IgEの発見から50年が経ち、マスト細胞によるアレルギー反応についてのメカニズムは徐々に解き明かされてきた。その一方で、食物アレルギーを代表とする、IgEが引き起こすI型アレルギー反応に対しては対症療法が主であり、根本的な治療法が存在していなかった。最近、新たな根治療法として免疫療法が注目されている。しかしながら、この免疫療法によるマスト細胞の減感作がどのようにして免疫応答の抑制につながるかについては、基礎的解析が乏しく今もなお不明である。本発表では、我々の研究グループが最近開発した経口免疫療法マウスモデルを用いて明らかとなったマスト細胞の新たな働きについて紹介すると共に、免疫細胞を取り巻く「微小環境」による免疫調節機構、免疫細胞―間葉系細胞の相互作用についても紹介する。

Resistin like molecule  (RELM) reportedly possesses the multiple functions including local immune response and regulation of microbiota. We revealed that not only mucus secreting epithelial cells but also macrophages in the atherosclerotic tissue and Kupffer cells in the liver express RELM High fat diet or saturated FFA increases RELMβ expression in both cells. Circulating RELMβ suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet.
Both RELM expression levels in the colon and the numbers of RELM-positive Kupffer cells were markedly increased in mice liver by methionine-choline deficient diet (MCD) feeding and in human liver of the patients with NASH. Furthermore, RELM mice were highly resistant to atherosclerosis in ApoEKO mice and the MCD-induced NASH. RELM regulated the intestinal environment, such as gut permeability measured by LPS absorption and microbiota. RELM directly enhanced immune responses of the macrophages, thus RELMKO macrophages showed less lipid accumulation and lower responsibility for LPS than control macrophages. The radiation chimeras between the wild-type and RELM KO mice revealed the requirement of both non-hematopoietic and hematopoietic cell-derived RELM for full manifestation of NASH. Increased RELM in the gut might contribute to the impaired barrier function of the colon and its resultant increased LPS absorption from the gut, while Kupffer cell-derived RELM to the high responsibility for LPS-induced inflammatory response in the liver.
We hypothesize that dietary saturated fatty acids induce RELMβ expression, signaling the necessity for inflammation into the systemic macrophages including remote foam cells and Kupffer cells, leading to chronic inflammation of lifestyle-related diseases.
1. Okubo H et al. Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice. Sci Rep. 2016 Jan 28;6:20157. doi: 10.1038/srep20157.
2. Kushiyama A et al. Resistin-like molecule β is abundantly expressed in foam cells and is involved in atherosclerosis development. Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1986-93. doi:10.1161/ATVBAHA.113.301546.
3. Kushiyama A et al. Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet. J Biol Chem. 2005 Dec 23;280(51):42016-25.

The health care system in Israel is a unique system, in which all residents have basic health insurance within one of 4 HMO's. In addition, all clinical data is digital. This allows having access to one's personal health information for decades, which then can be used for the development of new diagnosis, better treatment and the development of new innovative developments for improving the health care in Israel as well as for all human kind. Hence, the Israeli health system not only treats patients, but by utilizing big data tools, nano-technology, system medicine, etc. allow improved innovative patient care.
Prof. Itamar Grotto (Associate Director General of Israel's Ministry of Health) will briefly describe the Israeli health care system, with emphasize on issues that we believe are interesting to academic and professional audience. For example: quality indicator measurements within the community and the hospitals; patient centered care etc.
Prof. Abraham (Avi)Israeli (Chief Scientist of Israel's Ministry of Health) will speak about some innovations that stem from our health care system. This will include some innovations in regard to clinical trials utilizing stem cells; issues concerning bio-banking.

The mammalian retina is an ideal system for studying how cell types of the central nervous system are formed. My group uses genome-wide approaches to comprehensively identify the transcriptional regulatory networks that control neuronal and glial cell fate in the developing retina. I will describe our recent work on identification of transcription factors that control developmental changes in retinal progenitor competence, that control the balance of retinal neurogenesis and gliogenesis, and that control the differentiation and function of retinal glia.

A broad array of inflammatory and stress responses is frequently evoked in insulin-targeted metabolic tissues during the pathogenesis of obesity. This atypical state engages immune response pathways, including activation of a variety of stress kinases, elevated production of an array of immune mediators, and recruitment of immune cells into metabolic tissues, which negatively impact nutrient metabolism and glucose metabolism. However, the molecular basis for the induction of metabolic inflammation and the vast network of pathological responses in obesity remains elusive. Recent evidence indicates that metabolic inflammation results from deregulated double-stranded RNA (dsRNA) processing/signaling in metabolic tissues, which adversely regulates systemic glucose metabolism in obesity. These findings suggest the involvement of altered RNA networks in the immunometabolic regulation of obesity. This presentation will focus on the regulation of endogenous dsRNA and microRNA-mediated events and how their functional changes are associated with inflammatory responses and metabolic deterioration in obesity.

Environmental factors, such as the microbiome, have critical control over health and disease. Dietary antigens also have a significant influence and a recent study showed that dietary antigens uniquely limit mucosal immunity by inducing Foxp3Treg in the lamina propria of the small intestine. In sharp contrast however in Celiac Disease, gluten-reactive CD4 T cells respond as pathogenic inflammatory effector cells and cause severe destruction of the small intestine barrier. This clearly demonstrates that immune regulation and suppression is of utmost importance to prevent aberrant immune responses against food antigens. The small intestine epithelium, though, is not only exposed to food but it is also the largest and most vulnerable entry port for pathogens. Furthermore, uncontrolled infections of the epithelial cells by intracellular pathogens can lead, not only to pathogen-induced damage but also to excessive recruitment of systemic inflammatory immune cells, which can fuel severe immune pathology. Therefore, although suppression is important, immune regulation at the mucosal epithelium must coincide with rapid and effective protective immunity to quickly eliminate infected intestinal epithelial cells before the pathogen or inflammatory immune cells can cause destruction of the barrier. We recently made a major discovery that might clarify this immunological conundrum. We found that instead of becoming Foxp3Treg, CD4 T helper cells in the small intestine epithelium that respond to dietary antigens convert to protective cytotoxic cells. Moreover, by converting dietary antigen-responding CD4 T cells they also divert away from becoming inflammatory Th1 or Th17 effector cells. Based on these exciting new findings, we postulate that the reprogramming process is an alternative way of immune regulation to prevent aberrant immune responses to the diet. Furthermore, because these cytotoxic CD4 T cells react with immediate protective function in response to antigen re-stimulation in the context of danger signals, we also propose that these diet antigen-responsive protective cells participate in the direct defense against invading pathogens and in doing so prevent excessive pathogen- and/or immune-induced pathology at this fragile mucosal border.

骨格筋は我々の日常動作に不可欠な組織であり、最終分化した多核細胞である筋線維により構成されている。生理的な環境下では、筋線維の脱分化は観察されず、代わりに稀に存在する骨格筋幹細胞（別名：筋衛星細胞）が新たな筋線維を生み出す。そのため筋衛星細胞は、筋恒常性維持に必要と考えられているが、「各筋疾患に対する筋衛星細胞の寄与度」に関しては整理して議論する必要がある。
我々は、静止期状態の筋衛星細胞に特異的に発現している遺伝子に着目し研究を進めてきた。その結果、1)古典的Notchシグナル経路の直接の標的遺伝子Hey1およびHeyLが筋衛星細胞の未分化性維持に働き、2)カルシトニン受容体-cAMP-PKA/Epac 経路が筋衛星細胞の静止期・局在維持に働いていることを明らかにした。本セミナーでは、我々の研究成果を元に筋衛星細胞の維持メカニズムと「各筋疾患に対する筋衛星細胞の寄与度」の関連について紹介したい。また、最重要骨格筋研究として現在注目を集めている、加齢性筋萎縮や癌悪液質についても、我々のこれまでの研究成果を元にしたアプローチ・筋衛星細胞の関与について紹介し、議論したい。

近年HIV治療においてウイルスの膜融合や逆転写、プロテアーゼによる成熟などの各ステップを多剤併用によって阻害するHAART療法がAIDS発症抑制に一定の成果を収めているが、副作用や耐性ウイルスの出現の問題から新規治療薬の開発が求められている。一方でMERSコロナウイルスやデングウイルスといった新興感染症の原因ウイルスの感染に対しては現在までに有効な治療法が存在しない。我々はこれらのエンベロープウイルスによる感染の最初のステップである膜融合に注目し、分割レポータータンパクの再構成を指標として、多数の化合物の抑制活性を測定可能なハイスループット細胞融合アッセイを樹立した。本セミナーではこのエンベロープタンパク依存的な細胞融合アッセイの特徴である高い安定性や、ウイルスを用いずにBSL1施設で実施可能な安全性および汎用性について議論したい。また最近我々がこのアッセイを用いて既存薬の中から発見したMERSコロナウイルスの感染を強力に抑制する阻害剤について併せて紹介したい。

ゲノム編集技術は基礎研究から医療や農業・畜産にいたるまで、非常に幅広い分野での応用が進められています。ゲノム編集技術は基本的に、標的とするゲノム配列を切断する配列特異的ヌクレアーゼであり、ゲノムDNAの切断によって惹起される細胞内在性のDNA修復機構に乗じて、切断箇所周辺のゲノムDNA配列を改変することができます。
　このDNA修復機構には大別して配列相同性を持つ鋳型DNAとの組換え依存的なHDR（Homology-Directed Repair, 相同組換え）と、切断されたDNAの末端が頻繁にランダムな欠失や挿入を伴いながら結合されるNHEJ（Non-Homologous End Joining, 非相同末端結合）の２つがあります。HDRによって狙い通りの編集を行いたい場合には、同時発生するNHEJによって生じるランダムな挿入や欠失が、ゲノム編集の正確性を著しく損なってしまいます。
　私はデジタルPCRを使って、ゲノム編集結果を簡便かつ高感度に検出する系を開発してきました（Miyaoka, Nature Methods 2014; Miyaoka, Scientific Reports 2016）。この発表では、このデジタルPCRを駆使して多様なゲノム編集条件の持つHDRとNHEJ誘導活性を測定することで、NHEJ活性を抑え、HDRを特異的に誘導できるゲノム編集技術の確立を目指した取り組みについてお話しします。

1部　 HTLV-1 is not a ubiquitous virus. Indeed, this retrovirus, whose origin is the STLV-1, endemic in many species of Old-World non human primates (NHPs), is present throughout the world with clusters highly endemic located often nearby areas where the virus is nearly absent. The main endemic areas are the Southwestern part of Japan, Sub-Saharan Africa and South America, the Caribbean area and foci in the Middle East and Australo-Melanesia. The origin of this puzzling repartition geographical or sometimes rather ethnic repartition is probably linked to a founder effect in some groups with the persistence of a high viral transmission rate. Despite different socio-economic and cultural environment, the HTLV-1 prevalence increases gradually with age, especially among women in nearly all highly endemic areas. The number of HTLV-1 infected carriers in the world is estimated to be at least 5-10 millions individuals. In most of the high endemic areas, HTLV-1 is mainly disseminated and maintained in the human population through intra-familial transmission (mother-to-child and by sexual intercourses). More rarely, transmission may also occur by transfusion or intra-venous drug use. In Central Africa, the relative contribution of each of the different transmission routes for HTLV-1/STLV-1 (inter-humans vs inter-species/NHP-Humans) still remains largely unexplored. We have thus performed epidemiological studies in order to get better knowledge on the possible still ongoing STLV-1 retroviral transmission from NHPs to human in a natural setting. These studies were done in populations of high-risk individuals living in villages or settlements in the rain-forest of South Cameroun and Gabon. Bantu and Pygmy groups, who still actively hunt diverse NHP species, inhabit this region. These hunters are thus frequently exposed to the body fluids of these NHPs. Furthermore, many of the NHPs species living in these areas are infected with simian retroviruses, including various STLV-1 strains. Our main results indicate that a severe bite by a NHP is a major risk factor for HTLV-1 infection in these hunters. Furthermore, some of the HTLV-1 strains present in hunters bitten by a NHP are very closely related to some of the STLV-1 strains present in NHPs from the same areas. Indeed, all the HTLV-1-positive hunters bitten by a gorilla or a chimpanzee were infected with a subtype B strain similar to that present in apes from the same areas. Two hunters bitten by small monkeys (C. agilis in one case) were infected with an HTLV-1 subtype F strain very similar to the STLV-1 strains present in such monkeys. These results strongly suggest ongoing direct zoonotic acquisition of STLV-1 in humans through severe NHP bites during hunting activities.

1) Filippone C, Betsem E, Tortevoye P, Cassar O, Bassot S, Froment A, Fontanet A, Gessain A. A Severe Bite From a Nonhuman Primate Is a Major Risk Factor for HTLV-1 Infection in Hunters From Central Africa. Clin Infect Dis. 2015 Jun 1;60(11):1667-76.
2) Kazanji M, Mouinga-Ondémé A, Lekana-Douki-Etenna S, Caron M, Makuwa M, Mahieux R, Gessain A. Origin of HTLV-1 in hunters of nonhuman primates in Central Africa. J Infect Dis. 2015 Feb 1;211(3):361-5.
3) Richard L, Mouinga-Ondémé A, Betsem E, Filippone C, Nerrienet E, Kazanji M, Gessain A. Zoonotic transmission of two Human T lymphotropic virus type 4 strains in hunters bitten by gorillas in Central Africa. C Infect Dis, in press, 2016.

2部　The Human T Lymphotropic Virus type 1 has a global prevalence, however, most people living with HTLV-1 reside in clusters of high endemicity in resource poor countries. One such endemic focus is present in central Australia where infection with the Australo-Melanesian HTLV-1c subtype is highly prevalent among Indigenous Australians. Australia is therefore one of few countries in which a socially disadvantaged population with a high HTLV-1 prevalence coexists with a sophisticated medical system. Studying the consequences of HTLV-1 infection in this setting may therefore provide insights relevant to resource poor HTLV-1 endemic areas elsewhere.
The prevalence rate of HTLV-1 infection among Indigenous Australians exceeds 40% among Indigenous adults residing in some remote communities. An increased risk of infection among older men is unique among epidemiological studies. In central Australia, cases of Adult T-cell leukemia and HTLV-1 associated myelopathy have been reported. However, HTLV-1 infection is most often associated with chronic respiratory disease and invasive bacterial infections. The region has the highest reported prevalence of adult bronchiectasis worldwide and 60 of 106 subjects (56.7%) in this cohort are HTLV-1 infected. We have demonstrated that the risk of bronchiectasis and the extent of pulmonary injury is strongly associated with the HTLV-1 proviral load. In a region with among the highest reported incidence rates of invasive bacterial disease worldwide, a higher HTLV-1 proviral load is a major predictor of a blood stream infection. A well characterized, hospital-based cohort of 843 Indigenous adults of known HTLV-1 serostatus has now been followed prospectively for up to eight years. In this cohort, an HTLV-1 proviral load 1000/100,000 copies per 105 peripheral buffy coat cells was associated with a significant increase in risk of death, which most often resulted from complications of bronchiectasis or sepsis.
In this presentation, the epidemiology, clinical associations and outcomes of HTLV-1 infection in central Australia will be described. Research seeking to elucidate the immunological basis for the heightened risk of bacterial infection is ongoing. However, repeated exposure to virulent pathogens is an inevitable consequence of the poor social circumstances of many people living with HTLV-1 and this may play a major role in the outcome of HTLV-1 infection in resource poor areas.