Fearing asthma episodes triggered by the notorious Beijing pollution, some athletes withdrew from events at the 2008 Summer Olympic Games, while others planned recovery therapies to protect their lungs from damage. As Chinese government officials temporarily closed factories and restricted traffic to decrease the particulates that can trigger asthma episodes, Mayo Clinic researchers were working on more permanent solutions for the huge health burden that asthma creates. Mayo immunologist Hirohito Kita, M.D., who directs the clinic's Allergic Diseases Research Laboratory, has produced eight symptom-free weeks for an asthma mouse model by administering an antibody recently identified as a potential cancer treatment. And husband and wife research team Y.S. Prakash, M.D., Ph.D., and Christina Pabelick, M.D., are anesthesiologists and physiologists who probe the cellular mechanisms in airway smooth muscle that trigger asthma episodes.

Cancer research meets immunology of asthma

During his pediatric residency in Japan, two of Dr. Kita's most memorable patients were a young girl who was highly allergic to eggs and a teenage boy who was not responding well to asthma therapies. These young patients increased his motivation to study the body's immunological responses to the environment.

In 1988, Dr. Kita began a Mayo postdoctoral fellowship in immunology. He quickly assimilated and embraced the Clinic's collaborative research environment. After returning home, he found the Japanese research culture no longer suited his temperament and he decided to seek a faculty position back at Mayo. More than once, his research has been aided by the unplanned encounters common to Mayo's collaboration-rich culture.

"All you have to do is walk outside your office," says Dr. Kita. "And when you run into other researchers and clinicians, just ask what they are doing."

That was the case four years ago when he ran into Larry Pease, Ph.D., co-director of Mayo's Cancer Immunology and Immunotherapy Program. Dr. Pease excitedly described his work on the B7-DC antibody. B7 is a family of naturally occurring molecules found on cells that activate T-cells (immune cells). DC stands for dendritic cell, a branching cell that affixes to tumor surfaces. The B7-DC antibody binds to B7-DC to stimulate it. Dr. Pease's research demonstrated a method that used the B7-DC antibody to prevent tumor growth (Cancer Research July, 2004).

"Larry's observations suggested that the immune system might respond to autoimmune and allergic diseases in a similar fashion to how it responds to cancer or cancer therapies," explains Dr. Kita. "But maybe it works in different ways."

In immunological diseases such as asthma, the patient's immune system overreacts to the environment, which Dr. Kita suspected could be similar to the overactive cell growth response in cancer. He knew that to induce cancer immunity, you need to activate certain types of T-cells. He hypothesized that the cancer T-cell response might have a corresponding but opposing effect on overactive immune responses.

"It's almost like opposite sides of a coin," says Dr. Kita, describing how he came to his hypothesis. "We call a cancer patient's response to this immunotherapy the ‘T-Helper 1 (Th-1) response.' But there are two types of responses, the Th-1 (good for cancer patients) and the Th-2 (bad for patients with immunological or autoimmune diseases). For good health, there should be a balance between Th-1 and Th-2."

The B7-DC antibody seems to be key to regulating the response. Then Dr. Kita wondered, "what if you could manipulate an asthma patient's Th-1 and Th-2 balance using the antibody? Would that inhibit the overactive immune response to our environment?"

Dr. Kita collaborated with Dr. Pease on studies that showed B7-DC blocked inflammatory airway disease in experimental animals (Journal of Allergy and Clinical Immunology, 2005 with follow up studies in the European Journal of Immunology, 2008). Because the antibody is currently being administered in clinical trials to patients with melanoma, there is already evidence about how B7-DC affects humans. The knowledge derived from the human studies will speed up the potential delivery of the B7-DC antibody as a novel treatment for asthma patients worldwide. "Clinical trials could begin within three years," says Dr. Kita.

Airway Smooth Muscle Remodeling

At home, Drs. Prakash and Pabelick work side-by-side in their spectacular flower and vegetable gardens. At Mayo, they also work side-by-side harvesting knowledge from their cell physiology labs. This dynamic research team met 10 years ago while studying calcium regulation in the laboratory of physiologist Gary Sieck, Ph.D. Their collaboration with Dr. Sieck, a world-renowned expert on airway smooth muscle, continues to this day. Drs. Prakash and Pabelick focus on advancing our understanding of how factors such as gender, and proteins such as caveolins and neurotrophins affect the airway smooth muscle tissue's physiologic responses to asthma. The scientists are also anesthesitists—a fact that Dr. Prakash says led him to be more interested in airway smooth muscle research.

"Classically, asthma is a wheezing disease," says Dr. Prakash. "When an attack is triggered by environmental irritants such as the industrial pollutants (as in Beijing), airway smooth muscle tissues constrict the bronchial openings — narrowing them to protect the body from inhaling potentially harmful substances."

Just as muscle tissue increases as an athlete trains, the bronchial airway smooth muscle walls thicken with asthma-induced episodes of constriction and relaxation, narrowing the bronchial walls and further restricting air exchange, which causes the wheezing sound. Not a good condition for anyone, much less an Olympic athlete. Scientists call this thickening of the muscle "remodeling." The more it occurs, the harder it is to treat asthma. So Drs. Prakash and Pabelick are looking for new ways to prevent excessive remodeling.

Calcium: It does more than build bones

Calcium is one of the most evolutionarily ancient cellular "signaling" molecules. Without it, no muscle can contract, including bronchial airway smooth muscle. If cells have too much calcium, they contract too much, signal incorrectly and create inappropriate responses to stimulation—such as in the over-reactive asthmatic airway smooth muscle.

Dr. Pabelick's research has found that one potential factor in normal vs. abnormal calcium signaling is the presence of caveolae, pit-like "scaffolding" structures within cell membranes. Caveolae contain many types of molecules that respond to triggers such as histamines and other factors that make smooth muscles contract. Dr. Pabelick and her team have found that airway smooth muscle inflammation (as occurs in asthma) leads to higher levels of caveolae and their corresponding proteins known as caveolins.

Preliminary data demonstrate that if airway tissue doesn't have as many caveolae or caveolins, there is less calcium within cells, which diminishes the airway inflammatory response and reduces the "remodeling effect." Dr. Pabelick hypothesizes that caveolae or their proteins could be altered, leading to a possible therapy for asthma patients.

Women and Asthma

Dr. Prakash's lab is conducting preliminary investigations to learn how and why men and women differ in the incidence and severity of asthma. They are focusing on the role of sex hormones such as estrogen and progesterone. With little previous clinical research data on asthma in women, this new basic research could be ground breaking.

"We know women are protected from coronary artery disease prior to the onset of menopause," says Dr. Prakash. "But some epidemiological data on asthma suggests that with puberty asthma increases in girls, oral contraceptives may worsen symptoms, and post-menopausal women may have less asthma. On the other hand, women with asthma may get better when they are pregnant. So much more research is needed to understand the role of sex hormones in asthma."

The lab is exploring how estrogens and progesterone affect the response of smooth muscle cells to inflammation. Their goal is to find out whether sex hormones will make things better or worse. Their findings have the potential to determine the risks and benefits of using estrogen replacement therapy and other similar approaches to address asthma in women at puberty, during pregnancy and with menopause.

Manipulating growth factors

A third project has the husband and wife team investigating how neurotrophins, agents that were previously thought to promote growth and development in the nervous system, turn on mechanisms in airway smooth muscle.

Dr. Prakash learned about neurotrophins while studying for his Ph.D. under Dr. Sieck in the early nineties. "At that time, we thought neurotrophins were working their magic just in the brain and spinal cord. We now know that neurotrophins are present in places we didn't previously expect them to be," says Dr. Prakash.

They have identified two neurotrophins located in airway smooth muscle—brain-derived neurotrophic factor (BDNF) and neurotrophin-3. The presence of BDNF may worsen an immune response by enhancing contraction of airway smooth muscle. On the other hand, the neurotrophin-3 tends to "dumb down" responses, explains Dr. Prakash. Establishing whether the neurotrophins originate from immune cells or from the smooth muscle itself, and understanding their role in the lungs and the mechanisms that control them, will allow the team to target these novel mechanisms. Their goal, then, will be to develop a therapeutic tool to prevent airway smooth muscle remodeling and airway hyperreactivity.

Asthma is a complex, common and pernicious disease. Mayo Clinic researchers are working toward bringing novel treatments and potential cures to asthma patients all over the world. Prevent the remodeling, stop the overactive immune responses to our environment, disable the disease—that is the hope of Mayo's asthma researchers.

—Kelly DeBrine, September 2008