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Researchers Prevent Lupus in Mice

Strengthening 'gatekeeper' receptor staved off disease, study says

THURSDAY, Jan. 27, 2005 (HealthDayNews) -- Scientists have prevented the development of lupus in mice by boosting levels of an immune system component, a new study reports.

The component -- a receptor gene known as Fc -- acts like a gatekeeper, helping to maintain a healthy immune system instead of one that turns on itself, as is the case in autoimmune diseases such as lupus. In mice and in humans with lupus, production of the Fc receptor is reduced.

The discovery of a way to increase production of the Fc receptor may eventually lead to therapies that could prevent, or even treat, lupus, according to the researchers.

"Despite the complexities of autoimmune diseases like lupus, where many changes are involved, it may be possible to reverse [autoimmunity] by changing just one of those components -- the gatekeeper," said study author Dr. Jeffrey Ravetch, a professor at The Rockefeller University in New York City. "Ours is a more optimistic viewpoint. You don't have to correct all of the components, just one."

The findings appear in the Jan. 28 issue of Science.

As many as 1.5 million Americans have lupus, and approximately 16,000 people are diagnosed with the disease every year, according to the Lupus Foundation of America.

It is one of many autoimmune diseases in which the body's immune system mistakenly turns against itself. Lupus can be mild or severe, depending on which organ systems it attacks. The disease also tends to come and go, flaring up periodically.

Symptoms can include arthritis and aching joints, fever, fatigue and skin rashes. When organs such as the kidneys or lungs are involved, the disease can be life-threatening. Recent research indicates that deaths from lupus are up more than 40 percent, and hospitalizations due to lupus complications are up more than 125 percent.

Previously, Ravetch and his colleagues had discovered that the production of the Fc receptor was reduced in mice with lupus. Later, that was also found to be the case with humans. He said that finding led the researchers to wonder if boosting levels of Fc production would prevent autoimmunity.

In the current experiments, Ravetch and his colleagues developed a form of gene therapy that was able to increase levels of Fc production in mice. According to Ravetch, the change wasn't enormous -- they boosted production by about 40 percent.

But, that small change was apparently enough.

Mice treated with the therapy didn't develop lupus, while mice in a control group did.

"These mice are predisposed to developing lupus. If you do nothing, they always get it. But, in the genetically modified mice, we were able to prevent the disease from developing," said Ravetch.

Ravetch said this receptor is on most immune system cells and has different functions for different cells, but it always acts in an inhibitory fashion. He likened the receptor to "brakes," and said in lupus and other autoimmune diseases, "the brakes aren't working as they should."

Next, the researchers are going to try to find out more about this receptor, and how it functions. "We found the brakes, but we don't know where the wheels are," he said.

Ravetch said he expects his findings would apply to humans, and there seemed to be no serious side effects from the therapy in mice.

Dr. Gary Gilkeson, chairman of the Lupus Foundation of America's Medical and Scientific Advisory Council, said, "This is an interesting, provocative study that gives us new insight into possible approaches to treating lupus."

"Manipulating these receptors may be a good way of approaching treatment of the disease," said Gilkeson. However, he cautioned that the current study didn't look at reversing already existing disease, but at preventing the disease from developing in the first place.

Also, he said, "Given the heterogeneity of the disease in humans, it's unlikely that one size will fit all. It may be that this is the silver bullet, but there's still a long way to go before we see that."

More information

To learn more about lupus, visit the Lupus Foundation of America.

SOURCES: Jeffrey Ravetch, M.D., Ph.D., Theresa and Eugene Lang professor, The Rockefeller University, New York City; Gary S. Gilkeson, M.D., chairman, Medical and Scientific Advisory Council, Lupus Foundation of America; Jan. 28, 2005, Science
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