研究等業績 - その他 - 海老原　敬

Antitumor NK activation induced by the Toll-like receptor 3-TICAM-1 (TRIF) pathway in myeloid dendritic cells

Akazawa, T., Ebihara, T., Okuno, M., Okuda, Y., Shingai, M., Tsujimura, K., Takahashi, T., Ikawa, M., Okabe, M., Inoue, N., Okamoto-Tanaka, M., Ishizaki, H., Miyoshi, J., Matsumoto, M., Seya, T.

Proceedings of the National Academy of Sciences of the United States of America   104 ( 1 ) 252 - 257   2007年

Myeloid dendritic cells (mDCs) recognize and respond to polyl:C, an analog of dsRNA, by endosomal Toll-like receptor (TLR) 3 and cytoplasmic receptors. Natural killer (NK) cells are activated in vivo by the administration of polyl:C to mice and in vitro are reciprocally activated by mDCs, although the molecular mechanisms are as yet undetermined. Here, we show that the TLR adaptor TICAM-1 (TRIF) participates in mDC-derived antitumor NK activation. In a syngeneic mouse tumor implant model (CS7BL/6 vs. B16 melanoma with low H-2 expresser), i.p. administration of polyl:C led to the retardation of tumor growth, an effect relied on by NK activation. This NK-dependent tumor regression did not occur in TICAM-1-/- or IFNAR-/- mice, whereas a normal NK antitumor response was induced in PKR-/-, MyD88-/-, IFN-β-/-, and wild-type mice. IFNAR was a prerequisite for the induction of IFN-α/β and TLR3. The lack of TICAM-1 did not affect IFN production but resulted in unresponsiveness to IL-12 production, mDC maturation, and polyl:C-mediated NK-antitumor activity. This NK activation required NK-mDC contact but not IL-12 function in in vitro transwell analysis. Implanted tumor growth in IFNAR-/- mice was retarded by adoptively transferring polyl:C-treated TICACM-1-positive mDCs but not TICAM-1 -/- mDCs. Thus, TICAM-1 in mDCs critically facilitated mDC-NK contact and activation of antitumor NK, resulting in the regression of low MHC-expressing tumors. © 2006 by The National Academy of Sciences of the USA.

DOI PubMed

Basic Studies on the Development of Adjuvant Immunotherapy

Tsukasa Seya, Misako Matsumoto, Takashi Ebihara, Takashi Akazawa

Nihon Kikan Shokudoka Gakkai Kaiho ( Japan Broncho-Esophagological Society )  58 ( 2 ) 85 - 95   2007年

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Differential type I IFN-inducing abilities of wild-type versus vaccine strains of measles virus

Shingai, M., Ebihara, T., Begum, N.A., Kato, A., Honma, T., Matsumoto, K., Saito, H., Ogura, H., Matsumoto, M., Seya, T.

Journal of Immunology   179 ( 9 )   2007年

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NK-Activating dendritic cells are elicited by stimulation with toll-like receptor 3

Seya, T., Matsumoto, M., Ebihara, T., Akazawa, T.

Hirosaki Medical Journal   59 ( SUPPL. )   2007年

Recombinant interleukin-12 and interleukin-18 antitumor therapy in a guinea-pig hepatoma cell implant model

Shiratori, I., Suzuki, Y., Oshiumi, H., Begum, N.A., Ebihara, T., Matsumoto, M., Hazeki, K., Kodama, K., Kashiwazaki, Y., Seya, T.

Cancer Science   98 ( 12 ) 1936 - 42   2007年

Interleukin (IL)-12 and IL-18 are secreted by myeloid cells activated with adjuvants such as Bacillus Calmette-Guérin (BCG) cell wall. They induce T-helper 1 polarization in the host immune system and upregulate production of lymphocyte interferon-gamma, which leads to the induction of an antitumor gene program. It has been reported that humans have an immune system that more closely resembles that of the guinea pig in adjuvant-response features rather than the mouse system, which prevents the mouse results being extrapolated to human immunotherapy. Here we have constructed a tumor-implant system in guinea pigs to evaluate the antitumor potential of guinea pig IL-12 (gpIL-12) and guinea pig IL-18 (gpIL-18). Purified recombinant gpIL-12 and gpIL-18 were prepared and applied intraperitoneally to tumor-bearing (line 10 hepatoma) guinea pigs as the basis of the adjuvant immunotherapy. Intraperitoneal administration of gpIL-12 and gpIL-18 led to retardation of primary tumor growth and suppression of lymph-node metastasis in tumor-bearing guinea pigs. The permissible range of IL-12 appeared wider in guinea pigs than in mice. Even at an IL-12 dose higher than that in mice, there was no evidence of side-effects until day 26, when the guinea pigs were killed. gpIL-18 augmented the antitumor effect of gpIL-12 but exerted less ability to suppress lymph-node metastasis. The effects of gpIL-12 and gpIL-18 on the tumors implanted in guinea pigs will encourage us to use IL-12- and IL-18-inducible adjuvants for immunotherapy in human patients with solid cancer.

DOI PubMed

Seroepidemiology of Human Bocavirus in Hokkaido Prefecture, Japan

Endo Rika, Ishiguro Nobuhisa, Kikuta Hideaki, Teramoto Shinobu, Shirkoohi Reza, Ma Xiaoming, Ebihara Takashi, Ishiko Hiroaki, Ariga Tadashi

Journal of Clinical Microbiology ( American Society for Microbiology )  45 ( 10 ) 3218 - 3223   2007年

A new human virus, provisionally named human bocavirus (HBoV), was discovered by Swedish researchers in 2005. A new immunofluorescence assay using Trichoplusia ni insect cells infected with a recombinant baculovirus expressing the VP1 protein of HBoV was developed, and the levels of immunoglobulin G antibody to the VP1 protein of HBoV in serum samples were measured. The overall seroprevalence rate of antibodies against the VP1 protein of HBoV in a Japanese population aged from 0 months to 41 years was 71.1% (145 of 204). The seropositive rate was lowest in the age group of 6 to 8 months and gradually increased with age. All of the children had been exposed to HBoV by the age of 6 years. A rise in titers of antibody against the VP1 protein of HBoV during the convalescent phase was observed for four patients with lower respiratory tract infections, and HBoV DNA was detected in nasopharyngeal swab and serum samples from all four patients. These results suggest that HBoV is a ubiquitous virus acquired early in life and that HBoV might play a role in the course of lower respiratory tract infections.

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NK-Activating Dendritic Cells Are Elicited by Stimulation with Toll-Like Receptor 3. [Emerging Theories of Host Defense. The 10th Meeting Hirosaki International Forum of Medical Science. Communication Center Hirosaki University School of Medicine. Hirosaki on November 21-22, 2006]

Seya Tsukasa, Matsumoto Misako, Ebihara Takashi, Akazawa Takashi

弘前醫學 ( 弘前大学 )  59   S43 - S51   2007年

Double-stranded （ds）RNA-recognition receptors reside in the cytoplasm and membranes of cells. Thesereceptors are implicated in the differential screening of microbes by the host. Myeloid dendritic cells （mDCs）recognize and respond to polyI:C, an analog of dsRNA, by endosomal TLR3 and cytoplasmic MDA5. NK cells areinduced in vivo by the administration of polyI:C to mice and in vitro are reciprocally activated by mDCs, although themolecular mechanisms as yet undetermined. Here, we show that the TLR adapter TICAM-1 （TRIF） participates inmDC-derived antitumor NK activation. In a syngeneic mouse tumor implant model, intraperitoneal administration ofpolyI:C led to the retardation of tumor growth, which eff ect relied largely on NK activation. This NK-dependent tumorregression did not occur in TICAM-1-/- or IFNAR-/- mice, while a normal NK antitumor response was induced in PKR-/-,MyD88-/-, IFN-β-/- and wild-type mice. IFNAR was a prerequisite for the induction of IFN-α/β and TLR3. The lackof TICAM-1 did not aff ect IFN production but resulted in unresponsiveness to IL-12 production, mDC maturation andpolyI:C-mediated antitumor activity. This NK activation required NK-mDC contact in in vitro transwell analysis. NKantitumoractivity was successfully introduced into tumor-implanted mice by transferring mDCs expressing TICAM-1.Implanted tumor growth in IFNAR-/- mice was retarded by adoptively transferring polyI:C-treated TICACM-1-positivemDCs but not TICAM-1-/- mDCs. Thus, TICAM-1 rather than MDA5 in mDCs critically facilitated mDC-NK contactand activation of antitumor NK, resulting in the regression of low MHC-expressing tumors

NK細胞とMHC受容体 TLRリガンド刺激及びRNAウイルス感染によるヒト樹状細胞上のNKG2Dリガンドの誘導(NKG2D ligands are induced on human dendritic cells by TLR ligand stimulation and RNA virus infection)

Ebihara Takashi, Shingai Masashi, Akazawa Takashi, Matsumoto Misako, Seya Tsukasa

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 )  36   253 - 253   2006年11月

ウイルス感染と宿主応答・宿主側の要因 感染樹状細胞における麻疹ウイルスによるI型IFN誘導メカニズム(A mechanism by which measles virus induces Type-I IFN in infected dendritic cells)

Shingai Masashi, Ebihara Takashi, Matsumoto Misako, Seya Tsukasa

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 )  36   207 - 207   2006年11月

小児の下気道感染症患者からのヒトボカウイルス(Human Bocavirus)の検出

石黒 信久, 遠藤 理香, 石古 博昭, 菊田 英明, 馬 暁明, 海老原 敬

感染症学雑誌 ( (一社)日本感染症学会 )  80 ( 6 ) 742 - 742   2006年11月

小児human metapneumovirusおよびrespiratory syncytial virus感染症の臨床像の比較

高橋 豊, 羽田 美保, 米川 元晴, 田端 祐一, 鹿野 高明, 海老原 敬, 遠藤 理香, 石黒 信久, 菊田 英明

小児科 ( 金原出版(株) )  47 ( 7 ) 1115 - 1120   2006年06月

human metapneumovirus(hMPV)感染症とrespiratory syncytial virus(RSV)感染症を比較した論文をレビューするとともに,入院症例についても検討した.対象はhMPV感染症患児が38例,RSV感染症は2001年と2002年の2年間に入院加療した215例であった.1)hMPV感染症は発熱症例の比率が高く,有熱期間がなく,また喘鳴を呈する比率が高かった.更に血小板数が少なく,血清LDHが低かった.2)レビューした報告では,hMPV感染症はRSV感染症より呼吸器症状の程度が軽いことが示されていたが,今回の調査では明らかにならなかった

小児の下気道感染症患者からのヒトボカウイルス(Human Bocavirus)の検出

石黒 信久, 遠藤 理香, 石古 博昭, 菊田 英明, 馬 暁明, 海老原 敬

感染症学雑誌 ( (一社)日本感染症学会 )  80 ( 臨増 ) 248 - 248   2006年03月

Detection of antibodies against human metapneumovirus by western blot using recombinant nucleocapsid and matrix proteins

Nobuhisa Ishiguro, Takashi Ebihara, Rika Endo, Xiaoming Ma, Eri Kawai, Hiroaki Ishiko, Hideaki Kikuta

Journal of Medical Virology ( Wiley )  78 ( 8 ) 1091 - 1095   2006年

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Detection of human bocavirus in Japanese children with lower respiratory tract infections

Ma Xiaoming, Endo RIka, Ishiguro Nobuhisa, Ebihara Takashi, Ishiko Hiroaki, Ariga Tadashi, Kikuta Hideaki

Journal of Clinical Microbiology ( American Society of Microbiology )  44 ( 3 ) 1132 - 1134   2006年

Human bocavirus (HBoV), a newly cloned human virus of the genus Bocavirus, was detected by PCR from nasopharyngeal swab samples collected from children with lower respiratory tract infections (8 of 318, 5.7%). HBoV may be one of the causative agents of lower respiratory tract infections in young children. (48 words)

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樹状細胞におけるULBPの発現とTLRシグナルによる発現上昇誘導

海老原 敬, 赤澤 隆, 松本 美佐子, 瀬谷 司

日本免疫学会総会・学術集会記録 ( (NPO)日本免疫学会 )  35   103 - 103   2005年11月

Production and Characterization of Neutralizing Monoclonal Antibodies Against Human Metapneumovirus F Protein

Xiaoming Ma, Rika Endo, Takashi Ebihara, Nobuhisa Ishiguro, Hiroaki Ishiko, Hideaki Kikuta

Hybridoma ( Mary Ann Liebert Inc )  24 ( 4 ) 201 - 205   2005年08月

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新たに発見された呼吸器感染症起因ウイルスであるヒト・メタニューモウイルスのG(attachment)蛋白塩基配列の多様性

石黒 信久, 遠藤 理香, 石古 博昭, 菊田 英明, 海老原 敬

感染症学雑誌 ( (一社)日本感染症学会 )  79 ( 8 ) 586 - 586   2005年08月

新しく発見されたhuman metapneumovirusに対する抗体の測定

海老原 敬, 遠藤 理香, 馬 暁明, 吉岡 幹朗, 石黒 信久, 菊田 英明

日本小児科学会雑誌 ( (公社)日本小児科学会 )  109 ( 7 ) 859 - 859   2005年07月

ラン藻類Spirulina抽出物の経口投与によるNK活性化とマウス移植がん退縮の検討

海老原 敬, 赤沢 隆, 増田 尚代, 松本 美佐子, 瀬谷 司

基盤的癌免疫研究会総会抄録 ( 日本がん免疫学会 )  9回   60 - 60   2005年06月

Differential gene expression of S100 protein family in leukocytes from patients with Kawasaki disease

Takashi Ebihara, Rika Endo, Hideaki Kikuta, Nobuhisa Ishiguro, Xiaoming Ma, Mitsunobu Shimazu, Takao Otoguro, Kunihiko Kobayashi

European Journal of Pediatrics ( Springer Nature )  164 ( 7 ) 427 - 431   2005年04月

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