Collaborative MS Research Center Award
$825,000; 4/1/04-3/31/10
Principal Investigator
Jeffery D. Kocsis, PhD
Yale University School of Medicine,
New Haven, CT
Collaborators
Nancy H. Ruddle, PhD
Stephen G. Waxman, MD, PhD
Diane S. Krause, MD, PhD
Peter Cresswell, PhD
Richard Flavell, PhD
Al Lo, MD, PhD
Yale University School of Medicine
Purpose
To explore facets of tissue damage in MS and test ways to protect and repair central nervous system tissue, ultimately to restore function in persons with MS. Among the team's focuses are cell transplantation and ways to improve or speed nerve transmission in damaged tissue.
Summary
In multiple sclerosis, an immune attack is launched that wreaks havoc in the central nervous system, damaging nerve-insulating myelin and nerve fibers (axons) in the brain and spinal cord. Jeffery D. Kocsis, PhD, and colleagues have shown that injecting bone marrow cells from the thigh bone of rats into their veins repairs myelin damage induced in their spinal cords. Bone marrow (spongy tissue found in bones) contains stem cells, immature cells that are capable of giving rise to other types of cells, including myelin-making cells.
Now Dr. Kocsis is applying his findings and taking them further in rodent models of EAE, an MS-like disease. Specifically, this team is exploring how myelin and axonal damage occurs in EAE, and whether bone marrow cell transplantation or other treatments can protect axons as well as repair myelin. This Center integrates the work of established MS researchers with outstanding scientists from other fields of expertise.
Team members Nancy H. Ruddle, PhD, and Peter Cresswell, PhD, are part of the effort to investigate how myelin and axons are damaged in EAE models. Dr. Ruddle is a noted immunologist whose findings have contributed to our understanding of the immune attack in MS. Dr. Cresswell is an expert on the biochemistry and cell biology of the initial events in an immune response, although he has not studied these events within the context of MS. Together, they are exploring how the immune attack in different models of EAE may lead to nerve tissue damage in different ways, depending upon the involvement of immune T cells or B cells. They also are seeking to determine which pathway may lead to progressive disease.
Dr. Kocsis is tackling the important question of tissue repair by transplanting bone marrow-derived stem cells into mice with EAE to determine if myelin damage can be repaired and the disease course altered. Cells will be "harvested" from bone marrow in collaboration with Diane S. Krause, MD, PhD, an expert in bone marrow cell biology.
A method of protecting axons is being investigated as well, involving sodium channels—tiny pores along axons that are essential for maintaining proper nerve impulse conduction. Stephen G. Waxman, MD, PhD, winner of the National MS Society/American Academy of Neurology's 2002 John Dystel Prize for MS Research, has shown that a drug that blocks sodium channels reduces axonal damage in one type of EAE. He is now extending these studies to other MS models, and is examining how specific abnormalities in sodium channels lead to nerve cell dysfunction. Al Lo, MD, PhD, has contributed important data toward this effort on the effects of sodium channel blockers in EAE, and will continue to work on these studies.
Another method of nerve tissue protection is being investigated by team member Richard Flavell, PhD, a noted expert in autoimmunity whose laboratory recently showed that the immune messenger protein TGF-beta plays a critical role in controlling autoimmune disease by inhibiting T cells. He is helping the team explore the role of TGF-ß in regulating EAE and possibly preventing nerve tissue damage.
These basic research efforts will address the clinically important areas of immunotherapy and neuroprotection. Combining established MS investigators and superb scientists from other fields will provide new approaches and expertise to help translate this basic research into novel treatment strategies for people with MS.
Recent Progress
Dr. Kocsis’ team demonstrated that when myelin-making cells from outside the brain and spinal cord are transplanted, the proper types of ion channels (tiny pores along nerve fibers essential to nerve impulse conduction) are formed and organized along remyelinated axons, and that secure impulse conduction along these axons is restored, and reported their findings in the Dec. 13, 2006 Brain.
The team also reported in the March 2006 Glia that transplantation of myelin-making cells from outside the brain and spinal cord is neuroprotective, in that it prevents death of brain cells.
This Collaborative MS Center Award has been extremely valuable in attracting junior investigators to the area of MS research, and in allowing the rapid initiation of several important pilot projects. Moreover, several of these pilot projects have led to support for full projects from competitive federal and private sources.