HARVARD GAZETTE ARCHIVES
Researchers uncover cause of asthma
Natural killer cells leave people breathless
By William J. Cromie
Harvard News Office
Medical experts have been baffled by what causes asthma. Most of them favor the idea that it stems from "helper" cells that have gone awry. But researchers at Harvard Medical School (HMS) have come up with convincing evidence that the answer lies in a special type of natural "killer" cell.
"We were very, very surprised," admits Dale Umetsu, a professor of pediatrics at the Medical School and at Harvard-affiliated Children's Hospital in Boston. "People have been confused about which cells in the lungs are responsible for all these years. Now, we have to rethink the results of so many studies. Our new findings were totally unexpected."
An estimated 17 million-20 million people in the United States suffer from asthma, and cases of it have been increasing since the early 1980s, according to the Asthma and Allergy Foundation of America. Every day, in this country, 30,000 people suffer an asthma attack, and 14 people die from the disease.
So, knowing exactly which cells should be targeted for treatment is a vital part of relieving a lot of misery for lots of people.
Asthma occurs when the body's natural system of defense against bacteria, viruses, and other harmful microbes becomes overprotective. It misidentifies relatively harmless pollens, dust, and dander, setting up a reaction that narrows and inflames small airways in the lungs. From that comes breathlessness, wheezing, tissue damage, and, in the worst cases, death.
In the standard textbook version of what happens, so-called T helper cells respond to ragweed, dust, and other irritants by secreting proteins that attack the irritants as if they are bits of disease-causing bacteria or viruses. Umetsu and his colleagues decided to take a look at this process from a new perspective. They checked the lung cells of 25 patients, 14 of whom were nonsmokers with moderate to severe asthma. To their surprise, they found that most of the trouble-raising cells in the lungs of asthmatics aren't helper cells but a little-known group of natural killer cells. In general, killer cells enjoy the reputation of destroying disease-causing invaders, but this special group wages war on otherwise normal lungs.
The finding means that physicians may not be treating asthma sufferers with the right kinds of drugs. For example, natural killer T cells seem to be resistant to the corticosteroids in widely used inhalers.
No helpers for asthma
As surprising as this discovery is, Umetsu and his colleagues had previously uncovered hints that killer cells might be implicated. Only recently has there been technology available to easily identify the presence of natural killer T cells. In 2003, at Stanford University, Umetsu and his colleagues took advantage of the new technology to study what went on in the lungs of asthmatic mice. They were startled to find that mice without natural killer T cells don't get asthma.
By 2005, Umetsu had moved to HMS and was part of a team whose investigations demonstrated that activating natural killer T cells in the complete absence of the helper T cells could give mice asthma. They reported the details of their work in the Feb. 21, 2006, issue of the Proceedings of the National Academy of Sciences.
Naturally, "our unexpected results in mice prodded us to ask if natural killer T cells are also critical to developing human asthma," Umetsu notes.
With the assistance of Omid Akbari, now an assistant professor at Harvard Medical School, Stanford's John Faul, and 25 volunteer patients, an Umetsu team became the first to show the major importance of natural killer cell activity in causing asthma in people. They reported the details of their experiments in the March 16 issue of The New England Journal of Medicine. Other members of the team include Rosemarie DeKruyff of HMS and researchers at the Karolinska Institute in Sweden and La Jolla Institute for Allergy and Immunology in California.
Stopping the killers
Umetsu and his colleagues expect that their astonishing results will lead to more effective treatments for a condition that accounts for one out of every four emergency room visits in the United States. New drugs, for example, may be aimed at blocking only the activities of the killer T cells.
"These cells actually make up a small population of cells in our blood," Umetsu points out. "But in the lungs of people with asthma, they apparently proliferate and overexpand. Novel drugs and other treatments would be aimed at reducing their numbers in the lungs, or preventing them from becoming activated.
That could be tricky. "We are working on ways to get at the natural killer T cells without knocking out helper T cells, which are involved in many different kinds of protective responses," Umetsu explains. Such responses include defenses against microbes like the AIDS and bird flu viruses, and bacteria that cause tuberculosis. Drugs that knock out the killer cells without hindering the work of helper cells would have fewer side effects, and should be more effective than the steroids in inhalers. The steroids were designed to cripple helper T cells only.
Before people can buy such drugs at local stores, however, more research is needed to understand better how the killers work. "We want to find out how natural killer T cells get into lungs in the first place, and exactly how they get activated," Umetsu explains. "We need to look at many more patients, including children, to determine if the number of natural killer T cells correlates with the severity of the asthma."
The role of these nasty killer cells is also being studied in other maladies, including inflammatory bowel disease, diabetes, and a number of infectious diseases. For example, a different Harvard group has recently found that natural killer T cells play a part in unexplained cases of recurring pregnancy loss and preterm births in mice.