研究者詳細 - 一宮　慎吾

論文 - 一宮　慎吾

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Unraveling Novel Subsets of Lymphocytes Involved in Sac Expansion in the Tertiary Lymphoid Structure Within an Abdominal Aortic Aneurysm.

Itaru Hosaka, Ippei Ikegami, Takuma Mikami, Tatsuya Sato, Toshifumi Ogawa, Kei Mukawa, Marenao Tanaka, Keisuke Endo, Yukinori Akiyama, Akihito Ohkawa, Junji Nakazawa, Tsuyoshi Shibata, Tomohiro Nakajima, Yutaka Iba, Chikara Shiiku, Satoshi Sumino, Ryuji Koshima, Kenichi Takano, Shingo Ichimiya, Nobuyoshi Kawaharada, Masato Furuhashi

Journal of the American Heart Association e040279 2025年02月 [国際誌]

BACKGROUND: Chronic inflammation is involved in the development of abdominal aortic aneurysm (AAA). A tertiary lymphoid structure (TLS) within vascular lesions has recently been focused on for its role in modulation of inflammation in local tissues. We aimed to elucidate the relationships between TLS and pathophysiology of AAA. METHODS: Abdominal aortic samples obtained from 37 patients with AAA (men/women: 34/3, age: 72.8±9.9 years) and 15 autopsied patients who died from non-aortic events (men/women: 11/4, age: 65.5±9.8 years) were investigated. RESULTS: TLSs in AAA lesions were confirmed by focal infiltration of CD3-positive cells surrounding germinal center-like structures containing CD20-positive cells between the tunica adventitia and tunica media layers. The formation of a TLS was significantly more prevalent in AAA patients than in autopsied patients. The number of TLSs in AAA lesions was positively correlated with sac diameter (r=0.357, P=0.035) and the amount of intraluminal thrombosis (r=0.466, P=0.005). T cells and B cells were predominant cellular populations among CD45+ cells in AAA lesions. There was a significantly positive correlation between the proportions of interfollicular T follicular helper (CD3+CD4+CD45RA-CXCR5+PD-1+) cells and double negative B (CD3-CD19+IgD-CD27-) cells, and they were positively correlated with sac diameter, intraluminal thrombosis, and serum lipids. Deposited single-cell RNA-sequencing data for AAA showed that T follicular helper cells and double negative B cells were associated with lipid metabolism, T cell activation/proliferation and inflammation. CONCLUSIONS: The formation of a TLS in AAA lesions is associated with sac diameter and intraluminal thrombosis in connection with interfollicular T follicular helper cells and double negative B cells, which may contribute to the pathophysiology of AAA and might be novel therapeutic targets for the development of AAA.

DOI PubMed

Interleukin 9 mediates T follicular helper cell activation to promote antibody responses

Taiki Sato, Ippei Ikegami, Masahiro Yanagi, Takeshi Ohyu, Taiki Sugaya, Shotaro Shirato, Masanobu Tanemoto, Shiori Kamiya, Kohei Kikuchi, Yuka Kamada, Takehito Nakata, Ryuta Kamekura, Akinori Sato, Ken-ichi Takano, Masahiro Miyajima, Atsushi Watanabe, Shingo Ichimiya

Frontiers in Immunology ( Frontiers Media SA ) 15 2024年09月

Antigen-specific humoral responses are orchestrated through complex interactions among immune cells in lymphoid tissues, including the collaboration between B cells and T follicular helper (Tfh) cells. Accumulating evidence indicates a crucial role for interleukin-9 (IL-9) in the formation of germinal centers (GCs), enhancing the generation of class-switched high-affinity antibodies. However, the exact function of IL-9 in Tfh cell regulation remains unclear. In this study, we examined the humoral immune responses of CD4^Cre/+Il9ra^fl/fl mice, which lack an IL-9-specific receptor in Tfh cells. Upon intraperitoneal immunization with sheep red blood cells (SRBCs), CD4^Cre/+Il9ra^fl/fl mice displayed diminished levels of SRBC-specific IgG antibodies in their sera, along with reduced levels of GC B cells and plasma cells. Notably, Il9ra-deficient Tfh cells in the spleen exhibited decreased expression of their signature molecules such as B-cell lymphoma 6, C-X-C chemokine receptor 5, IL-4, and IL-21 compared to control mice. In models of allergic asthma induced by house dust mite (HDM) inhalation, CD4^Cre/+Il9ra^fl/fl mice failed to elevate serum levels of HDM-specific IgE and IgG. This was accompanied by reductions in Tfh cells, GC B cells, and plasma cells in mediastinal lymph nodes. Furthermore, group 2 innate lymphoid cells (ILC2s) were identified as producers of IL-9 under immunizing conditions, possibly induced by leukotrienes released by activated IgD⁺ B cells around the T-B border. These observations may indicate the critical role of IL-9 receptor signaling in the activation of Tfh cells, with ILC2s potentially capable of supplying IL-9 in organized lymphoid tissues.

DOI

Bob1 maintains T follicular helper cells for long-term humoral immunity.

Masahiro Yanagi, Ippei Ikegami, Ryuta Kamekura, Tatsuya Sato, Taiki Sato, Shiori Kamiya, Kosuke Murayama, Sumito Jitsukawa, Fumie Ito, Akira Yorozu, Miho Kihara, Takaya Abe, Hiromi Takaki, Koji Kawata, Katsunori Shigehara, Satsuki Miyajima, Hirotaka Nishikiori, Akinori Sato, Noritsugu Tohse, Ken-Ichi Takano, Hirofumi Chiba, Shingo Ichimiya

Communications biology 7 ( 1 ) 185 - 185 2024年02月 [国際誌]

Humoral immunity is vital for host protection, yet aberrant antibody responses can trigger harmful inflammation and immune-related disorders. T follicular helper (Tfh) cells, central to humoral immunity, have garnered significant attention for unraveling immune mechanisms. This study shows the role of B-cell Oct-binding protein 1 (Bob1), a transcriptional coactivator, in Tfh cell regulation. Our investigation, utilizing conditional Bob1-deficient mice, suggests that Bob1 plays a critical role in modulating inducible T-cell costimulator expression and cellular respiration in Tfh cells. This regulation maintains the long-term functionality of Tfh cells, enabling their reactivation from central memory T cells to produce antibodies during recall responses. In a bronchial asthma model induced by house dust mite (HDM) inhalation, Bob1 is observed to enhance HDM-specific antibodies, including IgE, highlighting its pivotal function in Tfh cell regulation. Further exploration of Bob1-dependent mechanisms in Tfh cells holds promise for governing protective immunity and addressing immune-related disorders.

DOI PubMed

Circulating T follicular helper 2 cells, T follicular regulatory cells and regulatory B cells are effective biomarkers for predicting the response to house dust mite sublingual immunotherapy in patients with allergic respiratory diseases

Katsunori Shigehara, Ryuta Kamekura, Ippei Ikegami, Hiroshi Sakamoto, Masahiro Yanagi, Shiori Kamiya, Kentaro Kodama, Yuichiro Asai, Satsuki Miyajima, Hirotaka Nishikiori, Eiji Uno, Keisuke Yamamoto, Kenichi Takano, Hirofumi Chiba, Hirofumi Ohnishi, Shingo Ichimiya

Frontiers in Immunology ( Frontiers Media SA ) 14 2023年11月

The relationships between T follicular helper (Tfh) cells and antigen-specific immunoglobulins (sIgs) in patients with allergic respiratory diseases who are receiving antigen immunotherapy (AIT) have not been fully clarified. Therefore, we started to perform house dust mite sublingual immunotherapy (HDM-SLIT) for 20 patients with atopic asthma comorbid with allergic rhinitis (AA+AR) who were already receiving ordinary treatments including inhaled corticosteroid (ICS). We examined percentages of circulating T follicular helper (cTfh) and regulatory (cTfr) cells and percentages of circulating regulatory T (cTreg) and B (cBreg) cells by FACS and we examined levels of Der-p/f sIgs by ELISA. Based on the symptom score (asthma control questionnaire: ACQ) and medication score ((global initiative for asthma: GINA) treatment step score) in patients with AA, the patients were divided into responders and non-responders. The percentage of cTfh2 cells significantly decreased and the percentage of cTfh1 cells significantly increased within the first year. Der-p/f sIgEs decreased after a transient elevation at 3 months in both groups. Notably, the percentage of cTfh2 cells and the ratio of cTfh2/cBreg cells and Der-p/f sIgEs greatly decreased in responders from 6 months to 12 months. The percentages of cTfr and cTreg cells showed significant negative correlations with the percentage of cTfh2 cells. The percentage of IL-4⁺ cTfh cells were significantly decreased and the percentage of IFN-γ⁺ cTfh cells were increased before treatment to 24 months in 6 patients examined (4 responders and 2 non-responders). We performed multi plelogistic regression analysis based on these results, the ratios of cTfh2/cTfr cells and cTfh2/cBreg cells at the start of therapy were statistically effective biomarkers for predicting the response to HDM-SLIT in patients with AA+AR.

DOI

通年性アレルギー性鼻炎・各種鼻炎:治療・管理・診断ダニ舌下免疫療法の新しい効果発現のメカニズムの解明

亀倉隆太, 重原克則, 山本圭佑, 一宮慎吾, 高野賢一

アレルギー ( (一社)日本アレルギー学会 ) 72 ( 6-7 ) 872 - 872 2023年08月

原発性肺癌浸潤CD4陽性T細胞組成と浸潤メカニズムの解析

佐藤太軌, 石井大智, 大湯岳, 千葉慶宜, 鶴田航大, 高橋有毅, 槙龍之輔, 高瀬貴章, 宮島正博, 渡辺敦, 池上一平, 一宮慎吾

肺癌 ( (NPO)日本肺癌学会 ) 63 ( 2 ) 130 - 130 2023年04月

Immunohistochemical analysis of arachidonate 5-lipoxygenase expression in B-cell lymphomas: Implication for B cell differentiation and its analogy with lymphomagenesis.

Terufumi Kubo, Tomoki Kikuchi, Masahiko Obata, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Shingo Ichimiya, Naoya Nakamura, Toshihiko Torigoe

Pathology, research and practice 242 154328 - 154328 2023年02月 [国際誌]

Arachidonate 5-lipoxygenase (ALOX5) is a cardinal enzyme in the synthesis of leukotrienes, which are powerful immune-regulating lipid mediators. We previously reported that ALOX5 is preferentially expressed in B lymphocytes in the mantle zone of human lymphoid tissue. In the context of physiological relevance, the loss of the Alox5 gene in mice significantly impairs the development of follicular B helper T cells and antibody production. However, ALOX5 expression in B-cell lymphomas has not been investigated in detail. In this study, we examined ALOX5 expression in representative B-cell lymphomas and non-neoplastic lymphoid tissues by immunohistochemistry with a commercially available anti-ALOX5 antibody that can be used on formalin-fixed paraffin-embedded specimens. Interestingly, 22/22 cases of mantle cell lymphoma, 7/7 cases of chronic lymphocytic leukemia/small cell lymphoma, and 20/20 cases of follicular lymphoma expressed ALOX5. A small proportion of extranodal marginal zone lymphoma/mucosa-associated lymphoid tissue lymphoma or nodal marginal zone lymphoma cases were positive for ALOX5 (2/13 or 1/3, respectively). In contrast, no cases with diffuse large B-cell lymphoma, regardless of germinal center B cell (GCB) or non-GCB type, expressed ALOX5 (0/25 cases). These findings suggest that ALOX5 may be a novel marker for identifying the cell of origin of B-cell lymphoma. Further investigation is required to clarify the biological significance of ALOX5 expression in lymphoma cells.

DOI PubMed

Functional Interplay between IL-9 and Peptide YY Contributes to Chronic Skin Inflammation.

Shiori Kamiya, Ippei Ikegami, Masahiro Yanagi, Hiromi Takaki, Ryuta Kamekura, Taiki Sato, Keiju Kobayashi, Takafumi Kamiya, Yuka Kamada, Takaya Abe, Ken-Ichi Inoue, Tokimasa Hida, Hisashi Uhara, Shingo Ichimiya

The Journal of investigative dermatology 142 ( 12 ) 3222 - 3231 2022年12月 [国際誌]

Complex interactions between keratinocytes and various cell types, such as inflammatory cells and stromal cells, contribute to the pathogenesis of chronic inflammatory skin lesions. In proinflammatory cytokine‒mediated disease settings, IL-9 plays a pathological role in inflammatory dermatitis. However, IL-9‒related mechanisms remain incompletely understood. In this study, we established tamoxifen-induced keratinocyte-specific IL-9RA-deficient mice (K14CRE/ERTIl9raΔ/Δ mice) to examine the role of IL-9 in multicellular interactions under chronic skin inflammatory conditions. Studies using an imiquimod-induced psoriasis-like model showed that K14CRE/ERTIl9raΔ/Δ mice exhibited a significantly reduced severity of dermatitis and mast cell infiltration compared with control K14WTIl9rafl/fl mice. Transcriptome analyses of psoriasis-like lesions showed that the level of peptide Y-Y (Pyy), a member of the neuropeptide Y family, was markedly downregulated in K14CRE/ERTIl9raΔ/Δ epidermis. Pyy blockade suppressed epidermal thickening and mast cell numbers in imiquimod-treated wild-type mice. Together with in vitro studies indicating that Pyy induced IL-9 production and chemotactic activity in bone marrow‒derived mast cells, these findings suggest that Pyy-mediated interplay between keratinocytes and mast cells contributes to psoriasiform inflammation. Further investigation focusing on the IL-9‒Pyy axis may provide valuable information for the development of new treatment modalities for inflammatory dermatitis.

DOI PubMed

アレルゲン・抗原・免疫療法・検査法ダニ舌下免疫療法における濾胞Tヘルパー細胞と特異的Igの2年間解析

重原克則, 亀倉隆太, 柳昌弘, 錦織博貴, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 71 ( 6-7 ) 817 - 817 2022年08月

CD4+CD8+ T follicular helper cells regulate humoral immunity in chronic inflammatory lesions.

Kosuke Murayama, Ippei Ikegami, Ryuta Kamekura, Hiroshi Sakamoto, Masahiro Yanagi, Shiori Kamiya, Taiki Sato, Akinori Sato, Katsunori Shigehara, Motohisa Yamamoto, Hiroki Takahashi, Ken-Ichi Takano, Shingo Ichimiya

Frontiers in immunology 13 941385 - 941385 2022年 [国際誌]

T follicular helper (Tfh) cells drive humoral immunity by facilitating B cell responses at the initial and recall phases. Recent studies have indicated the possible involvement of Tfh cells in the process of chronic inflammation. However, the functional role of Tfh cells in persistent immune settings remains unclear. Here, we report that CD4+CD8+ (double-positive, DP; CD3+CD4+CD8+CXCR5hiPD-1hi) Tfh cells, a subset of germinal-center-type Tfh cells, were abundantly present in the fibroinflammatory lesions of patients with immunoglobulin G4-related disease (IgG4-RD). Transcriptome analyses showed that these DP-Tfh cells in the lesions of IgG4-RD preferentially expressed signature genes characteristic of cytotoxic CD8+ T cells, such as Eomes, CRTAM, GPR56, and granzymes, in addition to CD70. Scatter diagram analyses to examine the relationships between tissue-resident lymphocytes and various clinical parameters revealed that the levels of DP-Tfh cells were inversely correlated to the levels of serum IgG4 and local IgG4-expressing (IgG4+) memory B cells (CD19+CD27+IgD-) in patients with IgG4-RD. Cell culture experiments using autologous tonsillar lymphocytes further suggested that DP-Tfh cells possess a poor B-cell helper function and instead regulate memory B cells. Since CD4+ (single positive, SP; CD3+CD4+CD8-CXCR5hiPD-1hi) Tfh cells differentiated into DP-Tfh cells under stimulation with IL-2 and IL-7 as assessed by in vitro experiments, these data imply that SP-Tfh cells are a possible origin of DP-Tfh cells under persistent inflammation. These findings highlight the potential feedback loop mechanism of Tfh cells in immune tolerance under chronic inflammatory conditions. Further studies on DP-Tfh cells may facilitate control of unresolved humoral responses in IgG4-RD pathological inflammation.

DOI PubMed

アレルギー性炎症疾患の病態形成における免疫系の役割細胞傷害性Tph細胞のオリゴクローナルな増殖がIgG4関連疾患の病態形成に関与する

亀倉隆太, 村山公介, 山本圭佑, 重原克則, 高野賢一, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 70 ( 6-7 ) 817 - 817 2021年08月

免疫療法鼻炎合併喘息患者におけるダニ舌下免疫療法の濾胞ヘルパー及び濾胞制御性T細胞を中心とした解析

重原克則, 亀倉隆太, 池上一平, 柳昌弘, 山本圭佑, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 70 ( 6-7 ) 789 - 789 2021年08月

Cytotoxic Tph-like cells are involved in persistent tissue damage in IgG4-related disease

Hayato Yabe, Ryuta Kamekura, Motohisa Yamamoto, Kosuke Murayama, Shiori Kamiya, Ippei Ikegami, Katsunori Shigehara, Hiromi Takaki, Hirofumi Chiba, Hiroki Takahashi, Kenichi Takano, Hiroki Takahashi, Shingo Ichimiya

Modern Rheumatology ( Informa UK Limited ) 31 ( 1 ) 249 - 260 2021年01月 [国際誌]

OBJECTIVES: The aim of this study was to determine pathological features of T peripheral helper (Tph)-like (PD-1+CXCR5-CD4+ T) cells in IgG4-related disease (IgG4-RD). METHODS: Tph-like cells in the blood and submandibular glands (SMGs) from IgG4-RD patients were analyzed by flow cytometry. Correlations between level of a Tph-like cell subset and clinical parameters of IgG4-RD were investigated. The cytotoxic capacity of Tph-like cells was also examined. Expression profiles of a molecule related to a Tph-like cell subset in IgG4-RD SMGs were assessed by immunohistochemistry. RESULTS: Tph-like cells from IgG4-RD patients highly expressed a fractalkine receptor, CX3CR1. Percentages of circulating CX3CR1+ Tph-like cells were significantly correlated with clinical parameters including IgG4-RD Responder Index, number of involved organs, and serum level of soluble IL-2 receptor. CX3CR1+ Tph-like cells abundantly possessed cytotoxic T lymphocyte-related molecules such as granzyme A, perforin, and G protein-coupled receptor 56. Functional assays revealed their cytotoxic potential against vascular endothelial cells and ductal epithelial cells. Immunohistochemistry showed that fractalkine was markedly expressed in vascular endothelial cells and ductal epithelial cells in IgG4-RD SMGs. CONCLUSION: CX3CR1+ Tph-like cells are thought to contribute to persistent tissue injury in IgG4-RD and are a potential clinical marker and/or therapeutic target for inhibiting progression of IgG4-RD.

DOI PubMed

Cigarette Smoke Underlies the Pathogenesis of Palmoplantar Pustulosis via an IL-17A-Induced Production of IL-36γ in Tonsillar Epithelial Cells.

Keiju Kobayashi, Ryuta Kamekura, Junji Kato, Shiori Kamiya, Takafumi Kamiya, Kenichi Takano, Shingo Ichimiya, Hisashi Uhara

The Journal of investigative dermatology 141 ( 6 ) 1533 - 1541 2020年11月 [国際誌]

Palmoplantar pustulosis (PPP) is characterized by sterile pustules on the palms and soles. A strong association between PPP and tobacco smoking has been reported, and it has been speculated that the IL-17A pathway may play an important role in PPP. Recent studies have suggested that IL-36 plays a pivotal role in the pathogenesis of psoriasis and its subtypes. The relationships among IL-36, smoking, and PPP have not been examined. Here, we investigated the relationships among the smoking index, severity of the clinical condition of PPP, and in vitro dynamics of IL-36 in human tonsillar epithelial cells under the condition of exposure to a cigarette smoke extract. The results demonstrated that the Palmoplantar Pustulosis Area and Severity Index was strongly and positively correlated with the smoking index in female patients. Immunohistochemical examinations showed that IL-36γ was highly expressed in tonsillar epithelial cells from patients with PPP but not in those from patients with recurrent tonsillitis without PPP. The in vitro study revealed that IL-17A synergistically induced a release of IL-36γ under cigarette smoke extract exposure. These results suggest that local production of IL-36γ by epithelial cells induced by cigarette smoke exposure plays an important role in the pathogenesis of PPP.

DOI PubMed

ダニSLIT中のアレルギー性鼻炎合併喘息における末梢血濾胞ヘルパーT細胞の検討

重原克則, 亀倉隆太, 矢部隼人, 針生寛之, 宇野英二, 一宮慎吾

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 9 ( 増刊 ) 324 - 324 2020年08月

Activated circulating T follicular helper cells and skewing of T follicular helper 2 cells are down-regulated by treatment including an inhaled corticosteroid in patients with allergic asthma

Satsuki Miyajima, Katsunori Shigehara, Ryuta Kamekura, Hiromi Takaki, Hayato Yabe, Ippei Ikegami, Yuichiro Asai, Hirotaka Nishikiori, Hirohumi Chiba, Eiji Uno, Hiroki Takahashi, Shingo Ichimiya

Allergology International ( Elsevier BV ) 69 ( 1 ) 66 - 77 2020年01月 [国際誌]

BACKGROUND: CXCR5+ T follicular helper (TFH) cells primarily promote B cells to produce an antigen-specific antibody through germinal centers (GCs). TFH cells exist in circulation, and circulating(c) TFH2 cells, a subset of cTFH cells, are able to help naïve B cells produce IgE in healthy individuals. Conversely, IL-10-producing regulatory B (Breg) cells inhibit an accelerated immune response. METHODS: We investigated the roles of cTFH cells and cBreg cells based on a TH2 response in patients with atopic asthma (AA). Thirty-two patients with AA and 35 healthy volunteers (HV) were enrolled. We examined cTFH cells including their subsets, their expression of ICOS and PD-1, and cBreg cells by flow cytometry and their associations with clinical biomarkers. Plasma levels of CXCL13, which is a counterpart of CXCR5, were also measured using ELISA. RESULTS: In patients with AA, cTFH2 cells were increased and cTFH1 cells were decreased compared with those in HV. The expression levels of ICOS on cTFH and their subset cells were elevated and Breg cells were greatly decreased. The plasma levels of CXCL13 in patients with AA were significantly elevated and correlated well with the cTFH2/cBreg ratio. These cells were examined in 10 patients AA before and after inhaled corticosteroid (ICS) treatment. Interestingly, the percentages and numbers of TFH2 and ICOS+ cTFH cells declined after ICS treatment together with improvements in symptoms and clinical biomarkers. CONCLUSIONS: The percentages and numbers of cTFH2 and ICOS+ cTFH cells might be useful as biomarkers of TH2 typed airway inflammation in patients with AA.

DOI PubMed

Aberrant populations of circulating T follicular helper cells and regulatory B cells underlying idiopathic pulmonary fibrosis.

Yuichiro Asai, Hirofumi Chiba, Hirotaka Nishikiori, Ryuta Kamekura, Hayato Yabe, Shun Kondo, Satsuki Miyajima, Katsunori Shigehara, Shingo Ichimiya, Hiroki Takahashi

Respiratory research 20 ( 1 ) 244 - 244 2019年11月 [国際誌]

BACKGROUND: T follicular helper (Tfh) cells have been identified as a new category of helper T cells, which express CXCR5 on their surface and induce the production of antigen-specific antibodies. Many investigations have found morbid proliferation and/or activation of Tfh cells in systemic autoimmune and allergic diseases. It is also known that Tfh cells are regulated by regulatory B (Breg) cells in the deteriorating such diseases. Recently, CXCL13, a ligand of CXCR5, has been reported to increase in the peripheral blood and lungs of patients with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the involvement of Tfh cells and Breg cells in IPF. METHODS: Peripheral blood samples were obtained from 18 patients with IPF. We isolated heparinized peripheral blood mononuclear cells and investigated the proportions of Breg cells, Tfh cells, PD-1+ICOS+ Tfh cells (activated form of Tfh cells), and the Tfh-cell subsets by flow cytometry. These cell profiles were compared with those of 21 healthy controls. Furthermore, we investigated the correlations between profiles of lymphocytes and lung physiology. RESULTS: The median proportions of Tfh cells per total CD4+ T cells and of PD-1+ICOS+ proportion of Tfh cells per total Tfh cells was significantly more in the IPF patients (20.4 and 5.2%, respectively) compared with healthy controls (15.4 and 2.1%, respectively; p = 0.042 and p = 0.004, respectively). The proportion of Tfh2 cells per total Tfh cells was significantly higher and the proportion of Tfh17 was smaller in the IPF patients than healthy controls. The percentage of Breg cells to total B cells was significantly decreased in the IPF patients (median, 8.5%) compared with that in the controls (median, 19.7%; p < 0.001). The proportion of Breg cells was positively correlated with the annual relative change in diffusing capacity of the lungs for carbon monoxide in the IPF patients (r = 0.583, p = 0.018). CONCLUSION: Proliferation and activation of Tfh cells and a decrease in Breg cells were observed in the peripheral blood of patients with IPF. The profile of the Tfh-cell subset also changed. Specific humoral immunity aberration would likely underlie complicated pathophysiology of IPF.

DOI PubMed

Interleukin 5-producing ST2+ memory Th2 cells in IgG4-related dacryoadenitis and sialadenitis.

Motohisa Yamamoto, Ken-Ichi Takano, Ryuta Kamekura, Satsuki Aochi, Chisako Suzuki, Shingo Ichimiya, Hiroshi Nakase, Tetsuo Himi, Hiroki Takahashi

Modern rheumatology ( TAYLOR & FRANCIS LTD ) 29 ( 5 ) 856 - 860 2019年09月 [査読有り] [国際誌]

Objectives: Immunoglobulin (Ig) G4-related disease (IgG4-RD) is often complicated by allergic disorders. This study was conducted to investigate the mechanism of type 2 helper T-inflammation (Th2-inflammation) in IgG4-related dacryoadenitis and sialadenitis (IgG4-DS). Methods: We separated and analyzed the proportion of growth stimulation expressed gene 2 (ST2)+ memory Th2 cells among the peripheral blood mononuclear cells by flow cytometry in cases with IgG4-DS and healthy individuals. Finally, we identified the role of ST2+ memory Th2 cells in the involved tissues. Results: The proportion of circulating ST2+ memory Th2 cells was much higher in the patients with IgG4-DS than in the healthy controls. Abundant infiltration of ST2+ memory Th2 cells was detected in the involved salivary glands and lymph nodes, and these cells produced interleukin-5. Conclusion: We demonstrated that there is an increase of interleukin-5 producing ST2+ memory Th2 cells in the involved tissues in IgG4-DS. This subset of cells is considered to be an important player in inducing the inflammatory Th2 environment characteristic of IgG4-DS.

DOI PubMed

Bob1 enhances RORγt-mediated IL-17A expression in Th17 cells through interaction with RORγt.

Ikegami I, Takaki H, Kamiya S, Kamekura R, Ichimiya S

Biochemical and biophysical research communications ( Elsevier BV ) 514 ( 4 ) 1167 - 1171 2019年07月 [査読有り] [国際誌]

POU domain class 2-associating factor 1 (also called Bob1), which is mainly expressed in B cells, regulates B cell homeostasis and controls humoral immune responses. Although Bob1 is known to function reliably in T cell subsets including follicular helper T cells, Th1 cells and Th2 cells, it is unknown whether Bob1 functions in other T cell subsets. In this study, we found that Bob1 knock out (KO) mice are resistant to experimental autoimmune encephalomyelitis (EAE) induced by MOG35-55 peptide and that Bob1 KO T cells are defective in Th17 differentiation. Importantly, Bob1 interacts with retinoid acid receptor-related orphan receptor (ROR) gamma t (RORγt), a signature transcription factor for Th17 cells, through the ligand-binding domain of RORγt, thereby enhancing IL-17A transcription activity. IL-17A induction by Bob1 requires the ability for its formation of a DNA-Oct1-Bobl ternary complex. Thus, our findings demonstrate that Bob1 enhances IL-17A expression in vivo and in vitro by interacting with RORγt in Th17 cells, suggesting that Bob1 plays a pivotal role in Th17-mediated autoimmune disease.

DOI PubMed

舌下免疫療法ダニ舌下免疫療法中の喘息合併アレルギー性鼻炎患者における濾胞ヘルパーT細胞を中心とした検討

重原克則, 亀倉隆太, 矢部勇人, 高木宏美, 宇野英二, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 68 ( 4-5 ) 503 - 503 2019年05月

生体バリア機構とアレルギー疾患アレルギー性鼻炎に関連するエピイムノームの新機能

亀倉隆太, 矢部勇人, 重原克則, 高野賢一, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 68 ( 4-5 ) 320 - 320 2019年05月

鼻炎合併アトピー型喘息患者のダニ抗原SLIT施行における濾胞ヘルパー細胞と濾胞制御性T細胞の検討

重原克則, 亀倉隆太, 矢部隼人, 宇野英二, 一宮慎吾

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 8 ( 増刊 ) 250 - 250 2019年03月

IL-10+ T follicular regulatory cells are associated with the pathogenesis of IgG4-related disease.

Ito F, Kamekura R, Yamamoto M, Takano K, Takaki H, Yabe H, Ikegami I, Shigehara K, Himi T, Takahashi H, Ichimiya S

Immunology letters ( Elsevier BV ) 207 56 - 63 2019年03月 [査読有り] [国際誌]

IgG4-related disease (IgG4-RD) is a chronic fibroinflammatory disease characterized by elevation of serum IgG4 level as well as infiltration of IgG4+ plasma cells in various affected organs. The etiology of IgG4-RD is still not fully understood. Since IgG4-RD is more prevalent in the elderly, aging in itself is considered to be an important risk factor of IgG4-RD. However, the relationship between the pathogenesis of IgG4-RD and immunosenescence remains unknown. To clarify age-related features underlying IgG4-RD, we focused on T follicular regulatory (Tfr) cells, which share forkhead box P3 with regulatory T cells, since the percentage of Tfr cells is known to depend on age. Studies of blood specimens from patients with IgG4-RD and from healthy volunteers demonstrated a marked elevation of circulating Tfr (cTfr) cells in patients with IgG4-RD. Moreover, the percentage of cTfr cells was significantly correlated with various clinical parameters including the level of serum IgG4 and the number of involved organs in IgG4-RD patients. The percentages of tonsillar and blood Tfr cells were increased with aging in healthy volunteers, whereas the suppressive effect of cTfr cells on B cell function in elderly subjects was impaired in comparison with that in young subjects due to a defect in the production of a regulatory cytokine, IL-10. Given that the number of IL-10-producing cTfr cells in IgG4-RD patients was markedly increased compared with that in healthy elderly subjects, these findings suggest that an abnormal aging process of Tfr cells may be related to the pathogenesis of IgG4-RD.

DOI PubMed

Retroperitoneal Fibrosis Diagnosed as IgG4-related Disease after 35 Years.

Konno S, Matsuno Y, Ichimiya S, Nishimura M, Kawakami Y

Internal medicine (Tokyo, Japan) 58 ( 4 ) 609 - 613 2019年02月 [査読有り] [国内誌]

In 1982, we reported a case of retroperitoneal fibrosis (RPF) exhibiting various clinical manifestations. Our current understanding of immunoglobulin G4 (IgG4)-related disease led us to consider it as a possible diagnosis because all of the patient's clinical features could be explained by this disease entity. To confirm our hypothesis, were investigated the histopathological findings of resected specimens that had been stored for 35 years postoperatively. Typical pathological findings together with predominant IgG4+ plasma cell infiltration confirmed a potential diagnosis of IgG4-related RPF. Furthermore, we observed positive immunohistochemical staining for several molecules associated with T regulatory and T follicular helper cells.

DOI PubMed

A unique subset of PD-1(+)CXCR5(-)CD4(+) T cells is involved in immunological mechanisms of IgG4-related disease

Kamekura Ryuta, Yamamoto Motohisa, Yabe Hayato, Takaki Hiromi, Takano Kenichi, Takahashi Hiroki, Takahashi Hiroki, Himi Tetsuo, Ichimiya Shingo

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 143 ( 2 ) AB231 2019年02月 [査読有り]

DOI

Analysis of allergic reaction in IgG4-related disease.

Yamamoto M, Takano KI, Kamekura R, Aochi S, Suzuki C, Ichimiya S, Takahashi H

Modern rheumatology ( TAYLOR & FRANCIS LTD ) 29 ( 6 ) 1 - 3 2019年01月 [査読有り] [国際誌]

DOI PubMed

New insights into IgG4-related disease: emerging new CD4+ T-cell subsets.

Kamekura R, Takahashi H, Ichimiya S

Current opinion in rheumatology 31 ( 1 ) 9 - 15 2019年01月 [査読有り] [国際誌]

PURPOSE OF REVIEW: New insights into IgG4-related disease (IgG4-RD) have recently been obtained. A better understanding of the mechanisms underlying this disease is important for identification of therapeutic targets, which will lead to the development of specific strategies for treatment. RECENT FINDINGS: Infiltration of activated T follicular helper (Tfh) cells is observed in affected tissues of IgG4-RD. Such Tfh cells have a greater capacity than tonsillar Tfh cells to help B cells produce IgG4. Circulating PD-1CXCR5 peripheral T helper (Tph)-like cells are also increased in patients with IgG4-RD. Because Tph-like cells express high levels of chemokine receptors and granzyme A, they have the capacity to infiltrate affected tissues and exert a cytotoxic function. Tph-like cells can also produce CXCL13, and CXCR5 Tfh cells and B cells are therefore preferentially recruited to form ectopic lymphoid structures in the sites. Tph cells may have a role to ignite inflammation and maintain persistent fibroinflammation in collaboration with Tfh cells in lesions of IgG4-RD. SUMMARY: Recent advances in understanding the pathogenesis of IgG4-RD are remarkable. In this review, we summarize and discuss the possible pathologic role of CD4 T-cell subsets in IgG4-RD.

DOI PubMed

Stage classification of IgG4-related dacryoadenitis and sialadenitis by the serum cytokine environment.

Motohisa Yamamoto, Kenichi Takano, Ryuta Kamekura, Chisako Suzuki, Shingo Ichimiya, Tetsuo Himi, Hiroshi Nakase, Hiroki Takahashi

Modern rheumatology ( TAYLOR & FRANCIS LTD ) 28 ( 6 ) 1004 - 1008 2018年11月 [査読有り] [国際誌]

OBJECTIVES: Patients with immunoglobulin-G4 related disease (IgG4-RD) diagnosed according to the comprehensive diagnostic criteria (CDC) show varied therapeutic responses and prognoses. We assumed that there are clinical stages in IgG4-RD and have verified it using serum cytokine levels in the groups classified by lesion distribution. METHODS: Definite IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) cases were divided according to the CDC for IgG4-RD into 11 cases with focal type and 30 cases with systemic type. The levels of serum interleukin (IL)-4, IL-5, IL-6, IL-10, IL-13, IL-15, IL-21, interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β1, and monocyte chemotactic protein (MCP)-1 were measured in healthy controls, allergic patients, probable IgG4-RD cases, and focal and systemic type cases. The cytokine environment was analyzed in each group. The 52 definite IgG4-RD cases were next classified into four groups with cluster analysis in terms of therapeutic responses and prognosis. The relationships between each cytokine level and therapeutic responses were also analyzed. RESULTS: Both serum IL-5 and IFN-α concentrations were very low in healthy controls, but they increased in the allergic cases, probable cases, and focal and systemic type cases. The level of serum IL-5 was significantly higher in definite cases than in healthy controls. The serum IL-5 level was also significantly increased in the groups with a poor prognosis than in the good prognosis group. CONCLUSION: These results suggest that there are clinical stages in IgG4-RD, and serum IL-5 play roles in the pathogenesis of IgG4-RD.

DOI PubMed

ダニ舌下免疫療法における血液機能性リンパ球サブセットの経時的変化

亀倉隆太, 重原克則, 伊藤史恵, 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 ) 67 ( 4-5 ) 598 - 598 2018年05月

アトピー型喘息における治療前後の末梢血濾胞ヘルパーT細胞および制御性B細胞の変化

重原克則, 宮島さつき, 亀倉隆太, 矢部隼人, 高橋弘毅, 一宮慎吾

アレルギー ( (一社)日本アレルギー学会 ) 67 ( 4-5 ) 637 - 637 2018年05月

「地域医療を支える人づくりプロジェクト事業」地域医療体験事業での教育手法の工夫

齊藤正樹, 神倫聡, 高野智史, 三瀬敬冶, 鈴木究, 田原勇人, 柴田亨, 橋本諭, 一宮慎吾, 下濱俊, 中村眞理子, 高橋弘毅

医療人育成センター紀要 ( 札幌医科大学医療人育成センター ) 9 ( 9 ) 9 - 14 2018年03月 [査読有り]

CiNii

Predicting therapeutic response in IgG4-related disease based on cluster analysis.

Motohisa Yamamoto, Ken-Ichi Takano, Ryuta Kamekura, Chisako Suzuki, Tetsuya Tabeya, Rieko Murakami, Saho Honda, Masaya Mukai, Masanori Nojima, Shingo Ichimiya, Tetsuo Himi, Hiroshi Nakase, Hiroki Takahashi

Immunological medicine 41 ( 1 ) 30 - 33 2018年03月 [査読有り] [国際誌]

To bring the clinical practice of immunoglobulin (Ig)G4-related disease (IgG4-RD) close to personalized medicine, we classified the patient groups and clarified the therapeutic responses of each group. A total of 147 patients enrolled in our registry were classified into four groups by cluster analysis with the software. The therapeutic responses and prognosis of each group were examined. The cluster analysis classified the subjects into four groups: Cluster 1, patients who presented with prominent hypergammaglobulinemia, elevated levels of serum IgG4, and hypocomplementemia; Cluster 2, patients who presented with eosinophilia, elevated concentrations of serum IgG, IgG4, and IgE, and in whom CRP tended to be positive; Cluster 3, patients with younger onset and serum levels of IgG, IgG4, and IgE and peripheral eosinophil counts lower than the other clusters; and Cluster 4, patients with elder onset and low peripheral eosinophil counts. The amounts of glucocorticoid for maintenance treatment were from 5 to 7 mg/d in all groups, but the amounts were significantly greater in Cluster 1 (patients with hypergammaglobulinemia, elevated levels of serum IgG4, and hypocomplementemia) than in Cluster 4 (elder onset patients, relatively low concentrations of peripheral eosinophils). With regard to the use of immunosuppressants and the relapse rate, there were high frequencies in Cluster 1 and Cluster 3 (younger onset patients who presented with mild elevations of serum IgG and IgG4). On the other hand, Cluster 4 showed a low rate of relapse and often could discontinue steroids. The present results suggest that personalized medicine could be provided in IgG4-RD by classifying patients based on their clinical features.

DOI PubMed

COPD患者における喘息患者との対比を含めた末梢血濾胞ヘルパーT細胞と制御性B細胞の検討

重原克則, 亀倉隆太, 川田耕司, 宮島さつき, 矢部勇人, 高橋弘毅, 一宮慎吾

日本呼吸器学会誌 ( (一社)日本呼吸器学会 ) 7 ( 増刊 ) 219 - 219 2018年03月

COPD患者における喘息患者との対比を含めた末梢血濾胞ヘルパーT細胞と制御性B細胞の検討

重原克則, 亀倉隆太, 宮島さつき, 矢部勇人, 高橋弘毅, 一宮慎吾

日本内科学会雑誌 ( (一社)日本内科学会 ) 107 ( Suppl. ) 215 - 215 2018年02月

Unique profiles of lesional T follicular helper cells in the pathogenesis of IgG4-related disease

Kamekura Ryuta, Yabe Hayato, Takano Kenichi, Yamamoto Motohisa, Ikegami Ippei, Ito Fumie, Takahashi Hiroki, Himi Tetsuo, Ichimiya Shingo

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 141 ( 2 ) AB284 2018年02月 [査読有り]

Circulating PD-1+CXCR5-CD4+ T cells underlying the immunological mechanisms of IgG4-related disease.

Kamekura R, Yamamoto M, Takano K, Yabe H, Ito F, Ikegami I, Takaki H, Shigehara K, Suzuki C, Himi T, Takahashi H, Ichimiya S

Rheumatology advances in practice ( Oxford University Press (OUP) ) 2 ( 2 ) rky043 2018年 [査読有り] [国際誌]

OBJECTIVE: The aim was to study the pathological role of lymphocytes with a peripheral T helper-cell-like phenotype (PD-1+CXCR5-CD4+) in IgG4-related disease (IgG4-RD). METHODS: PD-1+CXCR5-CD4+ T cells in the blood of patients with IgG4-RD (n = 53), patients with SS (n = 16) and healthy volunteers (n = 34) as controls were analysed by flow cytometry. Correlations between results obtained by flow cytometry and clinical parameters relevant to IgG4-RD were also analysed. RESULTS: The percentage and absolute number of PD-1+CXCR5- cells within total CD4+ T cells in IgG4-RD patients were significantly increased compared with those in healthy volunteers. Further analysis showed that there were marked positive correlations of the percentage of PD-1+CXCR5-CD4+ T cells with the serum level of IgG4 and the number of organs involved. Interestingly, granzyme A (GZMA)+ cells were enriched in PD-1+CXCR5-CD4+ T cells, and the percentage and absolute number of GZMA+PD-1+CXCR5-CD4+ T cells were significantly elevated in IgG4-RD patients. Although no obvious change was observed in the percentage of total CD4+ T cells, the percentage and absolute number of PD-1+CXCR5-CD4+ T cells decreased in accordance with a reduction of serum IgG4 level after treatment with glucocorticoids. CONCLUSION: In IgG4-RD, circulating CD4+ T-cell populations were composed of PD-1+CXCR5- cells, and the ratios of these cells were correlated with clinical manifestations of IgG4-RD. Further analysis of GZMA+PD-1+CXCR5-CD4+ T cells might lead to a deeper understanding of the pathogenesis of ectopic lymphoid follicles and the persistent inflammation in IgG4-RD.

DOI PubMed

Mucosal Immune Response in Nasal-Associated Lymphoid Tissue upon Intranasal Administration by Adjuvants.

Takaki H, Ichimiya S, Matsumoto M, Seya T

Journal of innate immunity ( KARGER ) 10 ( 5-6 ) 515 - 521 2018年 [査読有り] [国際誌]

The nasal administration of vaccines directed against diseases caused by upper respiratory tract infections of pathogens, such as the influenza virus, mimics the natural infection of pathogens and induces immunoglobulin A (IgA) production in the nasal cavity to effectively protect viral entry. Therefore, the development of a nasally administered vaccine is a research objective. Because the antigenicity of influenza split vaccines is low, nasal inoculation with the vaccine alone does not induce strong IgA production in the nasal cavity. However, the addition of adjuvants activates the innate immune response, enhancing antigen-specific IgA production and the T-cell response. Although the development of suitable adjuvants for nasal vaccinations is in progress, the mechanism by which adjuvants promote the immune response is still unclear. In this review, we discuss the mucosal immune response, especially in the nasal-associated lymphoid tissue, induced in response to the intranasal inoculation of an influenza vaccine and adjuvants in animal models.

DOI PubMed

Loss of sorting nexin 5 stabilizes internalized growth factor receptors to promote thyroid cancer progression

Sumito Jitsukawa, Ryuta Kamekura, Koji Kawata, Fumie Ito, Akinori Sato, Hiroshi Matsumiya, Tomonori Nagaya, Keiji Yamashita, Terufumi Kubo, Tomoki Kikuchi, Noriyuki Sato, Tadashi Hasegawa, Hiroshi Kiyonari, Yoshiko Mukumoto, Ken-ichi Takano, Tetsuo Himi, Shingo Ichimiya

JOURNAL OF PATHOLOGY ( WILEY ) 243 ( 3 ) 342 - 353 2017年11月 [査読有り] [国際誌]

Thyroid carcinoma is the most common endocrine malignancy and its prevalence has recently been increasing worldwide. We previously reported that the level of sorting nexin 5 (Snx5), an endosomal translocator, is preferentially decreased during the progression of well-differentiated thyroid carcinoma into poorly differentiated carcinoma. To address the functional role of Snx5 in the development and progression of thyroid carcinoma, we established Snx5-deficient (Snx5(-/-)) mice. In comparison to wild-type (Snx5(+/+)) mice, Snx5(-/-) mice showed enlarged thyroid glands that consisted of thyrocytes with large irregular-shaped vacuoles. Snx5(-/-) thyrocytes exhibited a higher growth potential and higher sensitivity to thyroid-stimulating hormone (TSH). A high content of early endosomes enriched with TSH receptors was found in Snx5(-/-) thyrocytes, suggesting that loss of Snx5 caused retention of the TSH receptor (TSHR) in response to TSH. Similar data were found for internalized EGF in primary thyrocytes. The increased TSH sensitivities in Snx5(-/-) thyrocytes were also confirmed by results showing that Snx5(-/-) mice steadily developed thyroid tumors with high metastatic potential under high TSH. Furthermore, a thyroid cancer model using carcinogen and an anti-thyroidal agent revealed that Snx5(-/-) mice developed metastasizing thyroid tumors with activation of MAP kinase and AKT pathways, which are postulated to be major pathways of malignant progression of human thyroid carcinoma. Our results suggest that thyrocytes require Snx5 to lessen tumorigenic signaling driven by TSH, which is a major risk factor for thyroid carcinoma. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DOI PubMed

Keratinocytes in atopic dermatitis express abundant ΔNp73 regulating thymic stromal lymphopoietin production via NF-κB.

Kumagai A, Kubo T, Kawata K, Kamekura R, Yamashita K, Jitsukawa S, Nagaya T, Sumikawa Y, Himi T, Yamashita T, Ichimiya S

Journal of dermatological science ( ELSEVIER IRELAND LTD ) 88 ( 2 ) 175 - 183 2017年11月 [査読有り]

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease that often cannot be completely controlled by modern medicine. Since multiple factors are intricately involved in the pathogenesis of AD, wide-ranging research is required for further advancement of AD treatment. Epidermal keratinocytes are the forefront to the external environment and play a pivotal role in the initiation of immune reaction against exogenous invasion. Objective: Thymic stromal lymphopoietin (TSLP) is a keratinocyte-derived cytokine that induces differentiation and activation of type 2 helper T cells and innate lymphoid cells, cardinal effectors in pathophysiology of AD. We previously reported that Delta Np63, a p53-related molecule, regulates the expression of TSLP receptors and suggested the entity of a potential TSLP autocrine loop in the AD epidermis. In this study, we further explored the significance of p53 family transcription factors in TSLP production from human keratinocytes. Method: Expression profile of p73, a p53-related molecule, was evaluated in human AD tissue by immunohistochemistry. In addition, the function of p73 in producing TSLP was investigated with in vitro cultured keratinocytes via molecular biological analysis. Results: Delta Np73 was abundantly expressed in the AD epidermis and increased the release of TSLP via NF-kappa B activation. Furthermore, the Toll-like receptor 3 signal enhanced Delta Np73 expression and thereby induced TSLP expression. Conclusion: Our results indicate that Delta Np73 is an additional participant in the mechanism of TSLP production. Amending the aberrant state of keratinocytes, represented by overexpression of ANp73, can be a novel therapeutic target of AD. (C) 2017 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

DOI PubMed

High frequency of Bob1(1o) T follicular helper cells in florid reactive follicular hyperplasia

Hiroshi Matsumiya, Koji Kawata, Ryuta Kamekura, Chieko Tsubomatsu, Sumito Jitsukawa, Takamasa Asai, Syunsuke Akasaka, Motonari Kamei, Keiji Yamashita, Fumie Ito, Terufumi Kubo, Noriyuki Sato, Ken-ichi Takano, Tetsuo Himi, Shingo Ichimiya

IMMUNOLOGY LETTERS ( ELSEVIER SCIENCE BV ) 191 23 - 30 2017年11月 [査読有り]

Florid reactive follicular hyperplasia (FRFH), which is characterized by large germinal centers (GCs) within normal lymphoid follicles, is often observed in benign lesions of lymph nodes and other tissues. Because of the histologic similarity of FRFH to tumorous lesions such as follicular lymphoma, careful pathological examination is required to evaluate such lesions; however, little is known about the mechanism underlying the development of FRFH. In this study, we investigated T follicular helper (Tfh) cells in hyperplastic tonsils of patients with obstructive sleep apnea syndrome (OSA), which frequently exhibits typical FRFH. When we analyzed tonsils of OSA and recurrent tonsillitis (RT) as a control, tonsils of OSA were found to harbor Tfh cells with a nearly 3-fold higher ratio in total CD4(+) T cells than that in tonsils of RT. Further analysis showed that, in comparison to Tfh cells of RT tonsils, Tfh cells of OSA tonsils were relatively tolerant to CD3-mediated activation-induced cell death (AICD) and also expressed lower levels of a Bob1 transcription coactivator and IL-4, which fosters the development of GC-B cells. Given that Bob1 controls the proliferative activity in response to CD3 stimulation and has been suggested to have a role in the production of IL-4 in Tfh cells, the unique structure of FRFH is possibly associated with the function of Bob1(lo) Tfh cells.

DOI PubMed

Cutting Edge: A Critical Role of Lesional T Follicular Helper Cells in the Pathogenesis of IgG4-Related Disease

Ryuta Kamekura, Kenichi Takano, Motohisa Yamamoto, Koji Kawata, Katsunori Shigehara, Sumito Jitsukawa, Tomonori Nagaya, Fumie Ito, Akinori Sato, Noriko Ogasawara, Chieko Tsubomatsu, Hiroki Takahashi, Hiroshi Nakase, Tetsuo Himi, Shingo Ichimiya

JOURNAL OF IMMUNOLOGY ( AMER ASSOC IMMUNOLOGISTS ) 199 ( 8 ) 2624 - 2629 2017年10月 [査読有り] [国際誌]

IgG4-related disease (IgG4-RD) is a newly recognized systemic chronic fibroinflammatory disease. However, the pathogenesis of IgG4-RD remains unknown. To determine the pathophysiologic features of IgG4-RD, we examined T follicular helper (Tfh) cells in lesions and blood from patients with IgG4-RD. Patients with IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) showed increased infiltration of Tfh cells highly expressing programmed death 1 and ICOS in submandibular glands. Tfh cells from IgG4-DS submandibular glands had higher expression of B cell lymphoma 6 and a greater capacity to help B cells produce IgG4 than did tonsillar Tfh cells. We also found that the percentage of programmed death 1 hi circulating Tfh cells in IgG4-DS patients was higher than that in healthy volunteers and was well correlated with clinical parameters. Our findings indicate that anomalous Tfh cells in tissue lesions of IgG4-RD have features distinct from those in lymphoid counterparts or blood and potentially regulate local IgG4 production in IgG4-RD.

DOI PubMed

Regulation of claudin-4 via p63 in human epithelial cells

Takashi Kojima, Takayuki Kohno, Terufumi Kubo, Yakuto Kaneko, Takuya Kakuki, Akito Kakiuchi, Makoto Kurose, Ken-ichi Takano, Noriko Ogasawara, Kazufumi Obata, Kazuaki Nomura, Ryo Miyata, Takumi Konno, Shingo Ichimiya, Tetsuo Himi

ANNALS OF THE NEW YORK ACADEMY OF SCIENCES ( WILEY ) 1405 ( 1 ) 25 - 31 2017年10月 [査読有り] [国際誌]

P63 is a regulator of cell-cell junction complexes in the epidermis. Claudin-4 is regulated via various factors in normal epithelial cells and diseases. We found that claudin-4 was directly regulated via p63 (TAp63 and Delta Np63) in human keratinocytes and nasal epithelial cells. In the epidermis of atopic dermatitis (AD), which contains Delta Np63-deficient keratinocytes, high expression of claudin-4 was observed. In primary keratinocytes, downregulation of Delta Np63 by treatment with short interfering RNA (siRNA)-p63 induced claudin-4 expression. In nasal epithelial cells in the context of rhinitis or nasal polyps, upregulation of TAp63 and downregulation of claudin-4 were observed. In primary nasal epithelial cells transfected with the human telomerase reverse transcriptase gene, knockdown of p63 by siRNAs induced claudin-4 expression. Taken together, these findings indicate that p63 is a negative regulator of claudin-4 expression. Understanding the regulation of claudin-4 via p63 in human epithelial cells may be important for developing therapies for allergies and drug delivery systems.

DOI PubMed

Deterioration of regulatory B cells and activation of follicular helper T cells in idiopathic interstitial pneumonias patients

Asai Yuichiro, Chiba Hirofumi, Kondoh Syun, Nishikiori Hirotaka, Takahashi Mamoru, Kuronuma Koji, Otsuka Mitsuo, Yamada Gen, Kamekura Ryuta, Ichimiya Shingo, Takahashi Hiroki

EUROPEAN RESPIRATORY JOURNAL 50 2017年09月 [査読有り]

DOI

「自然免疫とアレルギー疾患最新の病態」に寄せる腸内細菌による濾胞ヘルパーT細胞制御の可能性と免疫アレルギー病態

川田耕司, 一宮慎吾

アレルギーの臨床 ( (株)北隆館 ) 37 ( 3 ) 252 - 255 2017年03月

Role of Lesional BCL6hiPD-1hi T Follicular Helper Cells As a Cardinal B-Cell Helper to Produce IgG4 in IgG4-Related Disease

Ryuta Kamekura, Kenichi Takano, Motohisa Yamamoto, Koji Kawata, Sumito Jitsukawa, Tomonori Nagaya, Fumie Ito, Chieko Tsubomatsu, Hiroki Takahashi, Tetsuo Himi, Shingo Ichimiya

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY ( MOSBY-ELSEVIER ) 139 ( 2 ) AB13 - AB13 2017年02月 [査読有り]

DOI

Functional RNAs control T follicular helper cells

Shingo Ichimiya, Ryuta Kamekura, Koji Kawata, Motonari Kamei, Tetsuo Himi

JOURNAL OF HUMAN GENETICS ( NATURE PUBLISHING GROUP ) 62 ( 1 ) 81 - 86 2017年01月 [査読有り]

T follicular helper cells (Tfh cells), which are a prototypic subset of effector CD4(+) T cells, regulate the production of high-affinity antibodies by controlling B cells at initial and recall phases. Since the discovery of Tfh cells in human tonsils, many notable studies focusing on Tfh cells have clarified mechanisms underlying Tfh-cell-related physiological and pathological settings. Results of these studies revealed a chief regulatory function of BCL6 in Tfh cells and the involvement of Tfh cells in the pathogenesis of various disorders including autoimmune diseases, allergies and cancers. Further, accumulating evidence has revealed microRNAs (miRNAs) of functional noncoding RNAs (ncRNAs) to be cardinal regulators of Tfh cells during the processes of development, differentiation and plasticity. In this review article, we summarize and discuss the results of recent studies about miRNAs operating Tfh-cell function and their relationships in diseases. Through the window of such functional ncRNAs, the functional significance of Tfh cells in CD4(+) T-cell biology is becoming apparent. Studies to determine the complex background of the genetic program of Tfh cells operated by functional RNAs should lead to an understanding of the manifestations of Tfh cells with unidentified pathophysiological relevance.

DOI PubMed

Lipid mediators foster the differentiation of T follicular helper cells

Tomonori Nagaya, Koji Kawata, Ryuta Kamekura, Sumito Jitsukawa, Terufumi Kubo, Motonari Kamei, Noriko Ogasawara, Ken-ichi Takano, Tetsuo Himi, Shingo Ichimiya

IMMUNOLOGY LETTERS ( ELSEVIER SCIENCE BV ) 181 51 - 57 2017年01月 [査読有り]

Lipid mediators such as leukotrienes and lipoxines broadly regulate innate and acquired immunity, and their dysfunction causes various immune -mediated disorders. We previously reported a salient feature of arachidonate 5-lipoxyganase (Alox5), which is responsible for the production of such lipid mediators, in the regulation of high affinity antibodies in vivo. The aim of this study was to determine the functional significance of Alox5-related lipid mediators during the processes of acquired humoral responses. The results of in vitro experiments using lymphocytes in tonsils and blood specimens showed that lipoxin A4 (LXA4) and leukotriene B4 (LTB4) have the capacity to differentiate naive CD4(+) T cells into T follicular helper (Tfh) cells, which activate naive B cells to form germinal centers. Such a function of LXA4 was further supported by results of in vitro studies using BML-111 and BOC-2, which are an agonist and an antagonist, respectively, of FPR2 of an LXA4-specific cell-surface receptor. The results suggest that such lipid mediators have a potential role in the development of lymphoid follicles through the regulation of Tfh cell differentiation. (C) 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

DOI PubMed

Assessing the usefulness of salivary gland biopsy for diagnosis of type-1 autoimmune pancreatitis

Kenichi Takano, Motohisa Yamamoto, Shingo Ichimiya, Hiroki Takahashi, Tetsuo Himi

MODERN RHEUMATOLOGY ( SPRINGER ) 27 ( 3 ) 548 - 550 2017年 [査読有り]

DOI PubMed

KS-2 IgG4関連涙腺・唾液腺炎の病態形成における濾胞ヘルパーT細胞の機能的役割

亀倉隆太, 高野賢一, 山本元久, 伊藤史恵, 矢部勇人, 川田耕司, 高橋裕樹, 氷見徹夫, 一宮慎吾

日本臨床免疫学会会誌 ( 日本臨床免疫学会 ) 40 ( 4 ) 292b - 292b 2017年

【目的】IgG4関連涙腺・唾液腺炎（IgG4-DS）は，涙腺・唾液腺の持続性腫脹と高IgG4血症，局所でのIgG4陽性形質細胞の浸潤を特徴とする疾患である．近年，IgG4産生に関連して，濾胞ヘルパーT（Tfh）細胞と本疾患との関連を示唆する報告が散見されるが，病変部位でのTfh細胞の機能的役割は不明である．【方法】IgG4-DS患者の顎下腺組織からTfh細胞（CD3⁺CD4⁺CXCR5⁺PD-1^hi）を分離し，DNAマイクロアレイやリアルタイムPCRによる遺伝子発現解析に加え，B細胞との共培養の系でIgG4産生について検討した．比較対照としてヒト口蓋扁桃由来のTfh細胞を用いた．【結果】IgG4-DSの顎下腺組織中に存在するCD4陽性T細胞の多くはCXCR5陽性，PD-1強陽性のTfh細胞であり，口蓋扁桃由来のTfh細胞と比較して，Tfh細胞関連分子（BCL6, CXCL13, IL-10）の発現上昇を認めた．また，IgG4-DSの顎下腺由来Tfh細胞とB細胞との共培養で，口蓋扁桃由来のTfh細胞とB細胞との共培養と比較して，より効率的にIgG4の産生が誘導された．さらにDNAマイクロアレイによる解析でIgG4-DSの顎下腺由来のTfh細胞ではCD8A, Granzyme Kといった細胞障害性T細胞関連遺伝子の発現上昇を認めた．【結論】今回の結果から，IgG4-DSの病態形成に強力な抗体産生誘導能と細胞障害能を併せ持つ特殊なTfh細胞が関与している可能性が考えられた．病変部位におけるTfh細胞が，IgG4-DSの新規治療法を開発する上での治療標的となる可能性が示唆された．

DOI CiNii

Importance of "epimmunome" as a new therapeutic target for allergic rhinitis

Ryuta Kamekura, Shingo Ichimiya, Tetsuo Himi

Japanese Journal of Allergology ( Japanese Society of Allergology ) 66 ( 2 ) 91 - 96 2017年 [査読有り]

DOI PubMed

Bob1 limits cellular frequency of T-follicular helper cells (vol 46, pg 1361, 2016)

Keiji Yamashita, Koji Kawata, Hiroshi Matsumiya, Ryuta Kamekura, Sumito Jitsukawa, Tomonori Nagaya, Noriko Ogasawara, Ken-ichi Takano, Terufumi Kubo, Sachiko Kimura, Katsunori Shigehara, Tetsuo Himi, Shingo Ichimiya

EUROPEAN JOURNAL OF IMMUNOLOGY ( WILEY-BLACKWELL ) 46 ( 8 ) 2054 - 2054 2016年08月 [査読有り]

Novel Mechanisms of Compromised Lymphatic Endothelial Cell Homeostasis in Obesity: The Role of Leptin in Lymphatic Endothelial Cell Tube Formation and Proliferation

Akinori Sato, Ryuta Kamekura, Koji Kawata, Masaya Kawada, Sumito Jitsukawa, Keiji Yamashita, Noriyuki Sato, Tetsuo Himi, Shingo Ichimiya

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 11 ( 7 ) e0158408 2016年07月 [査読有り]

Leptin is a hormone produced by adipose tissue that regulates various physiological processes. Recent studies have shown that the level of circulating leptin is elevated in obese patients and have suggested a relationship between obesity and postoperative lymphedema. However, the mechanisms by which postoperative lymphedema develops in obese patients and the mechanisms by which leptin regulates lymphatic endothelial cell homeostasis such as tube formation and cell proliferation remain unknown. Here we report that leptin regulates tube formation and cell proliferation in human dermal lymphatic endothelial cells (HDLECs) by activation of the signal transducer and activator of transcription 3 pathway, which is downstream signaling of the leptin receptor. Additionally, we found that upregulation of suppressor of cytokine signaling 3 underlies the mechanisms by which a high dose of leptin inhibits cell proliferation and tube formation. Leptin also enhanced expression of the proinflammatory cytokine IL-6 in HDLECs. Interestingly, IL-6 rescues the compromised cell proliferation and tube formation caused by treatment with a high dose of leptin in an autocrine or paracrine manner. Taken together, our findings reveal a novel mechanism by which compromised HDLECs maintain their homeostasis during inflammation mediated by leptin and IL-6. Thus, regulating the level of leptin or IL-6 may be a viable strategy to reduce the incidence of postoperative lymphedema.

DOI PubMed

Clinicopathological analysis of salivary gland tissue from patients with IgG4-related disease

Kenichi Takano, Kazuaki Nomura, Ayumi Abe, Ryuta Kamekura, Motohisa Yamamoto, Shingo Ichimiya, Hiroki Takahashi, Tetsuo Himi

ACTA OTO-LARYNGOLOGICA ( TAYLOR & FRANCIS LTD ) 136 ( 7 ) 717 - 721 2016年07月 [査読有り]

Conclusion The diagnosis of immunoglobulin G4-related disease (IgG4-RD) should be based on the morphology of tissue biopsy, and this study recommends a submandibular gland (SMG) biopsy for accurate diagnosis and to exclude malignant disease. Objective To clarify which type of biopsy specimen (SMG or labial salivary gland [LSG]) should be taken from patients with IgG4-RD. Methods This study included 33 patients with IgG4-RD (21 women; 12 men) who were subjected to both SMG and LSG biopsies at Sapporo Medical University between 2011-2015. Tissues obtained from the SMG and LSG specimens were evaluated. Results All SMG specimens satisfied the diagnostic criteria for IgG4-RD, whereas 19 (57.6%) LSG specimens satisfied the diagnostic criteria for IgG4-RD. Histological evaluation showed fibrosis in all the SMG specimens and in eight LSG specimens (24.2%). Obliterative phlebitis was seen in nine SMG specimens (27.3%), but it was absent in all the LSG specimens.

DOI PubMed

Identification of a novel human memory T-cell population with the characteristics of stem-like chemo-resistance

Kenji Murata, Tomohide Tsukahara, Makoto Emori, Yuji Shibayama, Emi Mizushima, Hiroshi Matsumiya, Keiji Yamashita, Mitsunori Kaya, Yoshihiko Hirohashi, Takayuki Kanaseki, Terufumi Kubo, Tetsuo Himi, Shingo Ichimiya, Toshihiko Yamashita, Noriyuki Sato, Toshihiko Torigoe

OncoImmunology ( Taylor and Francis Inc. ) 5 ( 6 ) e1165376 2016年06月 [査読有り]

High-dose chemotherapy may kill not only tumor cells but also immunocytes, and frequently induces severe lymphocytopenia. On the other hand, patients who recover from the nadir maintain immunity against infection, suggesting the existence of an unknown memory T-cell population with stress resistance, long-living capacity, proliferation and differentiation. Recently, the differentiation system of T-cell memory has been clarified using mouse models. However, the human T-cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. Here we report a novel human T-cell memory population, “young memory” T (TYM) cells. TYM cells are defined by positive expression of CD73, which represents high aldehyde dehydrogenase 1 (ALDH1) activity and CXCR3 among CD8+CD45RA+CD62L+ T cells. TYM proliferate upon TCR stimulation, with differentiation capacity into TCM and TEM and drug resistance. Moreover, TYM are involved in memory function for viral and tumor-associated antigens in healthy donors and cancer patients, respectively. Regulation of TYM might be very attractive for peptide vaccination, adoptive cell-transfer therapy and hematopoietic stem cell transplantation.

DOI PubMed

Bob1 limits cellular frequency of T-follicular helper cells

EUROPEAN JOURNAL OF IMMUNOLOGY ( WILEY ) 46 ( 6 ) 1361 - 1370 2016年06月 [査読有り]

T follicular helper (Tfh) cells are involved in specific humoral immunity at initial and recall phases. The fact that the transcription repressors B-cell lymphoma-6 and Blimp-1 determine lineages of Tfh cells and other types of effector CD4(+) T cells, respectively, suggests that there are unique mechanisms to establish Tfh-cell identity. In this study, we found that Tfh cells preferentially express the transcriptional coactivator Bob1. Bob1 of Tfh cells was dispensable for the expression of B-cell lymphoma-6 and the functional property of the cells for B cell help. However, upon initial immunization of foreign antigens, the percentages of Tfh cells in Bob1(-/-) mice were much higher than those inwild-type (WT) mice. In addition, expansion of Tfh cells within Bob1(-/-)CD4(+) T cells transferred into WT mice revealed that the high frequency of Tfh cells was caused by a T-cell-intrinsic mechanism. These findings were further supported by the results of in vitro studies demonstrating that Bob1(-/-) Tfh cells had greater proliferative activity in response to stimuli by CD3/CD28 monoclonal antibody and were also refractory to CD3-induced cell death in comparison to WT Tfh cells. These results suggest that Tfh cells harbor a Bob1-related mechanism to restrict numerical frequency against stimulation of TCRs.

DOI PubMed

Narrow-Band Ultraviolet B Phototherapy Ameliorates Acute Graft-Versus-Host Disease of the Intestine by Expansion of Regulatory T Cells

Akari Hashimoto, Tsutomu Sato, Satoshi Iyama, Masahiro Yoshida, Soushi Ibata, Ayumi Tatekoshi, Yusuke Kamihara, Hiroto Horiguchi, Kazuyuki Murase, Yutaka Kawano, Kohichi Takada, Koji Miyanishi, Masayoshi Kobune, Shingo Ichimiya, Junji Kato

PLOS ONE ( PUBLIC LIBRARY SCIENCE ) 11 ( 3 ) e0152823 2016年03月 [査読有り]

Narrowband ultraviolet B (NB-UVB) has been widely used in dermatological phototherapy. As for the application of NB-UVB phototherapy to graft-versus-host disease (GVHD), we previously reported that it was highly efficacious for cutaneous lesions of acute GVHD (aGVHD) and that expansion of regulatory T (Treg) cells induced by NB-UVB might be one of the mechanisms. In order to examine whether NB-UVB irradiation through expansion of Treg cells is effective for the treatment of not only cutaneous aGVHD but also aGVHD of inner organs such as the intestine or liver, we conducted experiments in which a murine lethal aGVHD model, characterized by severe involvement of the intestine, was irradiated with NB-UVB. We found that NB-UVB irradiation improved the clinical score and survival rate. The pathological score of aGVHD was improved in all affected organs: intestine, liver, and skin. In the serum of mice irradiated with NB-UVB, the levels of Treg cells-associated cytokines such as transforming growth factor beta (TGF beta) and interleukin-10 (IL-10) were elevated. The numbers of infiltrating Treg cells in inflamed tissue of the intestine and those in spleen were increased in mice treated with NB-UVB. This is the first report demonstrating that NB-UVB phototherapy has the ability to ameliorate intestinal aGVHD through the expansion of Treg cells.

DOI PubMed

Role of Circulating ICOS plus Follicular Helper T Cells in the Pathogenesis of Birch Pollen Allergy

Ryuta Kamekura, Koji Kawata, Sumito Jitsukawa, Tomonori Nagaya, Keiji Yamashita, Fumie Ito, Kenichi Takano, Katsunori Shigehara, Tetsuo Himi, Shingo Ichimiya

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY ( MOSBY-ELSEVIER ) 137 ( 2 ) AB393 - AB393 2016年02月 [査読有り]

DOI

Identification of a novel human memory T-cell population with the characteristics of stem-like chemo-resistance

ONCOIMMUNOLOGY ( TAYLOR & FRANCIS INC ) 5 ( 6 ) 2016年 [査読有り]

High-dose chemotherapy may kill not only tumor cells but also immunocytes, and frequently induces severe lymphocytopenia. On the other hand, patients who recover from the nadir maintain immunity against infection, suggesting the existence of an unknown memory T-cell population with stress resistance, long-living capacity, proliferation and differentiation. Recently, the differentiation system of T-cell memory has been clarified using mouse models. However, the human T-cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. Here we report a novel human T-cell memory population, "young memory" T (T-YM) cells. T-YM cells are defined by positive expression of CD73, which represents high aldehyde dehydrogenase 1 (ALDH1) activity and CXCR3 among CD8(+)CD45RA(+)CD62L(+) T cells. T-YM proliferate upon TCR stimulation, with differentiation capacity into T-CM and T-EM and drug resistance. Moreover, T-YM are involved in memory function for viral and tumor-associated antigens in healthy donors and cancer patients, respectively. Regulation of T-YM might be very attractive for peptide vaccination, adoptive cell-transfer therapy and hematopoietic stem cell transplantation.

DOI

Studies of tonsils in basic and clinical perspectives: From the past to the future

Keiji Yamashita, Shingo Ichimiya, Ryuta Kamekura, Tomonori Nagaya, Sumito Jitsukawa, Hiroshi Matsumiya, Kenichi Takano, Tetsuo Himi

Advances in Oto-Rhino-Laryngology ( S. Karger AG ) 77 119 - 124 2016年 [査読有り]

The tonsils are located at the entrance of the pharynx as a cardinal constituent of Waldeyer's ring, taking part not only in local immune responses, but also in systemic immunity. Functional deficits of tonsils primarily underlie the pathogenesis of various characteristic disorders, including tonsillar focal infections such as palmoplantar pustulosis and IgA nephropathy, in addition to the highly prevalent sleep disorder called obstructive sleep apnea syndrome. Although the mechanisms underlying these disorders remain unknown, the tonsils have long been postulated as a unique and enigmatic immune organ. Lymphoid cells and tissues from surgically resected tonsils are often employed to analyze the human immune response from a retrospective view. This approach has provided much new fundamental evidence for understanding innate and acquired immune responses, thereby facilitating further studies in the fields of mucosal immunity and specific humoral immunity originating in the germinal center. Future studies of the tonsils in basic and clinical research are expected to reveal the mechanisms of tonsil-related disorders as well as the nature of human immunity. In this review, which is primarily based on our original research over the past 3 decades, we summarize our findings and discuss the future prospects of studies focusing on the tonsils.

DOI PubMed

Role of crosstalk between epithelial and immune cells, the epimmunome, in allergic rhinitis pathogenesis

Ryuta Kamekura, Keiji Yamashita, Sumito Jitsukawa, Tomonori Nagaya, Fumie Ito, Shingo Ichimiya, Tetsuo Himi

Advances in Oto-Rhino-Laryngology ( S. Karger AG ) 77 75 - 82 2016年 [査読有り]

Recently, the prevalence of allergic rhinitis has been dramatically increasing worldwide. As conventional therapies for allergic rhinitis, such as antihistamines, leukotriene receptor antagonists, nasal sprays and allergen immunotherapy, have limitations, the development of new drugs is required. Recent studies have revealed that epithelial cell-derived cytokines, including thymic stromal lymphopoietin, interleukin (IL)-25 and IL-33, are able to control immune cells, such as dendritic cells and T cells, thereby acting as 'master switches' in allergic disease. In addition, new roles have been identified for follicular helper T cells and regulatory B cells in allergic disease, and they are considered to be promising targets for new therapies. Thus, crosstalk between epithelial and immune cells, the epimmunome, underlies the pathogenesis of allergic rhinitis. Greater understanding of the epimmunome may lead to breakthroughs in the development of new treatments for allergic rhinitis and will help us cure many patients suffering from its severe symptoms in the future.

DOI PubMed

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

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

胸腺上皮ストローマのネットワーク形成と免疫機能調節機構

一宮慎吾, 外岡暁子, 小柴茂, 菊地智樹, 久保輝文, 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 ) 199 - 199 2006年04月

Current progress and perspectives for human tumor immunotherapy

Sato Noriyuki, Hirohashi Yoshihiko, Kamiguchi Kenjiro, Ichimiya Shingo, Sahara Hiroeki, Hirata Koichi, Tsukamoto Taiji, Yamashita Toshihiko, Torigoe Toshihiko

Tumor Research ( Sapporo Medical University ) 41 1 - 13 2006年

The investigation of human tumor immunotherapy has remarkably advanced in the past decade. In our laboratory, human tumor antigens and their HLA-A24-restricted immunogenic peptide epitopes were determined to develop therapeutic and prophylactic human cancer vaccines. Among these peptides, survivin 2B peptide derived from survivin, an inhibitor of apoptosis protein (IAP), is immunogenic in more than 50% of cancer patients with a wide variety of tumors, including colon, pancreas, lung, breast, urinary bladder and oral cancers. It is now under clinical trials, and with careful immunological monitoring we will finally be able to know if these vaccines can work clinically.To develop a potent clinical therapeutic protocol, the immunological tumor escape mechanism should be more thoroughly examined in human tumor materials. To this end, anti-HLA-A, B, and C allele-specific monoclonal antibody EMR8-5, which can be used in routine paraffin-embedded sections, was successfully established. Unexpectedly, our data indicated that a high percentage of human cancers, particularly breast and prostate cancers, lost HLA-class I molecules in their primary cancer tissues. We will discuss possibilities for resolution of this important old but yet new problem.Although recent evidence has been accumulating for an important role of the heat shock proteins (HSPs) as so-called danger signals in initiating innate immunity and consequently activating acquired immunity, the precise immunological basis for this phenomenon remains to be elucidated. Our study indicated that certain HSP-chaperoned immunogenic peptides, particularly HSP90, could efficiently enter the cross-priming pathway in dendritic cells. Interestingly, this cross-priming was TAP-independent and followed endocytic pathways. We also showed that HSP90-chaperoned peptide complexes could work as a potential tumor therapeutic vaccine in the HLA-A24 transgenic mouse model.

DOI CiNii

AIRE-1およびp53ファミリーによるMHCクラスII分子発現調節機構

外岡暁子, 一宮慎吾, 小柴茂, 木村幸子, 横山繁昭, 佐藤昇志

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 ) 35 65 - 65 2005年11月

p53関連分子による胸腺ストローマの細胞間結合制御

小柴茂, 一宮慎吾, 小島隆, 外岡暁子, 村田雅樹, 木村幸子, 横山繁昭, 氷見徹夫, 佐藤昇志

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 ) 35 65 - 65 2005年11月

p63,p73転写因子による胸腺上皮細胞の機能調節機構

外岡暁子, 一宮慎吾, 小柴茂, 木村幸子, 横山繁昭, 佐藤昌明, 佐藤昇志

日本病理学会会誌 ( (一社)日本病理学会 ) 94 ( 1 ) 219 - 219 2005年03月

胸腺ストローマの細胞間結合とその制御

小柴茂, 一宮慎吾, 小島隆, 村田雅樹, 外岡暁子, 木村幸子, 横山繁昭, 氷見徹夫, 佐藤昇志

日本病理学会会誌 ( (一社)日本病理学会 ) 94 ( 1 ) 367 - 367 2005年03月

Napsin A is useful to distinguish primary lung adenocarcinoma from adenocarcinomas of other organs

A Suzuki, N Shijubo, G Yamada, S Ichimiya, M Satoh, S Abe, N Sato

PATHOLOGY RESEARCH AND PRACTICE ( ELSEVIER GMBH, URBAN & FISCHER VERLAG ) 201 ( 8-9 ) 579 - 586 2005年 [査読有り]

The aim of the present study was to compare the usefulness of the peripheral airway cell markers, naspin A and surfactant protein A (SP-A), for distinguishing primary lung adenocarcinoma from adenocarcinomas of other organs in various clinical conditions. Immunohistochemical expression of napsin A and SP-A was analyzed at primary sites of 120 lung carcinomas and 40 adenocarcinomas of other organs, at lung metastatic sites of 32 adenocarcinomas of other organs, and in metastatic lymph nodes of 21 lung adenocarcinomas and 45 adenocarcinomas of other organs. Napsin A and SP-A expressions were compared between primary and recurrent sites in 8 lung adenocarcinomas. Napsin A and SP-A expressions were noted in 84.3% and 53.0% of primary sites of 83 lung adenocarcinomas, respectively, but neither napsin A nor SP-A was expressed at primary sites of other histological types of lung carcinomas or at primary or metastatic sites of adenocarcinomas of other organs. In lung adenocarcinomas, napsin A and SP-A were expressed in metastatic lymph nodes in 81.0% and 19.0%, respectively, and at recurrent sites in 87.5% and 37.5%, respectively. Napsin A is superior to SP-A for distinguishing primary lung adenocarcinoma from adenocarcinomas of other organs at primary, metastatic, and recurrent sites. (c) 2005 Elsevier GmbH. All rights reserved.

DOI PubMed

胸腺上皮細胞におけるHLA分子の発現制御機構

外岡暁子, 一宮慎吾, 小柴茂, 近藤伸彦, 上口権二郎, 田村保明, 鳥越俊彦, 池田英之, 高桑麗子, 横山繁昭, 佐藤昌明, 佐藤昇志

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 ) 34 72 - 72 2004年11月

胸腺スカフォールドの組織構築とその制御

小柴茂, 一宮慎吾, 小島隆, 近藤伸彦, 外岡暁子, 村田雅樹, 高桑麗子, 横山繁昭, 氷見徹夫, 佐藤昇志

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 ) 34 72 - 72 2004年11月

サルコイドーシス(サ症)のTh1反応におけるオステオポンチンの意義の検討

四十坊典晴, 市村志保, 重原克則, 猪股慎一郎, 山田玄, 一宮慎吾, 阿部庄作, 佐藤昇志, 平賀洋明

サルコイドーシス/肉芽腫性疾患 ( 日本サルコイドーシス ) 24 ( Suppl. ) 48 - 48 2004年10月

Role of the p38 MAP-kinase signaling pathway for Cx32 and claudin-1 in the rat liver

Takashi Kojima, Toshinobu Yamamoto, Masaki Murata, Mengdong Lan, Ken-Ichi Takano, Mitsuru Go, Shingo Ichimiya, Hideki Chiba, Norimasa Sawada

Cell Communication and Adhesion 10 ( 4-6 ) 437 - 443 2003年07月 [査読有り]

Liver regeneration and cholestasis are associated with adaptive changes in expression of gap and tight junctions through signal transduction. The roles of stress responsitive MAP-kinase, p38 MAP-kinase, in the signaling pathway for gap junction protein, Cx32, and tight junction protein, claudin-1, were examined in rat liver in vivo and in vitro, including regeneration following partial hepatectomy and cholestasis after common bile duct ligation. Changes in the expression and function of Cx32 and claudin-1 in hepatocytes in vivo were studied using the p38 MAP-kinase inhibitor SB203580. Following partial hepatectomy and common bile duct ligation, down-regulation of Cx32 protein was inhibited by SB203580 treatment. Up-regulation of claudin-1 protein was enhanced by SB203580 treatment after partial hepatectomy but not common bile duct ligation. However, no change of the Ki-67 labeling index (which is a marker for cell proliferation) in the livers treated with SB203580, was observed compared to that without SB203580 treatment. In primary cultures of rat hepatocytes, however, treatment with a p38 MAP-kinase activator, anisomycin, decreased Cx32 and claudin-1 protein levels. p38 MAP-kinase may be an important signaling pathway for regulation of gap and tight junctions in hepatocytes. Changes of gap and tight junctions during liver regeneration and cholestasis are shown to be in part controlled via the p38 MAP-kinase signaling pathway and are independent of cell growth.

PubMed

頭蓋咽頭腫におけるp53ファミリーの発現とその意義

百田洋之, 一宮慎吾, 池田健, 八巻稔明, 宝金清博, 佐藤昇志

Brain Tumor Pathology ( 日本脳腫瘍病理学会 ) 20 ( Suppl. ) 59 - 59 2003年05月

Improved generation of HLA class I/peptide tetramers

Y Sato, H Sahara, T Tsukahara, M Kondo, Y Hirohashi, Y Nabeta, S Kawaguchi, H Ikeda, T Torigoe, S Ichimiya, Y Tamura, T Wada, T Yamashita, M Goto, H Takasu, N Sato

JOURNAL OF IMMUNOLOGICAL METHODS ( ELSEVIER SCIENCE BV ) 271 ( 1-2 ) 177 - 184 2002年12月 [査読有り]

As a tetrameric major histocompatibility complex (MHC) class I-peptide complex (tetramer) is capable of detecting antigen-specific cytotoxic T lymphocyte (CTL) by flow cytometry, significant information about the generation of in vivo immunity can be obtained. It is, however, difficult to make a soluble wild type of MHC class I heavy chain by the prokaryotic expression system. Therefore, we developed a new method for making soluble mutant HLA-A*2402 heavy chain. In this method, signal sequences were deleted, and the codon was changed to silent mutated nucleotide sequences that bacteria could use as preferable codon. When purified mutant HLA-A*2402 molecules were examined for the protein generation by SDS-polyacrylamide gel electrophoresis (PAGE) and western blotting using anti-HLA class I monoclonal antibody (mAb) as compared with wild type, a large amount of mutant heavy chain could be detected. In contrast, the expression of wild-type stable HLA-A*2402 heavy chain molecule was not detected in this system. Consequently, by using mutant HLA-A*2402/peptide tetramers, CTL precursors (CTLp) that specifically recognize antigenic peptide derived from the X;18 chromosomal translocations of synovial sarcoma were detected in patients' PBL. (C) 2002 Elsevier Science B.V. All rights reserved.

DOI PubMed

原発性肺癌患者におけるClara cell 10kilodalton protein(CC10)遺伝子多型についての検討

大地貴, 四十坊典晴, 山田玄, 阿部庄作, 山口昭弘, 一宮慎吾, 佐藤昇志, 河端薫雄, 伊藤喜久

肺癌 ( (NPO)日本肺癌学会 ) 42 ( 5 ) 412 - 412 2002年10月

Comparative analysis of the structure and chromosomal assignment of CD1: an evidence for different evolutionary histories between classic CD1 and CD1D class genes

A Matsuura, M Kinebuchi, S Katabami, HZ Chen, K Kasai, S Ichimiya, K Yamada, MC Yoshida, M Horie, N Sato

JOURNAL OF EXPERIMENTAL ANIMAL SCIENCE ( GUSTAV FISCHER VERLAG ) 41 ( 1-2 ) 87 - 90 2000年03月 [査読有り]

The non-MHC-encoded CD1 family has recently emerged as a novel antigen-presenting system that is distinct from MHC class I and class II molecules. In the present study, we determined the genomic structure of that rat CD1, and compared with those of other previously reported CD1 genes. Rat CD1 was extremely similar to mouse CD1 genes, especially to CD1D1. It is of interest that a tyrosine-based motif for endosomal localization, identified in the human CD1b cytoplasmic tail, was conserved in all CD1 molecules except for CD1a, that was encoded by a single short exon. Comparison of the overall exon-intron organization of CD1 genes revealed that the length of the introns was also characteristic to each of the two classes of CD1 genes; classic (CD1A, CD1B, CD1C and CD1E), and CD1D, which have been categorized by comparison of coding regions. These findings support a hypothesis that the two classes have different evolutionary histories. In contrast to the absence of the classic CD1 genes in rats and mice, the entire region of nonpolymorphic CD1D gene has been conserved through mammalian evolution. Furthermore, we determined chromosomal localization of rat CD1 gene using the fluorescence in situ hybridization method with several probes derived from genomic rat CD1 clones. Similar to human and mouse CD1, rat CD1 mapped outside the MHC loci despite the structural and functional resemblance to MHC. Conserved syntheny of chromosomal segments of RNO2 and MMU3 is implied.

非古典的MHCクラスI分子の役割

Matsuura A, Kinebuchi M, Chen HZ, Ichimiya S, Kasai K

臨床免疫 30 1376 - 1384 1998年 [招待有り]

Interaction of DA41, a DAN-binding protein, with the epidermal growth factor-like protein, S(1-5)

T Ozaki, K Kondo, Y Nakamura, S Ichimiya, A Nakagawara, S Sakiyama

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ( ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS ) 237 ( 2 ) 245 - 250 1997年08月 [査読有り]

Recently, we have identified a new protein (DA41) which can associate with candidate tumor-suppressor DAN protein. In the present study, we have searched for DA41-interacting protein(s), using a yeast two-hybrid system. An adult rat lung cDNA library was screened by using a truncal;ed form of DA41 (1-308) which lacks a DAN-binding region as bait. One of the positive clones, T16, contained a cDNA sequence of 1934 nucleotides with a single open reading frame of 493 amino acids. A data base search revealed that T16 exhibited a strong sequence similarity to the human epidermal growth factor (EGF)-like protein, S(1-5). The region encoding amino acids 155-232 of DA41 was identified for the interaction with T16. Since DAN and 5(1-5) proteins are known to suppress and stimulate DNA synthesis, respectively, it is possible that functional interaction of DAN with 5(1-5) through DA41 might play an important role(s) in the regulation of cell growth. (C) 1997 Academic Press.

Expression of CD1 molecules but not authentic TL antigens by rat thymus: Possible functional substitution between class Ib molecules in the thymu

Matsuura A, Takayama S, Kinebuchi M, Hashimoto Y, Kasai K, Kozutsumi D, Ichimiya S, Honda R, Natori T, Kikuchi K

Proceedings of International Symposium on Evolution of Network and Molecular Information 1996年 [査読有り]

A new mAb 3B6 distingnishes a novel subpopulation from adult rat bone marrow cells.

Matsuura A, Kinebuchi M, Ichimiya S, Hashimoto Y, Shen M, Katabami S, Kikuchi K

Proceedings of Xth International Workshop on alloantigenic systems in the Rat 10 1994年 [査読有り]

MOLECULAR-CLONING OF A CDNA-ENCODING THE RAT HOMOLOG OF CD1

S ICHIMIYA, A MATSUURA, S TAKAYAMA, K KIKUCHI

TRANSPLANTATION PROCEEDINGS ( ELSEVIER SCIENCE INC ) 25 ( 5 ) 2773 - 2774 1993年10月 [査読有り]

Cell sorterを用いた発現クローニング法の改良―ラットCD8α鎖cDNAクローニング

小野寺一史, 松浦晃洋, 今信一郎, 村上俊也, 高山晋一, 一宮慎吾, 菊地浩吉

日本免疫学会記録 21 285 1991年 [査読有り]

ラットにおけるTla 遺伝子とその発現

高山晋一, 一宮慎吾, 松浦晃洋, 菊地浩吉

日本免疫学会記録 21 465 1991年 [査読有り]

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