New View Of Asthma's Cause

"Our findings were unexpected," says Dale Umetsu, MD, PhD, an immunologist at Children's Hospital Boston and senior investigator on both the human and mouse studies. "They suggest we need to look at asthma in a different way in terms of therapies."

Asthma affects 20 million people in the U.S., and in 2003 caused nearly 2 million emergency-department visits. Previously, scientists believed that conventional CD4+ T lymphocytes - specifically, type 2 helper cells (Th2 cells) - were causing the inflammatory process that is central in the disease. Corticosteroids, the current mainstay of asthma therapy, target Th2 cells, along with other inflammatory cells.

But in 2003, Umetsu and co-investigator Omid Akbari, PhD, both then at Stanford University, showed in Nature Medicine that activation of NKT cells is required for the development of asthma in mice: Mice that lacked NKT cells did not develop airway hyperreactivity, a cardinal feature of asthma. And this year, in the February 21 Proceedings of the National Academy of Sciences (PNAS), Umetsu and Stanford graduate student Everett Meyer went on to show that NKT-cell activation alone is sufficient to cause asthma in mice, even when Th2 cells are completely absent.

"These findings were intriguing," Umetsu says. "But to apply them to humans, we needed to examine patients with asthma."

In the New England Journal of Medicine study, Umetsu and Akbari, both now in Children's Hospital Boston's Division of Immunology, did just that. They examined specimens from the lungs of 25 adults: 14 with moderate-to-severe bronchial asthma, 6 healthy subjects and 5 patients with sarcoidosis, a respiratory inflammatory disease. They demonstrated that, on average, at least two-thirds of the asthma patients' pulmonary T cells were actually NKT cells, not conventional Th2 cells. In contrast, NKT cells were virtually absent in the lungs of healthy subjects and in patients with sarcoidosis (chosen as a control group because their lungs have high levels of CD4+ T lymphocytes).

"Conventional Th2 cells may not be as important in causing asthma as was thought," says Umetsu, also a Professor of Pediatrics at Harvard Medical School. "We now believe that NKT cells may be equally or more important. They produce the same cytokines [chemical messengers that affect the immune response] as Th2 cells, and therefore theoretically could completely replace Th2 cells in the development of asthma."

Umetsu and Akbari believe that NKT cells may have been mistaken for conventional Th2 cells in the past because they carry many of the same molecular markers. Since NKT cells constitute only 0.1 percent of circulating white blood cells, they were easy to miss; only recently have researchers had the techniques to be able to isolate and study them.

A rapid, direct effect

Th2 cells are part of the adaptive immune system, which requires exposure to antigens before a response can be mounted. They are thought to work through other cells (such as eosinophils and B cells) to cause asthma. In contrast, NKT cells are part of the innate immune system, which is inborn and ready to respond rapidly to external threats. In the February PNAS study, activation of NKT cells induced asthma independently of eosinophils and B cells.

"NKT cells are the 'BMWs' of the immune system," says Akbari. "They can produce cytokines very rapidly and directly cause asthma."

NKT cells have another unique property: while conventional T cells recognize protein antigens, NKT cells are triggered by glycolipid antigens.

"In the past, most of the focus in allergy and asthma has been on protein antigens," Umetsu says. "Our current studies suggest that other classes of antigens may be involved. And since NKT cells have a receptor that varies little between mice and humans, we believe that the antigens they recognize are very important. These findings open whole new areas of research."

The still-unidentified glycolipid antigens that NKT cells "see" in asthma may come from plant pollens, bacteria, or even the body itself. Understanding their origins and how they activate NKT cells to cause asthma may reveal new biological pathways that can be targeted by drugs, the researchers say.

In addition to searching for these antigens, Umetsu, Akbari and colleagues plan to look at milder asthma and extend their studies to children to see if NKT cells play a similar role. They will also seek ways of switching off or counteracting NKT cells, which could be developed into new drugs.

Corticosteroids, which target Th2 cells and other inflammatory cells, reduce inflammation but appear to have little effect on NKT cells, Umetsu says. This perhaps explains why they don't always work in asthma.

"If we can specifically eliminate NKT cells, we should be able to treat asthma much more effectively," Umetsu says.

Umetsu's other collaborators include Rosemarie DeKruyff, PhD, in Children's Division of Immunology, and John Faul, MD, currently at Connolly Memorial Hospital, Dublin, Ireland. The research was funded by the National Heart Lung and Blood Institute, the National Institute of Allergy and Infectious Diseases and the American Lung Association of California.

(C) 2006 - Children's Hospital Boston

Akbari O, Faul JL, Hoyte EG, Berry GJ, Wahlstrom J, Kronenberg M, DeKruyff RH, Umetsu DT.
CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma.
N Engl J Med. 2006 Mar 16;354(11):1117-29.

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