Contacts:
Bianca Conti-Fine, Biochemistry Department, (612) 624-6796
Deane Morrison, University News Service, (612) 624-2346, [email protected]
U of Minnesota Researchers Sniff Out New Autoimmune Disease Therapy
A new treatment for myasthenia gravis (MG), the muscle weakening disease that killed Aristotle Onassis and affects one in 8,000 people in the United States, has been devised by University of Minnesota researchers. In MG, the immune system attacks the patient's own muscle cells. The new treatment essentially "tricks" the immune system into halting its attack and "tolerating" the muscle parts it had previously targeted. A pilot clinical trial may begin soon for the nasally administered therapy, which prevented the disease in mice. The work is described in the Dec. 15 issue of the Journal of Clinical Investigation.
"We concentrated on a mechanism used by our bodies to avoid mounting an immune response against everything," said biochemistry professor Bianca Conti-Fine, who led the study. "This mechanism prevents our bodies from getting hyperactive against everything we breathe or eat." The university has filed a patent on the therapy.
Pilot clinical trials are expected to begin at the University of North Carolina-Chapel Hill sometime early next year, said James Howard, professor of neurology and head of UNC's Division of Neuromuscular Disorders. Howard said probably four to six patients would be treated, and it would take about a year to determine the efficacy of the new therapy.
"For humans, this therapy could be a phenomenal breakthrough," Howard said.
In healthy people, muscles contract when they receive a message from a nerve. When a nerve signals a muscle to contract, a chemical messenger known as acetylcholine diffuses from the nerve ending across a small gap--the synapse--and attaches to the muscle at special receiving stations. These stations are protein structures called acetylcholine receptors. A muscle that lacks working acetylcholine receptors will be unable to contract on command from nerves.
A healthy immune system will leave the body's acetylcholine receptors alone. In MG, an autoimmune disease, a patient's own receptors are slowly destroyed by his or her immune system. MG can be simulated in experimental animals by coaxing their immune system to make antibodies against acetylcholine receptors extracted from the tissues of another species. In certain cases, those antibodies cross-react with the animal's own receptors. This is what happens when mice are injected under the skin with receptors taken from an electric fish, Conti-Fine said. The mice's immune systems start producing antibodies against their own receptors and begin the destruction characteristic of MG.
Conti-Fine's group tested its treatment in mice injected with electric fish receptors. The treatment took advantage of the fact that, while our immune system is confronted daily with all manner of debris that gets through the lining of our respiratory or gastrointestinal tracts, generally no immune response is mounted. (When the system fails, we develop allergies.) The researchers caused mice to sniff mists containing fragments of electric fish receptor known to be recognized by the mouse immune system. But when presented that way--nasally--the fragments failed to provoke a full-blown immune response and prevented the appearance of MG.
Conti-Fine hopes to test a similar treatment in humans soon. After studying MG for 12 years, she has identified specific fragments of human acetylcholine receptors that trigger an immune response in MG patients. By administering those fragments nasally, she hopes to accustom the patients' immune systems to the fragments and to the intact receptors. This treatment could be coupled with plasma exchange, in which the patients' antibody-loaded plasma is replaced by normal plasma. This brings temporary relief to MG patients but doesn't get at the root of the problem: the "rogue" immune cells that work together to produce those antibodies, she said.
The culprits are two types of immune cells: B cells and T helper cells. B cells are the ones that actually make antibodies. In MG patients, B cells produce antibodies against acetylcholine receptors. But if the B cells are working without assistance from T helper cells, those antibodies don't stick to the receptors very well, and little harm is done. With "guidance" from T helper cells, however, the B cells begin producing antibodies that do a much better job of recognizing their targets; they stick to acetylcholine receptors very well, and thus mark them for destruction by the patient's own body.
"The antibodies are like bullets," said Conti-Fine. "The B cell is the gun, and the T helper cell is the bad guy who pulls the trigger." A crucial factor in the development of MG is that the "bad guys" target the patient's acetylcholine receptors, she said. Likewise, a crucial factor in treating the disease may be the bad guys' ability to mend their ways. Nasally administered receptor fragments may do the trick by teaching the T helpers to tolerate the intact receptors.
Conti-Fine's therapy may also work in hemophilia A. Hemophilic patients suffer bleedings that begin when they learn to walk and continue throughout life. Those patients lack a substance called clotting factor VIII, without which blood clots cannot form. But when treated with the factor, the patients mount an immune response to it. Such patients are now treated by exposing them to factor VIII in high doses in an effort to defeat the immune response a strategy that works about 70 percent of the time, said Nigel Key, an assistant professor of medicine at the University of Minnesota. That treatment, however, costs hundreds of thousands of dollars per patient. Also, the efficacy of this treatment is uncertain and transitory. Key has been working with Conti-Fine to apply the MG therapy to hemophilia A patients.
"We see the potential for both counteracting the antibodies in patients after they've developed and, possibly, in preventing their appearance," Key said.
"The 'sniffing' therapy originally devised to control the rogue immune responses that cause autoimmune diseases may directly lead to a state-of-the-art, innovative treatment of the complications of hemophilia A," said Conti-Fine.
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