研究者詳細 - 植木　重治

There is considerable interest in expanding B cell-targeted therapies in human autoimmune diseases. However, clinical trials in human primary biliary cholangitis (PBC) using a chimeric antibody against human CD20 (hCD20) have showed limited efficacy. Two potential explanations for these disappointing results are the appearance of anti-drug antibodies (ADAs) and the high frequency of patients with moderate PBC or patients who had failed ursodeoxycholic acid treatment. Here, we studied a novel humanized IgG1 antibody against hCD20 and explored its efficacy in early stage PBC using a well-defined murine model. We developed a unique murine model consisting of dnTGF-βRII mice expressing hCD20 and human Fcγ receptors (hFcγRs). Beginning at 4-6 weeks of age, equivalent to stage I/II human PBC, female mice were given weekly injections of an anti-hCD20 antibody (TKM-011) or vehicle control, and monitored for liver histology as well as a broad panel of immunological readouts. After 16 weeks' treatment, we observed a significant reduction in portal inflammation, a decrease in liver-infiltrating mononuclear cells as well as a reduction in liver CD8+ T cells. Importantly, direct correlations between numbers of liver non-B cells and B cells (r = 0.7426, p = 0.0006) and between numbers of liver memory CD8+ T cells and B cells (r = 0.6423, p = 0.0054) were apparent. Accompanying these changes was a dramatic reduction in anti-mitochondrial antibodies (AMAs), interleukin (IL)-12p40 and IL-5, and elevated levels of the anti-inflammatory chemokine CXCL1/KC. In mice that developed ADAs, clinical improvements were less pronounced. Sustained treatment with B cell-targeted therapies may broadly inhibit effector pathways in PBC, but may need to be administered early in the natural history of PBC.

DOI PubMed

Charcot-Leyden crystal formation is closely associated with eosinophil extracellular trap cell death

Ueki S.

Blood ( Blood ) 132 ( 20 ) 2183 - 2187 2018年11月

Protein crystallization in human tissue rarely occurs. Charcot-Leyden crystals (CLCs) were described in various eosinophilic diseases >150 years ago, but our understanding of CLC formation still remains limited. In this study, we demonstrate that CLCs observed in varied inflamed human tissues are closely associated with eosinophil cell-free granules and nuclear envelope/plasma membrane disintegration with release of filamentous chromatin (extracellular traps), typical morphologies of a regulated pathway of extracellular trap cell death (ETosis). During the process of eosinophil ETosis, eccentrically localized cytoplasmic and perinuclear CLC protein (galectin-10) is homogeneously redistributed in the cytoplasm. Rapid (1-2 minutes) formation of intracytoplasmic CLCs was observed using time-lapse imaging. Plasma membrane rupture enabled the release of both intracellularly formed CLCs and soluble galectin-10 that further contributed to formation of CLCs extracellularly, in parallel with the expulsion of free intact granules and extracellular traps. CLC formation and galectin-10 release were dependent on nicotinamide adenine dinucleotide phosphate oxidase activation. To our knowledge, this is the first demonstration of natural formation of CLCs in association with an active physiological process (ie, ETosis). These results indicate that dynamic changes in intracellular localization and release of galectin-10 contribute to CLC formation in vivo and suggest that CLC/galectin-10 might serve as an indicator of ETosis.

DOI PubMed

Eosinophil extracellular traps and inflammatory pathologies-untangling the web!

Mukherjee M.

Frontiers in Immunology ( Frontiers in Immunology ) 9 ( NOV ) 2763 - 2763 2018年11月

Eosinophils are an enigmatic white blood cell, whose immune functions are still under intense investigation. Classically, the eosinophil was considered to fulfill a protective role against parasitic infections, primarily large multicellular helminths. Although eosinophils are predominantly associated with parasite infections, evidence of a role for eosinophils in mediating immunity against bacterial, viral, and fungal infections has been recently reported. Among the mechanisms by which eosinophils are proposed to exert their protective effects is the production of DNA-based extracellular traps (ETs). Remarkably, DNA serves a role that extends beyond its biochemical function in encoding RNA and protein sequences; it is also a highly effective substance for entrapment of bacteria and other extracellular pathogens, and serves as valuable scaffolding for antimicrobial mediators such as granule proteins from immune cells. Extracellular trap formation from eosinophils appears to fulfill an important immune response against extracellular pathogens, although overproduction of traps is evident in pathologies. Here, we discuss the discovery and characterization of eosinophil extracellular traps (EETs) in response to a variety of stimuli, and suggest a role for these structures in the pathogenesis of disease as well as the establishment of autoimmunity in chronic, unresolved inflammation.

DOI PubMed

Topical 3-bromopyruvate is a novel targeted therapy for melanoma in a preclinical model

Yamada M.

Journal of Dermatological Science ( Journal of Dermatological Science ) 92 ( 2 ) 134 - 142 2018年11月

BACKGROUND: Targeting cancer metabolism is a promising strategy in improving cancer treatment. OBJECTIVE: To introduce a targeted therapy with topical 3-bromopyruvate (3BP), aglycolytic inhibitor, into the clinic in the near future. METHOD: We investigated the anti-tumor efficacy of 3BP on melanoma cells in vitro and in a preclinical model. RESULTS: Our cell-based study demonstrated that 3BP showed cytotoxicity for melanoma cells under anchorage-dependent or independent cell growth via a reactive oxygen species-mediated and caspase-independent cell death pathway. Moreover, 3BP inhibited both self-renewal potential and growth of slow-cycling phenotype in melanoma cells. Remarkably, the preclinical mouse xenograft model shed light on topical application of 3BP, showing significant anti-tumor effects with no apparent toxicity in surrounding normal tissues. CONCLUSION: We have now proposed that a targeted therapy with topical 3BP is an innovative strategy for adjuvant chemotherapy of technically or medically unresectable melanoma and possibly other skin cancers.

DOI PubMed

Somatic Mutations of Myeloid Malignancy-Associated Genes in Acquired Pure Red Cell Aplasia in Adults

Makoto Hirokawa, Junki Kohmaru, Souichi Koyota, Keiji Kuba, Naohito Fujishima, Tomoo Saga, Ayumi Omokawa, Shigeharu Ueki, Fumihiro Ishida, Shinji Nakao, Akira Matsuda, Akiko Ohta, Kaoru Tohyama, Ryuji Suzuki, Kinuko Mitani

BLOOD ( AMER SOC HEMATOLOGY ) 132 2018年11月

研究発表要旨（国際会議）

DOI

Allergic bronchopulmonary aspergillosis-A luminal hypereosinophilic disease with extracellular trap cell death

Ueki S.

Frontiers in Immunology ( Frontiers in Immunology ) 9 ( OCT ) 2346 - 2346 2018年10月

Allergic bronchopulmonary aspergillosis (ABPA) is characterized by an early allergic response and late-phase lung injury in response to repeated exposure to Aspergillus antigens, as a consequence of persistent fungal colonization of the airways. Here, we summarize the clinical and pathological features of ABPA, focusing on thick mucus plugging, a key observation in ABPA. Recent findings have indicated that luminal eosinophils undergo cytolytic extracellular trap cell death (ETosis) and release filamentous chromatin fibers (extracellular traps, ETs) by direct interaction with Aspergillus fumigatus. Production of ETs is considered to be an innate immune response against non-phagocytable pathogens using a "trap and kill" mechanism, although eosinophil ETs do not promote A. fumigatus damage or killing. Compared with neutrophils, eosinophil ETs are composed of stable and condensed chromatin fibers and thus might contribute to the higher viscosity of eosinophilic mucus. The major fate of massively accumulated eosinophils in the airways is ETosis, which potentially induces the release of toxic granule proteins and damage-associated molecular patterns, epithelial damage, and further decreases mucus clearance. This new perspective on ABPA as a luminal hypereosinophilic disease with ETosis/ETs could provide a better understanding of airway mucus plugging and contribute to future therapeutic strategies for this challenging disease.

DOI PubMed

Efficacy of Humanized Anti-Human CD20 on Early Stage Murine Autoimmune Cholangitis Using Human CD20 and Fc gamma r Expressing DnTGF beta RII Mice

Moritoki Yuki, Tsuneyama Koichi, Nakamura Yuka, Kikuchi Kentaro, Shiota Akira, Ohsugi Yoshiyuki, Lian Zhe-Xiong, Zhang Weici, Yang Guo-Xiang, Ueki Shigeharu, Takeda Masahide, Omokawa Ayumi, Saga Tomoo, Saga Akiko, Watanabe Daisuke, Miura Masahito, Ueno Yoshiyuki, Tanake Atsushi, Leung Patrick S. C, Gershwin M. Eric, Hirokawa Makoto

HEPATOLOGY ( WILEY ) 68 1103A - 1103A 2018年10月

Urine Xanthine Crystals in Tumor Lysis Syndrome

Omokawa A.

Urology ( Urology ) 120 e9 - e10 2018年10月

Urine xanthine crystals are remarkably rare but can be observed by routine urine microscopy. We report the results of a 67-year-old man with T-cell-prolymphocytic leukemia whose urine contained xanthine crystals after chemotherapy and prophylactic administration of febuxostat. Accumulation of xanthine was due to tumor lysis syndrome causing a massive release of DNA. The metabolized DNA caused an increase of xanthine, which was not readily converted to uric acid by xanthine oxidase because of febuxostat inhibition of this enzyme.

DOI PubMed

好酸球のETosisによるシャルコー・ライデン結晶の形成

植木重治, 竹田正秀, 面川歩, 嵯峨知生, 守時由起, 鎌田由美子, 廣川誠, 福地峰世, 丹典子, Weller Peter F., Melo Rosana C.N.

臨床病理 ( 日本臨床検査医学会 ) 66 ( 補冊 ) 216 - 216 2018年10月

当院臨床分離株を対象としたPOT法によるAcinetobacter属菌の菌種推定性能評価

安保康太郎, 鎌田尚未, 岩谷麻由, 達子瑠美, 高橋智映, 小林則子, 長谷川諒, 渡部健, 面川歩, 植木重治, 嵯峨知生, 廣川誠

緑膿菌感染症研究会講演記録 ( 緑膿菌感染症研究会 ) 52回 83 - 86 2018年10月

自施設およびゲノムデータベース上のST131大腸菌におけるキノロン標的酵素遺伝子多型とfimH亜系統との関連

嵯峨知生, 長谷川諒, 面川歩, 竹田正秀, 守時由起, 植木重治, 廣川誠

臨床病理 ( 日本臨床検査医学会 ) 66 ( 補冊 ) 159 - 159 2018年10月

【病棟管理栄養士のための臨床検査ファーストガイド-項目別&疾患別検査値の意味と読み方のポイント】(Part 2)検査項目別検査値の意味と読み方のポイント免疫血清検査アレルゲン検査

齊藤由紀子, 鎌田由美子, 植木重治, 廣川誠

臨床栄養 ( 医歯薬出版(株) ) 133 ( 4 ) 466 - 468 2018年09月

グリコヘモグロビン/グルコース分析装置ADAMS HYBRID AH-8290の性能評価

平澤裕之, 山本梨絵, 阿部綾奈, 小林則子, 植木重治, 廣川誠

日本臨床検査自動化学会会誌 ( (一社)日本臨床検査自動化学会 ) 43 ( 4 ) 448 - 448 2018年09月

成人特発性血小板減少症におけるIGHV4-28/IGHJ4再構成由来IgG型B細胞抗原受容体の高発現(Overexpression of the rearranged IGHV4-28//IGHJ4 gene-derived IgG B-cell receptors in adult ITP)

藤島直仁, 富樫賢, 長谷川諒, 渡部健, 嵯峨亜希子, 面川歩, 嵯峨知生, 植木重治, 高橋直人, 北浦一孝, 鈴木隆二, 廣川誠

臨床血液 ( (一社)日本血液学会-東京事務局 ) 59 ( 9 ) 1579 - 1579 2018年09月

INCREASED MEAN PLATELET VOLUME (MPV) AS A POTENTIAL PREDICTOR OF THROMBOPOIETIC RECOVERY FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANTATION OR CHEMOTHERAPY

Yuko Kikuchi, Ayako Naganuma, Kana Haseyama, Kyoko Ono, Takeshi Kobayashi, Noriko Kobayashi, Ayumi Omokawa, Tomoo Saga, Shigeharu Ueki, Naoto Takahashi, Hironobu Shimizu, Makoto Hirokawa

INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY ( WILEY ) 40 68 - 69 2018年09月

研究発表要旨（国際会議）

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