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Stanford Report, December 4, 2002

Cholesterol fighter may help reduce MS symptoms

By AMY ADAMS

Researchers have seen tantalizing evidence that the cholesterol-fighting drug Lipitor also treats multiple sclerosis-like symptoms in mice. This finding, published in the Nov. 7 issue of the journal Nature, clears the way for human trials testing Lipitor’s ability to treat human MS and possibly other autoimmune diseases such as diabetes or rheumatoid arthritis.

"We just have to hope that we see some of the same beneficial effects in people," said Sawsan Youssef, PhD, first author on the paper and postdoctoral scholar in the lab of Lawrence Steinman, MD, professor of neurology and neurological science.

The first hint that Lipitor played a role beyond cholesterol containment came when heart transplant patients who were prescribed a class of drugs called statins experienced fewer rejection episodes after heart transplantation than did people who were not taking the drugs. People who took statins also lived longer.

Follow-up studies found that statins blocked inflammation by preventing immune cells from producing a molecule — called MHC class II antigen — that can trigger an inappropriate immune response. Immune cells called T helper (Th0) cells recognize the MHC class II antigen and develop into Th1 cells, which go on to cause inflammation. In the case of MS, the Th1 cells attack the lining of nerve cells, leading to visual problems, poor balance, paralysis of the arms and legs, numbness, and possible loss of bladder and bowel control.

By blocking MHC class II antigens, statins prevent the conversion from Th0 to Th1 in tissue culture and instead pushed Th0 cells down the developmental path to become inflammation-preventing Th2 cells. Of all statins tested, Lipitor was most effective in blocking MHC class II antigen.

Based on these findings, Steinman and his colleagues at UC-San Francisco tested Lipitor’s ability to treat MS in two mouse models that closely mimic the two forms of human MS. In mice that develop chronic paralysis, similar to late stage MS in humans, statins restored some movement and prevented further paralysis during attacks.

Although some people with MS later develop chronic disease, most go through disease flare-ups followed by a recovery period. In mice that mimic this form of the disease, Lipitor given during the first attack prevented any further attacks. In mice that were having their second attack, Lipitor prevented the paralysis that normally would have occurred.

This work has led to one multicenter trial testing a related statin in people who have had their first MS attack. The UCSF researchers have also submitted a similar proposal to test Lipitor. If these trials pan out, statins would be the first oral drugs for treating MS. The only current treatments must be injected and are effective in only about one-third of patients.

Steinman points out that juvenile diabetes and rheumatoid arthritis both begin with Th0 cells being misdirected by MHC class II antigens. Statins, which are taken by tens of millions of people to lower cholesterol, could end up having a wide-ranging role in disease treatment. "Sometimes the pathways that we think of in one context involve the same characters in different roles," Steinman said, adding that statins are currently being tested as a preventive treatment for Alzheimer’s disease.

Youssef said the next step will be to find out exactly how statins modify the immune response. "We want to see what happens — to really get to the bottom of this," he said.




Stanford, UCSF researchers home in on key gene in MS progression (11/28/01)