Department of Immunobiology
Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences
Okayama University

Japanese


Research Projects

Mast cells are distributed through the entire body. Previous studies have demonstrated the roles of mast cells as an important effector cell in allergic responses and intestinal parasite infection. However, accumulating evidence suggests that mast cells can modulate a variety of immune responses, such as autoiimunity, immune tolerance, tumor immunity, chronic inflammmation, and so on. Mast cells can respond to a variety of stimuli, which cover from acquired immnity (IgE) to neuronal regulation (NGF, substance P etc.), and can release a wide variety of immune and inflammatory mediators (histamine, prostanoids, leukotrienes, neutral proteases, cytokines, and chemokines). It is fascinating to determine when and how mast cells are activated and participate in immune reactions.

 

1. Modulation of Immune Responses by Mast Cells

Mast cells originate in hematopietic stem cells in the bone marrow. Since no cells that exhibit the characteristics of mast cells are found in the blood, it is assumed that mast cells should undergo their terminal differentiation in the tissues where they ultimately reside. This means that mast cells can be characterized by their variety; mast cells distributed in different tissues possess different phenotypes. We focus on the process of mast cell maturation in the tissues and investigate its meachanism. The information that we will obtain will contribute to understanding the role of mast cells in modulation of immune responses, which is one of the hot topic in today's immunology.

We recently established a murine culture method to develop mature mast cells that can mimic the dermal mast cells by modifying the previous method (Takano, H. et al. FEBS Lett. 2008). In addition, we identified a series of genes, of which expression levels are significantly changed during maturation, through microarray analyses. Our purpose in this project is to determine the roles of these genes in mast cell maturation.

(left) Mast cell maturation in vitro

Bone marrow-derived cultured mast cells were co-cultured with a fibroblastic cell line in the presence of stem cell factor. At Day-16, greater than 80% of the cells were found to be Safranin-O staining positive mature mast cells. Drastic increase in granule protease activities and compound 48/80-induced degranulation were also confirmed in this system.

CD44, which is known as a dominant receptor for hyaluronate, was found in the cluster of genes that is up-regulated during mast cell maturation. We demonstrataed that CD44 is involved in regulation of mast cell number in murine cutaneous tissues (Takano, H. et al. Lab. Invest. 2009).

2. Mast Cell Activation by Monomeric IgE

"Monomeric IgE response" means that mast cells can be activated by IgE in the absence of its antigen. Two studies demonstrated this response for the first time in 2001. We reported that monomeric IgE drastically induces histamine synthesis in bone marrow-derived cultured mast cells (Tanaka, S. et al. J. Exp. Med. 2002). Extremely high concentrations of IgE in the blood are often observed in patients with chronic allergy. "Monomeric IgE response" may give an adequate explanation to the problem why high concentrations of IgE should deteriorate the chronic allergy diseases. Our purpose in this project is to determine the molecular mechanism of this response and to find chemicals that regulate this process.

Refs: Tanaka, S. et al. Eur. J. Immunol. 2005, Liu, Y. et al. J. Biol. Chem. 2005

3. Regulation of Immune Responses by Histamine

Histamine has a long histroy as an immune modulator. A series of recent studies revealed that histamine can potentiate Th1 responses by acting on the H1 receptor expressed in Th1 cells and can suppress Th1/Th2 responses by acting on the H2 receptors dominantly expressed in Th2 cells. Modulatory roles of histamine were also demonstrated in cytokine production from macrophages and dendritic cell migration. Furthermore, a novel histamine receptor subtype, H4 receptor, was recently identified. The H4 receptor is expressed in eosinophils and mast cells and is involved in histamine-induced chemotaxis. Immune modulation by histamine should be revisited.

Ref: Furuta, K. et al. J. Biol. Chem. 2007

by Satoshi Tanaka, Ph.D