研究者詳細 - 一宮　慎吾

論文 - 一宮　慎吾

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Alteration of circulating type 2 follicular helper T cells and regulatory B cells underlies the comorbid association of allergic rhinitis with bronchial asthma

Ryuta Karnekura, Katsunori Shigehara, Satsuki Miyajima, Sumito Jitsukawa, Koji Kawata, Keiji Yamashita, Tomonori Nagaya, Ayako Kumagai, Akinori Sato, Hiroshi Matsumiya, Noriko Ogasawara, Nobuhiko Seki, Kenichi Takano, Yasuo Kokai, Hiroki Takahashi, Tetsuo Himi, Shingo Ichimiya

CLINICAL IMMUNOLOGY ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 158 ( 2 ) 204 - 211 2015年06月 [査読有り]

Allergic rhinitis (AR), the most common allergic disorder of the airway, is often accompanied by bronchial asthma. However, little is known about the mechanism by which AR advances to AR comorbid with bronchial asthma (AR + Asthma). To determine the pathophysiologic features of AR and AR + Asthma, we examined subsets of follicular helper T (Tfh) cells and regulatory B (Breg) cells in peripheral blood from AR and AR + Asthma patients. The results showed polarization of Tfh2 cells within Tfh cell subsets in both AR and AR + Asthma cases. Interestingly, the %Breg cells in total B cells were decreased in AR cases and, more extensively, in AR + Asthma cases. Moreover, we found significant correlations of fractional exhaled nitricoxide and blood eosinophil levels with the index %Tfh2 cells per %Breg cells. Our findings indicate that relative decrease in Breg cells under the condition of Tfh2 cell skewing is a putative exaggerating factor of AR to bronchial asthma. (C) 2015 The Authors. Published by Elsevier Inc.

DOI PubMed

Alteration of human blood type 2 follicular helper T cells and regulatory B cells underlies comorbid association of allergic rhinitis with bronchial asthma

Ryuta Kamekura, Katsunori Shigehara, Sumito Jitsukawa, Koji Kawata, Tetsuo Himi, Shingo Ichimiya

JOURNAL OF IMMUNOLOGY ( AMER ASSOC IMMUNOLOGISTS ) 194 2015年05月 [査読有り]

アレルギー性気道疾患の病態形成における濾胞ヘルパーT細胞と制御性B細胞の役割

亀倉隆太, 重原克則, 實川純人, 小笠原徳子, 高野賢一, 氷見徹夫, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 64 ( 3-4 ) 570 - 570 2015年04月

アトピー型気管支喘息における末梢血濾胞ヘルパーT細胞の解析

重原克則, 亀倉隆太, 宮島さつき, 高橋弘毅, 伊藤進, 一宮慎吾

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 4 ( 増刊 ) 244 - 244 2015年03月

扁桃・アデノイドはなぜあるのか?鼻はなにをしているのか? 粘膜免疫・粘膜防御の最前線を探る

氷見徹夫, 高野賢一, 山下恵司, 小笠原徳子, 山本圭佑, 堤裕幸, 小島隆, 一宮慎吾, 澤田典均, 横田伸一

顎顔面口腔育成会誌 ( 顎顔面口腔育成研究会 ) 3 ( 1 ) 3 - 6 2015年03月

粘膜防御機構は自然免疫の最前線であり、上皮細胞に加えて免疫系細胞などを含む複合的なシステムで構築されている。耳鼻咽喉科領域では扁桃・アデノイドに代表される粘膜関連リンパ装置は、その抗原捕捉機構を駆使して、免疫記憶の形成と特異的抗体産生機構に関与している。一方、上気道の最前線である鼻粘膜もまた抗原捕捉に伴う免疫反応を行っているとともに、ウイルス・細菌感染やアレルギー炎症の場としても重要である。われわれは、扁桃やアデノイド、そして鼻粘膜の上皮についての研究を行い、機械的バリアを含む自然免疫の新しい概念を提唱してきた。ここでは、われわれの研究より得られた知見をもとに、扁桃、鼻粘膜の基本的な免疫臓器としての機能解析と、それぞれの類似性・相違性、自然免疫・獲得免疫での位置づけについて言及する。(著者抄録)

Tight junction protein claudin-4 is modulated via ΔNp63 in human keratinocytes.

Kubo T, Sugimoto K, Kojima T, Sawada N, Sato N, Ichimiya S

Biochemical and biophysical research communications ( 3-4 ) 455 ( 3-4 ) 205 - 211 2014年12月 [査読有り]

In the epidermis, tight junction (TJ) structure is specifically located in the stratum granulosum, where the expression of Delta Np63, a p53 family transcription factor, is attenuated. Since the relationship between Delta Np63 and barrier function has not been fully uncovered, we assessed expression profiles of TJ proteins in skin tissues and cultured keratinocytes. The results showed that expression of Delta Np63 and that of claudin-4 were inversely correlated in healthy human epidermis. In vitro studies using HaCaT keratinocytes revealed functional relevance of Delta Np63 and claudin-4. Curiously, Toll-like receptor (TLR)-3 ligand, which is known to be liberated from damaged cells, suppressed Delta Np63 expression and concomitantly up regulated claudin-4 expression in primary keratinocytes. More interestingly, a broad expression pattern of claudin-4 was found in the epidermis of atopic dermatitis (AD), a barrier defect disorder, which contains Delta Np63-lacking keratinocytes as we reported previously. Therefore, upregulation of claudin-4 expression regulated by Delta Np63 might be associated with complementary or repair responses of damaged keratinocytes with AD. (C) 2014 Elsevier Inc. All rights reserved.

DOI PubMed

Specific Targeting of a Naturally Presented Osteosarcoma Antigen, Papillomavirus Binding Factor Peptide, Using an Artificial Monoclonal Antibody

Tomohide Tsukahara, Makoto Emori, Kenji Murata, Takahisa Hirano, Norihiro Muroi, Masanori Kyono, Shingo Toji, Kazue Watanabe, Toshihiko Torigoe, Vitaly Kochin, Hiroko Asanuma, Hiroshi Matsumiya, Keiji Yamashita, Tetsuo Himi, Shingo Ichimiya, Takuro Wada, Toshihiko Yamashita, Tadashi Hasegawa, Noriyuki Sato

JOURNAL OF BIOLOGICAL CHEMISTRY ( AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC ) 289 ( 32 ) 22035 - 22047 2014年08月 [査読有り]

Osteosarcoma is a rare but highly malignant tumor occurring most frequently in adolescents. The prognosis of non-responders to chemotherapy is still poor, and new treatment modalities are needed. To develop peptide-based immunotherapy, we previously identified autologous cytotoxic T lymphocyte-defined osteosarcoma antigen papillomavirus binding factor (PBF) in the context of HLA-B55 and the cytotoxic T lymphocyte epitope (PBF A2.2) presented by HLA-A2. PBF and HLA class I are expressed in similar to 90 and 70% of various sarcomas, respectively. However, the expression status of peptide PBF A2.2 presented by HLA-A2 on osteosarcoma cells has remained unknown because it is difficult to generate a specific probe that reacts with the HLA.peptide complex. For detection and qualification of the HLA-A*02:01.PBF A2.2 peptide complex on osteosarcoma cells, we tried to isolate a single chain variable fragment (scFv) antibody directed to the HLA-*A0201.PBF A2.2 complex using a naive scFv phage display library. As a result, scFv clone D12 with high affinity (K-D = 1.53 x 10(-9) M) was isolated. D12 could react with PBF A2.2 peptide-pulsed T2 cells and HLA-A2+PBF+ osteosarcoma cell lines and simultaneously demonstrated that the HLA.peptide complex was expressed on osteosarcoma cells. In conclusion, scFv clone D12 might be useful to select candidate patients for PBF A2.2 peptide-based immunotherapy and develop antibody-based immunotherapy.

DOI PubMed

ΔNp63 controls a TLR3-mediated mechanism that abundantly provides thymic stromal lymphopoietin in atopic dermatitis.

Kubo T, Kamekura R, Kumagai A, Kawata K, Yamashita K, Mitsuhashi Y, Kojima T, Sugimoto K, Yoneta A, Sumikawa Y, Yamashita T, Sato N, Himi T, Ichimiya S

PloS one ( 8 ) 9 ( 8 ) e105498 2014年08月 [査読有り]

In the skin lesions of atopic dermatitis (AD), keratinocytes release large quantities of thymic stromal lymphopoietin (TSLP), causing unfavorable inflammation along with skin damage. Nevertheless, how TSLP influences keratinocytes themselves is still unknown. In this study, we showed that Delta Np63, a p53-homologue, predominantly expressed in keratinocytes regulated the receptor complex of TSLP, which determines susceptibility to self-derived TSLP. Expression of TSLP receptors in skin tissues and keratinocytes was assessed by immunohistochemistry and quantitative RT-PCR, and in vitro studies were also performed to examine the functional relevance of Delta Np63 in the expression of TSLP receptors and the constituting autocrine and/or paracrine pathway of TSLP under the condition of stimuli to innate receptors sensing cell damage. The results showed that normal keratinocytes in the upper epidermis preferentially expressed TSLP receptors and conversely lacked Delta Np63, which has an inhibitory effect on the expression of TSLP receptors. Interestingly, the epidermis of AD lesions was found to abundantly contain keratinocytes with low or undetectable levels of Delta Np63 (Delta Np63(lo/-)). Moreover, in the absence of Delta Np63, keratinocytes readily presented TSLP and other cytokines by stimuli through Toll-like receptor 3 (TLR3). Together with the evidence that extrinsic TSLP itself augments TSLP production by keratinocytes without Delta Np63, the results indicate that Delta Np63(lo/-) keratinocytes generate TSLP through a putative autocrine and/or paracrine pathway upon TLR3 stimulation within AD lesions, since moieties of damaged cells and pathogens stimulate TLR3.

DOI PubMed

Multifocal and microscopic chromophobe renal cell carcinomatous lesions associated with 'capsulomas' without FCLN gene abnormality

Kotaro Sugimoto, Akira Takasawa, Shingo Ichimiya, Masaki Murata, Hiromichi Kimura, Tomoyuki Aoyama, Johan J.P. Gille, Naoto Kuroda, Hiroshi Shimizu, Tadashi Hasegawa, Norimasa Sawada, Mitsuko Furuya, Yoji Nagashima

Pathology International ( 10 ) 63 ( 10 ) 510 - 515 2013年10月 [査読有り]

Chromophobe renal cell carcinoma (RCC) accounts for approximately 5% of renal epithelial neoplasms. Multiple and/or bilateral chromophobe RCCs in an individual are generally rare but frequently occur in patients with Birt-Hogg-Dubé syndrome (BHDS) and in patients with tuberous sclerosis complex (TSC). The responsible genes in both BHDS and TSC act as tumor suppressors. Therefore, it seems that some genetic backgrounds are required for the generation and progression of multiple chromophobe RCCs. Here, we report a case of multiple and bilateral chromophobe RCCs along with several small-sized capsular angiomyolipomas known as 'capsulomas' in a 39-year-old woman who had neither a particular medical history nor specific gene mutation. There has been no report of sporadic multiple chromophobe RCCs and 'capsulomas' developing in a patient without genetic features, having potential for novel genetic variation. © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

DOI PubMed

アトピー型気管支喘息患者における血清IL-9の検討

重原克則, 伊藤進, 一宮慎吾

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 2 ( 増刊 ) 156 - 156 2013年03月

Sorting nexin 5 of a new diagnostic marker of papillary thyroid carcinoma regulates Caspase-2

Shihoko Ara, Tomoki Kikuchi, Hiroshi Matsumiya, Takashi Kojima, Terufumi Kubo, Rui Carrie Ye, Akinori Sato, Shin-ichiro Kon, Tomo Honma, Kohji Asakura, Tadashi Hasegawa, Tetsuo Himi, Noriyuki Sato, Shingo Ichimiya

CANCER SCIENCE ( WILEY-BLACKWELL ) 103 ( 7 ) 1356 - 1362 2012年07月 [査読有り]

Papillary thyroid carcinoma (PTC) is a well-differentiated endocrine malignant tumor that develops from thyroid follicular epithelium. The tumor represents the most common type of endocrine malignancy; however, its tumorigenesis is not fully elucidated. The aim of this study was to address the functional role of the sorting nexin (SNX) family in PTC because of recent experimental evidence suggesting that the SNX family members actively control endocytotic transportation as well as cell fate. Expression profiles of SNX family members of PTC showed a significant quantity of transcripts of SNX5. Further immunohistochemical analysis with an SNX5-specific monoclonal antibody established in this study consistently demonstrated the preferential expression of SNX5 in PTC (94.2%, 113/120 cases) as indicated by studies on 440 cases of various tumors. In contrast, other major carcinomas originating from the lung (2.6%, 1/38 cases), breast (5.1%, 2/39 cases), and intestine (4.2%, 1/24 cases) scarcely expressed SNX5. When we investigated models of murine thyroid tumors induced by the administration of carcinogens, high expression of Snx5 was also observed in well-differentiated thyroid tumors, further implying that the tumorigenesis of the thyroid gland was tightly associated with the abundance of SNX5/Snx5. Moreover epithelial cells expressing excess SNX5 showed high levels of Caspase-2 of an initiator caspase. Collectively these findings suggest that the evaluation of SNX5 expression would support pathological diagnosis of primary and secondary PTC. (Cancer Sci 2012; 103: 13561362)

DOI PubMed

A novel autocrine-paracrine loop of TSLP in atopic dermatitis is modulated by p63

Terufumi Kubo, Rui Ye, Shihoko Ara, Hiroshi Matsumiya, Takashi Kojima, Tomoki Kikuchi, Noriyuki Sato, Shingo Ichimiya

JOURNAL OF IMMUNOLOGY ( AMER ASSOC IMMUNOLOGISTS ) 188 2012年05月 [査読有り]

POU2AF1(+) follicular helper T (Tfh) cells in obstructive sleep apnea syndrome (OSAS)

Shingo Ichimiya, Hiroshi Matsumiya, Terufumi Kubo, Shihoko Ara, Rui Ye, Akinori Sato, Tomoki Kikuchi, Keiji Yamashita, Yukari Mitsuhashi, Nobuhiko Seki, Hideaki Shirasaki, Sachiko Kimura, Shigeaki Yokoyama, Noriyuki Sato, Tetsuo Himi

JOURNAL OF IMMUNOLOGY ( AMER ASSOC IMMUNOLOGISTS ) 188 2012年05月 [査読有り]

Immunogenic enhancement and clinical effect by type-I interferon of anti-apoptotic protein, survivin-derived peptide vaccine, in advanced colorectal cancer patients

Hidekazu Kameshima, Tetsuhiro Tsuruma, Toshihiko Torigoe, Akari Takahashi, Yoshihiko Hirohashi, Yasuaki Tamura, Tomohide Tsukahara, Shingo Ichimiya, Takayuki Kanaseki, Yuji Iwayama, Noriyuki Sato, Koichi Hirata

CANCER SCIENCE ( WILEY-BLACKWELL ) 102 ( 6 ) 1181 - 1187 2011年06月 [査読有り]

We previously identified a human leukocyte antigen (HLA)-A24-restricted antigenic peptide, survivin-2B80-88, recognized by CD8+ cytotoxic T lymphocytes (CTL). Subsequently, we attempted clinical trials with this epitope peptide alone for some malignancies, resulting in clinical and immunological responses, although their potential was not strong enough for routine clinical use as a cancer vaccine. In the current study, to assess whether immunogenicity of the survivin-2B80-88 peptide could be enhanced with other vaccination protocols, we performed clinical trials in advanced colon cancer patients with two vaccination protocols: (i) survivin-2B80-88 plus incomplete Freund's adjuvant (IFA); and (ii) survivin-2B80-88 plus IFA and a type-I interferon (IFN), IFN alpha. Our data clearly indicated that, although the effect of survivin-2B80-88 plus IFA was not significantly different from that with survivin-2B80-88 alone, treatment with the vaccination protocol of survivin-2B80-88 plus IFA and IFN alpha resulted in clinical improvement and enhanced immunological responses of patients. Tetramer analysis of survivin-2B80-88 peptide-specific CTL demonstrated that such CTL were increased at least twofold after vaccination with this protocol in four of eight patients. In these patients, enzyme-linked immunosorbent spot (ELISPOT) results were also enhanced. Subsequent study of single-cell clone separation by cell sorting of peptide-specific CTL showed that each CTL clone was indeed not only peptide-specific but also cytotoxic against human cancer cells in the context of the expression of both HLA-A24 and survivin molecules. Taken together, these results indicate that vaccination of colon cancer patients with survivin-2B80-88 plus IFA and IFN alpha can be considered to be a very potent immunotherapeutic regimen, and that this protocol might work for other cancers. (Cancer Sci 2011; 102: 1181-1187).

DOI PubMed

Anti-CADM-140 Antibody-positive Juvenile Dermatomyositis with Rapidly Progressive Interstitial Lung Disease and Cardiac Involvement

Nodoka Sakurai, Kazushige Nagai, Hiroyuki Tsutsumi, Shingo Ichimiya

JOURNAL OF RHEUMATOLOGY ( J RHEUMATOL PUBL CO ) 38 ( 5 ) 963 - 965 2011年05月 [査読有り]

DOI PubMed

Poly(I:C) reduces expression of JAM-A and induces secretion of IL-8 and TNF-α via distinct NF-κB pathways in human nasal epithelial cells.

Ohkuni T, Kojima T, Ogasawara N, Masaki T, Fuchimoto J, Kamekura R, Koizumi J, Ichimiya S, Murata M, Tanaka S, Himi T, Sawada N

Toxicology and applied pharmacology ( 1 ) 250 ( 1 ) 29 - 38 2011年01月 [査読有り]

Human nasal epithelium is an important physical barrier and innate immune defense protecting against inhaled substances and pathogens. Toll-like receptor (TLR) signaling, which plays a key role in the innate immune response, has not been well characterized in human nasal epithelial cells (HNECs), including the epithelial tight junctional barrier. In the present study, mRNAs of TLR1-10 were detected in hTERT-transfected HNECs, which can be used as an indispensable and stable model of normal HNECs, similar to primary cultured HNECs. To investigate the changes of tight junction proteins and the signal transduction pathways via TLRs in HNECs in vitro, hTERT-transfected HNECs were treated with TLR2 ligand P(3)CSK(4), TLR3 ligand poly(I:C), TLR4 ligand LPS, TLR7/8 ligand CL097, TLR8 ligand ssRNA40/LyoVec, and TLR9 ligand ODN2006. In hTERT-transfected HNECs, treatment with poly(I:C) significantly reduced expression of the tight junction protein JAM-A and induced secretion of proinflammatory cytokines IL-8 and TNF-alpha. Both the reduction of JAM-A expression and the induction of secretion of IL-8 and TNF-alpha after treatment with poly(I:C) were modulated by distinct signal transduction pathways via EGFR. PI3K, and p38 MAPK and finally regulated by a TLR3-mediated NF-kappa B pathway. The control of TLR3-mediated signaling pathways in HNECs may be important not only in infection by viral dsRNA but also in autoimmune diseases caused by endogenous dsRNA released from necrotic cells. (C) 2010 Elsevier Inc. All rights reserved.

DOI PubMed

Arachidonate 5-Lipoxygenase Establishes Adaptive Humoral Immunity by Controlling Primary B Cells and Their Cognate T-Cell Help

Tsutomu Nagashima, Shingo Ichimiya, Tomoki Kikuchi, Yoshiyuki Saito, Hiroshi Matsumiya, Shihoko Ara, Shigeru Koshiba, Jun Zhang, Chizuru Hatate, Akiko Tonooka, Terufumi Kubo, Rui Carrie Ye, Bungo Hirose, Hideaki Shirasaki, Takashi Izumi, Tsuyoshi Takami, Tetsuo Himi, Noriyuki Sato

AMERICAN JOURNAL OF PATHOLOGY ( AMER SOC INVESTIGATIVE PATHOLOGY, INC ) 178 ( 1 ) 222 - 232 2011年01月 [査読有り]

In this study, we report the unique role of arachidonate 5-lipoxygenase (Alox5) in the regulation of specific humoral immune responses. We previously reported an L22 monoclonal antibody with which human primary resting B cells in the mantle zones of lymphoid follicles are well-defined. Proteomics analyses enabled identification of an L22 antigen as Alox5, which was highly expressed by naive and memory B cells surrounding germinal centers. Cellular growth of mantle cell lymphoma cells also seemed to depend on Alox5. Alox5(-/-) mice exhibited weak antibody responses specific to foreign antigens at the initial and recall phases. This was probably attributable to the low number of follicular and memory B cells and the functional loss of interleukin-21-mediated responses of follicular B cells. Moreover, Alox5(-/-) mice could not fully foster the development of follicular B helper T (Tfh) cells even after immunization with foreign antigens. Further experiments indicated that Alox5 affected mortality in experimentally induced enterocolitis in germ-prone circumstances, indicating that Alox5 would endow immunologic milieu. Our results illustrate the novel role of Alox5 in adaptive humoral immunity by managing primary B cells and Tfh cells in vivo. (Am J Pathol 2011, 178: 222-232; DOI: 10.1016/j.ajpath.2010.11.033)

DOI PubMed

Arachidonate 5-Lipoxygenase Establishes Adaptive Humoral Immunity by Controlling Primary B Cells and Follicular B Helper T Cells

Tsutomu Nagashima, Shingo Ichimiya, Shigeru Koshibal, Hiroshi Matsumiya, Shihoko Ara, Terufumi Kubo, Noriyuki Sato, Tetsuo Himi

RECENT ADVANCES IN TONSILS AND MUCOSAL BARRIERS OF THE UPPER AIRWAYS ( KARGER ) 72 184 - 184 2011年 [査読有り]

Thymic stromal lymphopoietin induces tight junction protein claudin-7 via NF-kappa B in dendritic cells

Ryuta Kamekura, Takashi Kojima, Akira Takashima, Jun-ichi Koizumi, Noriko Ogasawara, Mitsuru Go, Ken-ichi Takano, Masaki Murata, Satoshi Tanaka, Shingo Ichimiya, Tetsuo Himi, Norimasa Sawada

HISTOCHEMISTRY AND CELL BIOLOGY ( SPRINGER ) 133 ( 3 ) 339 - 348 2010年03月 [査読有り]

Epithelial-derived thymic stromal lymphopoietin (TSLP) is an IL-7-like cytokine that triggers dendritic cell (DC)-mediated Th2-type inflammatory responses. The activated DCs can penetrate the epithelium to directly take up antigen without compromising the barrier function. Although it is reported that DCs express tight junction molecules and can establish tight junction-like structures with adjacent epithelial cells to preserve the epithelial barrier, the regulation of expression of tight junction molecules in DCs remains unknown. In the present study, to investigate the mechanical regulation of expression of tight junction molecules in DCs, XS52 DCs that was a long-term DC line established from the epidermis of a newborn BALB/c mouse, were treated with TSLP or toll-like receptor (TLR) ligands. In XS52 cells, tight junction molecules claudin-1, -3, -4, -6, -7, -8, and occludin were detected. mRNA expression of TSLP receptor and all these tight junction molecules was significantly increased in activated XS52 cells after treatment with TSLP. In addition, expression of claudin-7 protein was increased in dose- and time-dependent manner. In XS52 cells, which express TLR2, TLR3, TLR4, and TLR7, but not TLR9, expression of claudin-7 protein was also increased after treatment with ligands of TLR2, TLR4 or TLR7/8, Pam(3)Cys-Ser-(Lys)(4), LPS, or CL097. The NF-kappa B inhibitor IMD-0354 prevented upregulation of claudin-7 after treatment with TSLP or TLR ligands. These findings indicate that TSLP induces expression of tight junction protein claudin-7 in DCs via NF-kappa B as well as via TLRs and may control tight junctions of DCs to preserve the epithelial barrier during allergic inflammation.

DOI PubMed

新たな甲状腺乳頭癌特異的バイオマーカーSNX5の意義とその臨床応用

荒志保子, 一宮慎吾, 菊地智樹, 松宮弘, 高野善英, 外岡暁子, 今信一郎, 長谷川匡, 氷見徹夫, 佐藤昇志

日本病理学会会誌 ( (一社)日本病理学会 ) 99 ( 1 ) 331 - 331 2010年03月

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