Investigators at the Stanford University School of Medicine have learned the signal that tumour cells display on their surfaces to protect themselves from being devoured by the immune system also plays a role in enabling atherosclerosis, the process underlying heart attacks and strokes. A biological drug capable of blocking this so-called "don’t eat me" signal is now being tested in clinical trials in cancer patients. The same agent, the investigators found, was able to prevent the build-up of atherosclerotic plaque in several mouse models of cardiovascular disease. If this success is borne out in human studies, the drug could be used to combat cardiovascular disease – the world’s No. 1 killer – and do so by targeting not mere risk factors such as high cholesterol or high blood pressure, but the actual lesions bearing direct responsibility for cardiovascular disease: atherosclerotic plaques.
"It seems that heart disease may be driven by our immune system’s inability to take out the trash,’" said Nicholas Leeper, MD, associate professor of vascular surgery and of cardiovascular medicine.
Atherosclerosis is caused by the deposition of fatty substances along arterial walls. Over the years, these substances form plaques. It’s now known that numerous dead and dying cells accumulate in atherosclerotic plaques, which inflammation renders brittle and vulnerable to rupture, the ultimate cause of heart attack and stroke.
Contributing to the pathology is malfeasance on the part of a class of immune cells that first arrive at the site with presumably benign intentions, said Leeper.
"Even a perfectly healthy body turns over more than 100 billion cells a day, every day," he said. "One of the several jobs performed by immune cells called macrophages is to come and gobble up those dead and dying cells, which might otherwise begin releasing substances that can foster inflammation."
Many cells in the human body feature a "don’t eat me" signal on their surface: a protein called CD47. The protein tells the immune system that a cell is alive, still going strong and part of a person’s healthy tissue.
Normally, as a cell approaches death, its CD47 surface proteins start disappearing, exposing the cell to macrophages’ garbage-disposal service. But atherosclerotic plaques are filled with dead and dying cells that should have been cleared by macrophages, yet weren’t. In fact, many of the cells piling up in these lesions are dead macrophages and other vascular cells that should have been cleared long ago.
In the new study, Leeper, Kojima and their colleagues performed genetic analyses of hundreds of human coronary and carotid artery tissue samples collected at Stanford and at Sweden’s Karolinska Institute. They found that CD47 is extremely abundant in atherosclerotic tissue compared with normal vascular tissue, and correlated with risk for adverse clinical outcomes such as stroke.
Alerted to the Leeper lab’s discovery, Weissman, a co-author of the new study, provided anti-CD47 antibodies so Leeper’s group could test their efficacy in battling atherosclerosis.
In a laboratory dish, anti-CD47 antibodies induced the clearance of diseased, dying and dead smooth muscle cells and macrophages incubated in conditions designed to simulate the atherosclerotic environment. And in several different mouse models of atherosclerosis, blocking CD47 with anti-CD47 antibodies dramatically countered the build-up of arterial plaque and made it less vulnerable to rupture. Many mice even experienced regression of their plaques – a phenomenon rarely observed in mouse models of cardiovascular disease.
Looking at data from other genetic research, the scientists learned that surplus CD47 in atherosclerotic plaques strongly correlates with elevated levels, in these plaques, of a well-known infl ammationpromoting substance called TNF-alpha. Further experiments showed that TNFalpha activity prevents what would otherwise be a progressive decrease of CD47 on dying cells. Hence, those cells are less susceptible to being eaten by macrophages, especially in an atherosclerosis-promoting environment.
"The problem could be an endless loop," said Leeper, "in which TNF-alpha-driven CD47 overexpression prevents macrophages from clearing dying cells in the lesion. Those cells release substances that promote the production of even more TNF-alpha in nearby cells."
Leeper and Weissman said they hope to find out, in clinical trials of human patients, whether CD47-blocking antibodies will prove effective in breaking that vicious circle.
Stanford Medicine http://tinyurl.com/zts8ws4