PITTSBURGH, June 29, 2015 - The immune response that occurs in patients with severe asthma is markedly different than what occurs in milder forms of the lung condition, according to researchers from the University of Pittsburgh School of Medicine. Those unique features could point the way to new treatments, they said in an article published online today in the Journal of Clinical Investigation (JCI).
People with severe asthma, in which the airways become inflamed and constrict to impair breathing, do not get better even with high doses of corticosteroids, the mainstay of treatment for typical asthma, explained Anuradha Ray, Ph.D., professor of medicine, Pitt School of Medicine.
"About 10 percent of asthma patients have a severe form of the disease, but they account for up to half of asthma costs in the U.S. and Europe," Dr. Ray said. "That's because these patients frequently need to go to the emergency room or be hospitalized when they have an acute asthma episode."
For the study, conducted as part of the doctoral thesis of Mahesh Raundhal, a graduate student in the laboratory of Prabir Ray, Ph.D., Pitt professor of medicine and co-senior author, the research team examined lung cell samples obtained from patients also participating in the Severe Asthma Research Program (SARP), a National Heart, Lung, and Blood Institute of the National Institutes of Health-sponsored program to improve the understanding of severe asthma. Sally Wenzel, M.D., director of the University of Pittsburgh Asthma Institute of UPMC, serves as the Pitt SARP principal investigator.
Researchers observed that the immune cells, called CD4 T-cells, in the airways of severe asthmatics secreted different inflammatory proteins than those in mild disease, particularly interferon gamma. The analysis of human samples helped them to develop a mouse model of the disease by introducing an allergen and a bacterial product to induce an immune profile and airway hyper-reactivity that were poorly controlled by corticosteroids, comparable to human severe asthma patients.
When they subjected mice that lacked the interferon gamma gene to the severe asthma model, they found that the mice could not be induced to develop severe asthma. Using computer modeling to identify links between interferon gamma and asthma-associated genes, they learned that as interferon gamma levels rose, the levels of a protein called secretory leukocyte protease inhibitor (SLPI) dropped.
In follow-up experiments, the team found that boosting SLPI levels reduced airway hyper-reactivity in the animal model.
"We'd like to better understand why severe asthma occurs in most people right from the start," Dr. Anuradha Ray said. "We also want to find agents that can raise SLPI levels for clinical use."
In a new project that began this month, Drs. Anuradha Ray and Wenzel were recently awarded a five-year, $8 million grant from the National Institute of Allergy and Infectious Diseases (NIAID), also part of the National Institutes of Health (NIH), to continue studying the immune response and genetic roots of severe asthma in 120 patients and in animal models.
The research effort signifies a union of Pitt and UPMC scientists, immunologists and clinicians working under the NIAID grant to bring bench to bedside and bedside to bench, Dr. Wenzel said.
"It's the unmet need of asthma," Dr. Wenzel said. "This is one of the first true opportunities to integrate top-tier immunologists with translational clinical science. To find the many different mechanisms involved, you need a team effort such as this one."
In addition to Drs. Wenzel and Anuradha Ray, the project leaders of this grant are core leaders Timothy B. Oriss, Ph.D., of the University of Pittsburgh, and Jay Kolls, M.D., of Children's Hospital of Pittsburgh of UPMC, who also co-authored the JCI paper. Other members of the research team are Prabir Ray, Ph.D., and Fernando Holguin, M.D., Douglas Landsittel, Ph.D., and Donald DeFranco, Ph.D., all of Pitt.
The published project was funded by NIH grants HL113956, Al106684, AI048927, AI100012, HL69174, HL079142, and DK072506; as well as the Cystic Fibrosis Foundation Research Development Program.
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