"We were quite surprised by the clarity with which the mice either got asthma or not depending on whether or not 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 will be published Monday in the online version of Nature Medicine.
The scientists found that, in a mouse model of asthma, a strain of mice lacking the ability 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 scientists were so surprised by the findings that they tested another strain of mice, also lacking NKT cells. The results were the same.
"The effect was very dramatic," said Umetsu. "In the absence of NKT cells we didn't get any airway hyper-reactivity, despite using different antigens and different 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."
The researchers hypothesize that NKT cells in the lungs of people with asthma are activated when an inhaled irritant exposes normally hidden proteins on the surface of cells in the respiratory tract. The activated NKT cells then license nearby Th2 cells to induce AHR. Permission slips in hand, the Th2 cells kick into gear, constricting airways and galvanizing the release of clogging mucous. People without asthma may have fewer or less proactive NKT cells in the lung.
"Prior to these studies, one assumed that Th2 cells were all that was needed to induce asthma, and they do play a very 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. Other collaborators include Mitchell Kronenberg, PhD, at the La Jolla Institute for Allergy & Immunology.
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