Scar trek; one scientist's search for information on MS scar formation, control and prevention.

With support from National Multiple Sclerosis Society grants, Dr. Etty Benveniste of the University of Alabama at Birmingham is focusing on the interaction between cells of the immune system and cells of the brain. "To find a way to limit and repair the damage done by MS, we need to understand how immune factors regulate the function of brain cells," she says.

As with many scientists, her interest was whetted way back in high school by a charismatic biology teacher. Then, as an undergraduate at California State University in Chico, she stumbled onto a course in immunology. By her last year she was certain she wanted to focus on human cellular immunology. She planned to go to graduate school, but wanted to do some research first, so she applied for an internship at the National Institutes of Health (NIH).

Her work was done in the metabolism branch of NIH under Dr. Thomas Waldmann, an internationally known immunologist who still runs the branch. She was lucky to work under the supervision of Dr. Michael Blaese, one of the NIH group now doing groundbreaking research on cancer gene therapy. Dr. Benveniste did basic immunological research on human T cells subgroups--called subsets--and her results were published in scientific journals.

"At the time we were just starting to understand that there were different types of T cells involved in the immune system," she says. "So we had to devise ways of characterizing them. We isolated the cells by various procedures and looked for different functions. We found that there were some cells that suppressed the action of other immune cells and some that enhanced action."

Following her NIH internship she was invited to say on in the immunology lab as a research biologist while she applied to various graduate schools. Her choice was UCLA's microbiology and immunology program, which she joined in 1979.

"This was an exciting time in immunology," she notes. "We were investigating immune cells called B cells that make a particular type of molecule called immunoglobulins (anti-bodies), as well as specific sets of other immune cells--T cells--that help those particular B cells. As your immune response matures, different B-cell and T-cell subsets are involved in your antibody and immune responses. All this work was just beginning, and we were getting a better appreciation of the complexities."

In 1983 Dr. Benveniste joined the laboratory team of NMSS grantee Dr. Jean Merrill at UCLA, who was doing immunological studies on people with multiple sclerosis. Under a post-doctoral fellowship from the National Multiple Sclerosis Society, Dr. Benveniste began to study the effects of cytokines, or chemicals produced by immune cells which promote growth and development of other cells. There was a suggestion at the time from several laboratories, based on studies of MS lesions, that one of the hallmarks of MS was the movement of immune cells from the blood stream into the brain and spinal cord. "The question we asked was," said Dr. Benveniste, "can immune cells and their cytokines affect the function of the astrocyte or the oligodendrocyte?

"These are brain cells with very different appearances and functions; the oligodendrocyte ("oligo") makes myelin and is gradually destroyed in MS. The astrocyte becomes important in later MS lesions, when it multiplies and eventually forms scar tissue that fills in where the oligos and myelin have been destroyed. We suspect that the scars caused by astrocytes interfere with remyelination and restoration of nerve signals. Remyelination and restoration of nerve signals are essential if we hope to cause improvement in function in MS. To find a way to limit and repair the damage done by MS, we need to understand how immune factors such as cytokines regulate the function of these cells."

In 1986, as her postdoctoral work at UCLA was ending, Dr. Benveniste accepted a faculty position at the University of Alabama in Birmingham. "I was very fortunate to find a place that suited both my interest in neurology and immunology," said Dr. Benveniste, who is now assistant professor of cell biology and neurology. "And I also had the good fortune to initially join the department of Dr. John Whitaker, who is well known in MS research." Dr. Whitaker is also a close advisor to the National Multiple Sclerosis Society.

With partial support from the remainder of hr Society postdoctoral fellowship, she began to study a particular kind of cytokine called tumor necrosis factor (TNF), which is an agent that affects a tumor by "chewing" up the blood vessels that nourish it, leading to tumor death.

"It was originally thought that tumor necrosis factor had an effect only on tumor cells, but now we know from a vast amount of research that TNF is a pleotropic cytokine--in other words, it is produced by many different cell types and acts upon many other different cells types--not just tumors."

In 1987, NMSS grantee and advisor Dr. Moon Shin at the University of Maryland published an article suggesting that astrocytes--the cells which form scars in MS lesions--might be capable of producing TNF themselves. So, Dr. Benveniste began to study this phenomenon and to examine the actual effect of TNF on the astrocyte itself, and vice versa.

"It turns out that, for the astrocyte, there is an "autocrine" pathway of stimulation--that is, the astrocyte cell feeds back on itself using TNF. The astrocyte can make TNF and it also has surface receptors for TNF: we deduced that TNF produced by the astrocyte may act back on the same cell. What's interesting is that TNF does not kill the astrocyte (as it does a tumor cell); it changes the function of the astrocyte." Since astrocytes are vital to the formation of scars in the brain and spinal cord in MS, learning that TNF can alter astrocyte function is extremely important in learning how scarring is caused and may be prevented.

Part of Dr. Benveniste's latest work under two full research grants from the NMSS is with strains of rats that are either susceptible or resistant to experimental allergic encephalomyelitis (EAE), the MS-like animal disease. She wants to determine whether these strains of rat with different susceptibility to disease show any differences in their ability to produce TNF.

"What we have found--and published--is that the astrocytes from the EAE-susceptible animals made a great deal of TNF, but astrocytes from the resistant strain made very little.

Dr. Benveniste thinks that the potential of the astrocyte to make TNF in the EAE-susceptible strains may contribute to their susceptibility to EAE as well as to the inflammation and demyelination that accompany the disease once it starts.

The way by which certain strains of rats are susceptible or resistant to EAE is in part through the presence and action of certain "major histocompatibility complex" (MHC) genes. These genes help the immune system discriminate "foreign" tissue, a target for attack, from normal tissue, which should be protected from immune attack. It happens that the gene controlling tumor necrosis factor is located very close to these MHC genes. This close link at a molecular genetic level may help explain why TNF production and susceptibility are related.

"One thing we are becoming more and more convinced of," says Dr. Benveniste, "is that the overproduction of TNF in some autoimmune diseases -- MS included -- may be detrimental even at very low concentrations."

Astrocytes and the cytokines they produce, like TNF, are clearly involved in the central nervous system pathology of MS. Permanent astrocyte scarring provides a major hindrance to myelin reformation and restoration of function in a disease like MS where the astrocyte scars replace lost myelin. Dr. Benveniste is among a group of scientists now linking astrocyte and TNF Function to susceptibility to animal diseases which resemble MS, and perhaps MS itself. The ultimate outcome of these basic experiments may be the control or prevention of scar formation, an essential component to any future therapeutic approach to multiple scleroris.