All of these cells "talk" to one another constantly and this is how they maintain normal function, says Dore-Duffy. "For instance, let's say you're climbing a mountain and your body is getting less oxygen in the blood. These are the cells that will pick up that low oxygen signal. They're like a sensor. Like an early warning system. One thing these cells will do in response to hypoxia is to form more vessels, so there is more surface area, through which you can absorb more oxygen. The cell regulatory mechanisms are thought to be a key to unlocking some of the doors to multiple sclerosis." Hypoxia, says Dore-Duffy, is a good example of cellular adaptation to injury. The cells talk to one another and try to restore normal function. There are many common elements cellular responses in inflammation, stroke and traumatic brain injury.

For example in stroke, plugs form or stenosis or platelet aggregation develop, all of which occur on the luminal surface of the blood-brain barrier. In stroke and trauma, damage and cell death take place when blood flow stops. Compensatory mechanisms will then take place at the blood-brain barrier level through the interactions of barrier cells. In traumatic brain injury you have tearing of the blood-brain barrier, and shear stress, which is like a vibration. All of those cause changes in the cells and how they talk to one another.

Says Dr. Dore-Duffy, "What happens to us in response to all of these changes is determined in large part by what these cells do. Sometimes their compensatory mechanisms are good and sometimes bad." In all forms of blood-brain barrier insult - which includes not only stroke and head injury, but also MS - there is an element of excess leukocyte migration into the brain, which is usually deleterious. She explains, "Leukocytes are the white blood cells. Under normal conditions, a few white cells go into the brain to kind of check things out. Normally they just go in and then out. They are usually monocytes or other cells involved in innate immunity. They help in repair; they are the first line of defense called immune surveillance. They can be helpful, but they can become detrimental when they are activated in great numbers."

In the early 1990s, Dr. Dore-Duffy's work described how the leukocytes, particularly the monocytes, interact with the blood brain-barrier in excess. In MS, the leukocytes migrate into the central nervous system and chew up the myelin sheath, which insulates the nerves, just like rubber insulates electrical wires. These cells release cytokines and prostaglandins, which promote cell injury and, in part, cause the debilitating symptoms of MS.

To examine this phenomenon more deeply, Dr. Dore-Duffy set up cultures of the microvessels. One of her papers, "Endothelial Activation in MS" (published in Neurology in 1994), is still cited frequently. This finding was very important says Dore-Duffy because, "In order for leukocytes to migrate you need a permissive barrier. The barrier becomes permissive under conditions of activation because they express a number of cell surface molecules, which are called adhesion molecules. The leukocytes recognize these adhesion molecules, and they stop as they flow through the blood. If there are no adhesion molecules, then they continue on their way."

Dr. Dore-Duffy and her colleagues isolated the microvessels from autopsy tissue and stained them to identify adhesion molecules. She utilized a special type of microscope called a laser cytometer, which shoots a laser beam into the tissue with an antibody that has a fluorochrome (a fluorescent marker). In looking at the expression of one of the adhesion molecules on the endothelium called E-selectin, an endothelial cell activation marker, Dr. Dore-Duffy took an antibody directed against E-selectin conjugated with a fluorochrome marker - when the laser hits the fluorochrome, the computer senses the energy released from the fluorochrome and translates it to a specific color on a color scale. It prints a picture of the cell based on fluorescence intensity. Other previously used techniques, such as FACS analysis which also gives a semi-quantitative indication of antibody binding, simply wouldn’t work with microvessels. They are much too large.

The laser cytometer has allowed scientists to see the actual cell activation and reception process. Dore-Duffy and colleagues discovered that microvessels from MS patients were activated with multiple adhesion molecules, both in areas where there were existing plaques and in areas which appeared to be putatively normal. What those results told them is that microvessels all over the white matter were primed or permissive for leukocyte. Says Dore-Duffy, "Basically we found what was responsible for the permissive barrier. How the barrier became activated was another question."

She then began to think about the differences between MS patients and patients with traumatic brain injury. Leukocyte influx occurred in both cases. Traumatic brain injury is characterized by leukocyte migration and demyelination, similar to what is seen in MS. The difference is, it stops, whereas in MS, demyelination is chronic, multifocal and it waxes and wanes. This may suggest to her an abnormality in a regulatory mechanism involved in acute inflammatory responses.

Her attention then turned to an intriguing little cell, which was part of the blood-brain barrier communication network, called the pericyte. In the scheme of the blood brain barrier cellular cooperative, the pericytes had been thought to play little or no role in blood-brain barrier permissivity. Through close examination of the cellular activity, Dr. Dore-Duffy noted that the pericytes were actually involved in important "communication" with the endothelial cells (the lining of the microvessels). Using the laser cytometer and other sophisticated equipment, she showed that white blood cells - leukocytes - actually cluster around the pericytes on their way through the blood brain barrier. This may be because pericytes secrete cytokines or regulatory proteins or have receptors that attract leukocytes.

What's more, the pericytes are able to activate T-cells. Dr. Dore-Duffy and her co-workers hypothesize that it is the pericyte that helps select T-cells to invade the brain and to inhibit migration when not needed. Exploring the pericyte regulatory mechanisms, that may explain neurologic damage both at onset of the disease and in perpetuation and relapse appears so promising, it has resulted in the awarding of a $380, 000 grant from the National Multiple Sclerosis Society. It may be possible to interrupt this cross-talk between pericytes and leukocytes and prevent their migration into the central nervous system.

Dore-Duffy credits the very supportive research environment at Wayne State and The Detroit Medical Center, which enabled her to establish this exciting new endeavor with its promise of help for patients with MS. "We have a strong neuroscience group at Wayne State and a large group of dedicated scientists who work on multiple sclerosis. A strong MS clinic also enables her to study human cells.

Dr. Dore-Duffy was recruited to Michigan by Dr. Robert Lisak 10 years ago from a tenured position at the University of Connecticut where she was director of its MS program. She moved here with her husband and three young children. "Although I was quite happy in Connecticut, I came to Wayne State because of the MS program Dr. Lisak proposed to develop. Southeast Michigan has a variety of excellent clinical venues, which meant my husband was able to find a good position, as well." Dr. Dore-Duffy's husband, Michael Duffy, MD, a gastroenterologist, works at Beaumont Hospital as director of the gastrointestinal training program.

Dr. Dore-Duffy is very pleased with her new grant and research directions. Her only complaint is that success and recognition have led to her appointment on the editorial boards of five professional journals, a number of grant review panels, as well as election to nine major professional societies. Certainly, this adds up to a desktop full of paperwork. "I guess this is the natural progression of successful scientists," she said. "We direct and we teach."