Allergies and Asthma: The Value of Tolerence

BY KRISTA CONGER

WINTER 2003 - Imagine a simple pill that could banish your allergies, asthma, or eczema -- forever. Rates of these diseases are skyrocketing, and inhalers and peanutbutter bans are common at grade schools nationwide. So what's going on? Recent research by Dale Umetsu, M.D., Ph.D., professor of pediatrics, has provided a few important clues.

Umetsu, chief of the Division of Allergy and Immunology, studies the immune cells that mediate the body's interaction with the outside world. Sometimes -- when the invaders are dangerous bacteria or viruses -- vigorous immune responses are necessary. But when the immune cells respond inappropriately to harmless particles, they can cause annoying or life-threatening allergic reactions and asthma.

Lexie Destefano holds the battery of medications she has taken to control her asthma. The 10-year-old is a patient of Dale Umetsu, M.D., Ph.D., who is searching for a way to prevent or possibly cure asthma by studying the molecular process underlying the immune system's tolerence of antigens.

"Normally when your body sees foreign, innocuous proteins in the food that you eat or in the air that you breathe, your immune system will recognize that they are not dangerous, and refrain from attacking. This normal immune response to innocuous antigens is called tolerance," says Umetsu. "But allergic and asthmatic individuals start to attack the allergens."

Lack of tolerance, leading to rising rates of allergy and asthma, seems to have a curious cause: too much cleanliness. Increased sanitation during the past 50 years may have robbed the immune system of valuable experience with infections that help it learn to tolerate innocuous antigens rather than responding with a full-blown attack.

However, it has not been clear if some infectious agents are better than others at inducing tolerance.

Umetsu's recent research, done with Rosemarie DeKruyff, Ph.D., professor of pediatrics, places the spotlight squarely on the hepatitis A virus, which usually causes a one-time, flu-like illness. Prior to 1950 nearly everyone in this country had been infected; now it's relatively rare.

The researchers found that the hepatitis A virus somehow tones down or eliminates the allergy-causing immune cells by binding to a newly identified protein on the cells' surface, called TIM-1. People previously infected with hepatitis A virus who also have a particular form of TIM-1 are protected against allergies and asthma. About 60 percent of people have the protective form of TIM-1.

The researchers' discovery links a very specific infection with protection against allergies and asthma, and is the first molecular link between environmental factors and genes involved in the development of these diseases. They are now exploring whether this protective effect can be conferred by vaccination with a killed version of the virus, or by administering a drug that mimics the virus. Such treatment might one day prevent or even cure allergies and asthma.

Dale Umetsu, M.D., PhD., chief of the Division of Allergy and Immunology (right), with Omid Akbari, Ph.D., senior research scientist in pediatric allergy and clinical immunology.

Umetsu is also trying other ways to relieve his patients' symptoms. Currently, tolerance to allergens can be induced with injections of increasing amounts of antigen, but the multiple-year process requires more than 100 shots. He's testing whether administering the allergens in a pill form could work much faster.

"We're learning about how tolerance develops in some people, and how it fails to develop in others who then become allergic," says Umetsu. "Many people start out with eczema associated with food allergies, which they may outgrow only to develop hay fever. About half of these children with allergies will go on to develop asthma. If we could interfere with this process early and increase the development of tolerance, we could help and possibly cure many of these patients with asthma and allergies."