Asthma

Current NIAID Research Highlights

• Asthma Counselors: Effort Make a Difference for Inner-City Kids
• Cats May Protect Against Asthma
• Cockroaches + Kids = Asthma
• Researcher Challenges Current Thinking
• Diesel Exhaust Aggravates Symptoms
• Specialized Cells May be Key to Chronic Asthma
• New Technique to Test Therapy Concept
• Understanding Regulatory DNA Could Lead to Three-in-One Drug

Asthma counselors are going to work in 23 community-based health organizations across the United States to improve the health of inner-city children with asthma. The counselors will be hired with $2.9 million provided by the Centers for Disease Control and Prevention (CDC). They will implement a treatment intervention developed and proven effective by NIAID-supported research. This research was carried out by the National Cooperative Inner-City Asthma Study, an NIAID effort launched in 1991 to find out why asthma disproportionately affects inner-city children and what can be done about it.

Asthma counselors are going to work in 23 community-based health organizations across the United States to improve the health of inner-city children with asthma.

The counselors will be hired with $2.9 million provided by the Centers for Disease Control and Prevention (CDC). They will implement a treatment intervention developed and proven effective by NIAID-supported research. This research was carried out by the National Cooperative Inner-City Asthma Study, an NIAID effort launched in 1991 to find out why asthma disproportionately affects inner-city children and what can be done about it.

Investigators studied the effects of making an asthma counselor available to about 1,000 inner-city children, aged 5 to 11 years old, with moderate-to-severe asthma. These counselors -- social workers trained in asthma management -- met regularly with the children and their families over the course of a year. The counselors educated children and families about the causes of asthma, facilitated interactions with physicians, and helped families take appropriate steps to alleviate asthma symptoms. For example, families of children allergic to cockroaches were taught how to control infestation. These efforts significantly reduced asthma symptoms and asthma-related hospital visits.

The full press release describing this effort, including a list of the 23 health centers that received grants from the CDC, can be found on the NIAID Web site at /news releases/asthmagrants.htm.

Contrary to popular belief, high levels of cat allergen in the home can sometimes decrease the risk of a child developing asthma, says grantee Thomas A. Platts-Mills, M.D., Ph.D., of the University of Virginia. Apparently, the presence of a cat can alter the immune system in a manner similar to allergy shots, he reports.

For other allergens that trigger asthma, such as the dust mite and cockroach, the higher the exposure level, the more likely it is that a child will produce "allergic" antibodies, called immunoglobulin-E or Ig-E antibodies, against them. This high exposure increases the child's risk of becoming allergic and developing asthma.

But with cats, high exposure actually can confer protection -- at least in some children, Dr. Platts-Mills says. He and colleagues measured the levels of allergic antibodies to cat allergen in 226 children, aged 12 to 14 years, and tested the children for asthma. They also measured the amount of cat allergen in the children's homes and discovered that low-to-moderate amounts of cat allergen seemed to trigger allergy, but high amounts -- greater than 20 micrograms per gram of house dust -- reduced both IgE antibodies and the likelihood of asthma.

"This result alters the advice we give patients," says Dr. Platts-Mills. "I would not recommend that all parents get rid of their cat because they are concerned their child might develop asthma. High exposure to cat allergen appears to be protective for some children and a risk factor for others. If the child is wheezing and has a positive skin test to cat allergen, then you should get rid of your cat."

The high levels of cat allergen prompted the children's immune systems to make mostly a particular subtype of immunoglobulin G (IgG), called IgG4 antibody, rather than IgE, Dr. Platts-Mills explains. Allergy shots are believed to produce a similar effect. "This research sheds more light on the relationship between allergen exposure and asthma," he says. "When we further understand this process, it might lead to new treatments for asthma."

Reference: T Platts-Mills et al. Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a populations-based cross-sectional study. The Lancet 357:752-56 (2001).

Researchers have known for some time about the connection between cockroach allergen and asthma, especially in inner-city children, but no one knows exactly how or why exposure to these insects leads to asthma. The work of grantee Diane Gold, M.D., of Brigham and Women's Hospital, and her colleagues gives us a closer look at this phenomenon.

Dr. Gold measured the level of cockroach allergen in the homes of 3-month-old infants born to parents with allergy and asthma. When these children reached about 2 years of age, many with high exposure had developed large numbers of immune system T cells that had learned to react specifically to cockroach allergen. Dr. Gold and her colleagues are now investigating whether these cockroach specific T cells are stimulating the airway inflammation seen in asthma.

Through questionnaires given to the parents, Dr. Gold also determined that children with high cockroach allergen levels in their homes wheezed more than other children during the first year of life, a sign that allergy or asthma might be developing. Moreover, their older siblings had a greater-than-usual incidence of asthma.

High exposure to cat and dust mite allergen, also connected with asthma, was not associated with early life wheezing or greater asthma incidence. One reason may be that dust mite allergen takes longer to affect the immune system, Dr. Gold says. In addition, some studies have shown that high levels of cat allergen can actually protect against asthma, she notes. (See "Cats May Protect Against Asthma.") Continuing this line of research should lead to a better understanding of both the risk factors and protective factors for asthma," she says.

Dr. Gold's group included children from diverse social and economic backgrounds in the Boston area, and she found that cockroach allergen affected them all the same. "Cockroaches don't respect social or economic boundaries," she says.

Reference: PW Finn et al. Children at risk for asthma: home allergen levels, lymphocyte proliferation, and wheeze. Journal of Allergy and Clinical Immunology 105 (5): 933-42 (2000).

Everybody's immune system reacts to the allergens that cause asthma, such as ragweed pollen, by producing antibodies against them. However, only a quarter of us produce the allergic antibodies that can lead to asthma; the rest of us somehow manage to suppress or avoid this allergic response, explains Andrea Keane-Myers, Ph.D., an NIAID researcher specializing in asthma and allergic diseases.

"Most scientists are focusing on what 'turns on' the allergic response, but a better question may be what turns it off in the majority of people," she says. "What are some of the 'stop signals' that prevent allergy? If we understood these, we could use that knowledge to make better treatments."

In order to find out, Dr. Keane-Myers observes genetic "double knockout" mice. These mice, which come in many varieties, lack the genes to produce any two of several cytokines. Cytokines are signaling molecules, secreted by immune system cells, that direct allergic reactions. Because cytokine function is often redundant, "the double knockouts allow you to see things you can't see in a single knockout where another cytokine compensates for the lost signal," she says.

So far, Dr. Keane-Myers knows at least one stop signal: She discovered that the cytokine interleukin-10, already known to control the numbers of Th1 cells that fight infection, similarly regulates the Th2 cells involved in allergy and asthma.

In addition, Dr. Keane-Myers is investigating how to turn on and off certain "inhibitory" receptor molecules on the surface of T cells and other immune system cells involved in asthma. Some of the receptors can stop these cells from activating, others prevent the cells from moving into the airways where they cause problems.

Diesel exhaust particles (DEPs) can worsen one's asthma symptoms, and the particles may contribute to the increased prevalence of the disease, according to grantee Andrew Saxon, M.D., of the University of California, Los Angeles. DEPs apparently help stimulate mast cells in the airway to release histamine, a chemical that causes inflammation, runny nose, and itching. Working with individuals allergic to dust mites, Dr. Saxon found that a combination of dust-mite allergen and DEPs administered nasally produced three times more histamine in the airway than dust mite allergen alone. In addition, he found that much smaller- than-usual amounts of allergen caused symptoms when combined with DEPs. By themselves, however, DEPs had no effect.

Diesel exhaust particles (DEPs) can worsen one's asthma symptoms, and the particles may contribute to the increased prevalence of the disease, according to grantee Andrew Saxon, M.D., of the University of California, Los Angeles.

DEPs apparently help stimulate mast cells in the airway to release histamine, a chemical that causes inflammation, runny nose, and itching. Working with individuals allergic to dust mites, Dr. Saxon found that a combination of dust-mite allergen and DEPs administered nasally produced three times more histamine in the airway than dust mite allergen alone. In addition, he found that much smaller- than-usual amounts of allergen caused symptoms when combined with DEPs. By themselves, however, DEPs had no effect.

"Asthma has increased since the industrial revolution, particularly in the last 20 years," says Dr. Saxon. "The cause can't be genetic -- humans haven't changed that much -- so it's likely the cause is environmental. Although there are certainly many environmental factors, we're examining diesel exhaust particles because they are all around -- about one-third of particles in the air are diesel."

The dosage of DEPs in the experiment, 0.3 milligrams, "is equivalent to the amount you'd get breathing the air for two days in Los Angeles or one day in Tokyo," Dr. Saxon says.

Previously, Dr. Saxon found that DEPs caused the immune system to make "allergic" antibodies to substances that normally would not trigger such a reaction, suggesting that DEPs may be involved in the early stages of allergic sensitization that lead to asthma. Dr. Saxon is currently looking for ways to block the effects of DEPs in the airway.

Reference: D Diaz-Sanchez et al. Diesel exhaust particles directly induce activated mast cells to degranulate and increase histamine levels and symptom severity. Journal of Allergy and Clinical Immunology 106 (6):1140-46 (2000).

Specialized defensive immune system cells called eosinophils have long been thought to cause the symptoms of late-stage asthma attacks by releasing toxins in the airway, but a new study shows these cells may play an even more fundamental role in allergy and asthma. A clearer understanding of how these cells work could lead to better asthma treatments.

Grantee Peter Weller, M.D., of Harvard Medical School's Beth Israel Deaconess Medical Center, and colleagues have shown that eosinophils may perpetuate the immune system's allergic reaction to certain substances, leading to chronic asthma. Dr. Weller discovered that eosinophils in the lungs also act as antigen-presenting cells (APCs). APCs are necessary to initiate and maintain an allergic reaction. They ingest foreign airborne substances, display bits of these substances on their surfaces, then come into contact with other defensive cells called T cells, stimulating the T cells to react to this substance. By constantly stimulating T cells to react to airborne particles, eosinophils may propagate asthma, Dr. Weller says.

Dr. Weller studied eosinophils in mice, so it is not certain his findings will hold true for humans. Should eosinophils play the same role in people, however, drugs that interrupt their activities could prove effective against chronic asthma, he says.

Reference: H Shi et al. Lymph node trafficking and antigen presentation by endobronchial eosinophils. Journal of Clinical Investigation 105(7): 945-53 (2000).

A strategy used to prevent rejection of transplanted organs might also help fight allergy and asthma, according to Calman Prussin, M.D. , head of the clinical allergy and immunology unit at NIAID.

Dr. Prussin and colleagues plan to test whether allergy shots will work better when combined with a tolerizing drug. Such drugs are currently used to make immune system cells non-reactive, or "tolerant," toward a transplanted organ. Achieving immune system tolerance toward the allergens that trigger allergy and asthma has been a major goal of Dr. Prussin's research. Dr. Prussin believes tolerizing drugs may increase the effectiveness of allergy shots by further curbing the immune system's inappropriate reaction to these harmless allergens.

Dr. Prussin can test this idea with a new laboratory technique he and his colleagues created. This technique, called intracellular cytokine staining (ICS), allows a much closer look than previously possible at immune system activity -- especially the system's response to various therapies. "It could be used to test the effect of a variety of new treatments," Dr. Prussin says.

ICS allows scientists to count the number of immune system T cells in a patient's blood sample that react to a specific allergen. This technique also determines cell type -- Th1 or Th2 -- more quickly and accurately than ever before. Th2 cells are known to play a major role in allergy and asthma. The information ICS provides helps researchers to gauge the effect of a particular therapy.

"I think we have a fairly good chance of proving this therapeutic concept," Dr. Prussin says, cautioning, however, that "much more effort would be necessary to produce a working drug."

Scientists have identified a snippet of DNA that regulates three key immune system substances involved in asthma, reports NIAID grantee Richard Locksley, M.D., an investigator at the University of California, San Francisco. Further understanding of how this regulatory DNA works could lead to drugs with a "three-in-one punch," lowering the amount of these substances in the airways and controlling asthma more effectively than do drugs that target only one substance.

The substances are called cytokines, Dr. Locksley explains. They are "messenger molecules" produced by the immune system's defensive white blood cells, particularly the Th2 cells involved in allergy and asthma. The cytokine interleukin-4 (IL-4) regulates the production of antibodies that help trigger asthma attacks. The cytokine IL-5 attracts cells called eosinophils to the airways. Eosinophils are believed to cause the tissue damage and symptoms of late-stage asthma. The third cytokine, IL-13, also regulates allergic antibodies.

Collaborating with Edward Rubin, M.D., Ph.D., of the University of California, Berkeley, Dr. Locksley determined that the section of DNA that regulates these cytokines lies on human chromosome 5q31. This is the same chromosome that contains the genes that make IL-4, IL-5, and IL-13. This regulatory DNA is not a gene. Rather, it is called a conserved non-coding sequence (CNS). Dr. Locksley speculates that this CNS works mechanically, causing the tightly packed and coiled DNA to change shape or "bend" in a way that triggers production of the cytokines. This shape change exposes the three cytokine genes to molecules that read their blueprint and trigger production of the cytokines.

"This CNS, designated CNS-1, is probably the most important regulator of these cytokines in Th2 cells," Dr. Locksley says. "It enhances the expression of the cytokine genes. If you take it out, you lose that effect." Dr. Locksley compared transgenic mice with CNS-1 to those that lacked it, and found that the Th2 cells of mice lacking CNS-1 made significantly less of all three cytokines.

The next step will be to understand more clearly how CNS-1 functions. Dr. Locksley speculates that another molecule may attach to CNS-1 and initiate a DNA shape change. Other signaling molecules are probably involved in the process, and any one of them might be a promising drug target, he says.

Reference: GG Loots et al. Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science 288 (5463): 136-140 (2000).