論文 - 丸山 治彦
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A familial case of visceral toxocariasis due to consumption of raw bovine liver.
Yoshikawa M, Nishiofuku M, Moriya K, Ouji Y, Ishizaka S, Kasahara K, Mikasa K, Hirai T, Mizuno Y, Ogawa S, Nakamura T, Maruyama H, Akao N.
Parasitology International 57 525 - 529 2008年12月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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A familial case of visceral toxocariasis due to consumption of raw bovine liver 査読あり
Yoshikawa M., Nishiofuku M., Moriya K., Ouji Y., Ishizaka S., Kasahara K., Mikasa K., Hirai T., Mizuno Y., Ogawa S., Nakamura T., Maruyama H., Akao N.
Parasitology International 57 ( 4 ) 525 - 529 2008年12月
記述言語：英語 掲載種別：症例報告 出版者・発行元：Parasitology International
We present 3 adult cases of visceral toxocariasis from the same family, who each consumed thin slices of raw bovine liver weekly, and developed eosinophilia and multiple small lesions in their livers and lungs. Serological examinations using the larval excretory-secretory product of Toxocara canis strongly indicated infection with Toxocara species larvae. The patients responded well to treatment with albendazole. Ingestion of raw liver from paratenic animals is considered to be a common transmission route of human toxocariasis, especially in adults. © 2008 Elsevier Ireland Ltd. All rights reserved.
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丸山 治彦
日本薬理学雑誌 132 ( 5 ) 292 - 296 2008年11月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：公益社団法人 日本薬理学会
わが国における寄生虫病・熱帯病治療の問題点は，国内承認薬が少なく，保険適用の効能の範囲も狭いことである．たとえば，重要な熱帯感染症であるマラリアに対してはメフロキンとキニーネ末が承認されているが，重症マラリアには対応できず，三日熱マラリアと卵形マラリアに必要な根治療法もおこなえない．また，近年増加傾向にある赤痢アメーバ症，国内の寄生虫病で比較的多い幼虫移行症に有効な薬剤は，承認されてはいるが効果効能では適用外である．トキソプラズマ症も国内承認薬だけでの治療は困難である．このような問題はあるが，「輸入熱帯病・寄生虫症に対する稀少疾病治療薬を用いた最適な治療法による医療対応の確立に関する研究」班（略称：熱帯病治療薬研究班）が，薬剤の輸入・保管・治療対応に関する研究活動を行っており，国内未承認薬での治療が可能になっている．<br>
DOI： 10.1254/fpj.132.292
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Goblet cell hyperplasia elicited by infection with an intestinal nematode, Strongyloides venezuelensis, is not protective against goblet cell-sensitive Nippostrongylus brasiliensis in mice. 査読あり
Chiyo Yamauchi-Kawaura, Hitomi Watanabe, Anna Nishimaki, Haruhiko Maruyama, Ayako Yoshida, Nobuo Ohta
Nagoya Mecical Journal 49 119 - 129 2008年3月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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山内(川浦) 稚代, 渡邊 仁美, 西牧 亜奈, 丸山 治彦, 吉田 彩子, 太田 伸生
Nagoya medical journal 49 ( 2 ) 119 - 129 2008年3月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：名古屋市立大学
Intestinal nematode infections usually elicit similar pathological changes in the intestinal mucosa, regardless of the parasite species. Because Th2 cytokines, such as IL-4, IL-5, IL-9, and IL-13, are produced simultaneously, similar cellular responses occur in a number of parasitic infections. In Strongyloides venezuelensis infection in mice, goblet cell hyperplasia was induced after infection as expected. However, the goblet cells induced in S. venezuelensis infection was not protective against another intestinal nematode, Nippostrongylus brasiliensis, whose expulsion was tightly associated with goblet cell hyperplasia. Lectin histochemistry revealed that there was no evidence for the sialation of mucin sugars, although the structure of goblet cell mucin changed after S. venezuelensis infection. Because N. brasiliensis infection induces highly sialated goblet cell mucin, not only Th 2 cytokines but specific factors from N. brasiliensis adult worms might be required for the sialation of intestinal goblet cell mucin.
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Goblet cell hyperplasia elicited by infection with an intestinal nematode, Strongyloides venezuelensis, is not protective against goblet cell-sensitive Nippostrongylus brasiliensis in mice. 査読あり
Chiyo Yamauchi-Kawaura, Hitomi Watanabe, Anna Nishimaki, Haruhiko Maruyama, Ayako Yoshida, Nobuo Ohta
Nagoya Mecical Journal 49 119 - 129 2008年3月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌）
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Successive changes in tissue migration capacityof developing larvae of an intestinal nematode, Strongyloides venezuelensis 査読あり
H. Maruyama, A. Nishimaki, Y. Takuma, M. Kurimoto, T. Suzuki, Y. Sakatoku, M. Ishikawa and N. Ohta
Parasitology 132 411 - 418 2007年4月
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Maruyama H., Nawa Y.
No to shinkei. Brain and nerve 58 ( 7 ) 571 - 581 2006年7月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：No to shinkei. Brain and nerve
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Shaohong L., Kumagai T., Qinghua A., Xiaolan Y., Ohmae H., Yabu Y., Siwen L., Liyong W., Maruyama H., Ohta N.
Parasitology International 55 ( 1 ) 63 - 68 2006年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Parasitology International
The therapeutic effects of artesunate against experimental Schistosoma mansoni infection in mice were analyzed. Previous studies showed that artesunate is highly effective against S. japonicum infection, but the action of this drug against S. mansoni remained uncovered. The present study examines the optical conditions for artesunate against S. mansoni and evaluates the effects of inhibiting the sexual maturation of adult worms. Mice infected with S. mansoni were orally administered with artesunate according to different schedules. Four consecutive administrations of 300 mg/kg of artesunate at 2-week intervals conferred almost total protection without the development of pathological lesions in the liver. The significant reduction in the number of eggs produced by surviving worms and the status of egg maturation suggested that artesunate inhibits sexual maturation. Electron microscopy revealed that artesunate caused morphological damage, especially on the worm tegument. Artesunate was also very effective in iron-deficient mice. Furthermore, the efficacy of artesunate was equal to or better than that of artemether against S. japonicum infection. Considering that artemether is more toxic, artesunate is currently one of the most efficient drugs against immature S. mansoni. © 2005 Elsevier Ireland Ltd. All rights reserved.
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Sasaki Y., Yoshimoto T., Maruyama H., Tegoshi T., Ohta N., Arizono N., Nakanishi K.
Journal of Experimental Medicine 202 ( 5 ) 607 - 616 2005年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Experimental Medicine
C57BL/6 (B6) and B6 background STAT6-/- mice pretreated with IL-18 plus IL-2 showed prominent intestinal mastocytosis and rapidly expelled implanted adult worms of the gastrointestinal nematode Strongyloides venezuelensis. In contrast, identically pretreated mast cell-deficient W/W v mice failed to do so. Thus, activated mucosal mast cells (MMC) are crucial for parasite expulsion. B6 mice infected with S. venezuelensis third-stage larvae (L3) completed parasite expulsion by day 12 after infection, whereas IL-18-/- or IL-18Rα-/- B6 mice exhibited marked impairment in parasite expulsion, suggesting a substantial contribution of IL-18-dependent MMC activation to parasite expulsion. Compared with IL-18-/- or IL-18Rα-/- mice, S. venezuelensis L3-infected STAT6-/- mice have poorly activated MMC and sustained infection; although their IL-18 production is normal. Neutralization of IL-18 and IL-2 further reduces expulsion in infected STAT6-/- mice. These results suggest that collaboration between IL-18-dependent and Th2 cell-dependent mastocytosis is important for prompt parasite expulsion. JEM © The Rockefeller University Press.
DOI： 10.1084/jem.20042202
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Schistosoma japonicum: Localization of calpain in the penetration glands and secretions of cercariae 査読あり
Kumagai T., Maruyama H., Hato M., Ohmae H., Osada Y., Kanazawa T., Ohta N.
Experimental Parasitology 109 ( 1 ) 53 - 57 2005年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Experimental Parasitology
A monoclonal antibody was generated against the large subunit of Schistosoma japonicum calpain to study the localization and possible function of the molecule in vivo. Mice were immunized with recombinant S. japonicum calpain and polyclonal antisera and a monoclonal antibody specific to schistosome calpain was obtained. In immunohistochemistry, a monoclonal antibody against S. japonicum calpain, KG-2E11, bound weakly to calpain expressed at the surface of adult worm tegument, however, it bound strongly to the cercarial secretions ("footprints") of S. japonicum, emitted from the penetration glands. The present study indicates that calpain is multifunctional as it is expressed at various locations in different developmental stages. Calpain-based vaccines could thus possibly induce protective immunity against cercariae and the following early developing stages. © 2004 Elsevier Inc. All rights reserved.
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El-Malky M., Shaohong L., Kumagai T., Yabu Y., Noureldin M., Saudy N., Maruyama H., Ohta N.
Microbiology and Immunology 49 ( 7 ) 639 - 646 2005年
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Microbiology and Immunology
Infection with the intracellular protozoan parasite Toxoplasma gondii causes serious public health problems to both humans and livestock and of great economic impact worldwide. Oligodeoxynucleotides (ODN) which contain immunostimulatory CG motifs (CpG ODN) can promote Th1 responses, an adjuvant activity that is desirable for vaccination against intracellular pathogens. We investigated the feasibility of using CpG as an adjuvant combined with Toxoplasma lysate antigen (TLA) as a vaccine against toxoplasmosis. Genetically susceptible C57BL/6 mice were vaccinated with TLA with or without CpG ODN as an adjuvant and then challenged with 85 cysts of the moderately virulent RRA (Beverley) strain of T. gondii. Prior to challenge infection, immunization with TLA plus CpG ODN directed cellular and humoral immunity toward a Th1 pattern, characterized by enhanced INFγ production by splenic cells in response to TLA, and enhanced production of toxoplasma-specific IgG and IgG2a antibodies. Consequently, CpG/TLA-treated mice showed prolonged survival and 64% reduction in brain parasite burden compared to non-CpG/TLA treated group. Our results suggest that CpG ODN would provide a stable and effective adjuvant for use in vaccination against toxoplasmosis.
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Hsieh G., Loukas A., Wahl A., Bhatia M., Wang Y., Williamson A., Kehn K., Maruyama H., Hotez P., Leitenberg D., Bethony J., Constant S.
Journal of Immunology 173 ( 4 ) 2699 - 2704 2004年8月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Immunology
Parasitic helminths induce chronic infections in their hosts although, with most human helminthiases, protective immunity gradually develops with age or exposure of the host. One exception is infection with the human hookworm, Necator americanus, where virtually no protection ensues over time. Such observations suggest these parasites have developed unique mechanisms to evade host immunity, leading us to investigate the role of the excretory/secretory (ES) products of adult N. americanus in manipulating host immune responses. Specifically, we found that a protein(s) from ES products of adult N. americanus bound selectively to mouse and human NK cells. Moreover, incubation of purified NK cells with N. americanus ES products stimulated the production of augmented (4- to 30-fold) levels of IFN-γ. This augmentation was dependent on the presence of both IL-2 and IL-12 and was endotoxin-independent. This is the first report of a pathogen protein that binds exclusively to NK cells and the first report of a nematode-derived product that induces abundant levels of cytokines from NK cells. Such an interaction could provide a means of cross-regulating deleterious Th2 immune responses in the host, thereby contributing to the long-term survival of N. americanus.
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Research on calpain of Schistosoma japonicum as a vaccine candidate 査読あり
Ohta N., Kumagai T., Maruyama H., Yoshida A., He Y., Zhang R.
Parasitology International 53 ( 2 ) 175 - 181 2004年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Parasitology International
Vaccine development by the use of calpain of Schistosoma japonicum has been tried in our laboratory. We cloned cDNA encoding the heavy chain of S. japonicum calpain, and prepared recombinant molecule of a possible vaccine region of the heavy chain. When BALB/c mice were immunized with our recombinant calpain of S. japonicum with Freund's complete adjuvant, we observed significant reduction in worm burden (41.2% reduction, P<0.05), and also significant anti-fecundity effects. In this sense, calpain of S. japonicum seems to have infection control as well as anti-disease effects. Mechanisms of vaccine effects of calpain remain to be clarified, however, several effecter mechanisms are suspected. In immunized mice, raised level of iNos expression was observed, while adhesion of peritoneal exudates cells were also observed in the presence of calpain-immunized sera, suggesting the possibilities of both cellular and humoral protective mechanisms. We examined tissue distribution of calpain in various developmental stages of S. japonicum. Strong signal was observed around excretory grand of cercariae, and they secreted calpain during their migratory movement tested in vitro. Together with the findings, calpain seems to induce larvicidal effects in the immunized mice. We observed time-course kinetics of antibody production against vaccine candidates in experimental S. japonicum infection in pigs. Although significant levels of antibody production were observed for paramyosin and GST, no significant antibody production was observed for calpain. This suggests that calpain is less immunogenic, and route of immunization and/or choice of adjuvant are important in future trials of calpain vaccine. © 2004 Elsevier Ireland Ltd. All rights reserved.
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Induction of cellular immunity by anti-idiotypic antibodies mimicking GD2 ganglioside 査読あり 国際共著
Basak S., Birebent B., Purev E., Somasundaram R., Maruyama H., Zaloudik J., Swoboda R., Strittmatter W., Li W., Luckenbach A., Song H., Li J., Sproesser K., Guerry D., Nair S., Furukawa K., Herlyn D.
Cancer Immunology, Immunotherapy 52 ( 3 ) 145 - 154 2003年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Cancer Immunology, Immunotherapy
Gangliosides are potentially useful targets for tumor destruction by antibodies. However, the role of gangliosides in T cell-mediated immunity to tumors is unclear. We produced three murine monoclonal anti-idiotypic antibodies (Ab2) against a monoclonal antibody (Ab1) that binds strongly to melanoma-associated GD2 ganglioside and weakly to GD3 ganglioside. All three Ab2 induced anti-anti-idiotypic antibodies (Ab3) with Ab1-like binding specificity to tumor cells and antigen in rabbits. The Ab3 specifically bound to GD2 + tumor cells and isolated GD2, and shared idiotopes with the Ab1. Two of the three Ab2 induced GD2-specific delayed-type hypersensitivity responses in BALB/c and C57BL/6 mice, but not in C57BL/6/CD4 -/- mice. Peripheral blood mononuclear cells (PBMC) from a melanoma patient proliferated specifically in response to in vitro stimulation with Ab2. Proliferation was accompanied by Th1-type cytokine production. Our studies demonstrate the induction of ganglioside-specific T cell-dependent immunity by Ab2 in mice. These T cells showed specific reactivity to ganglioside expressed by tumor cells.
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Maruyama H., Aoki M., Okamura S., Yoshida A., Itagaki T., Ohta N.
Parasitology International 52 ( 1 ) 35 - 39 2003年3月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Parasitology International
In order to study the mucosal invasion of a rodent intestinal nematode in bird intestine, chicks were infected with the intestinal nematode of rodents, Strongyloides venezuelensis, by subcutaneous larva inoculation and adult worm implantation. No evidence was obtained for larvae reaching the lungs or the intestine after infective larva inoculation. Adult worms implanted in the small intestine invaded the mucosa and remained there at least for 24 h, whereas those implanted in the caecum were trapped by mucus, and did not invade the mucosa. Mucosal invasion of adult worms in the small intestine was confirmed by histological examination. The number of adult worms in the intestinal mucosal tissue dropped rapidly within the first 24 h, which was associated with infiltrating granulocytes around the worms. The present study suggests that S. venezuelensis adult worms are able to invade the intestinal tissue of chicks, which do not belong to the vertebrate class of its normal definitive host, but that they are eliminated rapidly by mucosal defense system of the bird. © 2002 Elsevier Science Ireland Ltd. All rights reserved.
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El-Malky M., Maruyama H., Hirabayashi Y., Shimada S., Yoshida A., Amano T., Tominaga A., Takatsu K., Ohta N.
Parasitology International 52 ( 1 ) 71 - 79 2003年3月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Parasitology International
Eosinophils were examined for the capacity of attacking Strongyloides venezuelensis adult worms in the intestinal mucosa by using interleukin (IL)-5 transgenic mice. In IL-5 transgenic mice, most of the subcutaneously inoculated infective larvae were killed during migration, and only a few worms could reach the small intestine. When the same number of adult worms were surgically implanted in the small intestine of IL-5 transgenic and control mice, fecal egg output as well as the number of adult worms recovered from the intestine was significantly lower in IL-5 transgenic mice. In the intestinal mucosa of IL-5 transgenic mice, large number of eosinophils was present in the lamina propria even before adult worm implantation. The number of eosinophils increased significantly as early as 24 h after implantation and tripled by day 3, whereas mucosal eosinophilia remained low in wild-type mice. Most notably, eosinophils infiltrated into the intestinal epithelium and surrounded adult worms in IL-5 transgenic mice, which was never seen in wild-type control mice. However, IL-5 transgenic mice required the same period as normal mice to completely expel implanted adult worms. The amount of specific IgA as well as total IgA in the stool was high in IL-5 transgenic mice before adult worm implantation, and dropped rapidly after adult worm implantation. The present study suggests that eosinophils are capable of attacking adult nematodes in the intestinal epithelia, probably in conjunction with secretory IgA, although they are not enough for the complete worm expulsion. © 2002 Elsevier Science Ireland Ltd. All rights reserved.
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Yoshida A., Maruyama H., Kumagai T., Amano T., Kobayashi F., Wang J., Kuribayashi K., Ohta N.
Parasitology International 51 ( 2 ) 177 - 186 2002年7月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Parasitology International
Effects of Schistosoma mansoni infection on anti-tumor immunity were examined in CBF1 mice with ultraviolet-induced UV♀1 fibrosarcoma cells. Although many laboratory established tumor cells had rejection mechanisms independent of CD4+ T cells, we confirmed that CD4+ cells had significant roles in rejection of UV♀1 cells in the syngeneic CBF1 mice. When we prepared two CBF1 mouse groups, S. mansoni-infected and schistosome-free, the former group showed up-regulation of Th2-like response to UV♀1 cells, whereas the latter group mice showed rather type 1-dominant patterns. Cytotoxic activity against UV♀1 cells tested in vitro, which was attributed to CD8+ cells, was significantly weaker in S. mansoni-infected mice compared with infection-free mice. In tumor challenge experiments in vivo, we observed that rapid and complete rejection of UV♀1 cells required the presence of CD8+ T cells. Under only CD4-depleted situation, survival of tumor cells in schistosome-free mice was prolonged up to 1 month or more. Under the presence of both CD4+ and CD8+ cells, S. mansoni infected mice rejected the challenged UV♀1 cells as was seen in normal mice. However, when CD8+ cells were depleted from S. mansoni-infected mice, inoculated UV♀1 cells grew more rapidly than in infection-free mice. Our results suggest that functionally polarized cytokine patterns in schistosome-infected hosts promote rapid tumor growth. © 2002 Elsevier Science Ireland Ltd. All rights reserved.
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Immunization procedures for anti-idiotypic antibody induction in mice and rats 査読あり 国際共著
Maruyama H., Sperlagh M., Zaloudik J., Liang S., Mizuki K., Molthoff C., Herlyn D.
Journal of Immunological Methods 264 ( 1-2 ) 121 - 133 2002年6月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Immunological Methods
Anti-idiotypic antibodies (Ab2) mimicking antigens (Ags)-defined by antibodies (Ab1) directed to tumors or pathogens have elicited Ag-specific humoral, cellular and/or protective immunity in experimental animals and in humans. In immunizations of rodents with Ab1, factors such as animal species, form of Ab1 and choice of adjuvant are crucial for the successful induction of Ab2 as candidate vaccines against tumors and pathogens. Here we survey the outcome of 362 fusion events (each event representing one animal), using nine immunization schedules in mice and seven schedules in rats and including 10 different Ab1 directed against human tumor- and immunodeficiency virus (HIV-1)-associated Ags. Ab1 IgG or F(ab′)2 were administered uncoupled or coupled to keyhole limpet hemocyanin (KLH). As adjuvants, complete and incomplete Freund's adjuvant (CFA/IFA), lipid A, aluminum hydroxide, TiterMax or vaccinia virus were used. In syngeneic immunizations with murine Ab1 in mice, F(ab′)2 coupled to KLH and emulsified in CFA/IFA preferentially induced Ab2 mimicking tumor or HIV-1 associated epitopes. In xenogeneic immunizations with mouse Ab1 in rats, various forms of Ab1 and adjuvants successfully induced Ab2 mimicking tumor Ags. © 2002 Elsevier Science B.V. All rights reserved.
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Maruyama H., Hirabayashi Y., El-Malky M., Okamura S., Aoki M., Itagaki T., Nakamura-Uchiyama F., Nawa Y., Shimada S., Ohta N.
Experimental Parasitology 100 ( 3 ) 179 - 185 2002年3月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Experimental Parasitology
Mechanisms for the longitudinal distribution of parasitic females of Strongyloides venezuelensis in the host intestine were investigated in mice. Adult worms were mostly recovered from the anterior-most one-third of the small intestine throughout the infection after infective larvae inoculation. Surgically implanted adult worms established well in the small intestinal mucosa, either in the duodenum or in the ileum, whereas a few worms could establish in the large intestine. Implanted worms in the small intestine remained where they were implanted until expelled. Mucosal mast cells were induced in the whole small intestine after the worm implantation. In the large intestine, a considerable number of adult worms settled in the mucosa of mutant mice, whose goblet cell mucins were undersulfated because of a mutation in sulfate-activating enzymes. In these mice, the degree of sulfation of goblet cell mucins in the large intestine was significantly reduced to the level of normal small intestine goblet cell mucins. Our results suggest that sulfated glycoconjugates, either from mucosal mast cells or goblet cells, have important effects on the longitudinal distribution of parasitic females of S. venezuelensis. Index Descriptors and Abbreviations: Strongyloides venezuelensis; Nematode; Tissue specificity; Goblet cell; Mucin; Mast cell; Sulfated carbohydrate; PBS, phosphate buffered saline. © 2002 Elsevier Science (USA). All rights reserved.