Aug. 25, 2005 Virginia Commonwealth University immunologists studying mast cells, known to play a central role in asthma and allergic disease, have identified a hormone-like molecule that can kill these cells by programming them to die in studies with mice.
The findings move researchers another step closer to understanding the life cycle of mast cells, and may help researchers develop new treatments for allergy and inflammatory responses in arthritis, multiple sclerosis and heart disease.
In the Journal of Immunology, published online Aug. 23, researchers demonstrated the means by which a cytokine called interferon gamma (IFNy) induces death of developing mast cells in a mouse model system. Although IFNy induced cell death in developing mast cells, it did not affect the survival of mast cells that had already undergone differentiation.
“We believe that cytokines, such as interferon gamma, are an important means of controlling mast cell function in the body,” said John J. Ryan, Ph.D., associate professor of biology at VCU and lead author of the study. “Because mast cells cause inflammation, regulating how many mast cells the body makes, where they go, what they do, and when they die can have a huge impact on health and disease.
“For example, there has been one report of a patient with mastocytosis, which is a type of pre-leukemia where mast cells proliferate abnormally, that showed improvement with IFNy treatment,” he said. “It is possible that other mast cell-related diseases, such as asthma, may respond to IFNy treatment.”
According to Ryan, mast cells are packed with granules containing histamine and are present in nearly all tissues except blood. When mast cells are activated, inflammatory substances such as histamine, heparin and a number of cytokines are rapidly released into the tissues and blood, promoting an allergic reaction.
Mast cells are believed to be generated by different precursor cells in the bone marrow. In the in vitro portion of the study, researchers used mouse bone marrow cells containing the stem cells that give rise to mast cells. They cultured these precursor cells in conditions that allow mast cells to develop, and then added IFNy to some of these cultures. A high rate of cell death yielding no living mast cells was observed in the cultures that received IFNy.
Similar results were reported in vivo using a mouse model. Mice with a mutation that causes them to overproduce IFNy were used, and again, researchers observed a significant decrease in mast cell numbers due to the excess of IFNy. When researchers tried to culture mast cells from the bone marrow of these mice, the mast cells died.
Furthermore, a separate strain of mice with the same mutation as the first strain, but that had also been engineered to prevent IFNy production, were found to have almost as many mast cells as normal mice, if not more. They concluded that the presence of high IFNy levels blocked mast cell development.
This research was supported by a grant from the National Institutes of Health.
Ryan collaborated with colleagues in the VCU Department of Biology, and the Department of Biochemistry at St. Jude Children’s Research Hospital in Memphis, Tenn.
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