ImmunoTox Lettervery impressive messages to audiences.

…

December,2017

I am so pleased

that his name has been inscribed in the history of our JSIT.
I was also lucky and honored to be the meeting president

Report on the 24th Annual Meeting of thebecause I could invite Dr. Danuta Herzyk (Merck & Co.) as

Japanese Society of Immunotoxicology

a part of the researcher exchange program between the(JSIT2017)

ITSS and JSIT.

Kazuichi Nakamura
President of the 24th JSIT Annual Meeting
Kitasato University.

I really appreciate Dr. Mitch Cohen for
Her lecture “Immunotoxicityhis efforts on this project.
AssessmentofBiopharmaceuticals”

received

greatattention from many audiences because it was well
prepared being based on the data and experiences in her

The 24th Annual Meeting of the Japanese Society ofimmunotoxicological research.

Another special lecture

Immunotoxicology (JSIT) was held on September 4th - 5th,

was presented by Dr. Tsuyoshi Yokoi (Nagoya University),

2017 at the School of Veterinary Medicine, Kitasato

who is now a distinguished researcher on the immunology

University in Towada, Aomori.

of drug-induced liver injury (DILI).

“New perspective ofHe reported hisimmunoenhancement and immunosuppression” was set asworks and clearly explained involvement of Th17 cells andthe main theme of the meeting by myself.

Autoimmunity

TLR4 of Kupffer cells in the liver injury.

orinitiatedbyMinamitani (National Institute of Biomedical Innovation,“immunoenhancement”, but can be caused by even

Health and Nutrition) gave an educational lecture on

immunosuppression

autoimmune

allergyisnotornecessarily

normalimmunityrecognizing altered-self antigen or MHC.
discuss

andtodisseminate

immunotoxicity in this meeting.

thissimplyI intended tonew

aspectof

In addition, I thoughtdiseases.

InhisDr. Takeharu

current

study,

hedemonstrated the molecular pathogenesis by which
Epstein-Barr virus infection induces autoimmune diseases.
Thesymposium“Reproductive

immunotoxicity:that we should consider the physiological (normal) state of

Immunological“immunosuppression”.

breakdown” discussed the immunological tolerance andIn this connection, a symposium

mechanism

ofpregnancyand

its

titled “Reproductive immunotoxicology: Immunologicalplacenta formation during pregnancy.

The symposium

mechanism of pregnancy and its breakdown” wasfocusedrolespresented.

gamma/delta T cells and uNK cells during pregnancy.

On September 3rd, one day before theon

Th1/Th2balance,theofTreg,

meeting, Dr. Fujio Kayama (Jichi Medical University) gave

Thea lecture to Towada citizens about “Safety of rice as apregnancy was also presented.

staplenationwide

safety evaluation method of biopharmaceuticals (protein

epidemiological study in cadmium intake” receiving keen

formulation) with the perspective of regulatory agency andquestions from them.

industry.

food:Findings

derivedfromDr. Jack H. Dean (University of Arizona) gave a keynotevivo

immunotoxicologicaleffects

ofnano-silica

onThe workshop dealt with

Expectation of in vitro studies to support instudies

andimmunogenicity

assessment

oflecture through a video over the internet from Eminent

antibody/antibody-drug conjugate therapeutics were main

Toxicologist

topics in the workshop.

Lecturehistorical perspective”.

Series“Immunotoxicology:A

It was a great honor and privilege

for me to invite him to the JSIT meeting.

Interpretation of ICH S6 (R1)guideline was also mentioned by the PMDA.

His lecture gave
No.1（12） 18

ImmunoTox Letter
The Best Presentation AwardAmong 11 oral and 22 poster presentations, the Best
Presentation Award went to Dr. Masashi Tachibana (OsakaUniversity) presenting “Regulation of myeloid-derived

Glutamate signaling regulates

suppressor cells by glutamate signaling” and the Students

the immunosuppressive function ofand Young Scientists Award to Dr. Toshiyuki Ohtake

myeloid-derived suppressor cells.

(Chemicals Evaluation and Research Institute) presenting

Masashi Tachibana“Comparison of skin sensitization potential of isocyanates

Laboratory of Biochemistry and Molecular Biology,

by a local lymph node assay and an integrated testing

Graduate School of Pharmaceutical Sciences,

strategy with an in silico, in chemico and in vitro assays”,

Osaka University

respectively.
The meeting held a ceremony to honor Dr. Hidekazu

Myeloid-derived suppressor cells (MDSCs) are anFujimaki (National Institute of for Environmental Studies)

immunosuppressive population of immature myeloid cells

for the JSIT Research Award and Dr. Katsumori Yamaurathat accumulate in tumor bearer. MDSCs suppress(Keio University) for the Prize for Encouragement 2017.

anti-tumor immunity, the activation of CD4+ T cells, CD8+

They gave an award lecture “Differential immunologic

T cells, and natural killer (NK) cells, resulting in theresponses in mice exposed to low levels of volatile organic

promotion of tumor growth. The relationship between

compounds” and “The role of skin immunogenicity

nutrition and cancer has been reported by several research

induced by topical steroid therapy in chronic pruritic skingroups. It has been reported that the levels of most amino

disorders” respectively.

acids, including glutamate, in tumor tissues obtained fromIt should be noted that Dr. Victor J. Johnson (Burlesonpatients with colon and stomach cancers are significantly

Research Technologies, Inc.) who gave a lecture at the lasthigher than those in the normal colon and stomach tissues

year’s JSIT meeting kindly sent me video messages fromof the patients. It has also been reported that high mobility

himself and his young colleagues Dr. Angela Grovesgroup box 1, consistently overexpressed in tumor bearer,(University of Rochester) and Jaijun (Brian) Zhou

leads to an increase in glutamate levels in the serum. These（Michigan State University）to be shown in the eveningfindings imply that glutamate could be a biomarker andbanquet.

modulator of cancer. However, how glutamate regulates

They introduced ITSS current activities.

Verybig cheers rose from the banquet participants.
The meeting gathered about 100 audiences.

tumor progression remains unclear.
Since theMDSCs suppress immune reactions owing to theJSIT encourages enthusiastic participation of researchers

exhaustion of arginine by arginase and by iNOS, which

especially from the next generation and the JSIT members

uses arginine to produce nitric oxide. Thus, arginine

know each other well, the discussion was very active inmetabolism is important for the immunosuppressive

very friendly atmosphere.

function of MDSCs. ATP production from the tricarboxylic

I would like to express mysincere gratitude for your support.
much.

Thank you very

acid cycle is decreased in tumor cells, and tumor cells often
relyonelevatedglutaminolysis.

Therefore,

intumor-bearing hosts, tumor cells require glutamine for
their energy production. Once imported into the cells,
glutamine is converted to glutamate, followed by ATPproduction.

No.2（13）19

ImmunoTox Letter
The Student and Young
Scientists Awardproduction. Furthermore, high glutaminase activity andlow glutamine synthase activity have been observed inseveral types of tumor cells, suggesting an elevatedComparison of skin sensitization potential of

glutamate level in tumor-bearing hosts; elevated glutamate

isocyanates by a Local Lymph Node Assaylevels in plasma and tumor tissues have been reported inand an Integrated Testing Strategy withtumor-bearing animals. Therefore, it is speculated thatan in silico, in chemico and in vitro assays

MDSCs are exposed to high glutamate concentrations. We
hypothesized that glutamate enhances tumor progression

Toshiyuki Ohtake

by inducing MDSCs or enhancing the immunosuppressive

Chemicals Evaluation and Research Institute, Japan (CERI)

function of MDSCs.
In this study, we revealed that the metabotropic

It is my great honor to receive the Student & Youngglutamate receptor (mGluR) 2/3 are expressed on MDSCs.

Scientists Award at the 24th Annual Meeting of Japanese

LY341495, an mGluR2/3 antagonist, attenuated theSociety of Immunotoxicology (JSIT). I would like to give aimmunosuppressive activity of MDSCs in vitro and MDSCs

special appreci ation to the JSIT committee.

fromvivo.

Firstly, I would like to introduce my research. The skin

Furthermore, we observed that LY341495 treatment

sensitization potential of chemicals has been traditionallyinhibited the growth of B16-F10 melanoma in vivo.

assessed using regulatory accepted in vivo methods, such asAdditionally, the frequency of NK cells increased, andguinea pig maximization test or mouse local lymph node+B16-F10melanoma-bearing

micein+CD4 and CD8 T cells were activated in the spleen. Taken

assays (LLNA). A huge effort to reduce or replace the use

together, these data suggest that LY341495 would enhanceof animals for safety assessments of chemicals because of

the anti-tumor immunity through the inhibition of MDSCs

regulatory requirements and ethical issues is presentlyin B16-F10 melanoma-bearing mice. These data suggest

underway, and alternative non-animal methods have beenthat glutamate signaling plays the role to promote tumor

greatly developed. However, so far, a few studies havegrowth by increasing the potency of immune suppression.

investigated the sensitization potencies of isocyanates

Furthermore, our findings suggest that targeting MDSCs

which is a group of highly reactive chemicals that are

would enhance the efficiency of immune checkpoint

known to be occupational allergens. The present study

blockade therapy that uses the anti-PD-1 antibody

evaluated nine commonly used isocyanates using an in vivo
LLNA and assessed the applicability of an Integrated
Testing Strategy (ITS) consisting of an in silico Derek
Nexus prediction, an in chemico direct peptide reactivity
assay (DPRA), and an in vitro human Cell Line Activation
Test (h-CLAT) to isocyanates. All nine isocyanates wereevaluated as positive using the LLNA, Derek Nexus andDPRA, whereas seven chemicals tested positive using theh-CLAT: hexamethylene diisocyanate tested negative, and1,5-diisocyanatonaphthalene could not be examinedbecause of a solubility issue. When assessed using the ITS,
No.2（14）20

ImmunoTox Letterthe positive/negative outcomes for skin sensitization hazard
were consistent with those assessed using the LLNA for all

Immunotoxicological Researchnine chemicals. However, the potency prediction results of
the ITS tended to be underestimated, compared with those

Testicular immune privilege andof the LLNA. The data presented in this work provide

Reproductive immunotoxicity

insights into the performance of non-animal testing

Ning Qu, Kou Sakabe

approaches for evaluating the skin sensitization potencies(Department of Anatomy, Division of Basic Medical Science,of isocyanates. The paper entitled “Applicability of an

Tokai University School of Medicine)

Integrated Testing Strategy consisting of in silico, inchemico and in vitro assays for evaluating the skinsensitization potencies of isocyanates” has been accepted in
Toxicology.

In generally, the testis is often viewed as one of several
immune-privileged organs in the body. Therefore, there is apossibility that xenogeneic Spermatogonia Stem Cells

Lastly, I would like to express my great gratitude to mycollaborators in CERI for the continuous support for myresearch, and giving me such a great opportunity topresent at this conference.

（SSC） transplantation could be also successful even in
immunocompetent adult recipient mice. Recently, we tried
to transplant rat SSCs into immunocompetent mice after
depletion of their own germ cells by means of busulfan, anddemonstrated that some transplanted rat SSCs could

Reference1.

undergo complete rat spermatogenesis in recipient mouse

Takenouchi, O. et al. Test battery with the human cellline activation test, direct peptide reactivity assay andDEREK based on a 139 chemical data set for predicting
skin sensitizing potential and potency of chemicals. J.
Appl. Toxicol. 35, 1318–1332 (2015).

immunesystemandspermatogenesisin

immune-competent recipient mice, we detected that afterbusulfan treatment, the recovery could be seen in theimmune system including cell counts and functions of T

2. Ohtake, T. et al. Applicability of an Integrated Testing
Strategy consisting of in silico, in chemico and in vitro
assays for evaluating the skin sensitization potencies ofisocyanates. Toxicology 393, 9-14 (2018).

testes. And then, to determine the effects of busulfan on theand B lymphocytes in the spleen, but the spermatogenesis
was more compromised. In the present study, we showedsome information about therapeutic drug on maleinfertility after busulfan treatment.

doi: 10.1016/j.tox.2017 .10.015.

No.2（15）21

ImmunoTox Letter
Q1. What was the most impressive event for you in yourReal Voices of International
Immunotoxicologists

trip to Japan this time?
The whole trip was very enjoyable and memorable.

What the other researchers think about? How can I do

The most impressive was the weekend prior to themore exciting research in the future? Most of the young

conference, when I (with my family members) had aJapanese immunotoxicologists may hope to listen to somechance to tour and stay around beautiful Lake Towada andkind of comments from the experts in this field, inAomori region.

particular from the outside of Japan. This time, weNakamura and Dr. R. Kamata for their efforts and timeinterviewed Dr. Victor J. Johnson from Burleson Research

spent on arranging and accompanying us on trips to Oirase

Technologies, Inc., USA. Let’s go to listen to his voice.

Mountain,

What will you feel and learn?

Sannai-Maruyama Historical Site, Nebuta Museum, andI am truly grateful to Dr. Kazuichi

HakkodaMountain,Samurai

Castle,Asamushi Sakura Kano. In addition to the beauty of theDanuta Herzyk, Ph.D.
Distinguished Scientist
Immunology & Oncology Therapeutic Area Leader
Safety Assessment & Laboratory Animal Resources
Merck Research Laboratories (Division of Merck Sharp &Dohme, a subsidiary of Merck& Co.)West Point, Pennsylvania, USAregion, the accommodations in traditional Japanese hotels
allowed us to experience local culture and customs,
including amazing dinners with delicious and beautifully
prepared and served food (I only regret that I do not know
Japanese language and cannot read menus and names ofJapanese dishes).
The second most impressive event was the Conference
Banquet. Apart from the beautiful setting at Sun Royal
Towada and very tasty food, the wonderful jazz concert
prepared and performed by the Student Band fromKitasato

Universitywasunforgettable.

These

supposedly amateur musicians were incredibly good!

At

the same time, I was pleasantly surprised by remarkably
high energy, happy atmosphere and much laughter among
the immunotoxicologists attending their annual conference.
This was in contrast to my previous perception thatJapanese people were quite serious-minded all the time.
Sometime it feels good to be proven wrong (big smile here).

No.2（16） 22

ImmunoTox Letter
Q2. What is the most exciting thing in your career todate.

Q4.

Whatisrequired

forbreakthroughinimmunotoxicology research in the future, do you think?

My background is in immunology and I had to learn

From my perspective, immunotoxicology research in thetoxicology sciences “on the job” after I started working in

future will focus on characterizing relationships between

the pharmaceutical industry, initially at SmithKline

autoimmunity and immune responses to tumors at

Beecham (currently GlaxoSmithKline) and then at Merck.

different stages of the cancer-immunity cycle. In this new

Therefore, I am not a typical immunotoxicologist and haveera of immune therapies in cancer treatment, the idea of an

not been exposed to the environmental immunotoxicology

association between autoimmune toxicity and therapeutic

field in contrast to my many esteemed colleagues in the US,

anti-cancer response has become a topic of debate and weJapan and other countries.

need to address this idea as we move forward.

The opportunity to work inWith thethe pharmaceutical industry in drug development has been

availability of novel technologies, models and approaches,the most existing thing in my career. A broad spectrum ofincluding humanized immune system mice and genomic

scientific challenges involving both immunopharmacology

and cellular biomarkers of immune interactions, we haveand immunotoxicology as two sides of the same coin is

new opportunities to move immunotoxicology research to afascinating and most interesting to me.

different level of scientific thinking.

Q3. What are the things you are doing energetically,
right now?
Ihavehadtheprivilegeofworking

inthe

immuno-oncology area, including the development of thecancer drug, KEYTRUDA®. This is a breakthroughtherapy, using anti-PD-1 monoclonal antibody, and is themost important and energizing work I have done in mycareer.

Research related to immune therapies in cancer is

growing and evolving, and we are discovering and learning
a lot about tumor biology and regulation of immune
responses to tumors.

At the same time, we face newchallenges in the evaluation of safety of these novelanti-cancer therapies that present very different profiles
than traditional chemotherapy drugs used to treat cancer
diseases for decades.

The need to better understand thisnew therapeutic class and work on new approaches to theirsafety evaluation stimulates my creative thinking and takes
the highest priority in my current work.

No.2（17） 23