“Ten to 20 percent of the population of industrialized countries suffers from some form of allergies. There is a huge need to understand this disease and to find therapeutic interventions.” – Toshiaki Kawakami, M.D., Ph.D.

Dr. Kawakami has been with LIAI since 1988, joining originally as an Assistant and then Associate Professor in the Biochemistry Section of the Division of Immunobiology. Dr. Kawakami then became an Associate Professor in the Allergy Division in 1996 and in 2000 he became a full Professor. He is also an Adjunct Professor at the University of California, San Diego's Department of Medicine. Dr. Kawakami's research at LIAI focuses on signal transduction, especially in mast cells, which trigger allergic reactions.

Dr. Kawakami received his M.D. from the University of Tokyo in 1978 and his Ph.D. in 1983 in the field of Molecular Biology. While working towards his Ph.D., Dr. Kawakami acted as an Assistant Professor in the department of Physiological Chemistry and Nutrition at the University of Tokyo but in 1984 he began work as a visiting fellow at the National Cancer Institute in Bethesda, Maryland. In 1987, Dr. Kawakami spent a year in the Cell Development and Oncology lab at the National Institute of Dental Research, also in Bethesda, before returning to Kyoto in 1988 where he spent two years as an Assistant Professor in the Department of Medical Chemistry, Kyoto University, Faculty of Medicine.

Dr. Kawakami received the Fogarty International Fellowship in 1984 and is currently an Associate Editor for the Journal of Immunology, and a reviewer for numerous publications. He gave three plenary lectures in 1998 at the First Annual Meeting of Surface Barrier Research against Infection, The Third Annual Meeting on New Topics of Clinical Immunology and Allergy and at The Thirty Fifth Annual Meeting of the Japanese Society of Pediatric Allergy. In 2004 he was inducted as a Member of the Collegium Internationale Allergologicum.

Toshiaki 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.

Short stat5-interacting peptide derived from phospholipase C-β3 inhits hematopoietic cell proliferation and myeloid differentiation. PLoS ONE. 2011

IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe-/- mice. J Clin Invest. 2011

Phospholipase C-β3 regulates FcεRI-mediated mast cell activation by recruiting the proteinphosphatase SHP-1. Immunity. 2011

Monomeric IgE and mast cell development, survival and function. Adv Exp Med Biol. 2011

Protective murine and human monoclonal antibodies against eczema vaccinatum.
Antivir Ther. 2011

Lyn- and PLC-{beta}3-dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease. Blood. 2010

JNK1 controls mast cell degranulation and IL-1{beta}production in inflammatory arthritis.
P Natl Acad Sci USA. 2010

Tyrosine phosphorylation of SHIP promotes its proteasomal degradation. Exp Hematol. 2010

FcepsilonRI beta-chain ITAM amplifies P13K-signaling to ensure synergistic degranulation response via FcepsilonRI and adenosine receptors. Eur J Immunol. 2010

A minor catalytic activity of Src family kinases is sufficient for maximal activation of mast cells via the highaffinity IgE receptor. J Immunol. 2010

Mast cells in atopic dermatitis. Curr Opin Immunol. 2009

A crucial door to the mast cell mystery knocked in. J Immunol. 2009

Small, mobile FcepsilonRI receptor aggregates are signaling competent. Immunity. 2009

Polyclonal IgE induces mast cell survival and cytokine production. Allergol Int. 2009 

Tumor suppression by phospholipase C-beta3 via SHP-1-mediated dephosphorylation of Stat5. Cancer Cell. 2009 

Inhibition of NK cell activity by IL-17 allows vaccinia virus to induce severe skin lesions in a mouse model of eczema vaccinatum. J Exp Med. 2009 

Pivotal advance: IgE accelerates in vitro development of mast cells and modifies their phenotype. J Leukoc Biol. 2008

Regulation of myeloproliferation and M2 macrophage programming in mice by Lyn/Hck, SHIP, and Stat5. J Clin Invest. 2008

Human IgE+ and IgE- are not equivalent to mouse highly cytokinergic IgE. J Allergy Clin Immunol. 2008 

Basophils now enhance memory. Nat Immunol. 2008

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