記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2021.04.094

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/intimm/dxaa066

リポジトリ公開URL： http://hdl.handle.net/2324/4495853

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.celrep.2019.10.091

Web of Science

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1183/23120541.00500-2023

記述言語：英語  

DOI： 10.1016/j.placenta.2023.08.053

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00277-023-05391-3

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Anti-cancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections is Pneumocystis jirovecii pneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs). Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+ T cell population, with the highest CD16+ T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.

DOI： 10.7554/elife.87288.1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1183/23120541.00033-2023

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3389/fimmu.2023.1145814

記述言語：英語   出版者・発行元：Oxford University Press  

腫瘍微小環境へのエフェクターT細胞の浸潤を排除するメカニズムの解明を試みた。硫酸基転移酵素SULT2B1bによって生成される癌由来のコレステロール硫酸(CS)がRac活性化因子DOCK2を阻害し、エフェクターT細胞の腫瘍浸潤を阻害することが明らかになった。臨床サンプルを用いて、CSが大腸癌などの特定の種類のヒト癌で豊富に産生されていることを見出した。機能的には、CSを産生する癌細胞は、癌特異的T細胞移植や免疫チェックポイント阻害に対して抵抗性を示した。SULT2B1bはオキシステロールを硫酸化し、その腫瘍促進活性を不活性化することが知られているが、SULT2B1bを発現する癌ではオキシステロール産生を媒介するコレステロール水酸化酵素の発現量が低かった。したがって、SULT2B1bの阻害は、オキシステロール非産生癌の腫瘍免疫回避を妨害する治療戦略となる可能性があった。以上より、新たな腫瘍の免疫回避のメカニズムを明らかになり、効果的な免疫療法の開発に新たな知見が得られた。

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.bbrc.2022.04.035

記述言語：英語   掲載種別：研究論文（学術雑誌）  

<title>Abstract</title>
Effective tumor immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute a specialized microenvironment that excludes T cells from the vicinity of cancer cells, and its underlying mechanisms are still poorly understood. DOCK2 is a Rac activator critical for migration and activation of lymphocytes. We herein show that cancer-derived cholesterol sulfate (CS), a lipid product of the sulfotransferase SULT2B1b, acts as a DOCK2 inhibitor and prevents tumor infiltration by effector T cells. Using clinical samples, we found that CS was abundantly produced in certain types of human cancers such as colon cancers. Functionally, CS-producing cancer cells exhibited resistance to cancer-specific T-cell transfer and immune checkpoint blockade. Although SULT2B1b is known to sulfate oxysterols and inactivate their tumor-promoting activity, the expression levels of cholesterol hydroxylases, which mediate oxysterol production, are low in SULT2B1b-expressing cancers. Therefore, SULT2B1b inhibition could be a therapeutic strategy to disrupt tumor immune evasion in oxysterol-non-producing cancers. Thus, our findings define a previously unknown mechanism for tumor immune evasion and provide a novel insight into the development of effective immunotherapies.

DOI： 10.1093/intimm/dxac002

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background
IL-31 is a major pruritogen associated with atopic dermatitis (AD). Although a specific antibody for IL-31 receptor has been shown to alleviate pruritus in patients with AD, therapeutic approaches to inhibition of IL-31 production remain unexploited. IL-31 production by Th cells critically depends on the transcription factor EPAS1, which mediates IL31 promoter activation in collaboration with SP1.

Objective
We aimed at developing small-molecule inhibitors that selectively block IL-31 production by Th cells.

Methods
We generated the reporter cell line that inducibly expressed EPAS1 in the presence of doxycycline to mediate Il31 promoter activation, and we screened 9600 chemical compounds. The selected compounds were further examined by using Th cells from a spontaneous mouse model of AD and Th cells from patients with AD.

Results
We have identified 4-(2-(4-isopropylbenzylidene)hydrazineyl)benzoic acid (IPHBA) as an inhibitor of IL31 induction. Although IPHBA did not affect nonspecific T-cell proliferation, IPHBA inhibited antigen-induced IL-31 production by Th cells from both an AD mouse model and patients with AD without affecting other cytokine production and hypoxic responses. In line with this, itch responses induced by adoptive transfer of IL-31–producing Th cells were attenuated when mice were orally treated with IPHBA. Mechanistically, IPHBA inhibited the association between EPAS1 and SP1, resulting in defective recruitment of both transcription factors to the specific sites of the IL31 promoter. We also determined the structure-activity relationship of IPHBA by synthesizing and analyzing 201 analogous compounds.

Conclusion
IPHBA could be a potential drug leading to inhibition of EPAS1-driven IL-31 production.

DOI： 10.1016/j.jaci.2021.03.029

記述言語：その他   掲載種別：研究論文（学術雑誌）  

DOCK8 is a Cdc42-specific guanine-nucleotide exchange factor that is essential for the development and functions of various subsets of leukocytes in innate and acquired immune responses. Although DOCK8 plays a critical role in the spatial control of Cdc42 activity during interstitial leukocyte migration, the mechanism remains unclear. We show that the DOCK homology region (DHR)-1 domain of DOCK8 binds specifically to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and is required for its recruitment to the plasma membrane. Structural and biochemical analyses reveal that DOCK8 DHR-1 domain consists of a C2 domain-like core with loops creating the upper surface pocket, where three basic residues are located for stereospecific recognition of phosphoinositides. Substitution of the two basic residues, K576 and R581, with alanine abolished PI(4,5)P2 binding in vitro, ablated the ability of DOCK8 to activate Cdc42 and support leukocyte migration in three-dimensional collagen gels. Dendritic cells carrying the mutation exhibited defective interstitial migration in vivo. Thus, our study uncovers a critical role of DOCK8 in coupling PI(4,5)P2 signaling with Cdc42 activation for immune regulation.

DOI： 10.26508/lsa.202000873

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jaci.2019.06.031

記述言語：英語   掲載種別：研究論文（学術雑誌）  

A hallmark of humoral immune responses is the production of antibodies. This process involves a complex cascade of molecular and cellular interactions, including recognition of specific antigen by the B cell receptor (BCR), which triggers activation of B cells and differentiation into plasma cells (PCs). Although activation of the small GTPase Rac has been implicated in BCR-mediated antigen recognition, its precise role in humoral immunity and the upstream regulator remain elusive. DOCK2 is a Rac-specific guanine nucleotide exchange factor predominantly expressed in hematopoietic cells. We found that BCR-mediated Rac activation was almost completely lost in DOCK2-deficient B cells, resulting in defects in B cell spreading over the target cell-membrane and sustained growth of BCR microclusters at the interface. When wild-type B cells were stimulated in vitro with anti-IgM F(ab')2 antibody in the presence of IL-4 and IL-5, they differentiated efficiently into PCs. However, BCR-mediated PC differentiation was severely impaired in the case of DOCK2-deficient B cells. Similar results were obtained in vivo when DOCK2-deficient B cells expressing a defined BCR specificity were adoptively transferred into mice and challenged with the cognate antigen. In addition, by generating the conditional knockout mice, we found that DOCK2 expression in B-cell lineage is required to mount antigen-specific IgG antibody. These results highlight important role of the DOCK2-Rac axis in PC differentiation and IgG antibody responses.

DOI： 10.3389/fimmu.2018.00243

開催年月日： 2023年12月

記述言語：その他   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

国名：その他  

Novel mechanism of inflammation resolution by intestinal metabolites with the ability to suppress immune cell migration

開催年月日： 2023年11月

記述言語：その他  

国名：その他  

A case of high-grade VUE diagnosed by additional immunostaining rather than H&E staining alone

開催年月日： 2023年6月

記述言語：英語  

国名：その他  

Developmental mechanisms of immune-privileged environment at the feto-maternal interface.

開催年月日： 2022年11月

記述言語：その他  

国名：その他  

Cholesterol sulfate mediates tissue-specific immune evasion in the eye

開催年月日： 2022年5月

記述言語：日本語  

国名：その他  

Discovery of a cholesterol sulfate-mediated immune evasion by tumors.

開催年月日： 2022年1月

記述言語：英語  

国名：その他  

Targeted inhibition of EPAS1-driven IL-31 production by a small-molecule compound

開催年月日： 2021年12月

記述言語：英語  

国名：その他  

Targeted inhibition of EPAS1–driven IL-31 production by a small-molecule compound

開催年月日： 2021年11月

記述言語：英語  

国名：その他  

The molecular basis for IL-31 production and IL-31-mediated itch transmission: from biology to drug development

開催年月日： 2021年10月

記述言語：日本語  

国名：その他  

The development of small-molecule compounds that inhibit EPAS1-induced IL-31 production in atopic dermatitis

開催年月日： 2020年2月

記述言語：英語  

国名：その他  

Identification of the novel environmental factor essential for M cell maturation in Peyer’s patches

開催年月日： 2018年9月

記述言語：英語  

国名：その他  

The transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction

開催年月日： 2017年12月

記述言語：英語  

国名：その他  

A novel function of DOCK8 in the mucosal immune system

開催年月日： 2016年8月

記述言語：その他  

国名：その他  

Coordinate regulation of dendritic cell migration by the DOCK family of Rac guanine exchange factors

開催年月日： 2014年5月

記述言語：日本語  

国名：その他  

記述言語：英語  

国名：オーストラリア連邦  

記述言語：日本語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：英語  

記述言語：日本語  

Regulatory mechanism of IL-31 production in atopic dermatitis

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

researchmap

記述言語：日本語  

The molecular basis of IL-31 as a drug target: DOCK8 and transcription factor EPAS1

記述言語：日本語   出版者・発行元：(有)科学評論社  

記述言語：英語  

Abstract

Introduction

Mutations of DOCK8 in humans cause a combined immunodeficiency characterized by atopic dermatitis. However, the molecular link between DOCK8 deficiency and atopic skin inflammation is unknown.

Materials and Methods

The skin disease development was compared between Dock8−/− and Dock8+/−mice expressing TCR transgene. After stimulation with the cognate antigen, CD4+T cells were used for cytokine production assay, microarray analysis and ChIP assay. IL-31 promoter activation, EMSA and immunoprecipitation were performed by standard techniques. Nuclear translocation of EPAS1 was examined in mouse embryonic fibroblasts generated from wild-type and Dock8−/−mice.

Results

We found that unlike Dock8+/−mice, Dock8−/−mice spontaneously developed severe atopic skin inflammation, when crossed with transgenic mice expressing TCR with a particular antigen specificity. Upon stimulation, CD4+T cells from Dock8−/−mice produced large amounts of IL-31, a major pruritogen associated with atopic dermatitis. This IL-31 induction critically depended on the transcription factor EPAS1, and its conditional deletion in CD4+ T cells abrogated skin disease development in Dock8−/−mice. Although EPAS1 is known to form a complex with aryl hydrocarbon receptor nuclear translocator (ARNT) and control hypoxic responses, EPAS1-mediated Il31 promoter activation was independent of ARNT, but in collaboration with SP1. In addition, we found that DOCK8 acted as an adaptor and negatively regulated nuclear translocation of EPAS1.

Conclusions

EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL31 induction in CD4+T cells.

DOI： 10.4049/jimmunol.202.supp.55.11

アトピー性⽪膚炎の発症や重症化に関わる機能的な遺伝⼦多型を発⾒ ～ 痒み誘発物質IL-31をターゲットにした治療応⽤に期待 ～

アトピー性皮膚炎の発症に関わる痒み物質の産生を抑制する化合物を開発 ー痒みを根元から絶つ新たな治療の実現に期待ー

アトピーの痒みを根元から断つ! 痒み発症する物質を抑制する化合物開発 九大ら