World Immunology & Vaccines Congress
World Immunology & Vaccines Congress
La Jolla Institute for Immunology
USA
INSTITUTION AND LOCATION |
DEGREE (if applicable)
|
Completion Date MM/YYYY
|
FIELD OF STUDY
|
University
of Tokyo, Faculty of Medicine |
M.D. |
03/1978 |
Medicine |
University
of Tokyo, Faculty of Medicine |
Ph.D. |
12/1983 |
Molecular
Biology |
National
Cancer Institute, NIH |
Postdoctoral |
03/1988 |
Oncogene
Research |
A.
Personal Statement
I have been studying FceRI-mediated mast
cell biology and signal transduction for the last 25 years. During this period,
I have acquired all necessary expertise for the advanced study of IgE, FceRI signaling,
mast cell biology, and allergy disease models. My laboratory has been supported
by NIH and institutional/foundations fundings since 1990. Our papers have been published
by Nature Immunology, Nature Reviews
Immunology, Immunity, Cancer Cell, Journal of Experimental Medicine, Journal of
Clinical Investigation, Journal of Allergy and Clinical Immunology, PNAS, Cell
Reports, Journal of Immunology, Journal of Biological Chemistry, Trends in
Immunology, Current Opinion in Immunology, etc. as research breakthroughs
and led to invited talks at a Major Symposium at an AAI meeting, AAAA&I,
FASEB and Aegean conferences as well as platform presentations at other
national and international meetings. I served as an Associate Editor and a
Section Editor for the Journal of
Immunology and as a board member of several research journals, and as a
reviewer for many major research journals. In addition, I recently edited a
Frontiers Special Topic for Frontiers in
Immunology (the official journal of the International Union of
Immunological Societies) and a Special Series issue for the Open Allergy Journal. I also organized the FASEB Conference “IgE and Allergy, 50 Years
& Onward” earlier this year (July 24-29, 2016) to celebrate the 50th
anniversary of the discovery of IgE by gathering more than 110 allergy
researchers. I am an elected member of Collegium Internationale Allergologicum.
As a Co-PI of a T32 Training grant together with David Broide, UC San Diego, I
hosted the monthly journal club meeting at the La Jolla Institute for Allergy
and Immunology. In addition to the NIH Study Sections and other NIH review
panels listed below, I have been serving as a reviewer of grants for Agency for Science, Technology and Research’s Biomedical
Research Council (Singapore), Arthritis National Research Foundation,
Asthma UK, British Lung Foundation, German-Israeli Foundation for Scientific
Research and Development, JAPAN Health Sciences Foundation, The Israel Science
Foundation, The Wellcome Trust, Deutsche Forschungsgemeinschaft, de l’Agence
Nationale de la Recherche (ANR) and Swedish Research Council. I also serve as a Consultant for The Japan Prize, The Science and
Technology Foundation of Japan and as a reviewer of research programs at the
Campus for Research Excellence and Technological Enterprise (CREATE) for the
National Research Foundation of Singapore.
In 2012, my group found that histamine-releasing factor (HRF) binds directly to about
25% of the tested monoclonal IgE and IgG molecules via their Fab region. We
also demonstrated that HRF inhibitors, which blocked HRF-Ig interactions, suppress
the mast cell- and IgE-dependent inflammation in multiple models of asthma and
food allergy. As HRF’s role in skin inflammation was
revealed in passive cutaneous anaphylaxis, it is highly likely that HRF plays a
similar critical role in causing atopic dermatitis, at least in a subset of the
patients. Separate from our HRF study, we established a highly efficient model
of atopic dermatitis using the dermatitis-prone mouse strain NC/Nga. As this
model dermatitis depends on high-affinity IgE receptors, FceRI, and is
sensitive to corticosteroids (e.g., dexamethasone), and HRF activates mast
cells and basophils via aggregation of IgE-bound FceRI, it should serve as an
ideal model in order to test efficacy of the HRF inhibitory peptides. To
highlight its utility, our murine model has been used to reveal the cellular
and molecular mechanisms by which atopic dermatitis patients are rendered
susceptible to severe viral infections as exemplified by eczema vaccinatum and
eczema herpeticum. During the course of our HRF study, we
have developed highly sensitive methods to quantify HRF-reactive IgE and
HRF-reactive IgG in human and mouse blood, which will allow us to extend our
mouse study to human applications smoothly in the future.
B. Positions
and Honors
Professional Experience:
1981-1984 Assist.
Prof., Dept. of Physiological Chem. and Nutrition, Faculty of Medicine, Univ.
of Tokyo
1984-1987 Visiting
Fellow, Lab. of Cell. and Mol. Biol., National Cancer Institute (NCI),
Bethesda, MD
1987-1987 Visiting Associate, Lab. of
Cell. and Mol. Biol., NCI, Bethesda, MD
1987-1988 Visiting Associate, Lab. of
Cell. Develop. and Oncology, NIDR/NIH, Bethesda, MD
1988-1990 Assist. Professor, Dept. of
Med. Chem., Faculty of Medicine, Kyoto University
1990-1994 Assist. Member, La Jolla
Institute for Allergy and Immunology, La Jolla, CA
1994-2000 Associate Member, La Jolla
Institute for Allergy and Immunology, La Jolla, CA
2003-2009 Adjunct
Professor, Department of Medicine, University of California, San Diego, School
of Medicine, La Jolla, CA
2007-pres. Visiting
Professor, Chiba University, School of Medicine, Chiba, Japan
2000-pres. Professor, La Jolla Institute
for Allergy and Immunology, La Jolla, CA (Title of ‘Member’ was changed
to ‘Professor’ in 2011)
Professional Activities:
1991-pres. Member: American Association of Immunologists
1992-pres. Reviewer: Science, Nat. Immunol., Cancer Cell,
Immunity, J. Exp. Med., J Clin. Invest., PNAS
2002-2006 Associate Editor, Journal of Immunology
2004-pres. Elected Member, Collegium Internationale
Allergologicum
2008-pres. Editorial Board, The Open Autoimmunity Journal
2009-2013 Section Editor, Journal of Immunology
2011-pres. Editorial Board, World Journal of Immunology
2011-pres. Editorial Board, World Journal of Translational
Medicine
2011-pres. Guest Editor for The Open Allergy Journal
2011-pres. Guest Editor for Frontiers in Immunology
2015-pres. Medical-Scientific Council, Asthma and Allergy
Foundation of America
Recent Grant/Program Reviews (since 2006):
2006 Lung Cellular, Molecular, and
Immunobiology Study Section, NIH
2006-pres. Advisory Review Committee,
Arthritis National Research Foundation
2006 British Lung
Foundation
2007-2010 The Welcome Trust
2007 Immunology IRG Special Study Section ZRG1
HAI-K (08) F, NIH
2008 Hypersensitivity,
Autoimmune, and Immune-med. Diseases Study Section, NIH
2008 Agency for Science, Technology and
Research’s (A*STAR) Biomedical Research Council (BMRC) in Singapore
2008 Cellular and
Molecular Immunology-A (CMIA) Study Section, NIH
2010 Lung Cellular,
Molecular, and Immunobiology Study Section, NIH
2011 Cellular and
Molecular Immunology Study Section ZRG1 IMM-G (02), NIH
2011 Microbiology,
Immunology and Infection Panel, French National Research Agency
2012 National Medical
Research Council, Ministry of Health, Singapore
2013-2014 Deutsche
Forschungsgemeinschaft
2014 Allergy, Immunology,
and Transplantation Committee, NIAID/NIH
2014 Special Emphasis
Panel ZRG1 MOSS-T12, NIH
2015 Institute of Biomedical Sciences, Academia Sinica,
Taiwan
2015 Campus for Research Excellence and Technological
Enterprise (CREATE), National Research Foundation, Singapore
2015 de l’Agence Nationale de
la Recherche (ANR), France
2015 Special
Emphasis Panel ZRG1 MOSS-C02, NIH
2016 RFA-AR-16-001 Special Emphasis Panel/NIAMS-NIH
2016 Swedish
Research Council
2016 Special Emphasis
Panel/SRG 2017/01 ZAI1 JTS-I(J3) 1, NIAID/NIH (2016)
C. Contribution to Science
I have been interested in immunology and
cancer from the beginning of my scientific career. After molecular cloning of immunoglobulin m gene during the
course of the graduate school at The University of Tokyo (the mentor Tasuku
Honjo), I discovered a novel Src family protein-tyrosine kinase (PTK), Fyn,
during my postdoctoral stint (the mentor Stuart A. Aaronson) at the National
Institutes of Health. These findings led me to study the normal function of PTKs
and their networks in immunological settings.
1. We have been using the high-affinity IgE
receptor (FceRI) signaling in mast cells as a model system. Following our
co-discovery of two Tec family PTKs, Btk and Itk, in mast cells, we revealed
crucial roles of these kinases in FceRI-mediated activation and apoptosis. By
introducing retroviral transduction into the field of mast cell research, we
established a standard methodology to investigate the FceRI signaling
system.
1.
Yamada, N., Kawakami, Y., Kimura, H., Fukamachi, H., Baier, G., Altman,
A., Kato, T., Inagaki, Y., and Kawakami, T. Structure and expression of
novel protein-tyrosine kinases, Emb and Emt, in hematopoietic cells. Biochem. Biophys. Res. Comm.
192:231-240, 1993.
2.
Kawakami, Y., Yao, L., Miura, T., Tsukada, S., Witte, O. N., and Kawakami,
T. Tyrosine phosphorylation and activation of Bruton tyrosine kinase (Btk)
upon FceRI
cross-linking. Mol. Cell. Biol.
14:5108-5113, 1994.
3.
Kawakami, Y., Miura, T., Bissonnette, R., Hata, D., Khan, W. N.,
Kitamura, T., Maeda-Yamamoto, M., Hartman, S. E., Yao, L., Alt, F. W., and Kawakami,
T. Bruton’s tyrosine kinase regulates apoptosis and JNK/SAPK kinase
activity. Proc. Natl. Acad. Sci. USA
94:3938-3942, 1997.
4.
Hata, D., Kawakami, Y., Inagaki, N., Lantz, C. S., Kitamura, T., Khan,
W. N., Tashiro, M., Maeda-Yamamoto, M., Miura, T., Han, W., Hartman, S. E.,
Yao, L., Nagai, H., Goldfeld, A. E., Alt, F. W., Galli, S. J., Witte, O. N.,
and Kawakami, T. Involvement of Bruton’s tyrosine kinase in FceRI-dependent mast cell
degranulation and cytokine production. J.
Exp. Med. 187:1235-1247, 1998.
2. During the course of the above-mentioned
study, we found interactions between Btk and protein kinase C (PKC)-b and terreic
acid as a novel Btk inhibitor that blocked Btk-PKC-b interactions. Our study
also showed that PKC-b and Akt are essential for degranulation and cytokine production via
activation of several transcription factors. These studies established how
cytokine production is regulated by FceRI-stimulated mast cells.
1.
Yao, L., Kawakami, Y., and Kawakami, T. The pleckstrin homology
domain of Btk tyrosine kinase interacts with protein kinase C. Proc. Natl. Acad. Sci. USA
91:9175-9179, 1994
2.
Kitaura, J., Asai, K., Maeda-Yamamoto, M., Kawakami, Y., Kikkawa, U.,
and Kawakami, T. Akt-dependent cytokine production in mast cells. J. Exp. Med. 192:729-739, 2000.
3.
Kawakami, Y., Kitaura, J., Hartman, S. E., Lowell, C. A., Siraganian, R.
P., and Kawakami, T. Regulation of protein kinase CbI by two protein-tyrosine
kinases, Btk and Syk. Proc. Natl. Acad.
Sci. USA. 97:7423-7428, 2000.
4.
Kawakami, Y., Kitaura, J., Yao, L., McHenry, R. W., Kawakami, Y.,
Newton, A. C., Kang, S., Kato, R. M., Leitges, M., Rawlings, D. J., and Kawakami,
T. A Ras activation pathway dependent on Syk phosphorylation of protein
kinase C. Proc. Natl. Acad. Sci. USA. 100:9470-9475,
2003.
3. As our knowledge of the FceRI-mediated
signal transduction has grown for the last two decades, the need to study in
vivo roles of this pathway in disease settings encouraged us to develop novel
in vivo models of allergic diseases. We devised a novel procedure to induce
atopic dermatitis (AD)-like skin lesions in mice using a house dust mite
extract and staphylococcal enterotoxin B. This model allowed us to show that mast
cells and T cells, but not B cells or eosinophils, are required for the full
expression of dermatitis. Its application to develop a model to study the
susceptibility of AD patients to vaccinia virus revealed the weakened ability
of NK cells to control this virus in AD-bearing mice, which recapitulates eczema
vaccinatum, a complication sometimes seen in severe cases of human AD. This
model was also useful to develop or confirm the efficacy of certain compounds
and monoclonal anti-viral antibodies to fight against eczema vaccinatum.
1.
Kawakami, Y., Yumoto, K., and Kawakami, T.
An improved mouse model of atopic dermatitis and suppression of skin lesions
by an inhibitor of Tec family kinases. Allergol.
International 56: 403-409, 2007.
2. Kawakami,
Y., Tomimori, Y., Yumoto, K., Hasegawa, S., Ando, T., Tagaya, Y., Crotty, S.,
and Kawakami, T. 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. 206:1219-1225, 2009.
3.
Tomimori, Y., Kawakami, Y., McCausland, M.M., Ando, T., Koriazova, L.,
Kato, S., Kawakami, T., and Crotty, S. Protective murine and human
monoclonal antibodies against eczema vaccinatum. Antivir. Ther. 16:67-75, 2011.
4.
Kawakami, Y., Ando, T., Lee, J.-R., Kim, G,
Kawakami, Y., Nakasaki, T., Nakasaki, M., Matsumoto, K., Choi, Y.S., and Kawakami,
T. Defective NK cell activity in a mouse model of eczema herpeticum. J. Allergy Clin. Immunol. I
http://dx.doi.org/10.1016/j.jaci.2016.06.034
4. Given our previous studies on crosstalks
between PTKs-dependent and G protein-coupled receptor-dependent signals in FceRI-stimulated
mast cells, we have been characterizing phospholipase C (PLC)-b isoforms. In
addition to its role in an early FceRI signal transduction, we found that
deficiency in PLC-b3 results in myeloproliferative neoplasm (MPN) and AD. We
demonstrated that a novel multi-molecular complex, SPS complex, that contains
SHP-1 (SH2 domain-containing protein phosphatase 1), PLC-b3 and Stat5,
regulates Stat5 activity. Increased Stat5 activity due to the loss of PLC-b3 was crucial
for the leukemogenesis of MPN as well as the development of AD. This mechanism
seems important in the
pathogenesis of Burkitt’s lymphoma, chronic lymphocytic leukemia, and human AD.
1. Xiao, W., Hong, H., Kawakami, Y.,
Kato, Y., Wu, D., Yasudo, H., Kimura, A., Kubagawa, H., Bertoli, L. F., Davis,
R. S., Chau, L. A., Madrenas. J., Hsia, C. C., Xenocostas. A., Kipps, T. J.,
Hennighausen, L., Iwama, A., Nakauchi, H., and Kawakami, T. Tumor
suppression by phospholipase C-b3 via SHP-1-mediated dephosphorylation of Stat5. Cancer Cell 16: 161-171, 2009.
2.
Xiao, W., Ando, T., Wang, H., Kawakami, Y., and Kawakami,
T. Lyn- and PLC-b3-dependent regulation of SHP-1
phosphorylation controls Stat5 activity and myelomonocytic leukemia-like
disease. Blood 116:6003-6013, 2010.
3. Xiao,
W., Kashiwakura, J., Hong, H., Yasudo, H., Ando, T., Maeda-Yamamoto, M., Wu,
D., Kawakami, Y., and Kawakami, T. Phospholipase C-b3 regulates FceRI-mediated mast
cell activation by recruiting the protein phosphatase SHP-1. Immunity 34:893-904, 2011.
4.
Ando, T., Xiao, W., Gao, P., Namiranian, S., Matsumoto, K., Tomimori,
Y., Hong, H., Yamashita, H., Kimura, M., Kashiwakura, J., Hata, T.R., Izuhara,
K., Gurish, M.F., Roers, A., Rafaels, N.M., Barnes, K.C., Jamora, C., Kawakami,
Y., and Kawakami, T. Critical role for mast-cell Stat5 activity in skin
inflammation. Cell Reports
6:366-376, 2014.
5. Since our finding of ‘monomeric IgE
effects’ on mast cell survival in 2001, we have shown that IgEs exhibit a
tremendous heterogeneity in their ability to induce mast cell activation, with
highly cytokinergic (HC) IgEs at one end of the spectrum and poorly
cytokinergic (PC) IgEs at the other: HC IgEs can induce strong survival
promotion, degranulation, cytokine production, and migration very efficiently,
whereas PC IgEs do so inefficiently. Intrigued by a similar dichotomy for the
requirement of a certain type of IgE to prime basophils and mast cells in
response to histamine releasing factor (HRF), a cytokine-like factor secreted into
body fluids during allergic reactions, we recently found that a subset (~25%) of IgE and
IgG molecules directly interact with HRF. HRF-reactive IgE together with HRF
could activate mast cells in vitro. By mapping the binding sites on both HRF
and IgE/IgG molecules, we developed competitive inhibitors of HRF-IgE (or IgG)
interactions, which inhibited IgE+HRF-induced mast cell activation. Using these
inhibitors, we could show that HRF promotes allergic inflammation in in vivo mouse
models of passive cutaneous anaphylaxis and asthma. Thus, our study discovered
the long sought receptors for HRF and enabled us to investigate the role of HRF
in allergic diseases and potential utility of HRF inhibitors as therapeutics.
Based on these studies, our current proposal will establish HRF inhibitors as efficacious
means to prevent and treat food allergy.
1.
Asai, K., Kitaura, J., Kawakami, Y., Yamagata, N, Tsai, M., Carbone, D.
P., Liu, F. –T., Galli, S. J., and Kawakami, T. Regulation of mast cell
survival by IgE. Immunity
14:791-800, 2001.
2.
Kitaura, J., Song, J., Tsai, M., Asai, K., Maeda-Yamamoto, M., Mocsai,
A., Kawakami, Y., Liu, F. -T., Lowell, C. A., Barisas, B. G., Galli, S. J., and
Kawakami, T. Highly or poorly cytokinergic IgE molecules mediate a
spectrum of effects on mast cell survival and activation. Proc. Natl. Acad. Sci. USA 100:12911-12916, 2003.
3.
Kitaura, J., Kinoshita, T., Matsumoto, M., Chung, S., Kawakami, Y.,
Leitges, M., Wu, D., Lowell, C. L., and Kawakami, T. IgE- and
IgE+Ag-mediated mast cell migration in an autocrine/paracrine fashion. Blood 105: 3222-3229, 2005.
4.
Kashiwakura, J.*, Ando, T.*, Matsumoto, K., Kimura,
M., Zajonc, D.M., Ozeki, T., Siraganian, R.P., Broide, D., Kawakami, Y., and Kawakami,
T. Histamine-releasing factor has a proinflammatory role in mouse models
of asthma and allergy. J.
Clin. Invest. 122:218-228, 2012. (*equal
contributions)
Complete
List of Published Work in My Bibliography:
D. Research Support
Ongoing Research Support
R01 AR064418-01A1 PI:
T. Kawakami 04/01/14-03/31/19
Mast cell
Stat5-regulatory pathway in atopic dermatitis
Major goals: 1) To
investigate the role of the mast cell Stat5-regulatory pathway in skin
inflammation. 2) To investigate the regulation of the Th2 cytokines (mast
cells)-periostin (fibroblasts)-TSLP (keratinocytes) vicious cycle by SPS
components. 3) To
investigate the role of PLC-b3 and other SPS
components in human mast cell biology.
R01 HL124283-01 PI:
T. Kawakami 08/01/14-05/31/18
Interaction of
histamine-releasing factor with immunoglobulins in asthma
Major goals: 1)
To identify the molecular signature of HRF-reactive IgE and IgG molecules. 2)
To analyze structural details of HRF-Ig interactions at the atomic level. 3) To evaluate the role of HRF in
asthma models with abundant HRF-Ig interactions. 4) To study HRF-related
molecules.
R21 AI 115534-01 PI:
T. Kawakami 12/01/2014-11/30/2016
Anaphylaxis and IgE heterogeneity
Major
goals: 1) To analyze the paired IgE heavy and light chain sequences in IgE+
B cells to find
distinct
structural features in IgE molecules between severely and mildly anaphylactic
mice. 2) To investigate their abilities to exhibit highly cytokinergic vs. poorly
cytokinergic property, to bind HRF, and to induce food allergy.
R41AI124734-01 PI: T. Kawakami
& T. Maruyama 08/01/2016-07/31/2017
Blockade
of histamine-releasing factor as a new prophylactic and therapeutic strategy
for food allergy
Major
goals: 1) To optimize HRF-inhibitory peptides as an
anti-food allergy drug. 2) To investigate the mechanisms by which HRF
inhibitors suppress food allergy.
Institutional
Funds
01/01/17-12/31/17 La
Jolla Institute for Allergy and Immunology
The amount,
which is determined annually on a per need basis, represents Institutional
support form the Scientific Director for a one-year term to the Principal
Investigator in his capacity as a Professor of the Division of Cell Biology.
These funds support research activities and other costs of operating the
Division that are not covered by outside grants sources.