By MICHELLE BRANDT

More than 17 million Americans suffer from asthma, a disorder marked by shortness of breath, chest tightness and frequent attacks of wheezing and coughing. Although a cure for the pesky, prevalent disease continues to elude them, scientists are making progress in understanding asthma. New Stanford research published in the August issue of Nature Immunology sheds light on how the immune system normally responds to inhaled foreign proteins and could pave the way for new therapies for asthma sufferers.

"Before this study there was very little understanding of what keeps immune responses in check in preventing asthma," said Dale Umetsu, MD, PhD, professor of pediatrics. Umetsu conducted the study with Rosemarie DeKruyff, PhD, professor of pediatrics, and Omid Akbari, PhD, a postdoctoral fellow in allergy and immunology. "Once we understand the mechanisms that induce immune responses that protect against asthma, we may be able to design therapies for asthma based on our findings."

When a person inhales antigens - foreign substances that produce an immune response - the immune system's job is to discriminate between those that are harmful (such as, bacteria or viruses) and those that are not (dust-mite allergen or pollen). Typically when the immune system encounters an innocuous allergen, it recognizes the substance as harmless. Certain immune cells, known as suppressor or regulatory cells, are thought to take charge and ensure that the immune system tolerates the substance and does not issue an attack, but little is known about how this happens.

When harmful antigens enter the respiratory system, however, immune cells called antigen-presenting cells or dendritic cells recognize them as dangerous intruders and "flag" them for the rest of the immune system to see. The dendritic cells then switch on other immune cells, which enlist cytokines -- proteins that tell other cells what to do -- to coordinate an attack against the invaders. Depending on the type of foreign substance the immune cells are fighting, this attack triggers a type of response called a Th1 response or a Th2 response.

Asthma is caused when the immune system responds inappropriately to an innocent substance. When an asthma sufferer is exposed to an innocuous allergen - dust-mite allergen, for example - the immune system launches a Th2 response, an attack normally launched to fight certain bacteria or parasitic worms that enter the body. The ensuing battle causes inflammation and excess mucous production in the airways, making it difficult for the sufferer to breathe.

To gain a better understanding of how the immune systems of asthma sufferers go awry, Umetsu and his team closely examined how the immune system normally responds to harmless substances. In their studies, the scientists aimed to define the mechanisms of what is referred to as immune tolerance and to detail the role that dendritic cells play in the process.

"While we know that dendritic cells in the lung can switch on the immune system, the role of dendritic cells in regulating the immune system has been poorly understood," said Umetsu. "People have suggested ways in which the cells might be involved in this process, but no one has actually shown it until now."

To model the events that occur when an asthma sufferer inhales a harmless allergen, the researchers exposed a number of mice to an egg allergen known as ovalbumin, or OVA. Within 24 hours of exposure to the allergen, dendritic cells migrated to the lymph nodes and induced the production of certain regulatory cells, as well as a specific type of cytokine called IL-10. The regulatory cells and IL-10 then worked to ensure that the innocent substance wasn't attacked.

The researchers did not find these so-called tolerogenic dendritic cells in mice that weren't exposed to OVA or in mice that were developing asthma. But they found that when dendritic cells from OVA-exposed mice were isolated and transferred into other mice, the recipients became tolerant to the allergen. Umetsu said this indicates the important role of dendritic cells in helping to suppress the immune system.

"Our paper shows that the role of dendritic cells in the lung is complex," said Akbari. "The cells not only switch on the immune system in many parts of the body but also conduct regulatory activity when necessary. In both cases, the dendritic cells stimulate immune cells - but in different ways."

By displaying the critical role of dendritic cells in maintaining immune tolerance to certain antigens, the study points to the possibility that defective dendritic cells may contribute to asthma. If dendritic cells can't produce IL-10, for example, the word might not get out that the foreign visitor is friendly, and the immune system might launch an unwarranted attack.

The team's next steps are to explore this possibility and more closely examine the regulatory cells. Umetsu said this research may be applied to other areas of immunology because these types of cells could be involved in other processes, such as autoimmune diseases like diabetes or multiple sclerosis. The work could also ultimately lead to the

development of new therapies for asthmatic sufferers.

"What we would like to do in the future is trick the immune system to induce these protective, suppressive immune responses," Umetsu said. "While current therapies focus on keeping symptoms away, this type of therapy could eventually cure patients."