New model illustrating how asthma develops shaped in medical center lab

By KRISTA CONGER

If you have asthma you’re familiar with the drill: take your medication, use your inhaler and avoid breathing irritating dust or pollen. But the complexity of living with the disease pales in comparison to the immunological battle that occurs behind the scenes in the lungs and lymph nodes when first exposed to potentially pesky particles called allergens. Now Stanford researchers have found a new pathway that protects people from developing asthma, modifying a widely held theory about how the disease forms.

"If we could induce this protective response in patients with asthma, we could cure them," said Dale Umetsu, MD, PhD, professor of pediatrics at the School of Medicine. Umetsu is also the chief of the division of allergy and immunology at Lucile Packard Children’s Hospital.

Omid Akbari and Dale Umetsu (right) discovered a new pathway that may protect people from developing asthma. Their research modifies a widely held theory about how the disease forms. PHOTO: KRISTA CONGER

First impressions are lasting, and not even allergens can escape snap judgments. Faced with unfamiliar dust motes, pollen grains or pet dander, the immune system must choose to respond in one of two ways: attack or tolerate. In the case of allergens, tolerance is the better decision. By suppressing a vigorous attack it’s possible to avoid life-long problems with allergy and asthma.

People with asthma must instead deal with an overeager immune system that launches what is called a Th2 response against the offenders. This overreaction leads to the airway inflammation and excess mucous production that make it difficult or impossible to breathe.

"We know the immunological processes that make asthma worse, but we don’t understand the immunological processes that prevent asthma," said Umetsu. In fact, until now many researchers thought that an opposing immune response, called Th1, worked to dampen the Th2 response in non-asthmatics and help the body tolerate the invaders.

Because Umetsu’s group previously showed that Th1 responses actually made the inflammation in asthma worse, they sought other types of protective responses. Umetsu and Omid Akbari, PhD, a postdoctoral research associate, found that a new type of immune cell, called a regulatory T cell, can quench the Th2 response and teach the body to accept the foreign particles. Although regulatory T cells have been studied in autoimmune diseases, the Stanford study, published in August in Nature Medicine, marks the first time these cells have been implicated in asthma protection.

The researchers found that by treating asthma-susceptible mice with allergen-specific regulatory T cells, they prevented the mice from developing the disease. The regulatory T cells inhibited the development of asthma by inhibiting the growth of other T cells that gear up to launch a Th2 response.

The regulatory T cells appear to work by secreting IL-10, one of several proteins known as cytokines that tell other immune cells how to react to invaders. The protective effect of the regulatory T cells also required the presence of a cell surface molecule called ICOS and a partner protein, ICOS ligand. If either IL-10 or the ICOS signaling pathway is blocked, the regulatory T cells can no longer prevent the susceptible mice from developing asthma.

The dependence on the ICOS pathway and IL-10 for asthma protection is interesting, said the researchers, since the proteins are also required for the abnormal Th2 response that causes asthma. The finding suggests that the two possible responses are related, and that timing and location of interactions can tip the balance in favor of developing or protecting against asthma.

"It’s like a piano melody," said Akbari. "The music depends on which molecules are interacting, how many of them there are and where they are."

But the complexity doesn’t stop there. Akbari also found that both IL-10 and the ICOS signaling pathway are required not only for the protective effect of the regulatory T cells, but also for their development. Because many of the cells and proteins involved in asthma development have multiple roles, it’s difficult to pinpoint any one obvious treatment for the disease, said the researchers.

"Our goal now is to understand more of the biology of regulatory T cells — how they grow and function, and the requirements for their development," said Umetsu. "These studies should help us determine why they don’t develop in allergic people. Once we understand how these regulatory T cells develop, we can design strategies to generate protective immune responses and potentially cure this disease."