ImmunoTox Letter

December 2022

Report on the 29th Annual Meeting of the Japanese Society of Immunotoxicology(JSIT 2022)
Hiroyuki Kojima
President of the 29th Annual Meeting of the JSIT
School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, JapanThe 29th Annual Meeting of the Japanese Society of Immunotoxicology was held in Sapporo
for two days, September 12th (Mon) and 13th (Tue), 2022. Since the spread of coronavirus
infections decreased, this meeting was fortunately held on-site after two years’ web-meetings. The
final number of abstract submissions was more than those in the web-meetings, and was similar
to those in the on-site meetings before pandemic of coronavirus. We are really grateful that wewere able to hold the annual meeting successfully with the cooperation and support of many
people.
At this meeting, symposium, special lectures and educational lectures were planned with themain theme of "Immunotoxicity and Diseases - Leave our footmark". Symposium was titled“Environment, Immunity and Diseases”. Dr. Takehiro Suzuki (National Institute forEnvironmental Studies) gave a lecture on "Multigenerational effects and epigenetic modification
changes by gestational inorganic arsenic exposure”, Dr. Naoki Takemura (Graduate School of
Pharmaceutical Sciences, Osaka University) gave a lecture on "Understanding and controlling
environmental particle-induced inflammatory diseases", Dr. Chikako Shimokawa (National
Institute of Infectious Diseases) gave a lecture on "Suppressive mechanisms on autoimmune
diseases by helminth infection”, Dr. Hiroto Hatakeyama (Graduate School of Pharmaceutical
Sciences, Chiba University) gave a lecture on “Exacerbation of an immune checkpoint inhibitorinduced anaphylaxis by tumor-associated myeloid cells in tumor-bearing mice models”, Dr.
Michihiko Aoyama (National Institute of Health Sciences) gave a lecture on “Off-target
cytotoxicity of antibody-drug conjugates”, and Dr. Shunsuke Ito (Chugai Pharmaceutical Co.,
Ltd.) gave a lecture on “Involvement of Fc receptors in the immunotoxicity ofbiopharmaceuticals”.
Special lectures of the annual meeting were “Indigo treatment targeting the mucosal healingof ulcerative colitis; Yin and yang" by Dr. Takanori Kanai (Keio University School of Medicine)and “Protecting public health from per- and polyfluoroalkyl substances : Focus on
immunotoxicity” by Dr. Jamie C. DeWitt (East Carolina University), who was sent by SOT-ITSS.
Educational lectures of the annual meeting were “Understanding efficacy, effectiveness and safety
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ImmunoTox Letterof vaccines: from an epidemiological perspective” by Dr. Wakaba Fukushima (Osaka
Metropolitan University Graduate School of Medicine) and “How far can cancer be prevented?”by Dr. Masahiro Asaka (Health Sciences University of Hokkaido).
Workshop on the test methods was titled “Challenges of immunotoxicity assessment fordiverse pharmaceutical modalities”, Drs. Yoshihiro Takahashi (Shin Nippon Biomedical
Laboratories, Ltd.), Tetsuo Aida (Daiichi Sankyo Co., LTD.), Chiyomi Kubo (Chugai
Pharmaceutical Co., Ltd.), and Shogo Matsumura (Astellas Pharma Inc.) presented on several
issues of in vivo and in vitro test methods for immunotoxicity evaluation of biopharmaceuticals
and so on. The comprehensive discussion had a precious time to improve our understanding.
General session included 7 oral presentations and 19 posters, and Young Scientist Session
included 13 presentations which were to be presented as oral presentations and/or posters. In
general session, fifteen minutes was given for each talk to ensure enough discussion time asprevious annual meetings. As a result, Dr. Toshinobu Kuroishi (Graduate School of Dentistry,
Tohoku University) received the Best Presenter Award. In addition, Mr. Issei Omori (Graduate
School of Engineering, Kyoto University) and Mr. Shin-Ichiro Yamaguchi (Graduate School of
Pharmaceutical Sciences, Ritsumeikan University) received the best Student and Young Scientist
Presentation Award.
We would like to express sincere appreciation for attendants who actively discuss both oral
and poster presentations. Totally over 110 people attended this on-site meeting. After all, I felt a
lot of advantages of on-site meeting, the so-called “face to face”. We wish the further developmentof the Society.

Photo, Situation of presentation by Dr. Jamie C.
DeWitt at the meeting room.

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The Best Presentation AwardNi-binding protein CXCL4 and vitamin D3 analogue augment sublingual
immunotherapy for Ni allergy

Toshinobu Kuroishi
Division of Oral Immunology
Tohoku University Graduate School of Dentistry
Metal allergens induce Th1-dependent type-IV allergies. The most frequent metal allergen isnickel (Ni). By taking advantage of pro-tolerogenic features of the oral mucosa, allergen-specificsublingual immunotherapy (SLIT) has become a promising non-invasive, safe, and effective
therapy for allergies. Our laboratory previously reported the identification of antigen-presenting
cells in the oral mucosa and the mechanisms by which SLIT induced allergen-specific regulatory
T (Treg) cells. In this study, we investigated the preventive and therapeutic effects of SLIT on an
Ni allergy mouse model.
An Ni allergy mouse model was constructed as reported previously. Briefly, mice weresensitized with an intraperitoneal injection of solution containing Ni and lipopolysaccharide. Two
weeks after sensitization, mice were challenged with Ni using an i.d. injection into both pinnae.
Ear swelling was measured 48 h after the challenge. SLIT was performed by applying an antigen
solution under the tongue of anesthetized mice.
First, we analyzed whether SLIT can induce immunotolerance to Ni ions. Naïve mice weretreated using SLIT, then Ni allergy was induced. We used an Ni-binding protein CXCL4 as anadditive to SLIT. SLIT with [Ni + CXCL4], but not Ni alone, significantly inhibited ear swelling
after Ni challenge, indicating that immunotolerance to Ni was induced by SLIT with [Ni +CXCL4].
To further analyze the induction of Ni-tolerance by SLIT with [Ni + CXCL4], adaptive transfer
experiments were performed. Mice were treated using SLIT followed by Ni-sensitization. NonTreg CD4+ cells were sorted from the spleen and transferred to recipient mice. The recipient mice
were sensitized and challenged with Ni. Mice receiving non-Treg CD4+ cells from control miceNo.2（23）49

ImmunoTox Letteror mice treated using Ni-SLIT showed ear swelling after Ni challenge. On the other hand, no
significant ear swelling was induced in recipient mice receiving non-Treg CD4+ cells from micetreated using [Ni + CXCL4]-SLIT. These results indicated that Ni-specific CD4+ cells were notinduced in mice treated using [Ni + CXCL4]-SLIT. Treg transfer experiments revealed that Treg
cells induced in the draining mandibular lymph nodes were indispensable in SLIT-induced
immune tolerance to Ni.
To investigate the therapeutic effects, SLIT was applied after the induction of Ni allergy. No
therapeutic effects were detected in mice treated using [Ni + CXCL4]-SLIT. However, theaddition of calcipotriol, a vitamin D3 analogue, to [Ni + CXCL4]-SLIT showed significant
therapeutic effects on Ni allergy. These results indicated that calcipotriol augments the therapeutic
effects of SLIT. Moreover, these therapeutic effects were detected even after 6 months, suggestingthat the therapeutic effects were not temporary desensitization, but permanent tolerance.
Our findings suggested that SLIT with metal-binding proteins and a vitamin D3 analogue ispromising as an effective therapy for metal allergies.

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The Student and Young Scientists Award

Macrophage responses to single-walled carbon nanotubes and multi-walled carbon
nanotubes

Shin-Ichiro Yamaguchi
Laboratory of Immunology and Microbiology,
Graduate School of Pharmacy, Ritsumeikan University
Multi-walled carbon nanotubes (MWCNTs), the highly representative products ofnanotechnology, induce macrophage cell death and NLRP3 inflammasome activation leading to
granuloma and mesothelioma in rodents1),2). Single-walled CNTs (SWCNTs) are considered to beless toxic3). SWCNTs and MWCNTs show different toxicity; however, the molecular mechanisms
remain unknown. Recently we identified T cell immunoglobulin mucin（Tim）4 and Tim1 as
CNT receptors in mice4). Here we identify a Tim4-like CNT receptor CNT-R1. The gain-offunction assay using THP-1 cells ectopically expressing CNT-R1 showed that CNT-R1 mediatedphagocytosis both of SWCNTs and MWCNTs by THP-1 cells; however, these THP-1
inflammatory responses were different. MWCNTs but not SWCNTs caused lysosomal damages
and NLRP3 inflammasome activation, resulting in IL-1b secretion. On the other hand, both
MWNCTs and SWCNTs induced IL-8 secretion. Taken together, these results suggest that
SWCNTs induce only CNT-R1-signal whereas MWCNTs induce both CNT-R1 signal andlysosomal damages, which may explain the difference in toxicity between SWCNTs and
MWCNTs.
References
1) De Volder et al., Science, vol. 339, pp535-539, 2013.
2) Poland et al., Nat. Nanotechnol., vol. 3, pp423-428, 2008.
3) Genady et al., ACS Appl. Nano Mater., vol. 3, pp11819-11824, 2020.
4) Omori et al., Cell Rep., vol. 34, pp108734-108754, 2021.
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The Student and Young Scientists Award

Effects of particulate matters on the expression and function of COVID-19-related
proteins

Issei Omori
Graduate School of Engineering,
Kyoto University
It was my honor to receive the Student and Young Scientists Award at the 29th annual
meeting of the Japanese Society of Immunotoxicology. I would like to appreciate president Dr.
Kojima and the selection committee.
After the outbreak of coronavirus disease 2019 (COVID-19), many epidemiologicalstudies were conducted to determine the association between COVID-19 and air pollution acrossthe world. They showed that short and long-term exposure to PM2.5 or PM10 is associated with
COVID-19 onset, severity, and mortality. However, the mechanism by which particulate matters(PMs) affect COVID-19 aggravation is not clear.
Our research group focused on the intracellular entry mechanism of the SARS-CoV-2
virus. Viral spike proteins bind to ACE2 receptors on the surface of the host cells. After that, thespike proteins are cleaved by the TMPRSS2 on the host cells, resulting in viral genome invasion
into the cells. Thus, ACE2 and TMPRSS2 play an important role in the intracellular entry of
SARS-CoV-2. We have revealed that exposure to ambient PMs upregulates ACE2 and TMPRSS2
in the murine lung (Environ. Res., 195, 110722, 2021). However, the component of ambient PMs
that affects ACE2 and TMPRSS2 expression levels and the variation of ACE2 and TMPRSS2
functional activity were still unclear.
In the study, human alveolar epithelial cells were exposed to titanium dioxide (TiO2),
diesel exhaust particle (DEP), and Asian sand dust (ASD). TiO2 nanoparticles have a wide range
of applications such as personal care products, food additives, and paints. DEP and ASD are majorambient PM constituents and they contain many kinds of chemical and biological components
such as sulfates, nitrates, metals, and microorganisms. Expression and function assay of ACE2
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and TMPRSS2 showed that some of these PMs can promote the intracellular entry of SARS-CoV2. Thus, we revealed one possible mechanism by which PMs affect COVID-19 aggravation.

Particulate matters promote intracellular entry of SARS-CoV-2

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ImmunoTox Letter

Real Voices of International Immunotoxicologists
Jamie DeWitt
Immunotoxicology is a boundary field, and so it’s important to exchange some information
obtained from one’s experience each other. Additionally, young immunotoxicologists andstudents may hope to know a hint: what they should do now and in future? In particular, we haveless chance to know actual experience of international and senior immunotoxicologists, that’re“Real Voices”. This time, we interviewed Dr. Jamie DeWitt from East Carolina University, USA.
Let’s go to listen to his voice. What will you feel and learn?
(Check the message on the board behind Jamie with her smile, very nice!)

Jamie DeWitt, PhD, DABTProfessor
Department of Pharmacology and Toxicology
Brody School of Medicine
East Carolina University
Greenville, NC, USA
Q1. What was the most impressive event for you in your trip to Japan this time?
This was my first ever trip to Japan so it all was impressive! However, I think that what impressedme the most was how welcoming and friendly everyone was to me and my husband, who traveledwith me. Professor Kojima was the most wonderful host who took care of each and every detailso that my husband and I could enjoy the science as well as the experience of being in Hokkaido
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ImmunoTox Letterfor the first time. The scientists who we met at the JSIT meeting and at Hokkaido University
shared not only their amazing scientific work but their love of immunotoxicology and theirkindness toward us as visitors. I really enjoyed my first dinner in Hokkaido as I was able to try
many different delicious foods that I wouldn’t normally find in the U.S. I loved everything that I
tried!
Q2. What is the most exciting thing in your career to date?
My work over the past decade has focused on the immunotoxicological effects of per- andpolyfluoroalkyl substances (PFAS) and we have been working to understand why T celldependent antibody responses (TDAR) are suppressed after exposure to PFAS. We have received
funding to try to uncover some of the molecular mechanisms underlying this suppression and
we’ve been focusing on the immunometabolic processes that PFAS might be disturbing as B cells
transition from naïve B cells to antibody secreting plasma cells. It’s been exhilarating to develop
protocols to evaluate mitochondrial function within B cells! As a result of this work, we’ve also
obtained funding to develop a cell-based assay for the TDAR based on the B cell metabolic“fingerprint.” I’m excited to take our research in a more biotechnology-focused direction that I
think will add to the immunotoxicological toolbox for more rapidly screening chemicals ofpotential immunotoxicological concern.
Q3. What are the things you are doing energetically, right now?
Again, most of our work focuses on the immunotoxicological effects of PFAS. We spend most of
our time and energy trying to describe the effects of understudied PFAS that have been found in
drinking water sources here in North Carolina in the US. Some of these PFAS have been measured
in the blood of people drinking the contaminated water and there is little to no toxicologicalinformation available for these PFAS! People living in communities impacted by PFAS
contamination are concerned about the effects of PFAS exposure on their health and many arescared because of knowledge gaps that exist for some of these PFAS. We are working very hardto generate high quality data that can inform decision-making so that our state leaders can decide
if they need to move forward with measures to reduce exposures to these understudied PFAS ornot. We also are working with many of different scientists to ensure that our research on PFAS
addresses many unanswered questions and so that the pool of scientific data for PFAS is available
to many different groups of stakeholders.
Q4. What is required for breakthrough in immunotoxicology research in the future, do you
think?

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New approaches to reduce in vivo experiments and to increases the speed at which different
chemicals can be evaluated for potential immunotoxicity. Developing new approaches is
especially important for developmental immunotoxicity (DIT) as we know that the developing
immune system is very sensitive to perturbations. Right now, immunotoxicity testing is not
required under many testing paradigms for industrial chemicals or pharmacological agents.
Although there is a harmonized test guideline for evaluating immunotoxicity in adult organisms
and DIT testing can be included in a harmonized test guideline to reproductive and developmental
toxicity testing, these are not generally conducted unless a “red flag” is raised in other types oftests. For example, changes in lymphoid organ weights might trigger an evaluation of the TDAR.
However, changes in lymphoid organ weights generally occur at higher administered doses thanthose that affect the TDAR. This means that we may be failing to recognize the immunotoxic
potential of many different agents. If we had more rapid cell-based approaches for evaluating DIT
and/or immunotoxicity, then immunotoxicity testing may become a required approach.
Q5. Any other comments?
When can I come back to Hokkaido? I thoroughly enjoyed my time there and want to say a very
special thank you to Professor Kojima, Assistant Professor Kubota, and graduate student Wataru
Murase for taking my husband and I on a very special trip around Hokkaido. We enjoyed talking
about science, traveling, laughing, eating, drinking, and bathing (in the mineral baths) with our
wonderful hosts!

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ImmunoTox Letter

Comment from a Special Honorary Member of JSIT
Jack H. Dean
It was a great pleasure to learn that I had been elected a Special Honorary Member of the JapaneseSociety of Immunotoxicology (JSIT). I will start by thanking Professor K. Nakamura for mynomination and this honor. For the past 25 years I have watched and been impressed with thegrowth, direction, and development of the JSIT from a small research group into an importantnational society that helped shape the direction of Immunotoxicology both in Japan andInternationally. I am grateful for both Professors K. Nakamura and T. Yoshida and others JSIT
leaders for their continued cooperation with the Immunotoxicology Specialty Section (ITSS) of
the Society of Toxicology (SOT). This cooperation encouraged joint symposium and exchangeof researcher at both groups’ national meetings.
As a founding member and first President of the ITSS (1988) it has been a great pleasure to watch
the maturation of Immunotoxicology from an observational science describing chemical anddrugs that produced immunotoxicity into a science defining molecular pathways targeted by theseagents. These studies have also focused on the relevance of these observations in animals forman. The JSIT has been a significant contributor to this maturation and molecular focus in
Immunotoxicology. Thank you again for this special honor.
Jack H. Dean, Ph.D., Sc.D. (Hon.), Diplo. ABT, Fellow ATS

Professor Jack Dean and wife Suellen on our patio in Arizona with the family dog

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Comment from a Special Honorary Member of JSIT
Michael I. Luster
To my Japanese colleagues:
I am humbled and deeply grateful for your invitation to be an honorary member of the JapaneseSociety of Immunotoxicology. I look with great fondness when recollecting upon the developmentof the ITSS in the U.S., which only had a few members in the 1970s and was tenaciously
spearheaded by my friend, Dr. Jack Dean and then later the formation of the JSIT in 1994 and thehard work of your first president, Dr. Hiroshi Nagura. Both societies not only have thrived but
have interacted well over the years and have been instrumental in the continued development of
Immunotoxicology as an important subdiscipline in toxicology. Over the past 25 years the JSIT
has made many outstanding international contributions in both basic and applied research to help
protect human health and the environment and I am sure will continue to do so. Between the JSIT
and ITSS there are now well over 500 members.
I am also very grateful to the many Japanese scientists that I had the honor to work with in thelaboratories at NIEHS/NIH and then later at NIOSH/CDC including Drs. Tadaki Sugawara,
Wataru Toriumi and Yasuhide Kouchi. I particularly want to thank my good friends and long-timecolleagues Drs. Takahiko Yoshida and Fujio Kayama for the many excellent scientificcollaborations and friendly dinners we had over many years. I would also like to pay tribute to Dr.
Motoyasu Ohsawa, who I first met in the 1980s when he was working on cadmium
immunotoxicity and I was working with dioxins. Over the years we shared the stage at numerous
conferences and had many wonderful conversations.
Again, thank you very much for this honor
ありがとうございました
Mike Luster

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