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Finding may lead to new drugs to treat autoimmune disorders

IOWA CITY, Iowa -- There is no cure for the autoimmune disease rheumatoid arthritis, but treatment with certain anti-malarial drugs often causes the disease to go into remission, in some cases permanently.

Unfortunately, the therapeutic dose of the anti-malarials is close to the toxic dose, so care must be taken when using them. It should be possible to design more effective and safer drugs to treat rheumatoid arthritis and other autoimmune disorders, but until now scientists haven't known how the drugs work to cause remission in rheumatoid arthritis.

A key advance in this area may have been found by Dr. Donald Macfarlane, professor of internal medicine at the University of Iowa and staff physician at the Iowa City Veterans Affairs Medical Center. Working with human and animal cells in the laboratory, Macfarlane and his colleague Lori Manzel, have shown that the anti-rheumatic anti-malarial drugs inhibit an activity of the defense system that may cause the body to attack itself. Understanding why a drug works clears the path for designing safer, more potent drugs. Macfarlane and Manzel's work is published in the current issue of The Journal of Immunology.

This is how it works: When bacteria invade the body, their DNA may be released when they are engulfed and killed by disease-fighting cells. Research by Dr. Arthur Krieg, UI associate professor of internal medicine, has shown that this bacterial DNA activates the body's defense system. Little pieces of the bacterial DNA, called CpG-oligodeoxynucleotides, activate the immune system in a manner similar to that of the whole DNA.

Macfarlane found that very small amounts of the anti-malarial drugs chloroquine, hydroxychloroquine and quinacrine completely inhibit the immune activity stimulated by CpG-oligodeoxynucleotides. Suspecting that this effect accounts for the useful anti-rheumatic action, he started looking for other chemical compounds that block this type of immune system activation.

"We have already tested over 230 chemicals in the test tube, and 50 or so are very interesting -- one is 150 fold more potent than Plaquenil, the most commonly prescribed drug of this type," Macfarlane says. "After we have identified the best test tube drugs, they can be tested in animals and eventually in humans."

Drugs discovered in this way could be useful in treating a wide range of disorders, including septic shock, inflammatory bowel disease and respiratory infections in addition to rheumatoid arthritis and lupus erythematosus. Macfarlane is starting to talk to drug companies with the resources to move the research into a preclinical phase.

This research was funded by the Iowa City Veterans Affairs Medical Center.