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August 18, 2005

A new model for MS research: Researcher focuses on how T-cells go awry

In the late 19th century, Louis Pasteur had already discovered the modern foundation for vaccinations — that exposure to a weakened form of an infection could help an organism’s immune system prepare for the infection and protect the body against a full-strength version of it.

He began applying that finding to rabies by taking brain tissue from infected rabbits and using that to inoculate test animals. But Pasteur found a strange side effect: Some subjects developed an inflammation of the brain, and the condition was linked to the immune system. He had discovered a condition called neural allergic encephalomyelitis, which researchers later found was remarkably similar to multiple sclerosis.

Multiple sclerosis (MS) takes many forms, but all types include nervous system inflammation and demyelination, a condition in which the protective myelin sheath that coats the axon is broken down, causing loss of function in neurons. Since the early 20th century, a laboratory-created form of animal brain inflammation and demyelination, known as experimental allergic encephalomyelitis (EAE), has served as an animal model of multiple sclerosis.

Though MS is a neurological disorder, many scientists think the disease is likely initiated by the immune system. They believe that T-cells, which usually attack infected cells, are mistakenly activated against myelin, and after crossing into the brain, the T-cells attack the myelin sheath around neurons.

EAE has similar mechanisms, so much of the basic research on multiple sclerosis has centered on that disease model. But some researchers, like UW immunologist Dr. Joan Goverman, are looking at other possible models for MS.

This is a disease that is clinically very diverse, and you need diverse models to learn about it,” explained Goverman, professor of immunology and adjunct professor of genome sciences.

One area of interest for Goverman is the type of T-cells involved in MS and similar diseases. EAE, for instance, is mediated by CD4+ T-cells, and for many years researchers have assumed that multiple sclerosis is as well. But researchers find more CD8+ T-cells than CD4+ cells in MS patients, so CD8+ cells could also be involved in the disease.

CD4+ and CD8+ T-cells fight infections by responding to different types of pathogens. CD4+ T-cells respond to a pathogen only after it has been phagocytosed — swallowed up by a specialized immune cell, chopped into pieces, and shuttled out to the surface of that specialized cell so the CD4+ T-cells can sample it. CD8+ T-cells, on the other hand, respond to pathogens like viruses, which are synthesized inside a cell and whose pieces appear on the outside of the cell without being phagocytosed.

Because EAE is initiated by feeding myelin proteins to the specialized immune cell responsible for phagocytosing pathogens, that method leads only to activation of CD4+ T-cells, not CD8+ cells.

Goverman and her colleagues have created a new model for MS that will activate CD8+ T-cells. They engineered a virus that contains a gene encoding a myelin protein — the protein that initiates EAE. This virus will cause the myelin protein to be synthesized inside a cell, so that its pieces will be displayed on the cell surface and visible to CD8+ T-cells. The researchers found that the CD8+ T-cells seeing the pieces of myelin protein spurred an autoimmune response that mimics multiple sclerosis in a different way than EAE.

“The CD4+ model is good, and we learn a great deal from it,” said Goverman. “But this CD8+ model may let us look at different aspects of the disease — different locations in the brain, different mechanisms. We’ll be seeing things in this model that we see in the human disease, MS, but not in the CD4+ model.”

Goverman will discuss her work on animal models of MS, as well as her other work in basic immunology, in the first Science in Medicine Lecture of the 2005-6 series. The lecture will be held at noon, Thursday, Sept. 29, in room T-625 of the UW Health Sciences Center. It is open to everyone.