Therapy Holds Promise for Arthritis : Medicine: A naturally occurring component that halts the progress of bone disease in rodents has been isolated from human white blood cells.
A new approach to therapy of rheumatoid arthritis and many other diseases--such as diabetes, septic shock and inflammatory bowel disease--may arise from new research reported Thursday in the British journal Nature by a group of Colorado scientists.
Molecular biologists from Synergen Inc. in Boulder and the University of Colorado Health Sciences Center in Denver have isolated from human white blood cells a naturally occurring component that halts the progress of arthritis in rodents, and they hope to begin human trials this year.
The newly discovered compound, called IL-1ra, inhibits the immune hormone interleukin-1. Excess production of interleukin-1 has been implicated in many so-called autoimmune diseases, such as arthritis and diabetes, in which the immune system attacks its host.
More than 2 million Americans, twice as many women as men, have been diagnosed with rheumatoid arthritis, which is marked by stiffening and pain in joints and their eventual destruction.
Meanwhile, other researchers are testing IL-1ra’s effects in animals against a variety of other diseases.
“It’s a nice piece of work, and I hope it will prove useful,” said immunologist Joost Oppenheim of the National Cancer Institute in Bethesda, Md. “I wish I had done it.”
The discovery may have even greater long-term implications, according to immunologist Charles Dinarello of Tufts University School of Medicine in Boston. At least 25 different immune hormones, or cytokines, have been linked to diseases ranging from arthritis to atherosclerosis, he said, “and each of them may have its own (inhibitor). Why would interleukin-1 be singled out? This introduces a whole new concept into the treatment of disease.”
Interleukin-1 was discovered in 1984 and it has been widely studied since. It is produced by virtually every type of cell in the body when cells are injured or stimulated by infections, Oppenheim said.
“It galvanizes the immune system’s reaction to injuries or infections,” he said, “but sometimes it overdoes it. When you get too much inflammation or excessive fever, it backfires,” producing autoimmune diseases.
That excessive inflammation, researchers believe, can lead to such ill effects as the deterioration of bone in joints, the death of insulin-secreting beta-cells in the pancreas and excessive irritation of the colon.
In 1985, three different groups of researchers, including Dinarello, showed that an interleukin-1 inhibitor exists in the urine or blood plasma of patients with certain inflammatory diseases. “The race was then on to isolate and clone it,” Dinarello said. “All the giant pharmaceutical companies have been working on it. Synergen has won the race.”
Interleukin-1 is a protein that exerts its effect by binding to a specific receptor on the cellular membrane of white blood cells, thereby triggering intracellular reactions.
The newly discovered IL-1ra (ra for receptor antagonist) is also a protein, with about 40% of its structure identical to interleukin-1, according to molecular biologist Robert C. Thompson of Synergen. It binds to the same receptors so that interleukin-1 cannot bind, but it apparently does not stimulate any intracellular reactions.
Thompson and his colleagues chose to study the effects of their new compound in an arthritis model because interleukin-1 has been most clearly linked to that disease. People with active rheumatoid arthritis have above-normal levels of interleukin-1 in their blood. The disease can also be produced in animals by injecting interleukin-1 into their joints.
He was reluctant to discuss Synergen’s results with IL-1ra in rats because they have not been published yet, but he did say “preliminary results indicate it is effective in reducing the severity of joint disease.” Synergen and Hoffmann-La Roche Inc. will apply to the U.S. Food and Drug Administration later this year to begin tests of IL-1ra in humans, Thompson added.
The principal disadvantage of IL-1ra is that, because it is a protein, it would be dissolved by digestive enzymes and thus must be administered intravenously. But the Synergen scientists plan to isolate just the part of the molecule that binds to the interleukin-1 receptor in hopes that it is less likely to be degraded when given as a pill.
They are also attempting to design completely synthetic molecules that might have the same interleukin-blocking ability, but that would be impervious to digestive enzymes.
