Blocking multiple sclerosis in a mouse model.

"When two proteins interact, it's kind of like making love--there's movement, and a signal is sent," says molecular pharmacologist Bradford A. Jameson, who is trying to figure out how and where to interrupt the complex cascade of signals that causes multiple sclerosis (MS).

A computer-designed peptide (a sequence of amino acids too small to be a protein) blocks the development of an MS-like disease in mice, Jameson and his coworkers at the Jefferson Cancer Institute in Philadelphia report in the April 21 NATURE.

"We think we can intervene [in mice]... at almost any stage," says coauthor Robert Korngold, "and prevent the progression of the disease."

Between 250,000 and 350,000 people in the United States suffer from MS. Their immune systems turn traitor, attacking the essential protein coverings that insulate nerves in the brain and spinal cord. The destruction of these myelin sheaths short-circuits the electrical signals that flow through the nerves, resulting in weakness, visual impairment, and loss of muscle control. In the most severe cases, MS can lead to paralysis. The disease is episodic--it attacks in bursts--and often worsens progressively.

Mice with experimental allergic encephalomyelitis (EAE) show many of the same symptoms as humans with MS, and the mouse disease progresses similarly. But researchers understand what triggers EAE while remaining in the dark about the cause of MS. "The problem is," says neurologists Moses Rodriguez of the Mayo Clinic in Rochester, Minn., "most remedies that have been successful in EAE have not worked in MS."

In the normal course of any disease, white blood cells called T cells replicate when presented with foreign substances and enlist the help of other cells in the immune system to attack the invader. In MS, a T cell gets a message that the myelin sheath is foreign.

Jameson wanted to prevent this message from getting through. Other researchers have implicated T cells carrying CD4 proteins in myelin sheath inflammation. Jameson theorized that if he designed a peptide to mimic the shape of a piece of the CD4 protein, that inactive peptide could replace the protein piece and no signal would connect. A simple copy of the peptide worked in test tubes but was quickly broken down in the mice.

So Jameson synthesized a reverse mirror image of the CD4 segment. This tiny peptide resists being broken down by the body yet still mimics the shape -- and thus can block the function -- of the CD4 protein piece. Surprisingly, the peptide does not stop the T cell from recognizing the myelin sheath as foreign, but it prevents the T cell from replicating. It may also cause the T cell to self-destruct, Jameson adds.

Only 20 to 40 percent of the mice treated with the peptide developed EAE, compared to between 71 and 83 percent of the untreated mice. Inoculated mice that did develop EAE developed it later, says Korngold, and with less severe symptoms. Because the peptide causes the death of activated T cells, not just the ones that trigger MS, it shouldn't be given to anyone fighting off other diseases, he says. The peptide is excreted by the body less than 2 hours after innoculation, Korngold adds, so it is unlikely to compromise overall immune function.

One injection may not get rid of EAE (or MS) permanently, says Jameson, because the immune system might produce more cells that react to myelin. Jameson and Korngold hope to begin human MS trials in 12 to 18 months.

"One of the advantages of this drug is that you don't have to redesign it for other diseases," says Korngold. They are looking at other autoimmune diseases, such as rheumatoid arthritis, and at AIDS, and they speculate that the synthesized peptide might also increase the success of bone-marrow transplants and skin grafts.