New Therapeutic Target in Chronic Inflammation
Autoimmune diseases are characterized by an inappropriate response of the immune system that results in chronic inflammation and tissue destruction. Rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes and multiple sclerosis are all autoimmune diseases in which inflammation destroys tissue, although a different tissue is targeted in each case.
One hallmark of inflammation is the recruitment and migration of leukocytes (white blood cells) to the inflamed tissue. This action is modulated by the combined action of certain receptors on the surfaces of leukocytes and of endothelial cells (these are the cells that line the inside of blood vessels). These receptors (analogous to locks) interact with ligands (analogous to keys); when a key finds its way to a lock, cells are triggered to migrate. The receptors studied were α4 integrins and their ligands.
Arthritis Foundation-funded researchers Christiane Kummer, PhD, and Mark H. Ginsberg, MD, PhD, both at University of California San Diego, recently reviewed their research into the role of α4-integrins in chronic inflammation and new approaches to blocking their action.
Because the α4-integrins play an important role in the inflammatory process, they have become a target for treatment of chronic inflammatory disorders. Antibodies that block the α4-integrins showed promise in animal models of asthma, rheumatoid arthritis, inflammatory bowel disease, and type-1 diabetes. Because of the success in treating these animals, humanized versions of the antibodies were developed. To date, approximately 8,000 patients have received natalizumab, an antibody directed against α4-integrins, for the treatment of multiple sclerosis or inflammatory bowel disease. However, side effects, some fatal, have restricted the distribution and use of this drug.
Along with the potential adverse events, antibodies blocking α4-integrins are expensive and require intravenous administration. Rather than blocking all actions of α4-integrins, Drs. Kummer and Ginsberg are researching a method to block only the downstream interaction that regulates leukocyte migration to inflammatory tissue. By blocking a downstream interaction, the other important functions of the integrins will be spared, and fewer side effects are expected.
In particular, Dr. Kummer is investigating the interaction between α4-integrin and paxillin. α4-Integrin binds to paxillin, and paxillin binding is required for α4-integrin to enhance cell migration. The potential exists for a small molecule, one that would not have to be administered by intravenous injection, to block the integrin–paxillin binding, thereby regulating the migration of leukocytes and diminishing inflammation. Having found such a molecule, its efficacy in decreasing the severity of RA or attenuating this disease can be tested in various mouse models of arthritis. Small-molecule inhibitors that reduce inflammation in mouse models of RA are very likely to translate into therapies for this disease in humans.
Kummer C, Ginsberg M. New approaches to blockade of α4-integrins, proven therapeutic targets in chronic inflammation. Biochem Pharmacol. In press.