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Stanford Report, April 2, 2003

Researchers ID cells critical for asthma development


A subset of immune cells required for the development of asthma in mice has been identified by medical center researchers. The scientists hypothesize that a person with too many of these cells in the lungs or whose cells are easily activated may have an increased risk of developing asthma. Selectively killing or interfering with the activity of these linchpins, called NKT cells, may one day allow doctors to cure or prevent asthma.

"We were quite surprised by the clarity with which the mice either got asthma or not depending on whether they had NKT cells," said Dale Umetsu, MD, PhD, professor of pediatrics at the School of Medicine and chief of the division of allergy and immunology at Lucile Packard Children’s Hospital. "The effect was very black and white." The researchers’ results were published this week in the online version of Nature Medicine.

Studying a mouse model of asthma, the scientists found a strain of mice unable to make the NKT cells remained steadfastly resistant to all of the usual asthma-inducing tricks. None succumbed to the usual wheezing and shortness of breath — a response called airway hyper-reactivity, or AHR — that occurred when control mice were exposed to the same combinations of irritating particles, or antigens.

"The effect was dramatic," said Umetsu. "In the absence of NKT cells we didn’t get any airway hyper-reactivity, despite using differing antigens and protocols. In none of those cases were we able to induce AHR."

In contrast, when the scientists injected compatible NKT cells into the mice lacking the cells before exposing them to the antigen, they began wheezing obligingly right along with the control group. The mice also panted when injected with IL-13, a chemical messenger that acts directly on muscles and glands in the lungs to cause AHR, proving they don’t just have tougher lungs than normal mice.

Asthma is caused by an inappropriately aggressive type of immune response, or Th2 response, to inhaled irritants. But a Th2 response alone is not sufficient to induce asthma; confined to the upper airways it causes the miserable sniffling and sneezing of allergies, but not wheezing and shortness of breath. That fact spurred Umetsu and his colleagues to go looking for the missing co-conspirator.

Circumstantial evidence fingered the NKT cells, or natural killer T cells, as potential asthma culprits: their location in the lungs, but not the upper airways, offered a theoretical answer to the ongoing mystery of why allergies and asthma don’t always go hand-in-hand. They’re also involved in regulating the immune response to autoimmune diseases; when activated, they protect against the development of diabetes and multiple sclerosis in mice by releasing IL-4, a chemical messenger that biases the immune system toward a Th2 response. Although their hunch paid off, the scientists were still surprised at how important NKT cells are to asthma development.

"We knew NKT cells play a very major regulatory role in autoimmune disease, so we wanted to examine their role in asthma," said Umetsu. "We were expecting more of a regulatory role for NKT cells, but they are clearly essential for asthma development."

Researchers hypothesize that NKT cells in the lungs of people with asthma are activated when an inhaled irritant exposes hidden proteins on the surface of cells in the respiratory tract. Activated NKT cells then license nearby Th2 cells to induce AHR. Permission slips in hand, Th2 cells kick into gear, constricting airways and galvanizing the release of clogging mucus. People without asthma may have fewer or less proactive NKT cells in the lungs.

"Prior to these studies, one assumed that Th2 cells were all that was needed to induce asthma, and they do play an important role in asthma pathogenesis," said Umetsu. "Now it’s clear that even if you have Th2 cells but you don’t have NKT cells, you don’t get asthma."

The essential role of the NKT cells makes them logical targets for asthma therapy. "We’re starting to look at people to see how these NKT cells may affect the development of asthma," said Umetsu. "If these NKT cells are increased in numbers or have increased potency, one way to treat or prevent the disease would be to remove those cells. If we can find specific surface markers, we may be able to direct therapies specifically against the NKT cells to eliminate them."

Umetsu’s Stanford collaborators include Omid Akbari, PhD; Philippe Stock, MD, PhD; graduate student Everett Meyer; and Rosemarie DeKruyff, PhD, professor of pediatrics.

Packard, Stanford team find gene family key to asthma development (12/5/01)

New model illustrating how asthma develops shaped in medical center lab (8/7/02)