For release: Monday, May 14, 2007
In multiple sclerosis (MS), the immune cells that patrol our blood for pathogens venture out of the bloodstream and attack the brain. Researchers have found that leakage of a blood-clotting protein into the brain, once considered merely a sign of damage in the MS brain, helps stimulate this attack.
In experiments on mice, the researchers were able to block the protein's effect on immune cells – and reduce the clinical signs of MS – without affecting the protein's vital role in blood clotting. Their findings appear in the Journal of Experimental Medicine,* and offer hope for new therapies against MS, the most common disabling neurological disorder of young adults.
Katerina Akassoglou, Ph.D., the study's senior investigator and an assistant professor of pharmacology at the University of California in San Diego, says she hopes the work will lead to improved drugs for MS. Various immunosuppressants are used to modify the course of MS, which can cause recurrent bouts of vision loss, weakness, and even paralysis, but there is currently no cure.
MS occurs when immune cells react against myelin – a protective sheath that insulates neurons in the brain. Why this inflammatory reaction occurs is unknown, but a rupture of the blood-brain barrier appears to be a key event. This structure normally keeps immune cells and microbes from creeping out of the blood and entering brain tissue. Breaks in the barrier – and leakage of the blood-clotting protein fibrinogen – are commonly observed near areas of myelin destruction, but until now, no one realized that fibrinogen might be more than a bystander.
"In brain tissue affected by MS, there's a striking co-localization of fibrinogen with areas of inflammation [a buildup of immune cells] and demyelination," says Dr. Akassoglou, who is supported by the National Institute of Neurological Disorders and Stroke (NINDS). "This led us to the idea that fibrinogen might be an active participant in the disease."
She suspected that fibrinogen – which helps stimulate platelets in the blood to form clots – might also stimulate microglia, the brain's resident immune cells. Prior studies suggest that microglia protect the brain by gobbling up toxins and debris, but that they can also participate in inflammatory reactions. Moreover, they are known to possess a receptor for fibrinogen, called Mac-1.
In an initial experiment, Dr. Akassoglou grew microglia in a laboratory dish and exposed them to fibrinogen. The cells "underwent dramatic changes," she says, swelling up and becoming capable of ingesting other cells.
Next, she probed fibrinogen's role in experimental autoimmune encephalomyelitis (EAE), an MS-like disease that can be induced in mice by sensitizing their immune systems to myelin. In one experiment, she gave mice with the disease ancrod – an anticoagulant, or anti-clotting drug. Mice that received the drug after their first bout of paralysis steadily regained their motor functions, while untreated mice tended to relapse.
Since chronic use of anticoagulants could cause hemorrhaging, Dr. Akassoglou sought a way to specifically inhibit the damaging effects of fibrinogen in the brain without affecting its beneficial effects in blood clotting.
She focused on a small fragment of fibrinogen known to bind exclusively to the Mac-1 receptor. She guessed that a synthetic version of this fragment – or peptide – might serve as a decoy, tying up the receptor and keeping the microglia from responding to the real protein. Indeed, when delivered daily via a nasal spray, the peptide protected mice against EAE induction. It also enhanced motor performance and reduced demyelination in mice that already had EAE. Importantly, the peptide had no effect on blood clotting.
"This is proof of principle that we can block the inflammatory effects of fibrinogen in the brain without impairing its role in blood clotting," says Dr. Akassoglou. "We are very interested in exploring whether this peptide or other fibrin-depleting agents would be safe and effective in MS patients." Antibodies or small molecules that target fibrinogen may prove to be suitable for drug development, she says.
Update: In November 2007, the White House feted Dr. Akassoglou for her research on MS with a 2006 Presidential Early Career Award for Scientists and Engineers (PECASE), the highest honor bestowed by the U.S. government on new scientists and engineers. Ravindra Singh, Ph.D., an assistant professor at the University of Massachusetts Medical School, received a PECASE for his research on the function of a pair of genes involved in spinal muscular atrophy, work that is also funded by NINDS. Click here for a full list of PECASE recipients whose work is supported by NIH.
*Adams RA et al. "The Fibrin-Derived gamma377-395 Peptide Inhibits Microglia Activation and Suppresses Relapsing Paralysis in Central Nervous System Autoimmune Disease." Journal of Experimental Medicine, March 19, 2007, Vol. 204(3), pp. 571-582.
-By Daniel Stimson, Ph.D.
Last Modified November 27, 2007