New Cellular Pathway Triggering Allergic Asthma Response Identified

With molecular target found comes possibility of new therapies for millions of Americans —

Researchers at the University of California, San Diego School of Medicine, with collaborators in Korea and Scotland, have identified a novel signaling pathway critical to the immune response of cells associated with the initiation of allergic asthma. The discovery, they say, could point the way to new therapies that suppress the inflammatory allergic response, offering potential relief to millions of Americans with the chronic lung condition and potentially other allergic diseases.

The results are published in the January 19 online Early Edition of the Proceedings of the National Academy of Sciences. . … Read the full story from the UC San Diego Newsroom


Dr. Eyal Raz

Dr. Eyal Raz

Principal investigator of the study is Eyal Raz, MD, professor of medicine in the Division of Rheumatology, Allergy and Immunology, whose research focuses on the fundamentals of innate immunity.

First author of the report is Jihyung Lee, PhD, a postdoctoral fellow in the Raz lab.

Coauthors include David H. Broide, MB, ChB, professor of medicine and director of the division’s National Institute of Allergy and Infectious Diseases-funded T32 training program in molecular and cell biology of allergy; Paul Insel, MD, professor of pharmacology and medicine; Maripat Corr, MD, professor of medicine; project scientist Jongdae Lee, PhD; all in the Division of Rheumatology, Allergy and Immunology; and Nicholas Webster, PhD, professor of medicine and chief of the UC San Diego Division of Endocrinology and Metabolism.

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Election to AAP Recognizes Distinguished Career of Dr. David H. Broide

David H. Broide, M.B., Ch.B., joined an elite group of physicians from around the world when he was inducted into the prestigious Association of American Physicians (AAP) in April, 2008.

A deeply respected clinician and physician scientist, Dr. Broide is Professor of Medicine and Director of the Research Training Program in the Section of Allergy/Immunology in the Division of Rheumatology, Allergy & Immunology at UC San Diego.

He is one of only 55 physicians elected to the AAP this year.

Dr. Broide devotes his patient care and his research to the treatment of asthma and allergic disorders. In his laboratory, he studies airway remodeling, which is the slow and irreversible damage that asthma produces in the bronchial tubes of a subset of asthmatics.

“Finding new therapies is our goal,” Dr. Broide says.

He seeks to discover precisely what causes the airway damage and how it can be stopped.

The causes are complex, but there is hope for new treatments

Severe asthma affects approximately 5-10% of individuals who have the disease, but it accounts for about half of the healthcare costs of asthma, which total $8 billion a year in the U.S.

Patients who have the severe form of asthma live with frequent emergency room visits and hospitalizations, the need for a variety of medications, and the loss of productivity that comes with a serious chronic illness.

Approximately 4,000 to 5,000 individuals die from asthma each year in the U.S.

Dr. Broide says the causes of asthma are complex and are not fully understood.  “Asthma,” he says, “is an example of a disease that has both a genetic as well as an environmental contribution.

“Over 100 genes have been linked to asthma, and probably more haven’t been discovered.”

No single gene has been found to be responsible for more than about 5% of the cases of asthma.

In the genetics of asthma, Dr. Broide looks for new treatment possibilities

Because so many gene products are involved in causing asthma, it has not been effective to treat it by targeting individual genes. An alternative strategy is to identify and block the “master genes” that regulate groups of other genes.

One such master gene, NF-ΚB, controls many genes that are important to asthma. It’s therefore a potential therapeutic target. If a compound can block NF-ΚB in the bronchial tubes, it could potentially be effective in treating asthma.

One of Dr. Broide’s chief collaborators in this effort is Michael Karin, Ph.D., Professor of Pharmacology in the Laboratory of Gene Regulation and Signal Transduction at UC San Diego. Dr. Karin is an authority on NF-ΚB.

Targeting a master gene in asthma: early results are promising

In a study with Dr. Karin, Dr. Broide and his laboratory found that inactivating NF-ΚB in the epithelial cells lining the interior of the bronchial tubes of mice results in a significant improvement in airway remodeling and other features of airway remodeling induced by long-term exposure to inhaled allergens.

The study was published in the Proceedings of the National Academic of Sciences in 2006. |  Read the article (free full text)

Recent discoveries uncover new treatment possibilities

“The field of immunology and asthma is full of opportunities for new discoveries,” Dr. Broide says. “It’s an exciting time to be in the field, which is changing very rapidly.

“We have a lot of interesting molecular advances in the field that will provide an opportunity to devise new therapies and better treat our patients.”

One such molecular advance is the study of Toll like receptor-9 (TLR-9) vaccines in allergy. Activation of TLR-9 receptors inhibits allergic responses in mouse models of allergy and asthma.

In an NIH-sponsored Immune Tolerance Network study, Dr. Broide in collaboration with Dr. Peter S. Creticos at Johns Hopkins University demonstrated that a TLR-9 vaccine significantly improved symptoms of sinus allergies in patients with ragweed allergy.

The study was published in the New England Journal of Medicine in 2006.  |  Read the article (free full text)

As this was a small pilot study, Dr. Broide says, further large-scale studies are needed to determine the effectiveness and safety of this approach.

Inspired to find better treatments for asthma sufferers

Dr. Broide is originally from South Africa, where he received his M.D. from the University of Cape Town and completed his internship at Groote Schuur Hospital in Cape Town.

During his internal medicine residency training at the Peter Bent Brigham Hospital in Boston, he became inspired to work in the field of asthma and immunology. From asthma and allergy specialists he learned of the hope that could be offered to the majority of asthma sufferers, and of the need to develop better treatments for those who have severe disease.

Dr. Broide came to UC San Diego for his Allergy and Immunology fellowship training in 1984. He joined the faculty in 1987.

He has received many academic and scientific honors. He has been named one of the Best Doctors in America each year since 1998.  From 2000 to 2005, he was on the Board of Directors of the American Board of Allergy and Immunology. He is currently Associate Editor of the Journal of Allergy and Clinical Immunology.

Dr. Broide directs an NIH training grant that supports physician-scientists in translational research in allergy and immunology

Dr. Broide is principal investigator of several NIH grants, including a MERIT award that provides research support for up to 10 years to NIH-funded researchers whose research is highly meritorious.

He is also principal investigator of an NIH-sponsored Asthma and Allergic Disease Center at UC San Diego. The center focuses on improving our understanding and therapy of airway remodeling in asthma.

Dr. Broide also directs an NIH T32 training grant that supports physician-scientists in translational research in allergy and immunology. Translational research is a high priority in the UC San Diego Department of Medicine.

Physician-scientists supported by this NIH training grant include Allergy/Immunology fellows Dr. Taylor Doherty and Dr. Chavi Gandhi, who are recent UC San Diego Internal Medicine chief residents.

“Physician-scientists are able to bring an important clinical perspective into their basic research studies,” Dr. Broide says.

The aim is to design laboratory studies in a way that leads to better diagnosis and treatment as quickly and safely as possible.

“In particular, we’re trying to help the 10% of severe asthmatics that don’t do that well on current asthma therapies,” Dr. Broide says. “That’s the challenge.”

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