Newly Synthesized Chemical Suppresses Immune System Without the Side Effects of Current Treatments
Irvine, Calif., July 3, 2000 -- A new, synthesized chemical that affects cells similarly to scorpion venom also can effectively suppress the immune system, a UC Irvine College of Medicine research team has found.
The chemical eventually could be used as a drug to assist with organ transplants and also treat disorders like lupus, multiple sclerosis and rheumatoid arthritis in which the immune system causes the body to attack itself, possibly without the severe side effects of existing anti-immune drugs. The findings appear in the July 3, 2000 edition of the Proceedings of the National Academy of Sciences.
Heike Wulff, postdoctoral researcher with UCI's Department of Physiology and Biophysics, synthesized the chemical, called TRAM-34, and found that it binds to a channel located on cells in the immune system known as T-cells. TRAM-34 suppressed the activation of these T-cells and prevented them from proliferating and performing their normal job of triggering immune responses to foreign objects. This normal immune response protects the body against disease but also can cause the body to reject transplanted organs and, in certain diseases of immunity, induce the body to attack itself.
While scorpion venom stuns prey or wards off predators with poisonous effect, the researchers used the venom's characteristics as an initial guide to develop a chemical with gentler, more therapeutic properties.
"From a study that started originally by looking at how scorpion venom inactivated cell functions, we synthesized the chemical TRAM-34 and found it suppressed T-cell function without affecting other biochemical processes in the cell," said Wulff. "If TRAM-34 proves effective in humans, we think it may be an effective way to keep the immune system from attacking itself in certain diseases or from rejecting transplanted organs."
The UCI team found that TRAM-34 inhibited T-cells by blocking a cell membrane channel called IKCa1, the same channel that is blocked by the scorpion venom. This channel is found on all T-cells; blocking it appears to curb the T-cell's ability to coordinate the body's attack against bacteria, viruses and other foreign bodies.
In addition, TRAM-34 did not block the action of other important enzymes in the body, which indicates that the chemical may not produce the side effects of other drugs either being used or currently in clinical trials for treating immune disorders and assisting organ transplants. Both cyclosporin, which suppresses the immune system and is now used in transplant surgery, and clotrimazole, an anti-fungal drug being tested for sickle cell anemia and considered for future tests as an immunosuppressant, can cause side effects, such as gastrointestinal and urinary system problems.
"Because TRAM-34 very specifically blocks only the IKCa1 channel and doesn't affect other functions in the cell that are affected by other drugs, we believe it may result in a drug that has fewer side effects," said Wulff. "Just as we used scorpion venom only as a jumping-off point to look for a possible drug that uses the same receptor, we're now looking to see if TRAM-34 points us to better treatments for immune system disorders."
The team is now working to determine whether TRAM-34 could be developed as a pharmaceutical agent and if other chemicals similar to TRAM-34 work as effectively at suppressing the immune system.
Wulff is one member of a group of researchers at UCI who, as part of their efforts to create treatments from chemicals that bind to a variety of T-cell channels, are looking at how channels' functions can be discerned by observing their interactions with animal venom and other chemicals. Recently, the group found that chemicals related to sea anemone toxin also have an effect on another T-cell channel and may be able to provide yet another group of treatments against immune system disorders.
Wulff 's colleagues on the study include Michael Cahalan, George Chandy and Mark Miller at UCI, Wolfram Haensel at the University of Kiel, Germany, and Stephan Grissmer at the University of Ulm, Germany.
The study was supported by a grant from the National Institute of Mental Health and the Deutsche Forschungsgemeinschaft, the German national research council.
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