Research explains one of the fundamental mysteries of multiple sclerosis

Scientists have pinpointed a chemical messenger that frees some white blood cells from the body's normal constraints, allowing the cells to act like renegades that could damage nerves in the central nervous system. The work, to be published in the July 15 issue of the Journal of Immunology and just published on-line, helps explain one of the fundamental mysteries of multiple sclerosis (MS).

The scientists discovered that a chemical messenger found at high levels in MS patients allows some immune cells known as T- effector cells to evade normal regulation. Instead, the cells bypass their usual gatekeepers and could become active in the body's tissues, including the brain and spinal cord. Scientists believe that during MS, renegade T-effector cells damage the myelin coating that covers nerve cells, causing the disease's symptoms. While another subset of white blood cells called T-regulatory cells normally control the activation of T-effector cells, investigators found that the chemical messenger interleukin-12 or IL12 allows some cells to sidestep that regulation and run amok.

"Normally effector T cells are under strict control as they circulate through the blood stream in order to prevent unnecessary inflammation that could be harmful to otherwise healthy tissues," says Benjamin Segal, M.D., the neurologist who led the University of Rochester study. "However, occasionally they escape the body's suppression system. We're learning how they do that."

In the 1990s, while working in the laboratory of Ethan Shevach, M.D., at the National Institute of Allergy and Infectious Diseases, Segal was one of the first scientists to show that IL12 could be important in autoimmune diseases like MS. He showed that the molecule empowers CD4+ T cells to enter the central nervous system, where they don't belong, and attack myelin. He has also shown that mice without the IL12 gene are completely protected against an MS-like disease, and that ordinary mice can be protected from developing MS-like symptoms if their IL12 is knocked out. In contrast, exposure of normally harmless T-effector cells to IL-12 appears to unmask a latent ability to induce MS-like disease in mice.

Building on this and the work of others, Segal and other doctors around the world are now testing in MS patients an experimental drug produced by Centocor that is designed to inhibit IL12 and hopefully suppress attacks.

In the latest paper, published in the journal's "Cutting Edge" section, Segal and neuroscience graduate student Irah L. King use funding from the National Institutes of Health and the National Multiple Sclerosis Society to show that IL12's effects are unexpectedly far-reaching and affect some of the immune system's most powerful cells. The team found that IL12 confers upon CD4+ T-effector cells the ability to overcome suppression by T-regulatory cells, whose job it is to keep the body from attacking itself. Without the order imposed by T-regulatory cells, scientists have shown that animals are more prone to develop autoimmune diseases like MS.

A drug that inhibits IL12, like the one under development by Centocor, could restore the function of the T-regulatory cells, allowing them to be more effective in clamping down on rogue T-effector cells. Such a medication might also be useful in other autoimmune diseases like Crohn's disease, psoriasis, and arthritis, where scientists suspect IL12 also plays a role.

"There are a variety of treatments for MS, but most are only modestly effective," says Segal, associate professor of Neurology and director of Neuroimmunology Research. "We are always looking for better treatments that are more convenient for our patients, with fewer side effects. Inhibiting IL12 offers one potential option."

Segal's work helps explain why MS patients are more likely to suffer a relapse of the disease when they get an infection like the flu. When a person is infected, IL12 levels rise to allow the person to fight off the infection. Segal's work showing that IL12 helps usher harmful white blood cells into the central nervous system clarifies why MS patients sometimes worsen when they get an infection.