研究者詳細 - 一宮　慎吾

論文 - 一宮　慎吾

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Induction of JAM-A during differentiation of human THP-1 dendritic cells

Noriko Ogasawara, Takashi Kojima, Mitsuru Go, Jun Fuchimoto, Ryuta Kamekura, Jun-ichi Koizumi, Tsuyoshi Ohkuni, Tomoyuki Masaki, Masaki Murata, Satoshi Tanaka, Shingo Ichimiya, Tetsuo Himi, Norimasa Sawada

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 389 ( 3 ) 543 - 549 2009年11月 [査読有り]

Junctional adhesion molecule (JAM)-A is not only localized at tight junctions of endothelial and epithelial cells but is also expressed on circulating leukocytes and dendritic cells (DCs). In the present study, to investigate the regulation of JAM-A in DCs, mature DCs were differentiated from the human monocytic cell THP-1 by treatment with IL-4, GM-CSF, TNF-alpha, and ionomycin, and some cells were pretreated with the PPAR-gamma agonists. In the THP-1 monocytes, mRNAs of tight junction molecules, occludin, tricellulin, JAM-A, ZO-1, ZO-2 and claudin-4, -7, -8, and -9 were detected by RT-PCR. In mature DCs that had elongated dendrites, mRNA and protein of JAM-A were significantly increased compared to the monocytes. PPAR-gamma agonists prevented the elongation of dentrites but not upregulation of JAM-A in mature DCs. These findings indicated that the induction of JAM-A Occurred during differentiation of human THP-1 DCs and was independent of PPAR-gamma and the p38 MAPK pathway. (C) 2009 Elsevier Inc. All rights reserved.

DOI PubMed

新たな甲状腺癌特異的バイオマーカーの生物学的意義とその臨床応用(A novel marker specific for detecting thyroid cancer: immunohistochemical analysis and biological implication)

菊地智樹, 一宮慎吾, 長島勉, 外岡暁子, 高野善英, 長谷川匡, 氷見徹夫, 佐藤昇志

日本癌学会総会記事 ( 日本癌学会 ) 68回 355 - 355 2009年08月

Molecular pathological approaches to human tumor immunology

Noriyuki Sato, Yoshihiko Hirohashi, Tomohide Tsukahara, Tomoki Kikuchi, Hiroeki Sahara, Kenjiro Kamiguchi, Shingo Ichimiya, Yasuaki Tamura, Toshihiko Torigoe

PATHOLOGY INTERNATIONAL ( WILEY-BLACKWELL PUBLISHING, INC ) 59 ( 4 ) 205 - 217 2009年04月 [査読有り]

Research on human tumor immunology has greatly advanced in the past two decades. Many immunogenic tumor antigens have been identified, and some of these antigens entered in clinical trials. Consequently, it has been shown that these antigens can inhibit tumor growth in patients to some extent, indicating that they act as potent immunogenic therapeutic vaccines in cancer patients with malignancies originating from various tissues. These patients had antigen-specific cytotoxic T-lymphocyte (CTL) responses when assessed on tetramer, enzyme-linked immunospot (ELISPOT), T-cell clonotype and CTL induction efficiency. Thus, it has become clear that human tumor vaccines can evoke clinical and immunological anti-tumor responses in patients. The tumor regression effects of tumor vaccines, however, are generally low, and it is obvious that current vaccination protocols are generally too weak to provide substantial and satisfactory clinical benefits. This means that other drastic and more potent clinical and immunological protocols are required in cancer immunotherapy. To find such efficient protocols the basic immunological and biological properties of cancers must be investigated. In the present review the identification of human tumor antigens recognized on CTL and the clinical trials are introduced. Next, the most recent analysis of human cancer-initiating cell (cancer stem cell)-associated antigens is described. These antigens might be able to act as 'universal, general and fundamental' tumor antigens. Also present is the authors' recent study for increasing cross-presentation efficiency in dendritic cells and subsequent enhancement of human leukocyte antigen (HLA)-class I-restricted peptide antigenicity by using HSP90 and ORP150 molecular chaperones that act as endogenous Toll-like receptor ligands. In addition to the aforementioned manipulation of the positive loop of tumor immunity, it is necessary to regulate and intervene in the negative loop. In particular, the potential of the expression of HLA class I molecule regulation by epigenetic mechanisms will be discussed. Finally, the type of basic and clinical tumor immunology research highly required currently, and in the very near future, are described.

DOI PubMed

新たな甲状腺特異的バイオマーカーの生物学的意義とその臨床応用

菊地智樹, 一宮慎吾, 長島勉, 外岡暁子, 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 ) 98 ( 1 ) 233 - 233 2009年03月

Wild-type AIRE cooperates with p63 in HLA class II expression of medullary thymic stromal cells

Akiko Tonooka, Terufumi Kubo, Shingo Ichimiya, Yutaka Tamura, Tanja Ilmarinen, Ismo Ulmanen, Sachiko Kimura, Shigeaki Yokoyama, Yoshihide Takano, Tomoki Kikuchi, Noriyuki Sato

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 379 ( 3 ) 765 - 770 2009年02月 [査読有り]

During T cell development in the thymus, autoreactive T cells are deleted through a mechanism that is actively Supported by medullary epithelial cells. These epithelial cells possess particular transcription factors including autoimmune regulator (AIRE), which is responsible for regulating expression of self-antigens, as well as p63, a p53-like molecule. Here we present evidence suggesting interaction of AIRE with p63 through a SAND domain and a transactivation domain, respectively. Interestingly an AIRE molecule with a mutated SAND domain of G228W, whose genetic alteration is inherited in an autosomal dominant manner, could not establish a complex with p63 as indicated by immunoprecipitation and molecular modeling analyses. Further in vitro study indicated that the G228W mutation led to downregulation of the transcription levels of CIITA and, accordingly, the cell surface expression of HLA class 11 molecules in thymic epithelial cells with p63. This indicates novel involvement of AIRE and p63 in the regulation of HLA class II, and Suggests that defects in the AIRE-p63 interaction may lead to malfunction of HLA-based selection of self-reactive helper CD4(+) T cells in the thymus. (C) 2008 Elsevier Inc. All rights reserved.

DOI PubMed

Scythe/BAT3 regulates apoptotic cell death induced by papillomavirus binding factor in human osteosarcoma

Tomohide Tsukahara, Shigeharu Kimura, Shingo Ichimiya, Toshihiko Torigoe, Satoshi Kawaguchi, Takuro Wada, Toshihiko Yamashita, Noriyuki Sato

CANCER SCIENCE ( WILEY-BLACKWELL PUBLISHING, INC ) 100 ( 1 ) 47 - 53 2009年01月 [査読有り]

Papillomavirus binding factor (PBF) was first identified as a transcription factor regulating the promoter activity of human papillomavirus. We previously demonstrated that PBF is an osteosarcoma-associated antigen and 92% of osteosarcoma tissues express PBF in the nucleus. Moreover, PBF-positive osteosarcoma has a significantly poorer prognosis than that with negative expression of PBF. In the present study, we assessed the biological role of PBF in cell survival. Overexpression of PBF induced cell death-mediated lactate dehydrase (LDH) release from 293EBNA cells. Cleaved poly(ADP-ribose) polymerase and active caspase-3 were also detected. However, PBF-induced apoptosis did not affect caspase-9 activity. Next, to identify the apoptosis regulator of PBF, we screened a cDNA library constructed from mRNA of the osteosarcoma cell line OS2000 using a yeast two-hybrid system and isolated Scythe/BAT3. Scythe/BAT3 mRNA was detected in 56% of osteosarcoma tissues and ubiquitously in various normal tissues. Although Scythe/BAT3 was localized to the cytoplasm in normal tissue, it was localized to the nucleus in osteosarcoma tissue. PBF and Scythe/BAT3 also colocalized to the cytoplasm in 293T cells and the nucleus in OS2000. Furthermore, overexpression of Scythe/BAT3 suppressed cell death events that resulted from overexpression of PBF in OS2000, but not in 293EBNA cells. Thus, our results support the ideas that: (i) PBF could induce apoptotic cell death via a caspase-9-independent pathway; (ii) the apoptosis regulator Scythe/BAT3 is a PBF-associated molecule acting as a nucleus-cytoplasm shuttling protein; and (iii) colocalization of PBF and Scythe/BAT3 in the nucleus might be an important factor for survival of osteosarcoma cells. (Cancer Sci 2009; 100: 47-53).

DOI PubMed

p63 Induces CD4(+) T-Cell Chemoattractant TARC/CCL17 in Human Epithelial Cells

Terufumi Kubo, Shingo Ichimiya, Akiko Tonooka, Tsutomu Nagashima, Tomoki Kikuchi, Noriyuki Sato

JOURNAL OF INTERFERON AND CYTOKINE RESEARCH ( MARY ANN LIEBERT INC ) 28 ( 12 ) 725 - 732 2008年12月 [査読有り]

To preserve immunosurveillance, epithelial cells support T-cell trafficking toward inflammatory foci. However, how epithelial cells are enrolled in recruiting T cells has not been fully elucidated. In this study we investigated the function of p63, a p53 family member, in the regulation of the expression of various types of chemokine ligands by focusing on the property of p63 as an epitheliotropic transcription factor. As assessed by experiments using three different human epithelial cell lines with small-interfering RNAs or plasmids of p63, certain CC chemokine ligands were found to be under the control of p63. In these CC chemokine ligands, p63 had the common capacity to upregulate TARC/CCL17 in the different cell lines, whose receptor CCR4 was preferentially presented on CD4(+) T cells such as memory, regulatory, IL-17-producing and type II helper T cells. More interestingly, when cells were stimulated with transforming growth factor-beta (TGF-beta) or epidermal growth factor (EGF) as observed during tissue repair process, the expression of p63 and TARC/CCL17 was concomitantly suppressed. This implies that, in local inflammatory regions with general epithelial tissue remodeling, the p63-TARC/CCL17 axis may participate in the engagement of efficient immune reactions by specified T-cell subsets.

DOI PubMed

Prognostic impact and immunogenicity of a novel osteosarcoma antigen, papillomavirus binding factor, in patients with osteosarcoma

Tomohide Tsukahara, Satoshi Kawaguchi, Toshihiko Torigoe, Shigeharu Kimura, Masaki Murase, Shingo Ichimiya, Takuro Wada, Mitsunori Kaya, Satoshi Nagoya, Takeshi Ishii, Shin-ichiro Tatezaki, Toshihiko Yamashita, Noriyuki Sato

CANCER SCIENCE ( BLACKWELL PUBLISHING ) 99 ( 2 ) 368 - 375 2008年02月 [査読有り]

To develop peptide-based immunotherapy for osteosarcoma, we previously identified papillomavirus binding factor (PBF) as a cytotoxic T lymphocytes (CTL)-defined osteosarcoma antigen in the context of human leukocyte antigen (HLA)-B55. In the present study, we analyzed the distribution profile of PBF in 83 biopsy specimens of osteosarcomas and also the prognostic impact of PBF expression in 78 patients with osteosarcoma who had completed the standard treatment protocols. Next, we determined the antigenic peptides from PBF that react with peripheral T lymphocytes of HLA-A24(+) patients with osteosarcoma. Immunohistochemical analysis revealed that 92% of biopsy specimens of osteosarcoma expressed PBF. PBF-positive osteosarcoma conferred significantly poorer prognosis than those with negative expression of PBF (P = 0.025). In accordance with the Bioinformatics and Molecular Analysis Section score, we synthesized 10 peptides from the PBF sequence. Subsequent screening with an HLA class I stabilization assay revealed that peptide PBF A24.2 had the highest affinity to HLA-A24. CD8(+) T cells reacting with a PBF A24.2 peptide were detected in eight of nine HLA-A24-positive patients with osteosarcoma at the frequency from 5 x 10(-7) to 7 x 10(-6) using limiting dilution/mixed lymphocyte peptide culture followed by tetramer-based frequency analysis. PBF A24.2 peptide induced CTL lines from an HLA-A24-positive patient, which specifically killed an osteosarcoma cell line that expresses both PBF and HLA-A24. These findings suggested prognostic significance and immunodominancy of PBF in patients with osteosarcoma. PBF is the candidate target for immunotherapy in patients with osteosarcoma.

DOI PubMed

The enhanced expression of the matrix metalloproteinase 9 in nasal NK/T-cell lymphoma (vol 7, pg 229, 2007)

Koh-ichi Sakata, Masanori Someya, Mutsuko Omatsu, Hiroko Asanuma, Tadashi Hasegawa, Shingo Ichimiya, Masato Hareyama, Tetsuo Himi

BMC CANCER ( BIOMED CENTRAL LTD ) 8 2008年02月 [査読有り]

DOI

Tonsillar crypt epithelium of palmoplantar pustulosis secretes interleukin-6 to support B-cell development via p63/p73 transcription factors

S. Koshiba, S. Ichimiya, T. Nagashima, A. Tonooka, T. Kubo, T. Kikuchi, T. Himi, N. Sato

JOURNAL OF PATHOLOGY ( JOHN WILEY & SONS LTD ) 214 ( 1 ) 75 - 84 2008年01月 [査読有り]

Palmoplantar pustulosis (PPP) is an autoimmune disease characterized by psoriasis-like erythematous lesions on palms and/or soles due to an abnormal humoral immune response. Tonsillectomy is effectively employed for the treatment of PPP; however, how tonsils are involved in the aetiology of PPP remains unclear. Here we analysed surgically resected palatine tonsils from 36 cases of PPP as well as usual recurrent tonsillitis (RT) as a control. Histological examination revealed that a unique lesion, with lymphoid follicles surrounded by reticular crypt epithelial cells, was more frequently observed in tonsils of patients with PPP than in those with RT (p < 0.0001; PPP vs RT). Interestingly, crypt epithelial cells in primary cultures derived from PPP tonsils showed marked production of interleukin-6 (IL-6). Moreover, these epithelial cells from PPP tonsils expressed p53-related transcription factors in their nuclei that were found to contribute to the up-regulation of IL-6 gene expression. These findings suggest that, at least in part, the specialized lymphoepithelial symbiosis of PPP tonsils, under the control of p53-related factors, may be relevant to the generation of the impaired micro-environment underlying the aberrant production of autoantibodies. Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DOI

The enhanced expression of the matrix metalloproteinase 9 in nasal NK/T-cell lymphoma

Koh-ichi Sakata, Masanori Someya, Mutsuko Omatsu, Hiroko Asanuma, Tadashi Hasegawa, Masato Hareyama, Tetsuo Himi

BMC CANCER ( BIOMED CENTRAL LTD ) 7 229 2007年12月 [査読有り]

Background: Nasal NK/T cell lymphoma is an aggressive disease and has a poor prognosis. Nasal NK/T cell lymphoma is refractory to conventional chemotherapy and has strong tendency of widespread relapse or dissemination into distant sites. Methods: We immunohistochemically studied nasal NK/T-cell lymphoma to elucidate the unique characteristics of nasal NK/T-cell lymphoma, such as its higher metastatic tendency and its vast necrosis which leads to destruction of the involved tissues. The expression of P-glycoprotein and MMP-9 was evaluated in the 20 patients with nasal NK/T-cell lymphoma and 25 with nasal non-NK/T-cell lymphoma and the relationship between expression of these proteins and clinical results were analyzed in this report. Results: Overall 5-year survival rates for patients with nasal NK/T cell lymphoma, and nasal non-NK/T cell lymphoma were 51%, and 84%. Distant involvement free 5-year survival rates for patients with nasal NK/T cell lymphoma, and nasal non-NK/T cell lymphoma were 53%, and 79%. Overall positivity for P-glycoprotein was observed in 10 of 19 patients with NTL and in 13 of 23 patients with non-NTL. When the overall survival rate was compared between patients with P-glycoprotein positive and negative, there was no difference between them. Sixteen of the 19 patients with nasal NK/T cell lymphoma expressed MMP-9. In contrast, only 8 of the 22 patients with nasal non-NK/T cell lymphoma expressed MMP-9. Distant involvement free 5-year survival rates for patients with MMP-9 negative, and MMP-9 positive were 92%, and 61%, respectively. The difference was statistically significant (p = 0.027). Conclusion: Positive immunoreactivity for P-glycoprotein was not an independent prognostic factor in nasal NK/T-cell lymphomas, which stresses the importance of exploring other mechanisms of drug resistance. The strong expression of MMP-9 is uniquely characteristic of nasal NK/T cell lymphoma and may contribute to its strong tendency to disseminatate and the extensive necrosis which is always seen. However, our results are based on univariate comparisons, and as such, should be viewed with some caution.

DOI PubMed

Induction of claudins in passaged hTERT-transfected human nasal epithelial cells with an extended life span

Makoto Kurose, Takashi Kojima, Jun-Ichi Koizumi, Ryuta Kamekura, Takafumi Ninomiya, Masaki Murata, Shingo Ichimiya, Makoto Osanai, Hideki Chiba, Tetsuo Himi, Norimasa Sawada

CELL AND TISSUE RESEARCH ( SPRINGER ) 330 ( 1 ) 63 - 74 2007年10月 [査読有り]

The epithelial barrier of the upper respiratory tract, such as that of the nasal mucosa, plays a crucial role in host defense. The epithelial barrier is regulated in large part by the apical-most intercellular junctions, referred to as tight junctions. However, the mechanisms regulating of tight junction barrier in human nasal epithelial cells remain unclear because the proliferation and storage of epithelial cells in primary cultures are limited. In the present study, we introduced the catalytic component of telomerase, the hTERT gene, into primary cultured human nasal epithelial cells and examined the properties of the transfectants, including their expression of tight junctions, compared with primary cultures. The ectopic expression of hTERT in the epithelial cells resulted in adequate growth potential and a longer lifespan of the cells. The properties of the passaged hTERT-transfected cells including tight junctions were similar to those of the cells in primary cultures. The barrier function in the transfectants after treatment with 10% FBS was significantly enhanced with increases of integral tight junction proteins claudin-1 and -4. When the transfectants were treated with TGF-beta, which is assosciated with nasal polyposis and chronic rhinosinusitis, upregulation of only claudin-4 was observed, without a change of barrier function. In human nasal epithelial cells, the claudins may be important for barrier function and a novel target for a drug-delivery system. Our results indicate that hTERT-transfected human nasal epithelial cells with an extended lifespan can be used as an indispensable and stable model for studying the regulation of claudins in human nasal epithelium.

DOI PubMed

Mapping of susceptibility and protective loci for acute GVHD in unrelated HLA-matched bone marrow transplantation donors and recipients using 155 microsatellite markers on chromosome 22

Tomoki Kikuchi, Taeko K. Naruse, Makoto Onizuka, Suyun Li, Tetsuaki Kimura, Akira Oka, Yasuo Morishima, Jerzy K. Kulski, Shingo Ichimiya, Noriyuki Sato, Hidetoshi Inoko

IMMUNOGENETICS ( SPRINGER ) 59 ( 2 ) 99 - 108 2007年02月 [査読有り]

Despite matching donors and recipients for the human leukocyte antigens (HLAs) expressed by the major histocompatibility genomic region of the short arm of chromosome 6, several recipients still develop acute graft-versus-host disease (aGVHD) after bone marrow transplantation (BMT). This is possibly due to non-HLA gene polymorphisms, such as minor histocompatibility antigens (mHas) and genes coding for cytokines. However, a detailed genetic background for aGVHD has not yet been established. To find novel susceptibility and/or protective loci for aGVHD, a whole genome-wide association study of donors and recipients needs to be performed. As the first step to such a study, we retrospectively analyzed polymorphisms of 155 microsatellite markers spread across the long arm of chromosome 22 in 70 pairs of HLA-matched unrelated BMT donors and recipients. We performed individual typing and then compared the markers' allele frequencies (1) between all the aGVHD (grades III and IV GVHD) and GVHD-free (grade 0 GVHD) groups in donors and recipients and (2) between the aGVHD and aGVHD-free groups in donor/recipient pairs that were matched and mismatched for the microsatellite marker's allele. Screening of the microsatellite markers revealed five loci with a significant difference between the aGVHD and GVHD-free groups and revealed eight loci on chromosome 22, where the microsatellite allele mismatched markers were associated with aGVHD. This screening analysis suggests that several aGVHD-associated susceptible and protective loci exist on chromosome 22, which may encompass novel gene regions that need to be elucidated for their role in aGVHD.

DOI PubMed

マントル領域B細胞におけるALOX5の役割

齋藤由幸, 一宮慎吾, 小柴茂, 外岡暁子, 久保輝文, 大黒浩, 佐藤昇志

日本病理学会会誌 ( (一社)日本病理学会 ) 96 ( 1 ) 188 - 188 2007年02月

Cellular networks of human thymic medullary stromas coordinated by p53-related transcription factors

Shingo Ichimiya, Takashi Kojima

JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY ( HISTOCHEMICAL SOC INC ) 54 ( 11 ) 1277 - 1289 2006年11月 [査読有り]

The final elimination step of self-reactive T cells occurs in the medulla of the thymus where a complex framework provided by stromal cells supports an optimal milieu for their selection. Here we present evidence that tight junctions (TJs) widely join medullary stromal cells of the human thymus. Occludin (OCLN) and claudin-1 (CLDN-1) of TJ-associated molecules were dominantly expressed in medullary thymic epithelial cells (mTECs), and CLDN-4 and CLDN-7 were also localized in some mTECs near Hassall's corpuscles. Interestingly, p53-like transcription factors were found to upregulate OCLN and CLDN-1 in human TEC lines, as recently suggested in the regulation of mTEC function. Furthermore, dendritic cells (DCs) of the medulla, with a major role for selection of thymocytes, expressed CLDN-1 and OCLN as well, implying that the interposition of DCs within the mTEC scaffold is also helped by TJs. Analysis of freeze-fracture replicas of the thymus revealed TJ strand structures in the vicinity of gap junction plaques through which small molecules might move, as implied by dye-transfer analysis of a medullary cell line. Thus, it is thought that p53-like molecules regulate TJ-associated interactions of medullary stromal cells and that this mechanism might be associated with an intercellular communication network, probably for preserving the medullary niches.

DOI PubMed

掌蹠膿疱症における扁桃陰窩上皮の機能解析

小柴茂, 一宮慎吾, 外岡暁子, 佐藤昇志, 氷見徹夫

耳鼻咽喉科免疫アレルギー ( 日本耳鼻咽喉科免疫アレルギー学会 ) 24 ( 2 ) 53 - 53 2006年09月

胸腺p53ファミリーによるT細胞選択とトレランス

一宮慎吾, 小柴茂, 外岡暁子, 菊地智樹, 齋藤由幸, 佐藤昇志

基盤的癌免疫研究会総会抄録 ( 日本がん免疫学会 ) 10回 75 - 75 2006年06月

胸腺上皮に発現するAIRE/p63複合体による中枢性免疫寛容獲得のメカニズム

外岡暁子, 一宮慎吾, 小柴茂, 久保輝文, 菊地智樹, 木村幸子, 横山繁昭, 佐藤昇志

日本病理学会会誌 ( (一社)日本病理学会 ) 95 ( 1 ) 199 - 199 2006年04月

掌蹠膿疱症における扁桃陰窩上皮の機能解析

小柴茂, 一宮慎吾, 外岡暁子, 氷見徹夫, 佐藤昇志

日本病理学会会誌 ( (一社)日本病理学会 ) 95 ( 1 ) 290 - 290 2006年04月

胸腺髄質上皮細胞におけるAIRE/p63複合体の機能的意義

久保輝文, 一宮慎吾, 小柴茂, 外岡暁子, 小島隆, 佐藤昇志

日本病理学会会誌 ( (一社)日本病理学会 ) 95 ( 1 ) 391 - 391 2006年04月

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