Dr. Mark Boothby, left, and Dr. James Sheller discuss the findings. (photo by Dana Johnson)
Asthma trigger studied
It starts as a tightening in the chest. Soon every breath is a wheezing, rumbling effort. A feeling of panic grows with each exhalation: will the next breath come? Millions of people in this country face the daily struggle of living with allergic asthma, never sure when an attack will occur or exactly why.
For the second year in a row, investigators at Vanderbilt University Medical Center are recipients of a $750,000 three-year grant recognizing especially novel approaches to asthma research.
This year’s award from the Sandler Program for Asthma Research goes to Dr. Mark Boothby and his colleagues for their proposal to explore the role of pathogens and immunologic memory in asthma. Identifying a causal link between viral exposure and allergic asthma could lead to therapeutic countermeasures for those racked by periodic asthma flares.
In supporting basic research, the goal of the private foundation is to develop new investigative pathways from disciplines outside the traditional asthma field. Risk and innovation in experimental approach are encouraged. Last year, Dr. L. Jackson Roberts II, professor of Pharmacology and Medicine, and colleagues received the award for their research on the role of isoprostanes and oxidant stress in asthma.
“It is tremendous that Vanderbilt has been recognized again in only the second year of this program, a tribute to long-term investments made by the leadership of our institution,” said Boothby, associate professor of Microbiology and Immunology and assistant professor of Medicine. “We are excited and honored to be included in such esteemed company.”
Respiratory viral infection is the most common cause of allergic asthma flares in adults. But this is an unexpected response, Boothby said, from an immunological point of view. Viral inflammation and allergic inflammation are characterized by distinctly different profiles of immune cells and signaling proteins. To have a virus trigger the cascade of events normally seen in an allergic reaction is perplexing.
Also paradoxical, viral induction of adult asthma runs counter to the so-called “hygiene hypothesis” – an epidemiological correlation between a higher frequency of microbial infections in youth and a lower incidence of immune-related disease, such as asthma, in adulthood.
Boothby speculates that immunologic memory – the ability of our immune system to remember exposure to certain microbes – might hold the key to explaining the conundrum.
One function of the white blood cells called T-lymphocytes is to recognize and combat antigenic invaders, such as cat dander. These allergen-specific immune cells can expand into memory T-cell populations capable of mounting a rapid defense upon re-exposure to that antigen, even if significant time has passed. From his knowledge of cell survival and immunity, Boothby suspects that these memory T-cell populations might be complicit in allergic asthma, specifically the asthma flares triggered by respiratory viruses.
“There are ways such an allergic response could be explained without the participation of memory T-cells,” he said, “but on the other hand, it just ‘smells’ like memory.”
Some 20 percent to 30 percent of the T-lymphocytes in humans – and in mice – are “programmed” to respond to two different antigens. The researchers will investigate the consequences that would result if such dual specificity T-cells were responsive to both a viral pathogen, such as the influenza virus, and a common allergen, such as ragweed. Under these circumstances, exposure to the flu virus might result in the same allergic asthma response normally elicited by ragweed exposure. The asthma flare would, in essence, be induced by mistake.
Conversely, these dual specificity cells could have a protective effect, which would lend support to the hygiene hypothesis. In this case, repeated exposure to a viral pathogen in childhood might create a large enough population of these dual-receptor cells that, later in life, an encounter with the allergen could generate a viral T-cell response capable of blocking infection.
Another question to be explored, Boothby said, is whether viral infection influences the survival of cells within the memory subset. That is, for example, whether simply having the flu at the time of ragweed exposure would make the survival of allergy-provoking T-cells more efficient.
The subsets of T-cells that develop after antigen exposure, and the signaling proteins released by each, are critical in the genesis of allergic inflammation. Specific aspects of this acute inflammatory reaction are typically the targets of interest for pharmaceutical companies, but it remains to be seen whether this approach to drug design will work.
“Since you don’t diagnose a patient with asthma until they develop full-fledged disease, designing a drug to intervene at the initial development of disease might not be prudent,” Boothby said. “Administering that drug to a patient beyond the acute phase could be useless.”
The preferable idea, in his mind, would be to block some aspect of the allergic response farther downstream, perhaps targeting memory T-cells. An ideal result of these studies, he said, would be to identify what signaling or transcription factors are critical to the survival of memory T-cell subsets. A drug designed to interrupt signaling would preferentially eliminate such cells in an asthma patient, reducing the incidence of flares.
Through collaborative efforts with the medical and clinical departments – in particular the work of Dr. Mark Aronica, a medical fellow in the Allergy/Pulmonary and Critical Care division – Boothby’s lab developed an animal model specific for the study of immunologic memory in asthma. Their work builds on the model of allergic lung disease developed by Dr. James R. Sheller, associate professor of Medicine.
Sheller, a co-investigator on the grant, indicated that the importance of the work to the field of asthma research is unmistakable. “Discovering how memory T-lymphocytes contribute to allergic diseases would be a major advance in our understanding,” he said.
Dr. Ana Mora, research instructor in Microbiology and Immunology, is also a collaborator on the project. This year 11 award recipients were chosen from 147 applications. For more information about the Sandler Program for Asthma Research, visit the Web site at www.sandlerresearch.org.