Mayo Clinic researchers have used a comparative genomic strategy to demonstrate a causative link between eosinophils, a rare type of white blood cell, and asthma.
Their research shows that the presence of these unique blood cells is absolutely required for the development of asthma. The details of this animal-based study appear in the Sept. 17, 2004, issue of Science, the journal of the American Association for the Advancement of Science (AAAS).
For more than a century, scientists have known that eosinophils are often the dominant inflammatory cells present in the lungs of asthma patients, but the importance of these white blood cells has been poorly understood with some studies even discounting a role for these cells. This new study demonstrates that eosinophils are required for the mucus accumulation and the lung dysfunction associated with asthma.
Using the tools of genomics, Mayo Clinic researchers have engineered a mouse that is specifically devoid of eosinophils, but otherwise has a full complement of blood-derived cells. Disease symptoms in these transgenic mice were dramatically reduced, and in some cases completely eliminated, following exposure to an allergen that in normal animals leads to asthma.
The development of a unique and novel transgenic mouse model without eosinophils now permits a definitive assessment of a number of human diseases besides asthma that have been linked to this white blood cell, including allergic diseases, parasite infections and cancer.
"Demonstrating that the eosinophil, a rare and often ignored cell, is a central mediator in the inflammation associated with asthma is a very important finding," says James J. Lee, Ph.D., director, Special Animal Services Laboratory at Mayo Clinic in Scottsdale, Ariz. "The outcomes of this study suggest the possibility of developing novel therapies and pharmaceuticals to treat and/or prevent asthma."
Researchers at Mayo Clinic Scottsdale created genetically-engineered transgenic mice that selectively express a toxic "suicide" gene, diphtheria toxin A, in bone marrow stem cells that go on to become circulating eosinophils in the blood. As a result of the selective expression of this toxin, unique marrow stem cells are eliminated and eosinophils never appear in circulation. The resulting mice have a normal complement of all red and white blood cell types except they are uniquely devoid of eosinophils.
Lung disease studies were conducted by comparing the responses of these transgenic mice without eosinophils relative to normal animals that contain eosinophils following exposure to an airborne allergen that provoked symptoms characteristic of asthma.
This study clearly shows that eosinophil activities are important contributing factors leading to symptoms classically defined as hallmark features of asthma. Future medical genomics studies will seek to confirm these findings in asthma patients and to further define the role of eosinophils in human disease, thereby widening the understanding of the principle causes of asthma and leading to targeted therapeutic approaches previously dismissed or overlooked. Because no known human patients or naturally occurring mutations in the mouse have been reported to be deficient of eosinophils without other additional consequences, this transgenic mouse model represents an important opportunity to define unambiguously the specific role of eosinophils in many diseases.
In addition to Dr. James J. Lee, others involved in the research include Dawn Dimina; MiMi P. Macias, PhD; Sergei I. Ochkur, PhD; Michael P. McGarry, PhD; Katie R. O'Neill, PhD; Cheryl Protheroe; Ralph Pero; Thanh Nguyen, M.D.; Stephania A. Cormier, PhD; Elizabeth Lenkiewicz; Dana Colbert; Lisa Rinaldi; Steven J. Ackerman, PhD; Charles G. Irvin, PhD; and Nancy A. Lee, PhD.
The research was supported by grants from the Mayo Foundation, the American Heart Association, and the National Institutes of Health.