Vol. 15 No. 2 (2010)

English pages

The 18th Annual Meeting of JSIT 2011
(Japanese Society of Immunotoxicology)

Report from the 17th Annual Meetingof the Japanese Societyof Immunotoxicology (JSIT2010)

September 8 - 9, 2011
KEYAKI-kaikan (University Hall), Chiba University

Hidekazu Fujimaki(Nishi-Chiba campus)(Research Center for Environmental Risk,

1-33 Yayoi-cho, Inage-ku Chiba, 263-8522 Japan

National Institute for Environmental Studies)

Theme: Crosstalk between clinical and experimental
immunotoxicology

The 17 Annual Meeting of the Japanese Society ofthImmunotoxicology (JSIT 2010) was held at Ohyama

・Invited Plenary Lecture:

Memorial Hall of National Institute for Environmental

Dr. Robin L. ThurmondStudies, Tsukuba during September 9-10, 2010. The(J & J Pharm R & D, L.L.C. Research Fellow)

theme of this meeting is
Susceptibility

Immunotoxicology and・Invited Special Lecture:
Prof. Chisato Mori.

(Depar tment of Bioenvironmental Medicine,
Graduate School of Medicine, Chiba University)

On the first day, Invited Plenar y Lecture Mast
cells and their regulation: Allergy, but so much more-

・Educational Lecture:

innate to adaptive immunity was given by Prof. A. D.

Dr. Nahoko Kaniwa

Befus, (Univ. of Alberta, CANADA). In main symposium:(Division of Medicinal Safety Science, NIHS)

Immunotoxicity and chemical susceptibility, we have・Symposium:

discussed determinants such as genetics, age, infection,

Dr. Reiko Teshimanutrition and chronic diseases of increased susceptibility(Division of Biochemistry and Immunochemistry,

to chemicals. Dr. Gar y R. Burleson (BRT-Burl eson

NIHS) and others

Research Technologies, Inc.) presented「Influenza viral・Workshop:
Oral ／ Poster presentationdisease: Dexamethasone and the role of age and genetics
on viral disease severity」as the exchange speaker from

Deadline for abstract submissions: June 27, 2011

SOT ImToxSS. Dr.Tetsurou Ishii (Tsukuba University)

Social gathering: September 8, 2011. 18:00 KEYAKI-

talked about「Responses of macrophages against

kaikan (3rd floor, Banquet room)oxidative stress-roles of transcription factor Nrf2 andPresident: Prof. Koichi Ueno

the induced proteins」.Dr. Naoki Kunugita (National

Department of Geriatric Pharmacology andInstitute of Public Health) presented「Effects of volatile

Therapeutics, Graduate School of Pharmaceuticalorganic compounds (VOCs) exposure on immunotoxicity

Sciences, Chiba University

in mice」.Dr. Takamichi Ichinose (Oita University of

Secretariat: Assoc. Prof. Katsunori Yamaura

Nursing and Health Sciences) presented「Yellow sandPhone: +81-43-226-2878

FAX: +81-43-226-2879

and allergy」. Finally, Dr. Reiko Teshima (National

e-mail: jsit18-office@umin.ac.jp

Institute of Health Sciences) talked about「Effect of

http://jsit18.umin.ne.jp (Open Jan. 2011)

chemicals like brominated flame retardants (BFRs) on
the development of the immune system in rodents」. As
a Special lecture, Prof. Kensuke Miyake (The Instituteto chemicals, infection and environmental pollutants.

of Medical Science, The University of Tokyo) presented

In addition, from the Special lecture, we got knowledge

Molecular mechanisms underlying pathogen sensing in

about microbial product-related molecular signaling not

the innate immune system

only induces innate immune response but also triggers. From this symposium, we

can learn the various factors play a role in susceptibility

adaptive immune response.

─ 13 ─

ImmunoTox LetterOn the second day, in the first time Student session,

A prize 年
for annual
convention
会 賞

four oral presentations were submitted by Seiko Takeda(Changes in expression pattern of human ß defensins inmouse tracheal epithelium induced by toluene exposure),

Particulates activate innate immune
systems and regulate type 2 immunity

Ning Ding (Enhancement of proliferation of splenocytes
induced by fullerene nanoparticles instillation), Kazuyuki

Etsushi Kuroda1 and Yasuo Morimoto2

Okamura (Mechanism of the suppression of lymphocyte（1Department of Immunology and Parasitology,

proliferation through an increase in p130 by inorganicand 2Department of Occupational Pneumology,

arsenic), and Masashi Asao (The mechanism for

University of Occupational and Environmental Health, Japan.）regulating the interleukin-6 in exposure to manganese).
As a Masters Lecture Dr. Jun-ichi Sawada (President

Introductionof JSIT) presented Allergenicity testing: current andfuture issues

Some particulates can stimulate the innate immune. In the Workshop, The latest move insystem to induce inflammatory responses. In particular,

the immunotoxicity studies: in silico, in vitro and in vivo

aluminum salts (referred to as alum) and silica

was discussed by the chairmen, Dr. Eiji Maki (former

crystals can induce type 2 inflammatory responses,

Biosafety Research Center, Foods, Drugs and Pesticides)

which are characterized by the elevation of antigen-and Dr. Yasuhide Kouchi (Taiho Pharmaceutical Co.

specific serum IgE and IgG1 levels in vivo. However,Ltd.）with six speakers and audience.「In silico

mechanism involved in the induction of type 2 immunity

prediction of immunogenicity: sense and non-sense」

has not been elucidated. Several reports have shownby Dr. Philippe Stas (Applied Protein Service, Lonza

that some particulates such as silica, asbestos andBiologics),「Current situation of in vitro testing on skinalum activate NALP3 inflammasome, which is one ofsensitization assay」by Dr. Hajime Kojima and (National

intracellular PPRs, and promote the secretion of theInstitute of Health Sciences),「The inter-laboratory KLH-

pro-inflammatory cytokines IL-1β and IL-18 by the

TDAR assay validation study (Study I)-investigation

action of caspase-1 (reference 1-3). In this study, wefor the experimental conditions-」by Dr. Kanako Morifound that some particulates induce macrophages (Mφ(Takeda Pharmaceutical Company Limited) and Dr.

s) to produce the lipid mediator prostaglandin (PG) via

Yasuhide Kouchi (Taiho Pharmaceutical Co. Ltd.),「TheNALP3 inflammasome-independent mechanisms and thatinter-laboratory KLH-TDAR assay validation study

the induction of PGE2 by particulates controls immune

II-investigation using an immunosuppressive agent-」by

response in vivo.

Dr. Ryota Kawai (Daiichi Sankyo Co., Ltd.,)and Dr. Yuko

Nagayama (Eisai Co., Ltd.,) were presented. From this

Methods

Workshop, we can learn interesting topics about method

We used 7~10 weeks old C57BL/6, BALB/c and severalof in vitro skin sensitization assay and parametersknock-out (mPGES-1, NALP3, ASC, caspase-1) mice.

reflecting immunotoxicity from speakers.

Thioglycollate-induced peritoneal Mφs and M-CSFinduced bone-marrow derived Mφs were used as Mφs

We have studied a various aspects of basic immunology

in this study. For in vitro study, Mφs were treated withand immunotoxicology from all delegates with their

1 ng/ml LPS for 2 hrs (priming) and then stimulated withexcellent presentation and discussion. Finally, we bid

crystalline silica, alum, nickel oxide, titanium dioxidea warm welcome to delegates not only from Japan, butor amorphous silica (20~50 µg/cm2) for 2~18 hrs. Afteralso from foreign countries to participate in this kindstimulation, cell-free supernatants were collected andof Conference to exchange our knowledge concerning

used for IL-1β and PGE2 ELISA. For in vivo study, mice

immunotoxicology globally. Then, we hope to meet again

were immunized twice (day 0 and 7) i.p. with 100 µg OVA

in next JSIT 2011 at Chiba.

plus 2 mg alum or 100 µg OVA plus 0.5 mg silica. Tendays after the last immunization, sera were collected andanalyzed for the OVA-specific IgE by ELISA.
─ 14 ─

Vol. 15 No. 2 (2010)

Results

immune responses in vivo. The studies presented herein

1. Silica induce IL-1β and PGE2 production in LPS-

suggest that manipulating particulates-induced cytokines

primed Mφs

and PGE2 production could open new possibilities for

Many reports have shown that alum, silica and asbestos

treating allergic inflammation, infectious diseases andstimulate Mφs to produce the caspase-1-dependent

cancer.

cytokines IL-1β and IL-18 by activating the NALP3
inflammasome (reference 1~3). We also found that

Acknowledgement

silica and alum induced LPS-primed Mφs to produce

We feel honored to be awarded a prize for annual

IL-1β and IL-18, which is in agreement with previous

convention. We also thank Dr. Ishii (National Institute ofreports. Interestingly, we found that these inflammasome

Biomedical Innovation), Dr. Akira and Dr. Uematsu (WPI

activators also induced LPS-primed Mφs to produce

Immunology Frontier Research Center, Osaka University)

PGE2. Titanium dioxide (TiO2), which does not cause

for their helpful collaboration.

severe inflammation on inhalational exposure, does not
activate the NALP3 inflammasome (reference 3). Worthy

Referencesof note was that TiO 2 did not induce IL-1β or PGE2

1. Dostert, C. et al. Innate immune activation throughproduction in LPS-primed Mφs.

Nalp3 inflammasome sensing of asbestos and silica.
Science 320, 674-677 (2008).

2. The inflammasome is not involved in silica-induced

2. Hornung, V. et al. Silica crystals and aluminum salts

PGE2 production in Mφs

activate the NALP3 inflammasome through phagosomal

To investigate whether the inflammasome is involved

destabilization. Nat Immunol 9, 847-856 (2008).

in silica-induced PGE2 production, we performed similar

3. Cassel, S. et al. The Nalp3 inflammasome is essential

experiments using NALP3-/-, ASC-/- and caspase-1-/- M

for the development of silicosis. Proc Natl Acad Sci U S

φs. Unexpectedly, the levels of PGE2 were comparable

A 105, 9035-9040 (2008).

between WT and inflammasome-deficient Mφs inresponse to silica and alum. These results indicate that

A prize
奨for encouragement
励 賞

silica and alum induce Mφs to produce PGE 2 throughinflammasome–independent mechanisms.

Effects of pesticides on IL-17 gene
expression via retinoid-related orphan
receptor α and γ

3. Silica-induced production of PGE2 by Mφs regulates
antigen-specific IgE production in vivo
Membrane-bound PGE synthase-1 (mPGES-1) plays
important role for PGE2 production in Mφs, because

Hiroyuki Kojima1, Shinji Takeuchi1,
Miki Takahashi2, Ryuta Muromoto2

mPGES-1-/- Mφs cannot produce PGE2 in response to（1Hokkaido Institute of Public Health, Sapporo, Japan,

silica and alum. Next we examined whether silica- and2alum-induced PGE2 production plays a role in regulating

Graduate School of Pharmaceutical Sciences,
Hokkaido University, Sapporo, Japan）

the immune responses in vivo. To this end, we immunized
mPGES-1+/+ and -/- mice with alum plus OVA or silica

Retinoid-related orphan receptor (ROR) is a key

plus OVA, and then analyzed for the levels of OVA-specificregulator of Th17 cell dif ferentiation in immune

IgE antibodies. Interestingly, mPGES-1-/- mice displayed

response. In this study, we characterized RORα/γ

reduced levels of OVA-specific IgE.

agonistic/inverse agonistic activity of a large numberof 200 pesticides, and investigated the effects of several

Discussion

pesticides showing ROR activity on IL-17 expression in

We found that particulates such as silica and alummouse T lymphoma EL4 cells. For detecting ROR activity

stimulated innate cells to produce PGE 2 via theamong 200 pesticides, the reporter gene assay using

inflammasome independent pathway and regulated type 2

Chinese hamster ovary cells, transiently transfected─ 15 ─

ImmunoTox Letterwith ROR expression plasmid as well as RORE-reporterシリーズ
Young powerfor immunotoxicological research「免疫毒性研究の若い力」8

plasmid was performed. As a result, we found that eightpesticides acted as RORα/γ inversed agonists at
concentrations in the order of 10-6-10-5 M. In addition,these pesticides were found to suppress IL-17 mRNA

Dysregulation of neuroimmune function byenvironmental pollutants

expression in EL4 cells treated with phorbor myristate

Tin Tin Win Shweacetate and ionomycin. Taken together, these results（National Institute for Environmental Studies）

suggest that several pesticides possess inhibitory effect of

In my mother land Myanmar, as I am a Medical

IL-17 expression via RORα/γ. This study also indicates

doctor and teaching staf f in Medical University, I

that our ROR-reporter gene assay is very suitable forhave experiences to teach and guide Medical, Dental

identifying effects of IL-17 production via RORα/γ inand Pharmacy students while doing clinical practice.

immune cells from a large number of chemicals.

Fortunately, I have an opportunity to study my Ph. D
course in Department of Physiology, Yokohama City
University Graduate School of Medicine. After the

シリ
Aーズ
prize
for excellent student「免疫毒性研究の若い力」8completion of my Ph. D course, in 2003, I joined to Project
studying the health effects of nanoparticles exposure asa Post-doctor Fellow in Environmental Health Sciences

Mechanism of the suppression oflymphocyte proliferation through anincrease in p130 by inorganic arsenic

Division, National Institute for Environmental Studies(NIES), Tsukuba. In 2006~2008, I was selected as a

Kazuyuki Okamura

Foreign researcher for JSPS Post-doctor Fellowship and(Graduate School of Life and Environmental Sciences,from 2008, I serve as a NIES Research Fellow in the same

University of Tsukuba)

Institute.

(Environmental Health Sciences Division, National

U p t o n o w, u s i n g b r a i n i n v i v o m i c r o d i a l y s i sInstitute for Environmental Studies)

technique, molecular gene expression assay andOne of the three molecules in the pocket protein

learning per formance test in a mouse model withfamily is p130. It is known to have an important role indifferent immunogenetic background, allergy, infection

restraining the G1-S transition or G0 exit through theand inflammation, I have reported the ef fects ofregulation of E2F-responsive genes. We investigatedexposure to toxic chemical toluene, carbon black

the mechanism of an arsenic-induced increase in p130

nanoparticles and diesel exhaust particles on brain

in the mouse A20 lymphoid cell line. We focused on theneurotransmitter level, memory function-related gene

cyclin dependent kinase inhibitors (CDKIs) and protein

expression, proinflammatory cytokine expression andphosphatases (PP1 and PP2A). The results of our studies

cognitive functions of mice in many Domestic andsuggest that the activity of PP1 is involved in the increase

International Conferences and International peer-review

of p130 by arsenic, however PP2A and CDKIs are not.

journals. Currently, I have been studying the effect oforganophosphate pesticide (diazinon) exposure during
developmental period on neuro-immune biomarkers andnovel object recognition in adult mice.
Recently, it has been increasing health problems
concerning with immuno-allergic system, metabolicendocrine system and nervous system inside and outside
Japan. The etiology of these life-style diseases may be
due to exposure of environmental pollutants. I strongly
suggest that it is important to establish techniques forearly detection of abnormality in lung function, immune
balance, learning behavior and enzyme and hormone
─ 16 ─

Vol. 15 No. 2 (2010)
levels to prevent environmental pollution induced theselife style diseases in next generation. It is also necessary

Interview with Imunotoxicologists
シリーズ「免疫毒性研究の若い力」8in the world

to search biomarkers for susceptibility to environmental
pollutants for early diagnosis and to understand themechanism of action of these pollutants for development

Dr A. Dean Befusof drug for appropriate treatment.

Professor, Pulmonar y Research

Finally, I would like to request to give opinion, guidanceGroup, School of Internal Medicine,and comments from senior and junior colleagues because

University of Alberta, Canada

my study and the experience are still dissatisfied withfield of Immunotoxicology. Then, I wish all of you for good
health, happiness and the research success at the New
Year.

Q1: How was your trip to Japan this time?
As with each of my previous trips, the latest trip was
most enjoyable and provided many fond memories ofyour beautiful country and its people.I was able to bringmy son along for his first visit to Japan. On the night wearrived, there was a typhoon. It was raining heavily, very
windy and for us quite humid. Thereafter, the weather
turned lovely and I had an opportunity to see manyfriends, previous trainees and scientific colleagues in
Tsukuba and Tokyo.Everyone was generous and most
hospitable. My son has fond memories of our trip and thewonderful people.

Q2: Is there a society of Immunotoxicology in
Canada?
To the best of my knowledge, there is not a societyof immunotoxicology in Canada. However, there is aSociety of Toxicology (http://www.stcweb.ca). The society s
web page contains information on the activities of theSociety with links to its documents, training programs
and other societies of toxicology. The webpage states that
The majority of toxicology training programs in Canada
currently exist within departments of pharmacology andtoxicology or schools of veterinary medicine, but there
are some notable exceptions.
In addition, Health Canada conducts research inmany areas of toxicology, especially as they relate tofoods and nutrition. Immunotoxicology is an importantcomponent of this research. Similarly, Environment
Canada also supports research on the immunotoxicity
of environmental contaminants. In my home province,
Alberta, the environmental impacts and toxicology of oil
and gas exploration and exploitation are an importantconcern.
─ 17 ─

ImmunoTox Letter
Q3: Hottest topics in my field?

out excellent people for teamwork and mentorship. I

My major field of interest is allergic diseases. A

continuously try to seek mentorship advice from senior as

hot topic in this field is the need to understand why

well as younger colleagues, and especially from trainees

there has been an epidemic of increasing prevalence

who often have insightful comments and suggestions.

of various allergic and other immune diseases, such as

Although career opportunities may appear to be aasthma. An important focus of research to understandbit limited in our current global economy, high quality

the basis of this epidemic is on early life events and thescience and intellectual capital are the basis for futurematernal-fetal-infant relationship. There is exciting new

progress and global health. It is your task as a young

information on how different environmental exposures,

researcher to strive for excellence and to work withboth physical and psychologic, early in life can havehonesty and integrity. The benefits of a career in

profound influences on development of allergy and many

science are many fold and well-worth the hard work

other chronic diseases. There appear to be windows

and commitment needed to be successful.My network ofof susceptibility early in life that can have long-termcolleagues and good friends in Japan is strong evidence of

impacts. Scientists are beginning to understand how

the benefits that I have received as a scientist.

gene-environment interactions especially early in life
influence health and disease.

Arigato gozaimus and sayonara

Q4: Happiest and toughest things in my career?
These are hard questions. I am happiest when I
see my trainees and mentees enthusiastic about theirresearch and their personal growth as professionals and

Dr. Gary R Burleson

individuals. It is great to see the spark of discovery andPresident & CEO, Burleson

the joy in having a long series of experimental insights

Research Technologies, Inc.

published. The toughest times have been when brightyoung scientists struggle with difficult experimental
models and become frustrated with challenging protocols
or inadequate or immature experimental systems.

Q1: How was my first trip to Japan?
Q5: Advice to young researchers starting acareer?

was fortunate to visit Japan as a representative ofScience can be challenging, but also intellectually

the SOT ImTox SS in the ongoing cooperation andboth stimulating and rewarding. It is essential to get

scientific interchange between the ImTox SS and thean outstanding training. You must work hard and seek

The trip to Japan was a wonder ful experience. I

Japanese Society of Immunotoxicology (JSIT), and toattend the 2010 Annual Meeting of the JSIT in the
Ohyama Memorial Hall of the National Institute forEnvironmental Studies in Tsukuba. This was my first trip
to Japan and I was very excited about the opportunity
to visit this country and meet new Japanese colleagues.
Dr. Hidekazu Fujimaki of the National Institute forEnvironmental Studies in Tsukuba, serving as Organizerof the meeting, and Dr. Kazuichi Nakamura of Shionogi
and Co Ltd, tirelessly answered the many e-mails andquestions that I had prior to my trip and were wonderfulhosts.I was accompanied on this trip by my wife Florence
and daughter Stefanie. We arrived in Tokyo on Friday

─ 18 ─

Vol. 15 No. 2 (2010)

Dr. Kazuichi Nakamura, who took us to a traditional

Q2: What are the hottest topics in my field, or
what are the topics I am interested in mostright now?

Japanese pub and introduced us to Japanese cuisine. It

Hot topics in immunotoxicology and my current

was a wonderful evening. During the weekend, we toured

interest include: (a) biologics – testing in non-humanTokyo and enjoyed many sights, including the Imperial

primates (NHP) and in rodents to evaluate innate, cell-

Palace gardens, the Tokyo Edo Museum, and the Senso-

mediated and humoral-mediated immune function;

ji temple in Asakusa, before taking the Shinkansen to(b) assessment of risk for EBV-related lymphomas

Kyoto on Monday. We had two days of sightseeing inin humans; (c) developmental immunotoxicity; (d)Kyoto where we visited beautiful temples and shrines,

immunotoxicity in the elderly; (d) incorporating theincluding the Sanjusangendo shrine with its 1001 statues

infectious disease paradigm (Environmental Healthof Kannon.During out trip, we were very thankful for the

Perspectives (2010); (e) testing strategies for unintended

many helpful strangers who prevented us from getting

immune responses and autoimmunity; and (e) research tolost and gave us directions. On Wednesday, we once again

better understand the role of environmentally- influenced

took advantage of the excellent and extremely punctual

immune dysfunction in disease.

3rd of September and familiarized ourselves with thetrains and subways in Tokyo. On Saturday night, we met

Japanese transportation system to whisk us to Tsukuba
the Executive Committee Meeting and were served a

Q3: W h a t a re t h e h a p p i e s t t h i n g a n d t h etoughest thing in my career?

traditional Japanese dinner. It was a truly magnificent

The toughest thing in my career was graduate school,

feast where we met the organizers of the meeting andas only 10% of the incoming students were successful

the officers of the JSIT.The following evening reception

in obtaining the Ph.D. degree.The happiest thing

for the JSIT meeting.That evening we were invited toat the Chateau Kamiya was an opportunity to havein my career was starting BRT-Burleson Research

further discussions with many of the scientists attending

Technologies, Inc. 14 years ago with my wife, Florence G.

the meeting, enjoy more wonderful food, and listen to

Burleson, Ph.D.

Professor Takemi Otsuki

s rendering of the theme songfor the 17th JSIT meeting. Our visit to Japan was truly
memorable as we visited old friends, made new friends,
enjoyed interesting scientific discussions, and were

Q4: Could you offer some advice for young
researchers who would like to start theircareer?
There are many opportunities in the field of

introduced to a new culture and excellent food.

immunotoxicology research.Utilize new cutting-edge
immunological techniques in order to advance the scienceand to obtain data useful for human safety assessment.

Q5: Other comments?
I look forward to the opportunity of a return visit toJapan.

─ 19 ─