What are a cancerous tumor and fat accumulation in an artery have in common? Their harmful cells may have the same way to hide from the immune system, a study suggests today. In the new work, researchers studying atherosclerosis gradual accumulation of fat cells in plaque-laden blood found a signaling molecule that can prevent dead cells in the arteries being eaten and disposed of. Blocking this signal, they found, reduced arterial plaque in mice. And because their signal blocker is an antibody already in Phase I clinical trials for the treatment of cancer, they hope to make a quick jump in human tests for cardiovascular disease.
"There will be a new platform of therapy, not just another cholesterol-lowering medication," says Nicholas Leeper, a vascular biologist at Stanford University in Palo Alto, California and lead author of the new study.
Although cholesterol contributes to atherosclerosis, the history of the progression of the disease is much more complex. When these fat deposits damage the artery wall , immune cells flock to the places-including macrophages, which engulf the dying and damaged cells all over the body. But when they get to the inflamed artery, they fail to perform the cleaning. Soon, death muscle cells and macrophages die to join a plate increasingly on the wall of the artery. Nested inside is a "necrotic core" cemetery cells destabilizing the rest of the plate and makes it vulnerable to rupture, which can block the artery and cause a heart attack or stroke.
Leeper and his colleagues studied the signaling between cells die and macrophages that are supposed to put them out of their misery. The team previously found that many of these dying cells lacking a surface molecule that labels for destruction called calreticulin in people at risk for cardiovascular disease. But other common surface molecules in the body send a different signal: "I am healthy, leave me alone!" And this may give scientists an opening. It might be easier to block this message to force the cells to express more "eat me" signals. In fact, Stanford researchers are already working on the first clinical trials of an antibody that blocks the cancer cells display an eluding death such a molecule called CD47 signal.
Atherosclerosis researchers have had their eye on "don" t eat me "molecules such as CD47 signaling for some time, said Matthias Nahrendorf, a cell biologist at Harvard Medical School in Boston who was not involved in the new study. But no one had measured this common molecule in arterial plaques. "I do not have a good reason why people have not looked at this particular molecule in atherosclerosis before," he said . "in retrospect, it is an obvious choice."
Leeper team analyzed samples of arterial plaque in people undergoing surgery for a clogged carotid artery and organ donors without cardiovascular disease. They found that arterial plaque contained significantly higher levels of CD47 than healthy arterial tissue. to see if blocking the CD47 could reverse the buildup of plaque, the group tested the experimental cancer drug antibodies in several disease models cardio- vascular different mice. On a diet rich in fat, these animals quickly develop plaques in their arteries because they lack a gene that regulates the metabolism of cholesterol. But the intravenous treatment with the anti-CD47 treatment reduced by about half of plaque buildup in these mice, Leeper and his colleagues report online today in Nature .
"These results are revolutionary for the field of research on atherosclerosis," says MacRae Linton, an endocrinologist at Vanderbilt University in Nashville, who was not involved in the study. The results are anti-CD47 antibody candidate promising drug for cardiovascular diseases, he notes, although there may be other "do not eat me" signal molecules in the plates he can not answer. If the drug progresses in human trials, researchers will also monitor anemia, a side effect suggested in the results of the mouse. CD47 is essential for the protection of red blood cells from macrophages, and red blood cells are particularly susceptible to the effects of blocking antibodies as they age, says Leeper. the treated mice in the study did show drops in number of red blood cells, but they showed no clinical signs of disease.
The researchers have patented their treatment approach and allowed to Forty Seven Inc., Stanford spinout already developing anti-CD47 antibody for cancer. Stanford biologist and stem cell Forty Seven Inc. founder Irving Weissman, whose pioneering group of research CD47 in cancer, is a co-author on the new paper. Although no new treatment faces a smooth or some way to the clinic, it can have a head start. The drug has already demonstrated the safety testing of non-human primates, and cardiovascular research may even be able to move directly to a Phase II trial largest database of safety data from the Phase I being studies, Leeper suggests. "This can be a very unusual circumstance which can be grafted."
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