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kawakami.jpgToshiaki Kawakami, M.D., Ph.D., and his team study signal transduction in the immune and hematopoietic systems. The laboratory has been studying mainly mast cells, an important cell type found in mucosal as well as connective tissues that is responsible for the allergic reactions that trigger itching, wheezing, and sneezing. These symptoms of allergic reactions occur after mast cells are activated.

When exposed to allergens (substances, such as pollen, that cause allergies), IgE-bound mast cells are activated and secrete numerous chemical, lipid, nucleotide, peptide, and protein mediators. These mediators, together with other immune cells, are believed to orchestrate complex cellular and molecular interactions to induce allergic reactions. Increasing numbers of signaling molecules are shown to be important for mast cell activation. Dr. Kawakami and his colleagues focus on dissecting the complex network of signaling molecules, particularly those involved in the early phase of mast cell activation.

Conventional belief was that IgE-mediated mast cell activation requires multivalent allergen or antigen to induce mast cell activation. However, in 2001 Dr. Kawakami and his colleagues found that IgE can induce mast activation without the involvement of allergen or antigen. They later showed a vast heterogeneity in IgE molecules in their ability to induce this IgE effect (so-called "monomeric IgE effect"): some IgEs can induce all kinds of activation events, but others can do so very inefficiently. Currently, they are trying to understand how these fundamental observations can be translated in allergic diseases.

Principles of signaling mechanisms in mast cells are shared not only by other immune and hematopoietic cells but also more distantly related cells. Abnormalities in signaling networks can lead to many types of disorders including cancer, autoimmune diseases, and immunodeficiencies. Microbes often hijack such intricate networks for their advantage. Therefore, Dr. Kawakami's team sometimes ends up studying cancer and virus infection, even when their original interest is in allergy research. An interesting extension of their study is an establishment of a mouse model of atopic dermatitis and a subsequent use of that model to study eczema vaccinatum. Eczema vaccinatum is a serious infection with vaccinia virus often experienced when patients with atopic dermatitis are vaccinated against smallpox. Another exciting finding is a recent identification of a novel tumor suppressor that was originally supposed to play an important role in mast cell activation. They hope their study of signaling molecules may lead to an increased understanding of these diseases and contribute to new preventive measures, diagnostics, and treatments.

 

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