My general research focus is the study of mast cells in the elicitation of allergic inflammation. We've also tried to carry this concept into other model systems and ask questions about what mast cells do in a global sense in inflammation. We've contributed a fair number of observations over the years about factors and conditions that regulate mast cell growth and differentiation.

We now know that mast cells arise from pluripotential stem cells and mature and survive under normal conditions only within tissues. Mast cells are also particularly numerous in the skin and gastrointestinal tract and have specific tissue distributions such as along nerves and blood vessels. There they survive for weeks to months. The usual association between allergic diseases and mast cells depends upon the mast cell's ability to bind IgE through the high-affinity IgE receptor. IgE, if it recognizes environmental proteins like ragweed, arms the mast cell to react to the environmental stimulus. So when a person is re-exposed to ragweed, these cells then release and generate a number of substances that induce an inflammatory response.

This laboratory has studied mast cells in this context. We've also asked whether mast cells have a role in other types of inflammation. In the last two years we've been working on a high-affinity IgG receptor that appears to allow mast cells to be armed in other inflammatory situations. For example, mast cells in psoriatic skin appear to express this high-affinity receptor.

This interest in mast cells led us to study mastocytosis in children and adults some 20 years ago, and these studies have continued through the present. Mastocytosis is a rare disease associated with a pathologic increase in mast cells in tissues such as the skin, lymph nodes, liver, spleen, and bone marrow. We've reported the pathology, participated in the classification of disease subsets, and have explored therapeutic options.

In 1995 in a paper in PNAS we first reported that cells obtained from patients with mastocytosis exhibited an activating mutation in Kit, the receptor for stem cell factor, the principal mast cell growth factor. From there, and in collaboration with other research groups, we reported other similar mutations and the association of these mutations with patterns of disease. Such studies are not only of value to the understanding of mastocytosis, but give insight into how mast cells impact the biology of other pathologic situations including allergic diseases.

  How did you become interested in your area of research?

I became interested in allergic diseases when I was a medical student. There was then far less known about the mechanisms of allergic inflammation, and treatment strategies were far less advanced. During my fellowship years I became interested in mast cells as principal effector cells in allergic diseases.

  What were some of the greatest challenges in performing your work?

At the time I began to study mast cells, culture systems were in their infancy. Early on the real challenge was simply trying to obtain mast cells for study. One common approach was to separate mast cells from other cells in lavage fluids from the rat peritoneal cavity. The breakthrough in developing approaches to study mast cells in vitro followed the discovery of IL-3 and stem cell factor that allowed the culture of mouse and human mast cells from bone marrow.

  How rapidly has the state of knowledge about your field evolved in the past decade, and what were the key discoveries that furthered the advancement of the field?

There's been a progressive evolution in the understanding of the biologic role of mast cells over the last 30 years. However, the pace of this evolution accelerated in the last decade with the application of improved culture techniques and the application of the modern tools of molecular biology. Key discoveries include the description of mast cell growth factors, documentation that mast cells are derived from CD 34+ pluripotential stem cells, recognition of the expression of key adhesion molecules on mast cells, description of mast cell apoptosis, discovery of the leukotrienes, and the recognition that mast cells produce cytokines.

  What is the implication of your work for the future of your field or neighboring fields?

One of the outcomes of this work is that we are close to, if not at, the point of understanding, what regulates mast cell number; and we could, if we chose, manipulate mast cell numbers to treat specific human diseases. We similarly have a much better understanding of the receptors that mediate mast cell function. The potential role of mast cells in non-allergic disorders, possibly recruited through the expression of the high-affinity IgG receptor, deserves further attention.

  What is your prediction for the state of knowledge in your field 10 years from now?

We now have the ability to examine the expression of thousands of genes at a time expressed by mast cells after mast cells are exposed to specific stimuli in vitro or examined in diseased tissues. This will generate a wealth of information leading to an understanding of how mast cells respond and, by inference, their biological roles. Manipulation of genes within mice will add further insight into how mast cells contribute to innate and acquired immunity. New molecules will become available to alter specific mast cell responses through targeting the interruption of specific signaling pathways.

  What advice would you give to those entering a research career?

Select an area of research and stick with it. Become a recognized expert. And evolve your approaches and the questions you ask in the context of current thought and with application of newer technologies.

  What would you like the general public to understand about your work?

This laboratory has focused on the mast cell as a critical effector cell in inflammation. The resulting research has contributed to an increased understanding of the mechanisms of allergic inflammation and to mastocytosis. In turn this information has played a role in the development of novel approaches to the treatment of inflammatory diseases.

Dean D. Metcalfe, M.D.
National Institute of Allergy and Infectious Disease
Bethesda, Maryland, USA