The research laboratory of Moses Rodriguez, M.D., 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:
Using these three established models, Dr. Rodriguez and his team have been investigating the molecular mechanisms underlying demyelination and remyelination in the central nervous system.
Studying the mechanisms of neurological deficits following demyelination. Dr. Rodriguez has previously shown 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, he has demonstrated that the MHC class I immune response is critical for the development of neurological deficits.
In the H-2b haplotype, mice that have a deficit in either class I or perforin develop demyelination but fail to develop neurological deficits. Experiments are under way to understand the mechanisms by which MHC class I-restricted CD8+ T cells contribute to neurological injury and axonal damage in this model system.
Understanding the immunogenetics of demyelination. A major project in Dr. Rodriguez's laboratory is understanding the role of specific Theiler's viral capsid proteins in resistance versus susceptibility.
His laboratory has 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 are therefore tolerant to the immune system. Experiments are under way to investigate these transgenic mice for development of demyelination and neurological deficits.
In collaboration with Chella S. David, Ph.D., Dr. Rodriguez and his team are also investigating the role of human HLA in demyelination and neurological deficits. These experiments use both Theiler's virus-induced demyelination and 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 enable the investigation of the role of human MHC in both Theiler's virus-induced demyelination and in experimental autoimmune demyelination.
Dr. Rodriguez, in collaboration with Larry R. Pease, Ph.D., is also dissecting the role of D- versus K-region mouse MHC molecules in resistance versus susceptibility to neurologic deficits.
Promoting remyelination. Dr. Rodriguez and his colleagues are particularly interested in developing strategies to promote remyelination in the central nervous system. They made a unique observation several years ago that immunization of Theiler's virus-infected mice with spinal cord homogenate induces remyelination. They subsequently showed that transfer of immunoglobulins directed against the spinal cord into animals chronically infected with Theiler's virus induces remyelination.
As a result, Dr. Rodriguez and his research team generated a series of monoclonal antibodies that promote remyelination. These antibodies are directed against surface components on oligodendrocytes. Most recently, they have generated two human monoclonal antibodies that also bind to the surface of rat and human oligodendrocytes; these 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.
Understanding the mechanism by which antibodies may promote remyelination. Dr. Rodriguez's laboratory is interested in understanding the mechanism by which antibodies may promote remyelination in the central nervous system. As a result, they have developed a series of assays to examine the direct stimulation of oligodendrocytes with the use of antibodies.
To date, the data suggest that there are second messenger pathways being stimulated that are dependent on calcium. It's expected that by understanding the signal transduction mechanism by which remyelination takes place, they will be able to develop a specific therapy to enhance remyelination.