Demyelination and Remyelination.
Our laboratory is focused on determining the mechanisms of demyelination and remyelination in diseases such as human multiple sclerosis. The laboratory works with three primary animal models of demyelination: 1.) Theiler's virus-induced demyelination; 2.) experimental autoimmune encephalomyelitis; and 3.) lysolecithin induced demyelination. Using these three established models, we have been investigating the molecular mechanisms underlying demyelination and remyelination in the central nervous system.

Specific Research Topics

One of the major areas of investigation in our laboratory is the mechanisms of neurological deficits following demyelination. We showed previously that the major histocompatible complex (MHC) plays a major role in determining susceptibility and resistance to Theiler's virus induced demyelination. Using a series of knockout mice, we have demonstrated that the MHC class I immune response is critical for the development of neurological deficits. In the H-2^bhaplotype, mice which have a deficit in either class I or perforin develop demyelination but fail to develop neurological deficits. Experiments are underway to understand the mechanisms by which MHC class I-restricted CD8⁺T cells contribute to neurological injury and axonal damage in this model system.

One major focus of the laboratory is to understand the immunogenetics of demyelination. A major project in my laboratory is understanding the role of specific Theiler's viral capsid proteins in resistance versus susceptibility. We have now generated a series of transgenic mice expressing various Theiler's virus capsid proteins under the control of ubiquitin promoters. These viral capsid proteins are expressed as self and, therefore, are tolerant to the immune system. Experiments are underway to investigate these transgenic mice for development of demyelination and neurological deficits. In collaboration with Dr. Chella David, we are also investigating the role of human HLA in demyelination and neurological deficits. These experiments use both Theiler's virus-induced demyelination as well as experimental autoimmune encephalomyelitis. Dr. David has generated a series of transgenic mice that express human class II MHC in which the mouse class II genes have been knocked out. These experiments allow us to investigate the role of human MHC in both Theiler's virus-induced demyelination and in experimental autoimmune demyelination. In collaboration with Dr. Pease, we are dissecting the role of D versus K region mouse MHC molecules in resistance versus susceptibility to neurologic deficits.

The laboratory is particularly interested in developing strategies to promote remyelination in the central nervous system. We made a unique observation a number of years ago that immunization of Theiler's virus-infected mice with spinal cord homogenate induces remyelination. We subsequently showed that transfer of immunoglobulins directed against spinal cord into animals chronically infected with Theiler's virus induces remyelination. As a result, we generated a series of monoclonal antibodies that promote remyelination. These antibodies are directed against surface components on oligodendrocytes. Most recently, we have generated two human monoclonal antibodies that also bind to the surface of rat and human oligodendrocytes which also promote remyelination in both the Theiler's virus system and the lysolecithin model system. Molecular sequences of these antibodies are now characterized under the direction of Dr. Pease. The goal is to begin to develop these antibodies for clinical trials to enhance remyelination in multiple sclerosis.

Our laboratory is interested in understanding the mechanism by which antibodies may promote remyelination in the central nervous system. As a result, we have developed a series of assays to examine the direct stimulation of oligodendrocytes with the use of antibodies. The data to date suggests that there are second messenger pathways being stimulated that are dependent on calcium. It is expected that by understanding the signal transduction mechanism by which remyelination takes place, we will be able to develop a specific therapy to enhance remyelination.

Mayo Clinic Distiguished Investigator

Read a conversation with Moses Rodriguez, M.D.
Designing New Treatments for Multiple Sclerosis