Central Nervous System Beckons Attack In MS-like Disease

"It's been clear for quite a while that our own lymphocytes (white blood cells) have the ability to enter the central nervous system and react with the cells there," says John Russell, Ph.D., professor of molecular biology and pharmacology. "Under normal circumstances, the brain and the immune system cooperate to keep out those cells that might harm the brain. But in people with multiple sclerosis, they get in."

The researchers found that they could prevent destructive immune cells from entering nervous system tissue by eliminating a molecular switch that sends "come here" messages to immune cells. Ordinarily, flipping that switch would cause immune cells to rush to the vicinity of the cells that sent the signals and destroy whatever they consider a danger — including nerve cell coatings.

But in the mice in which the switch was removed, the researchers saw that immune cells previously primed by the scientists to attack the central nervous system (CNS) did not enter the CNS, and the mice stayed healthy.

In contrast, normal mice treated with the same hostile immune cells had numerous immune cells in their CNS tissue and developed symptoms similar to multiple sclerosis.

"What allows the primed lymphocytes into the CNS are signals from the CNS asking them in," Russell says. "We determined that the astrocytes, the specialized cells that provide nutrients to neurons, are among the cells most active in sending signals to attract lymphocytes."

The molecular switch that sends the call to immune cells is termed the tumor necrosis factor receptor (TNFR). When TNFR is activated, it causes cells to send out signal molecules called chemokines that direct immune cells to the site of damage or infection. The researchers found that astrocytes in mice were producing chemokines in response to activation of their TNFR molecules.

TNFR activation also makes the astrocytes bristle with specific adhesion molecules that act like Velcro to bind to similar molecules on the surface of the immune cells. That allows the immune cells that are attracted by the chemokines to stick around and do more harm.

One of the most promising new drugs for treating multiple sclerosis, natalizumab (tradename Tysabri), works by blocking the ability of the immune cells to stick in the CNS through this Velcro mechanism, Russell notes. Natalizumab is being tested in clinical trials and appears to be much better at preventing the nerve cell destruction associated with multiple sclerosis than previous therapies.

"Experiments by others suggested that natalizumab prevented immune cells from crossing the blood-brain barrier — it was thought to prevent the cells from leaving the blood stream," Russell says. "We are working on that question, and we think that it doesn't necessarily prevent them from getting out of the blood, but it does keep them from getting further into the brain. The immune cells pile up in the space around the blood vessels. This space, the perivascular space, serves as a gatekeeper to determine what gets in and what doesn't."

Next, the research team will study various regions of the brain to determine the types of signals sent to and from different areas of the CNS to the immune system.

Reference: Gimenez MA, Sim J, Archambault AS, Klein RS, Russell JH. A tumor necrosis factor dependent receptor 1-dependent conversation between central nervous system-specific T cells and the central nervous system is required for inflammatory infiltration of the spinal cord. American Journal of Pathology 2006;168(4):1200-1209.

Funding from the National Institutes of Health, the National Multiple Sclerosis Society and Pfizer Inc. supported this research.