Inner conflict: the fight to regulate the immune system in MS.

The FDA approval of Tysabri in 2004 and its withdrawal from the market three months later almost seemed like a cruel joke. As Ed Duggan, Maryland Chapter Board of Directors member, saw it: "Tysabri was the result of a rational, focused exploitation of a key new insight about the disease process in MS." There was a sense that researchers were gaining the upper hand.

And then, in early 2005, three people who had been given Tysabri developed PML, a rare but lethal disease seen in people whose immune systems have been suppressed. The promise of Tysabri's benefits was momentarily snatched away, and it became clear that the scientific establishment may not know as much as it needs to about how the immune system works, and fails to work, in MS.

Now that the FDA has approved Tysabri's return to the market after deliberating over the results of recent safety studies (see page 38), it seems like a good time to step back and look at the progress that researchers are making toward a full understanding of what goes wrong in the immune system in people with multiple sclerosis.

When the body's defense system attacks

The story of what goes wrong in MS goes something like this:

Patrolling T cells, foot soldiers in the immune system's constant war against the viruses and bacteria that cause disease, are alerted by exposure to some environmental trigger. Once armed and ready, these T cells break through the blood-brain barrier and enter forbidden territory--the central nervous system (e.g., the brain and spinal cord)--where they attack myelin.

The blood-brain barrier is a layer of cells lining the blood vessels in the brain. It is supposed to keep immune system cells out, except when there are signs of an infection in the brain. So this mission--attacking myelin in the central nervous system--should not be in the T cells' strategy books--and yet, in MS, there they are, destroying myelin and nerve fibers as though they were the "enemy."

Much of the progress in treating MS has been made by focusing on stopping this attack. Interferons countersignal the T cells and other warriors, instructing them to cool down. Chemotherapy actually destroys immune cells.

Glatiramer acetate (Copaxone) was thought to work by gumming up T cells and other fighters' weapons, but recent research suggests that some of its benefits derive from its ability to call up another unit in the immune system--special forces trained to block the immune cells that are attacking.

Calling a cease fire

Immunologists have suspected for decades that the immune system doesn't go off on a campaign without also enlisting special cells designed to cool down these warrior cells once the enemy--the invading virus or bacteria--has been deterred. But the suspicions were just that. Proof, in the form of a detailed description of the cells charged with cooling down an immune response, remained elusive.

Conventional wisdom held that the problem in MS and other autoimmune diseases was a loss of tolerance to our own proteins. Something in the body of a person with MS was responsible for the reappearance or reawakening of cells armed to attack one's own tissue, even though these "intolerant" cells were thought to have been drummed out of the service when the immune system was developing. Why did these guys intent on friendly fire reappear?

As it turns out, just about everyone has "friendly fire" cells in their blood, including cells with the potential to target and attack myelin. But they don't cause trouble in most people. So the problem in MS may not be the reappearance of these cells, but a loss of the system's ability to call a cease fire.

Researchers have been uncovering a network of cells and signals that the immune system relies on to rein in armed or "activated" T cells. Breaking the code of one set of signals led to the use of beta interferon treatments for MS (Betaseron, Avonex, and Rebif).

All of the cells, proteins, and mechanisms that may be involved are still not yet known, but progress is being made in developing a full understanding of the command and control structure. We need that understanding to turn on a permanent cease fire--and an end to MS.

Getting down to the Tregs

A new type of cell has been discovered, and with it, a promising lead. Tregs--which get their funny name (pronounced "Tee-regs") from the fact that they REGulate T cells--stop T cells from girding up for battle. National MS Society-funded researchers are playing a leading role in uncovering what Tregs do--and don't do in MS.

David Hafler, MD, and colleagues at Harvard Medical School, have found that the number of Tregs in healthy people is the same as it is in people with MS, but that Tregs in people with MS don't seem to be working very well. Hafler and his team are working to figure out why they don't and to see if there are safe ways to motivate them to do their job.

Crossing signals and suspended animation 

The immune system has another trick for keeping its soldiers in line: Sometimes the troops get a set of conflicting or incomplete instructions and that freezes them in their tracks.

The immune system employs some of the same signal cells to call a cease fire that it uses to call up an attack. The signal cells just give different signals for each function. Signal cells chew up myelin proteins and then display the bits to the T cells. Depending on other signals from these same cells, the T cells will either prepare to attack or actually be rendered immobile, in a sort of suspended animation.

Stephen Miller, PhD, and his team at Northwestern University Feinberg School of Medicine in Chicago, have shown that mice with an MS-like disease called EAE have fewer relapses when they are treated with a mixture of small bits of myelin proteins and signal cells programmed to suspend T cell activation. Dr. Miller is now developing plans to test this strategy in people with MS.

Samia Khoury, MD, and her associates at Harvard School of Medicine, are working on still another approach to an immune system cease fire in MS. Signal cells send their messages to disarm T cells along specific pathways. One of them is called PD. Dr. Khoury's studies in mice with EAE suggests that Tregs (remember them?) influence the PD pathway and that the PD pathway influences disease progression.

The PD pathway also may have a role in recruiting myelin repair cells and sending them to sites of MS inflammation and damage. If so, a better understanding of the PD pathway might lead to treatments that could simultaneously call off the attack and repair damage already done.

The gender question

Women are more likely than men to develop MS. But relapse rates decrease late in pregnancy when estrogen-related hormones are in greater abundance.

In 2002, Rhonda Voskuhl, MD, and colleagues at the University of California at Los Angeles reported positive results from a small-scale, early-phase trial of the hormone estriol, a form of estrogen. Women with relapsing-remitting MS showed decreases in MRI-detected brain lesion activity and immune responses during treatment, and Dr. Voskuhl is planning a larger clinical trial to further study estriol.

More recently, Dr. Voskuhl, along with Nancy Sicotte, MD, and colleagues at UCLA reported that administering Androgel (testosterone gel applied to the skin) to 10 men with relapsing-remitting MS for one year resulted in significant improvements in cognitive function, and in slowing brain tissue loss.

Halina Offner, PhD, and her colleagues at the Oregon Health and Science University in Portland, Oregon, have found that some estrogen-related hormones, called DHEA derivatives, seem to send a "wake-up call" to the Tregs. Dr. Offner is testing a series of DHEA derivatives in mice with an MS-like disease to look for one that has this useful effect on immune system cells without other undesirable effects.

Estrogen also protects the brain, so Dr. Offner is looking for a DHEA derivative that will provide brain protection as it awakens Tregs.

Looking at lipids

Myelin is made up of many proteins and fatty substances called lipids. Identifying which of them are the targets of armed T cells would also help scientists develop cease fire instructions.

Lawrence Steinman, MD, and his team at Stanford University, have uncovered evidence pointing to certain myelin lipids. Antibody proteins are often increased in the spinal fluid of people with MS, and Dr. Steinman suspects that antibodies to myelin lipids as well as T cells may orchestrate myelin destruction and, moreover, go on to prevent nerve cell regrowth. "Stopping antibody production could have important benefits in MS," Dr. Steinman told InsideMS.

Currently, rituximab (Rituxan), a laboratory-engineered antibody that marks antibody producing cells for destruction, is being studied and evaluated for safety for use in people with progressive and relapsing forms of MS. It is FDA-approved for use in some forms of arthritis and blood cancers.

Strengthening the blood-brain barrier

In order for T cells to sneak into the central nervous system from their home base in the blood stream and lymph nodes (small balls of tissue strategically placed throughout the body), the T cells must first stick to the lining cells of the barrier. Once firmly attached, they crawl through. A pair of very sticky proteins, one on the lining cells and the other on T cells--think of them as the two sides of Velcro--allows this process.

Tysabri is an engineered antibody protein that covers up the sticky protein on the T cells so they have a harder time attaching to the barrier. But there are other ways to keep the attacking soldiers away from myelin. A new drug on the horizon, a pill called FTY720 (Fingolimod), seems to work by keeping T cells in their lymph node "barracks."

A permanent cease-fire and reconstruction

While researchers still lack complete understanding of the subtle battles being waged in our bodies, the scientific community is making real progress. Through the relentless efforts of researchers, the immune system in people with MS is giving up its command and control secrets. More opportunities to rein in attacks and to stop them entirely are on the way.

Dr. Bernice Schacter has more than 25 years of biomedical research experience, and is the author of The New Medicines: How Drugs Are Created, Marketed, and Sold (Praeger Publishers, 2006). She has been living with MS since 1991.