Researchers uncover a new clue in asthma development

May 2006

Researchers at Children’s Hospital Boston have found convincing evidence that CD4 natural killer T (NKT) cells, may play a prominent pathogenic role in causing asthma, perhaps, explaining why current therapies sometimes fail and what causes asthma.

“We showed that there are large numbers of CD4 NKT cells in the lungs of patients with asthma. These cells produce Th2 cytokines and may have been mistakenly identified in the past as Th2 cells,” lead researcher Dale T. Umetsu, MD, PhD, told Infectious Diseases in Children.

CD4 NKT cells were virtually absent in the lungs of healthy patients, supporting recent findings in mice showing a direct causative role for NKT cells, according to the study, which is published in The New England Journal of Medicine.

“Our findings were unexpected,” added Umetsu, immunologist at Children’s Hospital Boston and professor of pediatrics at Harvard Medical School. “They suggest we need to look at asthma in a different way in terms of therapies.”

Asthma and prior notions

Asthma affects 20 million Americans and cases have been increasing across all ages, sex and racial groups since the early 1980s, according to the Asthma and Allergy Foundation of America. It caused nearly 2 million emergency department visits in 2003. Each year, 5,000 deaths due to asthma occur and each day, 14 Americans die from asthma, many of the deaths are avoidable with proper treatment and care. The death rate for children younger than 19 has increased by nearly 80% since 1980, according to the foundation.

Asthma is characterized by airway inflammation dominated by the presence of eosinophils and CD4 T lymphocytes, according to the study.

The CD4 cells in asthmatic patients produce the Th2 cytokines interleukin-4 (IL-4), IL-5 and IL-13. These enhance the growth, differentiation and recruitment of eosinophils, basophils, mast cells and Immunoglobulin E (IgE)-producing B cells, and directly induces airway hyperreactivity, according to the study.

Previously, scientists believed that conventional CD4 T lymphocytes, specifically Th2 cells, were causing the inflammatory process.

But in 2003, a study published in Nature Medicine and conducted by Umetsu and co-investigator Omid Akbari, PhD, both then researchers at Stanford University, showed that activation of NKT cells is required for the development of asthma in mice: Mice that lacked NKT cells did not develop airway hyperreactivity. And this year, in Proceedings of the National Academy of Sciences, Umetsu and colleagues reported that NK T-cell activation alone is sufficient to cause asthma in mice, even when Th2 cells are completely absent.

“These findings were intriguing,” Umetsu said in a statement. “But to apply them to humans, we needed to examine patients with asthma.”

New findings, new view

Umetsu and Akbari, both now in the division of immunology at Children’s Hospital Boston, did just that in this most recent study.

They examined specimens from the lungs of 25 participants: 14 with moderate-to-severe bronchial asthma who were lifelong nonsmokers, six healthy participants (the control group) and five participants with sarcoidosis, a respiratory inflammatory disease in which large numbers of CD4 Th1 cells are present in the lungs.

Findings indicated that 60% of the asthma patients’ pulmonary T cells were actually NKT cells, not conventional T cells. However, they found much lower levels of NKT cells in the lung samples of the six healthy participants and five participants with sarcoidosis.

“Conventional Th2 cells may not be as important in causing asthma as was thought,” said Umetsu. “We now believe that NKT cells may be equally or more important. They produce the same cytokines as Th2 cells, and therefore, theoretically could completely replace Th2 cells in the development of asthma.”

The researchers 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% 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.

“Together with studies in mice indicating the requirement of invariant natural killer T cells for the development of allergen-induced airway hyperreactivity, our results strongly suggest that invariant natural killer T cells in asthma represent a new paradigm in which CD4 invariant natural killer T cells, in concert with conventional CD4 T cells, produce interleukin-4 and interleukin-13, driving the development of inflammation in bronchial asthma,” the researchers wrote in their study. “If invariant natural killer T cells do indeed play a prominent role in the pathogenesis of asthma, therapies for asthma that target pulmonary invariant natural killer T cells may be highly effective.”

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 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. Activation of NKT cells induced asthma independently of eosinophils and B cells, according to the study published in the Proceedings of the National Academy of Sciences.

“NKT cells are the ‘BMWs’ of the immune system. They can produce cytokines very rapidly and directly cause asthma,” added Akbari, an immunologist at Children’s Hospital Boston and assistant professor at Harvard Medical School.

NKT cells have another unique property: Although conventional T cells recognize protein antigens, glycolipid antigens trigger NKT cells.

“In the past, most of the focus in allergy and asthma has been on protein antigens,” Umetsu said. “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, according to the researchers.

In addition to searching for these antigens, they 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, according to Umetsu. Although current therapies are useful, the research explains why they do not always work in asthmatic patients and may lead to new treatments.

“Treatments for asthma in the future may be improved by targeting NKT cells,” he suggested.

The National Heart, Lung and Blood Institute, the National Institute of Allergy and Infectious Diseases and the American Lung Association of California funded this study.

For more information:

• Akbari O, Faul JL, Hoyte EG, et al. CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N Engl J Med. 2006;354:1117-1129.
• Meyer EH, Goya S, Akbari O, et al. Glycolipid activation of invariant T cell receptor+ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells. Proc Natl Acad Sci USA. 2006;103:2782-2787.