Vaccine and Immunity -1

Immune response to SARS-CoV-2〇Akiko Iwasaki
Yale University School of Medicine, HHMI
The clinical presentation of COVID-19 involves a broad range of symptoms and disease
trajectories. Understanding the nature of the immune response that leads to recovery over
severe disease is key to developing effective treatments for COVID-19. In this talk, I will
discuss immune responses in COVID-19 patients with moderate and severe disease. I willcompare viral load, immune phenotype and cytokines that are predictive of mortality, anddiscuss signatures of cytokines and growth factors that associate with recovery vs. disease
exacerbation. I will also discuss sex differences in immunity to SARS-CoV-2 and how suchdifferences correspond to disease outcomes.

Vaccine and Immunity -2

Immunological memory to SARS-CoV-2 over six to eight months after
infection〇Alessandro Sette1,2 Daniela Weiskopf1 and Shane Crotty1,2
1Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology(LJI), La Jolla, CA 92037, USA, 2 Department of Medicine, Division of Infectious Diseases
and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA 92037,
USA
Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics andvaccines, and for assessing the likely future course of the pandemic. We analyzed multiple
compartments of circulating immune memory to SARS-CoV-2 in 185 COVID-19 cases,
including many cases at > 6 months post-infection. Spike IgG was relatively stable over 6+months. Spike-specific memory B cells were more abundant at 6 months than at 1 month.
SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months.
By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV2 in an integrated manner, we observed that each component of SARS-CoV-2 immune
memory exhibited distinct kinetics.

Vaccine and Immunity -3

COVID-19: Prevention and control in China and vaccine development〇George F. Gao
Chinese Center for Disease Control and Prevention
As of 1 November, nearly 46 million cases and 1.2 million deaths have been reported globally.
COVID-19 has been a global health threat and important factor that would impact theeconomic and social life worldwide in the long-term. How did China achieve the containmentof Wuhan outbreak, the following seven interventions were very important, which included
detection, isolation and quarantine of cases and close contacts, social distancing, movement
restriction, personal protective measure, social mobilization, infection prevention and control,
environment measures. Of them, active case finding and management is the core measure,which means to test each suspected case, to isolate and manage each case and to trace andquarantine each close contact. Also an effective commanding system led by State Council is
crucial. Now most areas of mainland China are virus-free and keep the containment status, so
precise COVID-19 response strategy is very important to balance the COVID-19 response
and socioeconomic development. Now we implement Aggressive Defense Strategy at New
Normal stage. The two focus include continuously and forcefully prevent importation andimplement the strategy of "protracted game of whack-a-mole" or "fire blanket strategy" tostem domestic epidemic resurgence. We should not only prevent imported by person but also
imported by contaminative cold food products. The key interventions without specificantivirals and vaccines are non-pharmaceutical interventions. The key point of current
COVID-19 response and control in China include the following aspects: early detection of
epidemic and early response, science-driven risk community classified and risk area control,
outbreak prevention and control in high risk places, strong normalization response of highrisk area, actively community mobilization and response, and powerful command and support
system. Vaccines are urgently needed to control the COVID-19 pandemic and to help thereturn to prepandemic normalcy. A great many vaccine candidates are being developed
globally, some of which have entered clinical trials. In this presentation, I will introduce thedevelopment of COVID-19 vaccines, in particular, for those under clinical evaluation in China,
including an inactivated virus vaccine, BBIBP-CorV and a protein subunit vaccine, ZF2001.

Vaccine and Immunity -4

Development of DNA vaccines targeting SARS-CoV-2〇Hironori Nakagami
Osaka University
To fight against the worldwide COVID-19 pandemic, the development of an effective andsafe vaccine against SARS-CoV-2 is required. We designed plasmid DNA vaccine targeting
the SARS-CoV-2 Spike glycoprotein (S protein) as pandemic vaccine, and the humoral,
cellular, and functional immune responses were characterized to support proceeding to initialhuman clinical trials. After intramuscular injection or intradermal injection with needlelessinjector of DNA vaccine encoding S protein (three times at 2-week intervals), the humoral
immunoreaction, as assessed by anti-S protein or anti-receptor-binding domain (RBD)
antibody titers, and the cellular immunoreaction, as assessed by antigen-induced IFN
expression, were up-regulated. We also confirmed the neutralizing action of DNA vaccineinduced antibodies. In IgG subclass analysis, IgG2b was induced as the main subclass. Basedon these analyses, DNA vaccine with alum adjuvant preferentially induced Th1-type T cell
polarization. Further B cell epitope mapping analysis using a peptide array showed that most
vaccine-induced antibodies recognized the S2 and RBD subunits. In conclusion, DNA vaccine
targeting the spike glycoprotein of SARS-CoV-2 might be an effective and safe approach.

Vaccine and Immunity -5

Nucleic acid-based immuno-prophylaxis and -therapy against COVID-19;
haste makes waste〇Ken J. Ishii
Division of Vaccine Science, The Institute of Medical Science, The University of Tokyo /Mock-up vaccine project, Center for Vaccine and Adjuvant Research, National Institute of
Biomedical Innovation, Health and Nutrition / Laboratory of Vaccine Science, Immunology
Frontier Research Center, Osaka University
Nucleic acids are an attractive molecule for both vaccine vector and immunotherapeutic
agents. It is because 1) nucleic acids are easy to produce large amount relatively in a shorttime of period, and relatively simpler and cheaper than those produced as viral or bacterial
vector or recombinant proteins. Synthetic DNA and RNA are also as an alternative
immunotherapeutic for natural compounds such as cell wall extracts and purified components
of bacteria and fungi.
While DNA vaccines have been used in animals and human, capable of priming humoral andcellular immune responses to the encoded antigen (Ag), their ability to induce Ag-specificCD8+ T cell responses remain lower than expected. Among the strategies for improving DNA
vaccine immunogenicity are booster vaccinations, alternate vaccine formulations,electroporation and genetic adjuvants, but few, such as extracellular vesicles (EVs), target
natural Ag delivery systems. I will present and discuss in detail about the results obtained by
DNA vaccination targeting EV. In addition, we are currently developing mock up vaccines
based on mRNA and lipid carrier, which seem better than conventional DNA vaccinations. I
will try to introduce our new data for COVID-19, if possible.
Clinical trials using immunostimulatory DNA or RNA, particularly agonistic as well as nonagonistic ligands for Toll-like receptors (TLRs) and stimulator of interferon genes (STING),
have revealed their therapeutic potential not only as vaccine adjuvants but also as monoimmuno-therapeutic agent such as an anti-tumor agent. I will overview the relevant R&D
against viral infections. We will discuss about new data obtained by various candidates fornext generation DNA/RNA vaccine, nucleic acid adjuvants including K/D type humanized
CpG ODN and unique STING ligands, such as nanoparticle using non-agonistic Dectin-1
ligand.

Cytokine storm and related diseases
Moderators: Hisashi Arase and Sujin Kang
The pandemic coronavirus disease 2019 (COVID-19), caused by severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), has become a serious global health threat. SARSCoV-2 infection is associated with a high risk of mortality, causing severe respiratory failure,
cardiovascular complications, and in some cases, affecting the nervous and mucosal systems.
Immunological analysis of COVID-19 patients shows that SARS-CoV-2 infection elicits acytokine storm, suggesting possible efficacy of anti-cytokine therapies. This session will
highlight the recent basic scientific breakthroughs in our understanding of the pathogenesis
of COVID-19 and related inflammatory diseases and focus on the development of new
therapeutics for COVID-19. Recent mechanistic insights into inflammatory airway disease
and their relevance to progressive lung diseases following respiratory viral infection (including
COVID-19) poses a particularly timely subject deserving of urgent attention. We anticipate
that the discussions during this session will serve to deepen our understanding of COVID-19
and look forward to your active participation.

Cytokine Storm and Related Disease -1

Interleukin-6; From Arthritis to CAR-T and COVID-19〇Tadamitsu Kishimoto
Immunology Frontier Research Center, Osaka University
Blockade of IL-6 function by anti-IL6R antibody（Tocilizumab or Actemra）has been shown
to be effective for the treatment of autoimmune inflammatory diseases including rheumatoid
arthritis. Interestingly, Actemra rescued cytokine storm induced by CAR-T cell therapy.
COVID-19 patients in the serious cases showed cytokine Release Syndrome (CRS) whichsuggested us that Actemra might be effective on the serious case of COVID-19. In thispresentation, in the first part, I will summarize the therapeutic effect of Actemra for the
disease induced by overproduction of IL-6. Then, I will talk to cytokine release syndrome by
CAR-T cell therapy and COVID-19.

Cytokine Storm and Related Disease -2

ACE2 – from fly hearts to the heart of a pandemic〇Josef penninger
Department of Medical Genetics, Life Sciences Institute, University of British Columbia,
Vancouver, Canada / IMBA, Institute of Molecular Biotechnology of the Austrian Academyof Sciences, Vienna, Austria
My group the first ACE2 mutant mice which we initially identified studying fly heartdevelopment (Crackower et al. Nature 2002). We then developed ICUs for lung failure inmice which allowed us to show that ACE2 is the essential SARS receptor in vivo (Kuba et a.
Nature Medicine) and that ACE2 protects from lung injury providing a molecular explanation
why SARS-CoV and now SARS-CoV2 become lethal diseases (as compared to other
Coronaviruses giving us the common cold) (Imai et al. Nature 2005). Over the years we also
showed that ACE2 protects multiple tissues such as the heart, lung, kidney, or blood vessels
from more serious disease and that ACE2 is also expressed in the kidney and the luminal
surface of the gut epithelium (e.g. Danilczyk et al. Nature 2006, Hashimoto et al. Nature 2012,etc). Therefore, our previous work has provided critical insights and a blueprint for thecurrent COVID-19 pandemic. I will discuss how this knowledge is being translated to clinical
trials in severe COVID-19 patients and provide new data the use of organoids in SAR-CoV-2
infection and how glycosylation affects Spike binding at real-time, single molecule resolution.

Cytokine Storm and Related Disease -3

Enhancement factors for SARS-CoV2 infection〇Hisashi Arase
Laboratory of Immunochemistry, Immunology Frontier Research Center, Osaka University /Department of Immunochemistry, Research Institute for Microbial Diseases, Osaka
University
SARS-CoV2 causes severe pneumonia in certain patients, although infected patients do notalways show severe diseases. Therefore, it is important to elucidate the factors that induce
severe diseases in SARS-CoV2-infected patients. Spike glycoprotein of SARS-CoV-2
associates with the ACE2 on host cells and mediates membrane fusion with host cell
membrane during infection. ACE2 is highly expressed on kidney and small intestine but ACE2
expression on lung is quite low. Therefore, there is a possibility that certain factors thatenhance the SARS-CoV2 infection are involved in the severe pneumonia. In order to identify
the enhancing factors for SARS-CoV2 infection, we have screened cDNA library from thelung as well as antibodies from infected patients. From these screening, we have identified
possible factors that are involved in the enhancement of SARS-CoV2 infection to host cells.
In this talk, I will discuss the function of these newly identified factors in severe pneumonia.

Cytokine Storm and Related Disease -4

Establishment and Progress of Joint Research Coronavirus Task Force inJapan〇Takanori Kanai
Department of Gastroenterology, Keio University School of Medicine
Formerly known scientists in the fields of clinical genetics, genetic informatics, molecular
oncology, basic and clinical immunology, and virology have come together to start COVID19 research (Joint Research Coronavirus Task Force). It is great that we were able to gather
together with a common passion to challenge this unknown enemy beyond academic groups
and academic societies. Now, we are fighting day and night to clarify the question "Why doJapanese people have an extremely low mortality rate due to COVID-19?" in the activities of
the Task Force. Fortunately, we were able to obtain large-scale research funding from thegovernment, and above all, we received support from medical professionals, entrepreneurs,
the media, and many hospitals fighting in the clinical setting of COVID-19 in the midst of thecorona disaster. It is becoming a base for Japan's leading corona research, clinical data, andsample biobanks. The power to abandon and mobilize against enemies that may threaten thesurvival of homo sapiens shares a sense of exhilaration and mission that has never been
experienced with members of the Task Force All the members of the Task Force think that "apinch is an opportunity" based on "helping if there is a person in need", and through thiscorona host gene research, gather the stupid power and wisdom of the fire place to control
the corona. Looking back on history, I hope that "pinch" (war and pandemic) will create
scientific innovation, and that the battle with the new corona will bring new treatments
through innovation, which will surely be overcome in the future. In this talk, I would like tointroduce the establishment and progress of the Joint Research Coronavirus Task Force, as
well as my personal views on the aspects of corona infection as an intestinal infectious disease
and its cytokine storm prevention.

Cytokine Storm and Related Disease -5

Dynamic changes in host nuclear system to virus infection〇Yumiko ImaiNational Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN)
Virus-host interaction controls immune and inflammatory responses in host, leading to theformation of severe pathology of infectious diseases. Here we focus on the dynamic changes
in host nuclear system to influenza virus infection from the aspect of lipid metabolism andvirus RNA transport as well as host chromatin 3D structures.

Review Talk and Panel Discussion
Current status and Mystery of Covid-19

Coordinator: 反町典子
国立研究開発法人国立国際医療研究センター研究所
本セッションでは、大阪大学宮坂昌之先生による COVID-19 の謎と現状についてオー
バービュートークで情報を整理いただいたのち、国内で COVID-19 の病態解析と治療法開発研究に携わるトップサイエンティストをパネリストとしてお迎えし、ワクチンや治療法開発の現状と展望、民族間の SARS-CoV-2 感受性の違いの謎、SARS-CoV-2 の免疫学的特性と治療開発における問題点などについて、多角的視野から議論いただきます。多くの情報が錯綜する現状、COVID-19 の病因病態論を正しく整理し、今後解決されるべき問題とそこに存在する困難を共有することで、今そこにある危機に免疫学研究
者はどう対応していくか、さらには SARS-CoV-2 に限らず、将来発生しうる未知の新興感染症に対して、免疫学はどのように貢献していくかを考える機会とさせていただければと考えています。言語は日本語としますが、英語の同時通訳がご利用できます。短
い時間ではありますが、可能な限りチャットを通じて質問、ご意見等も反映させながら進めて参ります。皆様の積極的なご参加をお待ちしております。
Review Talk: 宮坂昌之

大阪大学免疫学フロンティア研究センター
新型コロナウイルス感染症にはお互いに真逆の意見が飛び交っている。たとえば、「新型
コロナウイルス感染症は恐ろしい病気。何もしないと何十万人も亡くなる」。
「いや、新型コロナはインフルエンザ程度。何を恐れているのか」。あるいは、「この病気は一度かかっ
たら、免疫ができて二度目はない。どんどんかかったほうがよい」、「いや、免疫はすぐに消えるので、再感染する。わざとかかる意味はない」。
「日本の社会には集団免疫がもうできている。第三波など来ない」。
「いや、集団免疫はなかなかできない。しばらくは感染の波が毎年繰り返すはず」、「検査が大事。PCR 検査をやりまくれば感染者が見つけられるので、流行が収束する」。
「いや、網羅的な PCR 検査はまるで意味がない」…。何が正しいのか？この review talk では、新型コロナウイルスに対する免疫反応とその問題点について討論する。

Technical Seminar 1

Regulation of tissue specific inflammation via the IL-6 amplifier andgateway reflexes〇Masaaki Murakami
Division of Psychoimmunology, Institute for Genetic Medicine, Hokkaido University
We discovered two mechanisms that regulate inflammatory diseases: the IL-6 amplifier andgateway reflex in 2008 and 2012, respectively. The IL-6 amplifier is hyper NFkB activation
machinery in nonimmune cells including fibroblasts and endothelial cells. It is activated by
the simultaneous activation of NFkB and STAT3 in cells of the affected regions, enhancing
the expression of NFkB targets such as cytokines, chemokines, and growth factors. Somedisease-associated genes activate the IL-6 amplifier by enhancing the NFkB pathway in tissuespecific populations such as kidney tubular cells and keratinocytes. The gateway reflex, which
is a new concept in the field of neuro-immune interactions, describes neural circuits that
establish gateways for autoreactive T cells to enter organs that have bloodbarriers, leading totissue-specific autoimmune diseases. Notably, the gateways are established at endothelial cellsby sympathetic-mediated activation of the IL-6 amplifier. I will explain the IL-6 amplifier andthe gateway reflex, beginning from their discoveries to recent advances with experiments
using CytoFLEX and MoFlo Astrios.

Technical Seminar 2

Introducing New StarBright Dyes, New bright fluorescent nanoparticles
developed for Flow Cytometry.
〇Nobuyuki Nakata
Bio-Rad Laboratories
StarBright Dyes are generated from different monomers, modification of the polymerization
process produces exacting excitation and emission characteristics with maximal brightness.
StarBright Dyes are conjugated to our highly validated flow antibodies, and the brightness
allows easy resolution of rare populations and low density antigens while maintaining theflexibility to fit to into any multicolor panel.

Technical Seminar 3

COVID-19: stimulation, analysis and safe sorting of rare antigen- and virusspecific T cells〇Marcello Stein and Felix Eppler
Miltenyi Biotec B.V. & Co. KG
Analysis of antigen- and virus-specific T cells is essential to the understanding of fundamental
immunological processes in the contexts of e.g. infectious diseases, immuno-oncology, as wellas immune tolerance.
In COVID-19, for instance, the presence of SARS-CoV-2 reactive T cells indicates an infected
or convalescent donor and may also allow conclusions on disease progress, severity, specificimmune reaction and status.
However, working with antigen- and virus-specific T cells poses several challenges toresearchers. Their low frequencies often hamper a reliable analysis. Specificity, inflammatoryenvironment, subtype as well as detection limit and background are determining factors andthus require optimized procedures in order to facilitate a successful experiment. Moreover,potentially hazardous material poses a high risk of infection to the operator.
In response, researchers are exploring more reliable and safe workflow solutions for efficient
stimulation, precise analysis as well as safe and gentle cell sorting in especially the context of
infectious diseases such as COVID-19.
Miltenyi Biotec hereby offers a complete workflow addressing said challenges, with the SARSCoV-2 PepTivator® Peptide Pools, REAfinity™ Recombinant Antibodies and flow analysis
kits as well as closed and aerosol-free cell sorting on the MACSQuant® Tyto®.
It’s all about finding the needle in the haystack!

Presentation by Outstanding Young Immunology Researcher Award Winners「若手免疫学研究支援事業受賞者成果発表」

Elucidation of surface marker profiles defining progenitor exhausted T
cells〇Yuki Kagoya
Division of Immune Response, Aichi Cancer Center Research Institute / Laboratory ofParasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutesof Health, Bethesda, USA.
Exhausted T cells comprise a heterogeneous population, in which only less differentiated T
cells called progenitor exhausted T cells (TPEX) can be reinvigorated by immune checkpoint
blockade. In this study, we thoroughly explored surface marker profiles that are able to define
TPEX using an in vivo adoptive cancer immunotherapy model. I will present our screening
experiment results and discuss functional roles of a candidate molecule in antitumor T cells.

Differentiation of a novel memory-phenotype CD4+ T lymphocyte
population and its immunological significance〇Takeshi Kawabe
Department of Microbiology and Immunology, Tohoku University Graduate School of
Medicine, Sendai, Japan / Laboratory of Parasitic Diseases, National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, USA
We recently reported that CD4+ T lymphocytes contain an innate memory-phenotype (MP)cell population in steady state. However, it is unclear whether MP cells are heterogeneous,and if so, what signals specify their differentiation. Here we show that among MP cells, Tbethi subset is the population with innate immune function and generated dependently of
DC1-derived IL-12. In the presentation we will discuss the detailed mechanism of this tonic
IL-12 production as well as further characterization of MP cells.

In vivo spatial transcriptomics reveals the effect of anti-PD-L1 treatment in
the supply of tumor-infiltrating CD8+ T cells in Lewis lung carcinoma modelin mice.
〇Shigeyuki Shichino, Satoshi Ueha, Chang-Yu Chen, and Kouji Matsushima
Tokyo University of Science, Japan
Immune-checkpoint blockades (ICB) exert anti-tumor effect by activating CD8+ T cells.
However, which supply of CD8+ T cell subsets are affected by ICB remains elusive. To address
this question, we analyzed LLC tumor by combining intravenous staining (IVS) and scRNAseq. We found that anti-PD-L1 treatment decreased the frequency of stem-like CD8+ T cells
and, increased terminally-exhausted/ proliferated CD8+ T cells. We also found that anti-PDL1 treatment only increased the frequency of 24hrs IVS+ exhaust progenitor-2 (Gzmahi
Nr4a1hi Ccr2hi Rorahi), suggesting that anti-PD-L1 might enhance supply of exhaustprogenitor-2 from blood circulation, and local proliferation of terminally-exhausted CD8+ T
cells. These results may point out the action of anti-PD-L1 therapy in the supply of tumorinfiltrating CD8+ T cells.

Clinical Seminar 1

Immunogenicity of biologic therapies in immune-mediated diseases〇Keishi Fujio
The University of Tokyo
In recent years, the use of antibodies and other biologics has become widespread in a variety
of diseases. Biologics have a clear mode of action which is associated with few side effects.
However, their foreign epitopes sometimes induce the immune response, which can beproblematic in reducing their effectiveness. Clinical data from a number of drugs, including
anti-TNF inhibitor antibodies, have shown that antidrug antibodies can attenuate the efficacyof treatment and prevent continuation of treatment. Although the appearance of antibodies
can be suppressed by immunosuppression, there are some cases in which immunosuppression
cannot be used due to patient complications. IL-6 receptor-inhibiting antibodies are lessfrequent than TNF-inhibiting antibiotic antibodies, which may be influenced by the class of
biologic agents. Therefore, less immunogenic preparations are being developed, and recently
approved drugs tend to be less immunogenic than existing drugs. This seminar will discuss
the immunogenicity of biologics and the treatment of immune-mediated diseases in light of
the latest reports.

Clinical Seminar 2

Multiple mechanisms of action of abatacept in treatment of rheumatoid
arthritis〇Masataka Kuwana
Nippon Medical School Graduate School of Medicine, Tokyo, Japan
Rheumatoid arthritis (RA) is one of systemic autoimmune diseases that mainly affects joint
synovium. More than 80% of the patients have circulating autoantibodies, such as rheumatoid
factor and anti-citrullinated antigen antibodies (ACPA), which are shown to be pathogenic.
In fact, rituximab and abatacept, CTLA4-Ig, are effective for RA. The mechanism of action ofabatacept is believed to be competitive inhibition of T-cell co-stimulation mediated throughbinding of CD28 to CD80/CD86 on antigen-presenting cells, resulting in induction of anergy
in antigen-exposed T cells. On the other hand, recent studies suggest that signal transduction
through binding of abatacept to CD80/CD86 on monocyte-lineage cells is potentiallyinvolved in the therapeutic action of abatacept. Namely, abatacept directly suppresses
differentiation of osteoclast precursors within circulating monocytes through upregulation ofIndolamine 2,3-dioxygenase (IDO), leading to inhibition of formation of bone erosions. We
have recently found direct effects of abatacept on circulating monocytes, which down-regulate
expression of CD64 and inhibit ACPA-immune complex-mediated inflammatory cytokine
production. Abatacept has a unique mechanism of action that suppresses pathogenic
processes of RA in multiple checkpoints.

Clinical Seminar 3

Treatment of rheumatoid arthritis under COVID19 pandemic - Mechanisms
and related immunosuppressive therapy〇Isao Matsumoto
Division of Rheumatology, Department of Internal Medicine, University of Tsukuba
The COVID-19 pandemic has significantly changed the landscape of healthcare. Somepatients with rheumatoid arthritis (RA) are concerned that RA may make them susceptible tosevere forms of infection, or avoid visiting crowded hospitals where possible, and/or wish tominimize immunosuppressive therapy. On the other hand, dramatic advances in the
management of RA are ongoing, and the earliest possible diagnosis and active intervention
are recommended, with the goal of inducing and maintaining remission even in patients withhigh disease activity. Currently, many types of drugs, such as TNF inhibitors, IL-6 inhibitors,
selective T-cell costimulation blockers, and JAK inhibitors, are available in Japan, but there
remains a gap between remission induction and maintenance; in real-world settings, somepatients achieve resolution of inflammation but still experience subjective symptoms such as
stiffness and pain, which fail to improve adequately.
JAK inhibitors, which are as effective as biologics, are currently approved in five drug
products. JAK inhibitors are small-molecule compounds that inhibit the activity of kinase
functioning downstream of cytokine receptors and have a variety of targets. Their availability
in oral forms offers great advantages, including improved treatment compliance.
This seminar discusses and provides an overview of the importance of remission maintenanceand its association with immunosuppressive therapy in the management of RA amid thecoronavirus pandemic, with some insights into new pathogenetic mechanisms of RA andcharacteristics of JAK inhibitors.

Clinical Seminar 4

Recent developments in eosinophilic granulomatosis with polyangiitis〇Shunsuke Furuta
Chiba University
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare form of anti-neutrophil
cytoplasm antibody (ANCA)-associated vasculitides characterized by small vessel vasculitis
associated with bronchial asthma and eosinophilia. This presentation will focus on recent
developments in EGPA. As to the criteria for EGPA, the new classification criteria for EGPA
was generated by a large international cohort and will be launched in the near future. The newcriteria are expected to have better sensitivity and specificity than the previous ones.
In contrast to other forms of ANCA-associated vasculitis, roles of ANCA in EGPA are stilllargely unknown. There are phenotypic differences between ANCA-positive and -negative
EGPA. A recent genome-wide association study revealed that there were two geneticallydistinct subgroups of EGPA, which correspond to ANCA-positive and -negative subgroups.
Reliable evidence of treatment for EGPA is still limited at the moment. Thus, there are nostrong recommendations for treatment of EGPA. Recently the efficacy of mepolizumab, antiIL-5 antibody, for EGPA were proved by a randomized controlled trial. Currently, various
new drugs are under evaluation.

Clinical Seminar 5

COVID-19 virological understanding and treatment / prevention strategy〇Kimiyasu Shiraki
Senri Kinran University
Favipiravir has been developed as an anti-influenza drug and showed a broad spectrum ofanti-RNA virus activity. The mode of antiviral action is a chain terminator of RNA strand
elongation at the incorporated site similar to acyclovir in herpes virus and favipiravir shows
the therapeutic efficacy in lethal RNA virus infection with high viral load by reducing viral
replication. Plasma level of favipiravir in influenza dose far exceeded the antiviralconcentration of favipiravir against SARS-CoV-2 and favipiravir demonstrating clinicalefficacy in clinical trials in COVID-19 patients. COVID-19 pneumonia is a 3-week illness
consisting of a viral growth period and an inflammatory reaction time due to an immune
response and Favipiravir significantly reduced the time to clinical improvement in patientswith COVID-19 pneumonia from 14.7 days to 11.9 days in the placebo group. This indicatedthat favipiravir reduced viral growth time by 2.8 days and inhibited 11 viral replication cycles,
because the antiviral drug cannot shorten the time of immune response and inflammation.

Clinical Seminar 6

Recent advances and challenges with immune checkpoint inhibitors〇Shohei Koyama
Division of Cancer Immunology, Research Institute/Exploratory Oncology Research &Clinical Trial Center (EPOC), National Cancer Center / Department of Respiratory
Medicine and Clinical Immunology, Osaka University Graduate School of Medicine
Immune checkpoint inhibitors (ICIs) have been approved for multiple types of cancers. A
long-term durable response is a feature of this treatment; however, only some patients havefavorable response to ICIs. To improve outcomes, mechanisms underlying either sensitivity
or resistance to ICIs need to be elucidated. In this seminar, I will talk about recent advancesand challenges with ICIs from immunologic and genetic perspectives.

Clinical Seminar 7

Reconsidering IL-6 receptor inhibition in autoimmune and inflammatory
conditions〇Isao Matsumoto
Division of Rheumatology, Department of Internal Medicine, University of Tsukuba
Recent therapies for rheumatoid arthritis (RA) are dramatically progressed continuously, anda lot of biologics targeting inflammatory cytokines (TNF alpha and IL-6), T cells-co
stimulator and JAK are available in Japan. From the view of the effective therapy with newmolecular, immunological and genetic studies, the etiology of RA has been reconsidered.
Especially, IL-6 blockade has been approved for the treatment of RA, juvenile idiopathic
arthritis, adult-onset Still's disease, giant cell arteritis and Takayasu arteritis, neuromyelitis
optica, Castleman disease and cytokine release syndrome. As well known, IL-6 isproinflammatory cytokine that has multiple roles in the dysfunction of the immune andinflammatory systems. In this seminar, we will discuss about the evidence of anti-IL-6R
therapy in bone destruction and skeletal muscle. Also, we will discuss about the mechanismsof autoimmune arthritis mainly focusing on another acute phase protein, such as inter-alphatrypsin inhibitor heavy chain4 (ITIH4),that is proved major increased protein in post RA
progression with native and its citrullinated form.

Clinical Seminar 8

Advance in synovial biology and blockade of TNF-induced signaling
pathways〇Shinsuke Yasuda
Tokyo Medical and Dental University
In patients with rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) play essential
roles such as pannus formation, invasion and release of several key molecules including IL-6,
RANKL and MMPs. Recently, multi-omics studies on RA-synovium revealed signal pathways
relevant to RA, FLS subsets related to RA which produce inflammatory cytokines and theexistence of FLS-like cells in peripheral blood from pre-flare patients. Nevertheless, TNFinduced behavioral changes in FLS substantially contribute to the pathophysiology of RA.
Under continuous stimulation of TNF, RA-FLS turns to inflammatory/proliferative
phenotype, mainly via activation of NF-kB and MAP kinase pathways. Recently we identified
that NF-kB, generally recognized as the downstream of RANKL-RANK, binds to thepromoter of RANKL and induce its expression. Such positive feedback loop would be arealistic treatment target for RA. microRNA-9 accelerated degradation of NF-kB1 andreduced RANKL expression in RA-FLS. Intra-articular microRNA-9 administration
ameliorated collagen-induced arthritis in rats. RasGRP1,3 and 4 activates Ras upstream of
MAP kinase pathway, while RasGRP2 activates Rap1 inducing actin aggregation and NF-kB
pathway activation. We identified high expression of RasGRP2/4 in a subset of RA patients.
Intra-articular knockdown of RasGRP2/4 also ameliorates collagen-induced arthritis. In
clinical practice, TNF-inhibitor with low immunogenicity exerts long-standing efficacy in the
majority of TA patients.

Thus, as treatment strategies for RA, TNF-induced signal

pathway could be currently inhibited by anti-TNFmonoclonal antibodies, and would be
abrogated at multiple steps in near future, hopefully.

Clinical Seminar 9

Recent advancement in immune-mediated neuropathies〇Sonoko Misawa
Department of Neurology, Graduate School of Medicine, Chiba University
There are numbers of immune mediated disorders that affect the central and peripheral
nervous systems. This walk will introduce recent advancement in pathophysiology, diagnosis,
and treatment of Guiilain Barré syndrome (GBS) and chronic inflammatory demyelinating
polyneuropathy (CIDP) that are representative immune mediated peripheral nervous
disorders.
GBS typically causes acute tetraplegia after preceding infection. Almost 20% of patientscannot walk independently even after one year from the onset if they are treated appropriately
by immunoglobulin of plasma pheresis. There can be numbers of pathological pathways
during acute phase of GBS. Among them, activation of complement and resulting membrane
attack complex formation can be the final step leading to irreversible nerve damage. Noveldrugs, such as monoclonal antibody that targets complement protein and IgG degrading
enzyme of Streptococcus pyogenes, have been applied to GBS.
CIDP is a demyelinating polyneuropathy that causes chronic progressive weakness andparesthesia. CIDP has been considered as a syndrome that consists of multiple disorders,
because there are different clinical phenotypes regarding symptoms, courses, and treatment
responsiveness. New pathogenic autoantibodies, such as NF155 and CNTN1 antibodies, were
found and clinical phenotypes of CIDP related those antibodies have been demonstrated.
They are usually refractory to standard care such as steroid, immunoglobuline, andplasmapheresis, and rituximab has been applied to treat them.

Clinical Seminar 10

Recent advances in understanding the JAK-related pathogenesis ofrheumatoid arthritis.
〇Hirofumi Shoda
Department of Allergy and Rheumatology, Graduate School of Medicine, the University of
Tokyo
Several cytokines contribute to the pathogenesis of rheumatoid arthritis (RA), and biologicalreagents against inflammatory cytokines, such as TNF-alpha and IL-6, occupy the main
position in the therapeutic strategy of RA. Recently, JAK inhibitors are also regarded as
indispensable drugs for the treatment of RA. Many clinical studies demonstrated the efficacy
of JAK inhibitors and long term observation revealed their safety profiles.
Recent advances in the basic studies shed light on the new players in the pathogenesis of RA.
Particularly, multi-omics study focuses on the synovial infiltrated cells. One of the important
players is peripheral helper T (Tph) cells. Tph cells infiltrate RA synovial tissue and help B
cell accumulation and differentiation. Tph cells induce antibody secretion from B cells via IL21. IL-21 signaling depends on JAK1/3. Indeed, there are some reports, which showed that
tofacitinib has an impact on B cells.
Another important player is fibroblast-like synoviocytes (FLS). Recent studies showed thatCD90+FLS has a pro-inflammatory phenotype and is a key player in the pathogenesis of RA.
Our recent study revealed that cytokine combination is required for epigenetic changes andthe transcription of inflammatory genes in FLS (Tsuchiya H, Ohta M, et al. Ann Rheu Dis.
accepted).
In this session, recent advances in understanding the JAK-related pathogenesis of RA will be
reviewed and discussed together.

Clinical Seminar 11

The current trend of Progressive-Fibrosing Interstitial Lung Disease (PFILD)〇Kenji Tsushima, MD, PhD
International University of Health and Welfare, School of Medicine, Professor and Chairmanof Department of Pulmonary Medicine
PF-ILD is a collective term used for indications that share a common progressive phenotype.
The phenotype is characterized by worsening respiratory symptoms, lung function decline,
limited response to immune-modulatory therapies, decreased quality of life, and potentially,
early death. Interstitial lung disease (ILD) encompasses a large group of more than 200
parenchymal pulmonary disorders, of which the majority are classified as rare. ILD is further
classifies into various types and subtypes. The major classification includes idiopathic
interstitial pneumonia (IIPs) including idiopathic pulmonary fibrosis (IPF), autoimmune
ILDs, hypersensitivity pneumonitis (HP), sarcoidosis, and several other ILDs. Further, IIPs
are classified into idiopathic pulmonary fibrosis (IPF), iNSIP, unclassifiable IIPs, and others
IIPs. Autoimmune ILDs are classified into interstitial pneumonia with autoimmune features(IPAF), RA-ILD, SSc-ILD, and other autoimmune ILDs.
Evidence-based treatment for patients with PF-ILD are currently limited, and often receive
corticosteroids. Because of commonalities between IPF and PF-ILDs, it has been proposedthat the potential efficacy and tolerability of antifibrotic drugs, like nintedanib, should be
evaluated in PF-ILDs. By far, the most commonly used first-line therapy for all the non-IPF
fibrosing ILDs was corticosteroids. Because PF-ILDs have been defined by fibrotic
progression despite conventional therapy, there is inherently a substantial unmet need for thetreatment of these conditions. Antifibrotic drugs effective to slow down disease progression
in IPF may conceivably have comparable efficacy in other PF-ILDs.