called proteinases, become activated after the T cells stick, and that these proteinases break down blood vessel walls. This facilitates the migration of the T cells into the brain. Dr. Madri is also performing experiments designed to determine whether proteinases also enable T cells to stay in the brain and spinal cord and continue to cause damage.

This study should provide crucial information on an early phase of the immune attack in MS and possible new targets for stopping the attack before it succeeds.
 

Nancy L. Monson, PhD
UT Southwestern Medical Center at Dallas
Dallas, TX
Area: Lone Star Chapter
Term: 4/1/01 - 3/31/05
Funding Required: $537,624

“Molecular analysis of the Ig repertoire in MS” Determining if immune cells produce significant antibodies that mark myelin and nerve cells for attack in MS.

Researchers believe that MS is caused when cells of the immune system attack myelin, the substance that insulates nerve fibers, and nerve fibers themselves. Immune T cells are believed to launch the immune attack. Nancy L. Monson, PhD, is studying the specific role of another type of immune cell, known as a “B cell,” in MS.

B cells produce proteins called “antibodies” that are part of the immune response. Dr. Monson believes that certain B cells produce an antibody that binds to myelin, and “tags” it so that other immune cells will be triggered to attack that spot, thereby contributing to immune-mediated damage in MS. In a novel approach, she is isolating B cells from the central nervous systems of a group of people with MS and determining whether myelin is targeted by any of the antibodies those B cells produce. Dr. Monson is also tracking this group of patients over time to determine whether the B cells capable of producing myelin antibodies persist over time.

If such B cells and antibodies are found, it opens another avenue for developing therapies to target the immune attack in MS and hopefully slow or stop the disease course.
 

Lindsay Nicholson, PhD
Brigham and Women’s Hospital Boston, MA
Area: Central New England Chapter
Term: 4/1/01 - 3/31/05
Funding Required: $568,511

“The role of low avidity cross-reactive T cells in the regulation of EAE” Developing a potential therapy that attempts to boost the immune system’s ability to turn off an attack in MS-like disease.

People with MS may experience a “relapsing-remitting” form of disease, in which flare-ups are followed by periods of remission. Lindsay B. Nicholson, PhD, believes that this may be explained by the immune response, which may be programmed to attack and then “turn off.” It is possible that the same cells that underlie the immune attack on myelin, the substance that insulates nerve fibers, in MS are the cells that subsequently switch off the immune response.

Dr. Nicholson has discovered a rodent model with MS-like disease that contains such T cells that accelerate and then slow the immune response. He is testing whether – and if so, how – these T cells can shut down the immune response and protect mice from EAE, a disease with many similarities to MS.

Figuring out the process by which the immune response is suppressed can lead to the development of therapies that exploit this innate ability, and help people with MS achieve remission of disease.
 

Christian W. Schindler, MD, PhD
Columbia University
New York, NY
Area: New York City Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $448,737

“Alpha/beta Interferon signaling in the treatment of MS” Understanding better how interferon-beta modulates the immune response in MS-like disease.

Interferon beta is available in two forms as a treatment for people with relapsing MS, and interferon alpha is under investigation for its potential to treat MS. These “type 1” interferons are messenger proteins, or “cytokines,” that occur naturally in the body, and serve to modulate immune responses. However, scientists do not know the exact mechanism by which type 1 interferons benefit MS.

Christian W. Schindler, MD, PhD, is seeking a better understanding of this mechanism by focusing on how type 1 interferons interact with immune cells to produce other cytokines, to alter the delicate balance that dictates whether an immune attack escalates or subsides.

Dr. Schindler is focusing on what happens on a molecular level inside an immune cell when interferon beta is taken up by the cell during the course of EAE, an MS-like disease in mice. In particular, he is examining a signaling molecule called “Stat2,” which may play a key role in how interferon beta modulates immune cells.

A better understanding of how interferons work should lead to the development of more effective therapeutic agents and strategies for MS.
 

Stephen A. Stohlman, PhD
University of Southern California
Los Angeles, CA
Area: Southern California Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $526,303

“The study of the mechanism of Th2-mediated suppression of EAE” Can a specific immune cell can be used to reduce or eliminate symptoms of MS-like disease?

Complex interactions of immune system cells and messenger chemicals lead to the immune attack against nervous system tissue in MS, and also underlie remission of the attack. Many researchers, including Stephen A. Stohlman, PhD, are searching for ways to harness the immune system’s innate ability to shut down an immune attack and bring about remission.

There are two main types of immune system “T cells,” which increase during immune responses: Th1 and Th2 cells. These cells differ in their ability to rev up (Th1) or inhibit (Th2) an immune response and in the type of messenger proteins, or cytokines, they produce. The strength of a particular immune response is the result of the balance between Th1 and Th2 cells.

Dr. Stohlman’s team is trying to inhibit the immune attack in mice with the MS-like disease called EAE by injecting specific Th2 cells. These Th2 cells secrete a cytokine that inhibits disease. The team is conducting a series of experiments to determine whether these therapeutic Th2 cells have to enter the brain and spinal cord to work and how they inhibit disease. They hope to gather enough information to apply this novel approach to developing a treatment for people with MS.
 

Jenny P. Ting, PhD
University of North Carolina at Chapel Hill
Chapel Hill, NC
Area: Eastern North Carolina Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $483,328

“Effects of immune response and cytokines on remyelination” Assessing possible roles for immune molecules in repairing myelin.

In MS, the immune system launches an attack against nervous tissue, especially myelin, the insulating coating on nerve fibers. Jenny Ting, PhD, is focusing on ways to reverse the myelin damage to restore function.

To marshall the immune attack in MS, immune T cells produce messenger chemicals, called cytokines, which can escalate inflammation and myelin destruction. One such cytokine is called tumor necrosis factor alpha (TNF alpha). Dr. Ting’s team is following up on what seems like a paradoxical finding: this apparently destructive immune chemical may also be critical for myelin regrowth, or remyelination.

The team is using laboratory mice that lack the genes responsible for various cytokines, including TNF alpha, in attempts to explore their various roles in myelin destruction and repair. Because TNF alpha appears to be both destructive and constructive, the team is studying genes that are affected by TNF alpha during remyelination.

This research should contribute to efforts to find ways to therapeutically stimulate myelin repair and at the same time bypass the destructive effects of TNF alpha.
 

E. Sally Ward, PhD
University of Texas Southwestern Medical
School
Dallas, TX
Area: Lone Star Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $442,768

“Structural analysis of pathogenic T cell receptors for therapy of murine EAE” Exploring characteristics of immune cells activated in MS-like disease, for clues to a new therapeutic approach for MS.

A key feature of the immune system is the ability of immune cells, such as T and B cells, to distinguish between normal proteins in the body and those proteins on the surface of invading viruses or bacteria. In MS, the immune system fails to recognize that myelin, the substance that insulates nerve fibers, is part of the body, and attacks myelin and also the nerve fibers themselves as if they were invaders.

E. Sally Ward, PhD, is examining the role of T cell receptors in activating this “autoimmune” response. These are molecules on the surface of T cells that serve as docking sites for proteins. Her team is studying two different types of T cells in mice with EAE, an MS-like disease. These two types of cells have different receptors. One T cell type is much more aggressive in causing disease. Dr. Ward is examining how each T cell “recognizes” proteins, in order to determine how certain T cells might be activated to spur on an aggressive immune attack in MS.

Investigating how T cells become activated can help us to understand and address how they contribute to the autoimmune response in MS.
 

Caroline C. Whitacre, PhD
Ohio State University
Columbus, OH
Area: Mid-Ohio Chapter
Term: 4/1/01 - 3/31/04
Funding Required: $481,160

“Antigen presenting cells in oral tolerance to myelin basic protein” Enhancing a potential MS therapy by studying immune reactions occurring when myelin proteins are fed to mice with MS-like disease.

MS is believed to be an immune reaction against the proteins that comprise myelin, the substance that insulates nerve fibers, and against the nerve fibers themselves. Caroline C. Whitacre, PhD, and her colleagues have administered a myelin protein (myelin basic protein, or MBP) orally to mice with EAE, an MS-like disease. The results: a single dose prevented EAE, and multiple doses suppressed disease once it had started. This seemingly simple approach to stopping an immune attack, called “oral tolerance,” was also tried in a clinical trial involving people with MS, but without success.

Dr. Whitacre is investigating the mechanisms behind oral tolerance and ways to enhance its effectiveness so that it might be better applied to human MS. She is studying how the consumed protein is delivered to the immune system, how it affects immune cells, and how disease may be suppressed. In particular, she is focusing on “dendritic” cells, which may facilitate the delivery of the protein to immune cells. She has identified a growth factor that can increase the number of dendritic cells in the gut, and which dramatically increases the effectiveness of oral tolerance in mice with EAE.

Understanding how oral tolerance works and finding ways to enhance its effectiveness may lead to the re-emergence of this simple approach to treating MS.
 

11 New Pilot Grants Test Innovative Ideas

Over the last six months, 11 new grants were awarded through the Pilot Research Program.
These projects are aimed at quickly exploring new, untested ideas and generating
preliminary data needed to apply for full grant support.

Biology of Glia

Charles Sanders, PhD “Structural studies of myelin proteins” Case Western Reserve
University, Cleveland, OH, $27,500; 11/01/00-10/31/01

Nada Zecevic, M.D., PhD “Expression of golli-mbp mRNAs and proteins in MS lesions”
University of Connecticut Health Center, Farmington, CT, $27,500; 01/01/01-12/31/01

CNS Repair

Steven Cramer, MD “Changes in cortical organization following an acute demyelinating
event” University of Washington, Seattle, WA, $27,500; 02/01/01-01/31/02

Immunology

K. George Chandy, MBBS, PhD “T-lymphocyte potassium channels: targets for MS”
University of California, Irvine, Irvine, CA, $27,500; 01/01/01-12/31/01

Marco Cosentino, MD, PhD “Synthesis of catecholamines by lymphocytes in MS”
University of Insubria, Varese, ITALY, $24,000; 04/01/01-03/31/02

Bonnie Dittel, PhD “Activation & specificity of regulatory CD4 T cells in a model of EAE”
The Blood Center of Southeastern Wisconsin, Milwaukee, $27,500; 02/01/01-01/31/02

Thomas Petro, PhD “IL-12 p35 gene expression in EAE resistance and susceptibility”
University of Nebraska Medical Center, Lincoln, NE, $27,500; 01/01/01-12/31/01

Measuring MS Disease Activity

Michael Meyer, MD “SPECT brain imaging of radiolabeled white blood cells in acute MS”
Millard Fillmore Hospital, Buffalo, NY, $24,507; 03/01/01-02/28/02

Psychosocial Aspects of MS

Lauren Krupp, MD “Neuropsychological profile of children with MS”
State University of New York at Stony Brook, Stony Brook, NY, $27,500; 01/01/01-12/31/01

Rehabilitation

Diane Moyer, PhD “Intensive multiple sclerosis exercise trial”
Cedar Crest College, Allentown, PA, $27,500; 01/01/01-12/31/01

Therapy/Management of MS

Hrayr Attarian, MD “Circadian rhythm abnormalities in people with multiple sclerosis”
Washington University, Saint Louis, MO, $27,500; 03/01/01-02/28/02
 

Index of New Projects, by National MS Society Chapter

Arkansas Division ................................. 6
Central New England ....................... 3,16
Eastern North Carolina ........................ 18
Georgia ................................................ 14
Greater Connecticut ............................. 15
Greater Delaware Valley ............. 2,8,9,11
Lone Star ................................... 15,16,18
Mid-America ....................................... 11
Mid-Ohio ............................................. 19
National Capital .................................... 4
New York City ................................ 10,17
Northeast Ohio ...................................... 6
Southern California ............................. 17
SW. Ohio/N. Kentucky .......................... 9
Upstate New York ............................ 7,14
Wisconsin .............................................. 7
Outside U.S.
Israel ................................................... 13

NOTE: Index does not include Pilot Projects, listed on page 12.
 

“New Research” is produced twice a year by the National Multiple Sclerosis Society, Research Programs, 733 Third Avenue, NY, NY 10017-3288. For more information about multiple sclerosis research, call: 1-800-FIGHT MS, or visit our Web site (http://www.nationalmssociety.org).