Technion researchers clear up the mystery of psoriasis [pg. 7]

January 22, 2006 01:31

Psoriasis - a non-contagious, chronic and disfiguring skin disease that produces itchy red scales and patches on up to 70% of the body - affects one to three percent of the world's population. About a third of the cases are severe, with the affected skin covering more than 3% of the body. Thousands of victims flock to the Dead Sea because the sun's rays, minus most of the UV light filtered out at the low altitude, and minerals in the water and air relieve the condition, which is caused when patients' white blood cells go into overdrive, triggering other immune responses that pile up skin cells at an abnormal rate. Now scientists at the Technion Institute and the State University of New York at Stony Brook have found that an immune molecule that normally assists in "cell suicide" may be an important trigger in the development of psoriasis. The culprit, a molecule called Fas, acts as a middleman between activated immune cells and a handful of inflammatory hormones involved in psoriasis flare-ups, says lead researcher, Technion Prof. Amos Gilhar and colleagues. Their study appears in the January issue of the American Journal of Pathology. Current treatments for psoriasis, such as the drug Enbrel, focus on these inflammatory hormones, but the researchers were able to stop the development of psoriasis in mice long before these hormones came into play by injecting a Fas-blocking antibody. "The finding that antibodies to Fas can prevent psoriasis further demonstrates the complexity of the disease and its numerous molecular pathways," Gilhar says. Prof. Alice Gottlieb, chair of the Clinical Research Center at the Robert Wood Johnson Medical School in New Jersey, agrees. "This research shows that activation of the Fas pathway is important in starting the ball rolling in psoriasis," comments Gottlieb, who was not involved with this study. "These findings could have implications for other immune diseases such as rheumatoid arthritis and Crohn's disease." The researchers suspected that the Fas molecule was involved in this process, since it is found at high levels in psoriatic skin and leads an intriguing dual life. Most of the time, Fas guides the normal process of cell suicide, known as apoptosis. But in cells where apoptosis is blocked by other molecules, as it is in psoriatic cells, Fas switches roles and encourages the production of common inflammatory hormones instead. To figure out exactly where Fas stood in the development of psoriasis, Gilhar and colleagues transferred grafts of clear, non-involved skin from human psoriasis patients to mice. They injected the mice with white blood cells bearing the Fas molecule on their surfaces to jump-start the formation of psoriatic skin lesions. By blocking Fas action with a special antibody, the researchers were able to show that Fas actually is the key middleman in psoriasis formation. Without Fas, the natural killer cells were unable to trigger the production of the inflammatory hormones that lead to the characteristic skin thickening and other signs of psoriasis. There is some evidence that Fas is involved in other skin conditions such as eczema, so future treatments targeting the Fas pathway may prove useful for a variety of diseases, suggests Prof. Richard Kalish, Gilhar's collaborator from SUNY. However, researchers need to develop a human antibody to Fas before the technique could be tested in people. BONES GO TO POT Substances produced in the body that act like those found in the cannabis plant (marijuana and hashish) help preserve bone density, according to Hebrew University researchers. Based on this finding, a prototype for a new drug to prevent osteoporosis but without any psychoactive side effects has already been developed. The bone-thinning disease is the most common degenerative ailment in developed countries, and can lead to multiple fractures, disability, complications and even death. An article describing this research has appeared in the latest issue of Proceedings of the [US] National Academy of Sciences . The HU bone lab researchers were headed by Prof. Itai Bab, and worked in cooperation with Prof. Esther Shohami of the brain trauma department; Prof. Raphael Mechoulam of the HU School of Pharmacy; doctoral students Orr Ofek, Vardit Krem and Yossi Tam; and master's degree student Meirav Fogel. Substances made in the body called endocannabinoids are composed mainly of fatty acids, and were discovered during the past 15 years; the fatty acid anandamid was discovered by Mechoulam 14 years ago. These materials, produced mainly in the brain, are present also in the bone and other tissues, and have similar effects to those of the active components in drugs produced from the cannabis plant. These substances bind to and activate two receptors, called CB1 and CB2. The former is found in the nervous system and responsible for the psychoactive effects of components in the cannabis plant and endocannanoids. The latter, located in the immune system, is not known to be involved with psychoactive responses; indeed, there has been little information about its physiological function. The researchers discovered a high level of CB2 receptors in bone, and found that it is needed to preserve normal bone density. Together with Prof. Andreas Zimmer and Dr. Malia Karasek at the University of Bonn, they studied the skeletons of genetically engineered mice lacking the CB2 receptor. As they aged, these CB2-deprived mice developed severe osteoporosis, similar to that in humans. The scientists' findings have thus assigned, for the first time, a physiological function to CB2 in preserving bone density, and showed that it stimulates bone building and reduces bone loss. This means that substances that activate the CB2 receptor can be used to develop osteoporosis drugs. The HU team have developed a new synthetic compound called HU-308 which activates CB2 and slows the development of osteoporosis in mice. This compound forms the basis for a cannabinoid-based drug which has been shown to have no side effects on the brain.

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