Vol. 12 No. 2 (2008)of monoclonal antibody pharmaceuticals” presented by

English pages

Dr. Kiyoshi Kobayashi from Amgen K.K., Tokyo and by Dr.

Report from the secretariat for The 14th
Annual Meeting of the Japanese Society of
Immunotoxicology
The 14thTomoaki Inoue from Fuji Gotemba Research Laboratories,
Chugai Pharmaceutical Co., Ltd., Gotemba. The “Annual
Award” in JSIT 2007 was won by Dr. Tomoko Shindo from

Annual Meeting of the Japanese Society

Hatano Research Institute, Food and Drug Safety Center,of Immunotoxicology (JSIT 2007) was held at Hyogo

Kanagawa and “Encouragement Award” was by the Ph.D.

Prefecture Civic Center in Kobe, Thursday, September

student Miss. Ayako Nakayama from the Center for Fish

20 ─ Friday, September 21, 2007. The Sub-theme

and Wildlife Health, University of Berne, Switzerland &of this annual meeting was “Toxicogenomics andKobe Women’s College.

Immunotoxicology”. In addition to 22 oral communications
and 15 poster presentations, there were two invitedlectures, a special lecture, a symposium, and a workshop
during the meeting. Invited lecturers include Dr.

The 15th Annual Meeting of the JapaneseSociety of Immunotoxicology (JSIT2008)(1st announcement)

Yukihiko Kitamura from Developmental ResearchLaboratories, Shionogi Co., Osaka who gave a talk about

September 11-12, 2008

“Mast cells and KIT receptor tyrosine kinase” and Prof.

Towerhall Hunabori, Edogawa, Tokyo, Japan

Edith Smith from Oxford University, U.K. who spoke
about “Drug induced allergy”. A special lecture was

Invited plenary lecture “Immunotoxicology of innatepresented by Prof. Tetsuro Urushidani from Doshisha

immunity” (Prof. Stephen B. Pruett)

Women’s College of Liberal Arts who talked about

Plenary lecture“Prediction of hepatotoxicity using toxicogenomics

Master’s lecture

project database (TG-GATEs)”. The theme of the

Symposium “Immunotoxicity of nanoparticles (tentative

symposium was “Developmental immunotoxicology” andtitle)”

the speakers include Dr. Orie Nakamura from Osaka

Symposium “Gut-associated lymphoid organs and their

Medical Center and Research Institute for Maternal

regulations (tentative title)”

and Child Health, Osaka who presented “Molecular

Workshop “Immunotoxicity and allergenicity ofmechanism of specific immune system on maternal

pharmaceuticals (tentative title)”

deciduas”. Other speakers include Dr. Hayssam Khalil

Oral and poster presentations

from Charles River laboratories, Canada, Dr. Gerhard
F. Weinbauer from Covance Laboratories GmbH, Prof.
Rodney R. Dietertl from Cornell University, USA, andPresident: Jun-ichi Sawada, Ph.D. (National
Institute of Health Sciences)Dr. Kenneth L. Hastings from FDA, USA who gave a

Secretary Office: TEL 03-3700-9453 FAX 03-3700-7438

talk about “Ontogeny and post-natal development of therodent immune system”, “Immune system developmentin the primate”, Developmental immunotoxicity andcritical windows of exposure for children’s health”, and“Regulatory concerns for developmental immunotoxicology”,
respectively. The workshop was divided into two
sessions. One was “Evaluation of immunotoxicity
using primates” that was introduced by Dr. Hiroshi
Maeda from the Tokyo Pathology Center, Shin Nippon
Biomedical laboratories, Tokyo and by Takayuki Okamura
from Kashima laboratory, Mitsubishi Chemical Safety
Institute, Kashima. The other was “The safety evaluation
─ 9 ─

E-mail jsit15@nihs.go.jp

ImmunoTox Letterin piscine immune cells such as B-lymphocytes andA prize for
年 annual
会 convention
賞

granulocytes. Our finding could provide a clue to explain
the immunotoxic mechanisms of PAHs in fish.

Murine Food Allergy Model with Oral
Sensitization and Oral Challenge
Tomoko Shindo1, Yukiko Kanazawa1,
Mami Furuya1, Yoshiyuki Tazura1,
Kohichi Kojima1 and Reiko Teshima2
1

Hatano Research Institute, Food and Drug Safety Center, Kanagawa, Japan
2

National Institute of Health Sciences, Tokyo, Japan

シリーズ
Young powerfor immunotoxicological research「免疫毒性研究の若い力」
3

Go west with asbestos!
-along with my thinking about this societyYasumitsu Nishimura, Ph. D.

We have established murine food allergy model onset

Assistant Professor/Lecturerof immediate anaphylactic reactions by oral sensitization

Dept of Hygiene, Kawasaki Medical Schoolwith oral challenge. The mice once administrated with
ovalbumin showed the change of T cell population in

I was introduced to asbestos in Hyogo College of

mesenteric lymph node. It shows that mesenteric lymph

Medicine, after completing my Ph. D. in the Graduate

node is an important organ for sensitization in this model.

School of Medicine at Kyoto University. Prof. H. Iguchi

Then linoleic acid-lecithin mixture vehicle combined

taught me the study method to test the ef fect ofwith sodium salicylate treatment as an essential factor

asbestos-exposure using rats. After finishing the studyof this model may provide food allergy by changing T cell

about alveolar macrophages, Otsuki T. Prof. accepted me

population.

as a lecturer in Kawasaki Medical School. I am currently
studying about the effect of asbestos-exposure on NK
and NKT cells. In this process from Kyoto University
to Kawasaki Medical School, that is, going west with

A prize年
for encouragement
会 賞

asbestos, I realized the significance of the study about
immunological ef fect of asbestos-exposure. I also

Understanding the immunotoxic
mechanisms of benzo[a]pyrene in fishusing the localization of an inducible
cytochrome P450(CYP)-1A protein in
piscine immune cells

understood social needs for immunotoxicological study
and the importance of this society. I will continue tocontribute to further development of this society.

Ayako Nakayama1,4, Ivan Riesen1,
Elisabeth Eppler2, Bernd Köllner3,
Kawai Shinichiro4 and Helmut Segner1Participation Report for The 14th Annual
Meeting of the Japanese Society of
Immunotoxicology

1

Centre for Fish and Wildlife Health, University of Berne, Switzerland
2
3

University of Zurich, Switzerland

Friedrich-Loeffler, Insel Riems, Germany
4

Kobe College, Japan

Greetings from the US
Contributed by Kenneth L. Hastings, Dr.P.H., D.A.B.T.

Polycyclic aromatic hydrocarbons (PAHs) such(sanofi-aventis, USA)as benzo[a]pyrene (BaP) are immunotoxic to fish.
Metabolism of PAHs in immune cells has been implicatedAs the year comes to an end, I would like to sendin PAH immunotoxicity in mammals, but for fish whether

greetings on behalf of your colleagues in the United

metabolic enzymes are present in immune cells andStates. It was a distinct pleasure to able to attend

whether piscine immune cells have the capability to

the 14th Annual Meeting of the Japanese Society of

metabolite PAHs are still unknown. The highlight of

Immunotoxicology in September, and to have thethis study was to be detected BaP-inducible CYP1A

opportunity to give a presentation at the meeting. I─ 10 ─

Vol. 12 No. 2 (2008)
have to say I was very impressed with the quality ofGraduate Training Medical Sciences Division, Professor

presentations, the venue, and the interest of participantsof Pharmacology, University of Oxford, UK)

in immunotoxicology issues we are dealing with in the
US. As it turns out, there is little difference between

Firstly, it is a great pleasure to thank Dr. Kazuichi

our issues and those dealt with in Japan. Partly, this is aNakamura and Professor Shin Yoshino, as President,

result of the recently concluded negotiations resulting in

who invited me to attend the 14th Annual Meeting of

publication of ICH S8. This document is one that we are

the Japanese Society for Immunotoxicology in Kobe andproud of and is an example of how good science, careful

to give a lecture on Drug induced Autoimmunity. Dr.

preparation, and collegial relations can result in guidance

Nakamura also invited me to speak at the Shionogi &that is both scientifically sound and serves to protect

Co., Ltd. in Osaka to deliver a lecture on Drug Induced

public health.

Allergy. Both experiences have been extremely rewarding

As I pointed out in my presentation, we have now toboth scientifically and culturally. The Japanese Society

deal with the issue of developmental immunotoxicology.

for Immunotoxicology is a vibrant scientific society with

Although this topic is addressed in ICH S8, the guidancetalks from young scientists which were highly polished.

is not sufficiently detailed to be of any great value. Thus,

The talk by Dr. Orie Nakamura on developmental

we may need to address this issue in a future guidance,

immunotoxicology showed beautiful staining techniques

either as a stand-alone document or as part of a broader

for following expression of markers as they appear during

document on juvenile animal studies needed to enablefoetal development. The poster session was also mostclinical trials and marketing of drugs for pediatricimpressive.

patients. As I pointed out in my presentation, and as

I am very grateful indeed for the opportunity to meet

Professor Dietert discussed in detail, the developingwith fellow scientists and also to sample some of theimmune system appears to be a uniquely sensitive

outstanding Heritage sites which we visited. I greatly

target for xenobiotic toxicity. It is questionable whether

appreciate the opportunity to visit these sites whichcurrent regulatory practices take this into account.

was only possible through the kindness and friendship

It is also likely that with the emergence of biologic

of Dr. Kazu Nakamura and also his young colleague andtherapeutics which target the immune system the issue ofstudents from the Kobe Pharmaceutical University.

developmental immunotoxicology will become even moreI arrived in Japan on 19th September with my husband,

important in the future. I was happy to see that researchin this area appears to be alive and well in Japan.

Prof. Bob Sim, and travelled from Narita to Kobe by

On another note, please remember that the International

train. Dr. Nakamura had arranged an excellent hotel

Journal of Immunotoxicology is exactly that, an international

near the centre of Kobe which allowed my husband andjournal. Your colleague Dr. Kazuichi Nakamura serves as

I to visit the harbour area on 20th September, including

an Editor, and we are very interested in continuing ourthe Earthquake Memorial Park. We were particularly

relationship with your professional Society. We are very

impressed by the architecture and sculpture in thisinterested in contributions from Japan for publication

beautiful city. That evening Dr. Nakamura met us atin the Journal, and encourage submissions. Please keep

the hotel together with Dr. Ken Hastings and Prof. Rod

us in mind the next time you are considering where you

Dieter. We were escorted to the conference Banquet on

would like to submit your research results for publication.

a ship from which we were able to see a major feat ofThank you very much for your hospitality, which asengineering ─ the 3.9 Km long Akashi Kaikyo Suspension

always in Japan was excellent. I very much enjoyed

Bridge.

participating in your meeting and hope to have theopportunity to do so in the future.

At the banquet, I was unprepared but very pleasantly
surprised to be able to express my gratitude to Dr.
Nakamura and Prof. Yoshino for the invitation to theTravels in Immunotoxicology and in Japan

conference and the opportunity to visit Japan for the firstContributed by Edith Sim, BSc, M.A., D. Phil. (Director oftime.

─ 11 ─

ImmunoTox Letter
On 20th September, we arrived at the conference. It

C4, may act as an immunogen also. This was an

was extremely interesting to hear the presentations on

interesting point raised during the thoughtful questions

developmental immunotoxicology. Science is best served

which were asked.

in a multi-disciplinary way. Basic research at the whole

Particularly in relation to the previous presentation

organism and also at the organ, protein and gene levelon genomics, it turns out that the major predisposing

all add together to aid in our understanding of a subject.

factor in hydralazine-induced SLE is the ability of an

From the perspective of an applied discipline whereindividual to metabolize the drug. The metabolism

legislation results from the research, a full descriptionof hydralazine is catalysed by the enzyme arylamineof events at the whole animal level through systemic

N-acetyltransferase and individuals can be either fast orinvestigation is essential. If there can also be a layerslow acetylators with slow acetylators being those whoof understanding at the molecular level this can open

develop the immunotoxic reaction. The molecular basis

up new avenues for investigation and ultimately forof the polymorphism in acetylation is now known withlegislation. The sessions on appropriate animal models

slow acetylators having point mutations in the NAT2

for understanding immunotoxicity and windows ofgene which result in the protein becoming unstable andvulnerability were fascinating for a molecular scientist,

accumulating intracellulary in regions in the cytosol

which is my own area. The caution expressed by Dr.

known as aggresomes. Proteins in aggresomes are

Lawrence in relation to the use of toxicogenomics was

identified for ubiquitination and intracellular destruction.

enlightening but again brings home the message that

Within the Japanese population, there is a different

understanding at many levels can be helpful both indistribution of NAT2 alleles such that the most common

understanding immunotoxic reactions and subsequently

allele causing slow acetylation in Caucasians is missing

informing the legislative process as was emphasized byin the Japanese but the mechanism of slow acetylation

Dr. Ken Hastings.

with the commonest Japanese NAT2 slow allele is likely

My own presentation which should have been entitledto occur through the same protein destabilisation

Drug Induced Autoimmunity covered work with whichmechanism. The final point I made was in relation to

I have been involved over many years at the molecularautoimmunity due to treatment with sulphasalazine andlevel. The drug hydralazine, and also procainamide,

mesalazine. Metabolism by gut bacteria may be important

induce, in certain individuals, a condition whichin generating immunotoxic metabolites. Azoreductase isresembles Systemic Lupus Erythematosus (SLE). In

such a metabolic enzyme where structural information is

drug-induced SLE, as well as in idiopathic SLE, immune

now available with an understanding of structure activity

complex clearance is disrupted and immune complex

relationships. The use of bacterial enzymes as well as

deposition is frequently associated with deficiencies

human enzymes for structure based drug design can beof the early components of the classical complement

informative and may well also have a role in predicting

pathway (C1, C4 and C3). These components promote

immunotoxicity once databases which cover molecular

the solubilisation and clearance through phagocytosis

and systems data are available in the future.

of immune complexes. I used hydralazine-induced SLE
as a model system for understanding multi-factorial

Following the scientific sessions at the Japanesedisease where the drug is the environmental trigger.

Society for Immunotoxicology, we had a very interesting

Hydralazine interferes with the role of the complement

series of visits organized by Dr. Nakamura both to Himeji

cascade in clearing these complexes. During this process,Castle and also to Nara where I was unfortunately too

hydralazine itself becomes covalently bound to thelarge to wriggle through the Buddha’s nostril. Dr.

complement proteins inhibiting the solubilisation and also

Nakamura and his colleagues made sure that we were

the phagocytosis of immune complexes such that they

able to sample Kobe beef and local fish delicacies withpersist and become deposited at inappropriate sites andconfidence. Their guidance through Osaka station was

hence SLE can develop. It is possible that hydralazine,

masterful. I am sure that otherwise I would still be there!

covalently bound to the activated complement component

We are very grateful to Dr Nakamura and his students

─ 12 ─

Vol. 12 No. 2 (2008)
for giving up their holiday weekend to take us to see such
wonderful sights.
On 25th September, Dr Dieter and I were invited to giveseminars at Shionogi & Co., Ltd. This was my first visit
to a Japanese drug company and was very enlightening.
It is also the first time that I have given a talk wearing
slippers. Dr. Nakamura had asked me to give a talkon Drug Induced Allergy at Shionogi and I discussed
work on penicillin and cephalosporin induced allergy.
It is not work which I have done myself but Oxford
University is well known for work in these areas in the
Sir William Dunn School of Pathology. I also presented
some of my own research work on development ofnovel anti-tubercular agents. The question session was
extremely lively and gave me much food for thought. We

Fig. 1

Himeji castle.

Fig. 2A trip to Nara.

discussed how a compound might generate an allergic
reaction and how this might be predicted. We discussed
that a covalent reaction between the compound, or its
metabolite, and a self molecule, usually a protein wasnecessary in order for a chemical to act as a hapten.
We discussed possible ways of identifying a covalent, as
opposed to a hydrophobic, interaction between a chemical
and a protein. The questions relating to animal models
were outside my area of expertise but Prof. Dieter’scomments were very helpful and informative. Prof. Dieter
gave an extremely elegant presentation at Shionogi
which again generated enthusiastic questions from theaudience. I felt privileged to have been invited to give a

On the following day my husband and I travelled to

JSIT and ImTOXSS Bring an International Focus
on Developmental Immunotoxicity (DIT) Safety
Testing

Hiroshima for the start of a short holiday travelling inContributed by Rodney R Dietert, PhD (Professor ofJapan which was most enjoyable and allowed us to see

Microbiology and Immunology, Cornell University, USA)

talk. Dr. Nakamura most graciously accompanied us backto our hotel in Osaka.

contrasting geographical areas of Japan, each with their
special blend of traditional and high-tech features. We

The Scientific Visit

would not have made the trip apart from the wonderful

It was a special honor to attend and present my research

opportunity as a result of the invitation of Prof. Yoshino

in developmental immunotoxicology at the 14th Annual

to speak at the Japanese Society for Immunotoxicology

Meeting of the Japanese Society of Immunotoxicology

and at the Shionogi & Co., Ltd.. It was a great pleasure toheld in Kobe, Japan 20-21 September, 2007. My lecture

meet and discuss with Japanese colleagues, to exchange

was entitled “Developmental Immunotoxicity andcultural experiences and to make new friends.

Critical Widows of Exposure for Children’s Health”.
Along with Dr. Kenneth Hastings, I was privileged torepresent the Immunotoxicology Section of the Society of
Toxicology (U.S.) as a speaker at this important scientific─ 13 ─

ImmunoTox Letter
immunotoxicology meeting and to join Drs. Edith andTh1 responses, T helper cell balance, and macrophage

Robert Sim as a guest at this special forum. Following

systemic modification in response to surfactants near

this forum I had the pleasure of visiting Shionogi & Co.,birth are critical developmental benchmarks that help

Ltd. for a second lecture and a discussion session on

define the postnatal immune system and its capacity.

developmental immunotoxicology testing.

Additionally, requirements of the pregnancy itself needed

Dr. Kazuichi Nakamura ser ved as the host andfor maintenance of a semi-allogeneic fetus place uniqueprovided an exceptional itinerary that featured both

restriction on fetal immune development. This helps toscientific enlightenment and historical inspiration.

define the particular susceptibilities that exist in DIT in

I am particularly grateful to Dr. Nakamura for acontrast with adult-induced immunotoxicity.

wonderfully planned visit and for the honor to meet

In this lecture, I made an additional point concerning

JSIT Executive President Dr. Motoyasu Ohsawa,

the spectrum of postnatal diseases influenced by DIT.

Meeting President Dr. Shin Yoshino, Dr. Keiko Nohara

Beyond the obvious immune-associated diseases suchand other members of the society. The meeting itself

as childhood asthma, infectious disease susceptibility,

was filled with exceptional research and new insights

risk of later life cancer and autoimmunity, a host ofon the immunotoxicity of drugs and environmental

inflammatory-associated conditions appear linked withcontaminants. I was particularly impressed by the new

DIT. These include various neurobehavioral conditions

research pertaining to both mechanism and outcomessuch as Parkinson’s disease, autism and schizophreniaof xenobiotic-induced immune dysfunction that reached

as well as vascular system and reproductive dysfunction.

far beyond traditional concepts of immunosuppression.

Such expanded disease associations increase the need

There were many presentations addressing dysfunction

to detect potential developmental immunotoxicants andthat included concern for hypersensitivity andhighlight the benefits that would arise from effective DIT

autoimmunity. Additionally, the idea was evident thatscreening of drugs and chemicals.

risk of immunotoxicity can include concomitant increases

The lecture continued in identifying specific drugs

in hypersensitivity and/or autoimmunity along withand chemicals that ser ve as model developmental

targeted immunosuppression.

immunotoxicants. These xenobiotics disrupt specific events
during one or more windows of immune vulnerability.

th

JSIT meeting covered theWith the DIT literature having expanded dramaticallybiological basis for the increased sensitivity of thein the past five years, the breadth and range of known

non-adult’s immune system to toxic alteration by

developmental immunotoxicants can now provide clues

drugs and environmental chemicals. It also addressed

as to categories of likely toxicants and the specificthe patterns of dysfunctional outcomes seen with DIT

immunotoxic risks. The significantly expanded literatureand the combinations of testing protocols that havealso permits an evaluation regarding the nature of DIT

proven most effective for detection of developmental

alterations and the most predictive assays for detecting

immunotoxicants. Critical windows of vulnerability exist

developmental immunotoxicants.

My lecture at the 14

for the developing immune system and have been defined

In considering specific testing assays and detection of

in previous review articles. These prenatal-perinatal

developmental immunotoxicants, the take-home message

windows constitute one-time immune maturational

was that function trumps structure. Dysfunction rather

events that must occur without environmental disruption

than major structural alterations is the most commonor result in risk of postnatal dysfunction and increased

DIT outcome. Not surprisingly, those combinations

disease susceptibility.

of assays that are capable of measuring across the

Events such as myelomonocytic cell seeding of tissues

spectrum of immune response capacities appear to be

and organs for homeoregulatory oversight, lymphoid

best for detecting developmental immunotoxicants.

seeding of the thymus, thymocyte positive and negative

As a result, a multiple isotype (e.g. (IgM and IgG

selection, generation, seeding and activation of T

subtypes) T-dependent antibody response (TDAR) canregulatory cells, dendritic cell maturation to promote

be combined with a Th1-dependent assay such as the─ 14 ─

Vol. 12 No. 2 (2008)
cytotoxic T lymphocyte (CTL) assay or the delayed typethe castle’s upper floors. We were even serenaded byhypersensitivity (DTH) assay for analysis of acquired

an all-day rock concert from the adjacent park since ourimmunity. Inclusion of a natural killer (NK) cell

visit to Himeji occurred on a national holiday period.

cytotoxicity assay further adds a useful measure of innate

In Kyoto, I found a very small temple that held a very

immunity. Cytokine measurements, immunohistology, andspecial contemplative opportunity for me.

immunophenotype are helpful as associated measures but

Of course Nara was a highlight of the social visit. I had

do not substitute for functional assays when it comes tovisited the park alone 26 years ago. But with the present

DIT.

tour, the students and Dr. Nakamura were able to provide

The question and answer discussion following the JSIT

wonderful additional information about the monuments

lecture was excellent and very thought provoking. It wasthat made the visit so much more inspiring. I think one

such an honor to be a part of the session dealing withnever forgets the magnificent Buddha. Being from thedevelopmental immunotoxicology at this meeting.

Cornell Veterinary College, I was sure to extend myuniversity’s best regard and wishes for good health to

My second presentation at Shionogi & Co., Ltd.

Nara’s population of sacred deer.

followed a similar outline. However, the lecture time

I returned with many wonderful photographs andwas slightly longer and it was possible to include

memories from the conference, the visit to Shionogi

additional materials concerning DIT testing. Much

& Co. Ltd. and the tours of the Osaka-Kobe areaof the subsequent discussion focused on testingmonuments. Dr. Nakamura provided the tour of a lifetime

options including the range of potential developmental

and I am so appreciative of his special hosting. It was

immunotoxicants and the benefits and limitations ofan honor to have represented our Immunotoxicology

various testing protocols.

Specialty Section at this conference and I look forward
to facilitating continuing exchanges between JSIT and
ImTox-SOT.

The Social Visit
A special treat for me was the opportunity tovisit places of historical significance in Japan in thecompany of the Dr. Sim, Dr. Hastings, several graduate
immunotoxicology graduate students and our host, Dr.
Nakamura. Of course our social program began with the
Kobe Bay cruise dinner associated with the conference.
The Kobe skyline was so impressive. The knowledge
that only a few years ago the city had been devastatedby an earthquake made the scenery from the ship all themore spectacular. I particularly enjoyed comparing thebridge lighted at night from the water vs. its daytime
appearance from shore.

Fig. 3

Dr. Dietert and Dr. Hastings.

Dr. Nakamura had arranged a magnificent schedule oftouring that provided an opportunity to see many places
I had read about but had only dreamed of seeing first
hand. Himeji Castle and the Philosopher’s Path with its
many temples in Kyoto were among those. Himeji castle
was both awe-inspiring in its grandeur and captivating
through its broad spectrum of art and diverse stone
work. I was particularly taken by the individual stone-cut
designs with different symbols that were connected toeach Shogun era. I will always remember the views from─ 15 ─

Fig. 4

With deer.