A newly recognized type of immune cell may play an important role in causing asthma

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A newly recognized type of immune cell may play an important role in

causing asthma

Medical Research News

Published: Tuesday, 21-Mar-2006

A newly recognized type of immune cell may play an important role in

causing asthma, perhaps explaining why current therapies sometimes

fail, report researchers from Children's Hospital Boston in the New

England Journal of Medicine.

These immune cells, known as natural-killer T cells (NKT cells), were

found to be abundant in the lungs of patients with asthma, but

virtually absent in the lungs of healthy people, supporting recent

findings in mice showing a direct causative role for NKT cells.

" 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.

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.

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