論文 - 山下　弘高

Oral allergy induction through skin exposure to previously tolerated food antigens in murine models

Yamashita Hirotaka, Matsuhara Hiroki, Tanaka Hiroyuki, Inagaki Naoki, Tsutsui Masato

Journal of Pharmacological Sciences   152   76 - 85   2023年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

関連する研究費コード: JP19K0761

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Prophylactic steroid use is ineffective in food allergy: A randomized-controlled clinical trial and a murine model.

Matsui T, Yamashita H, Kitamura K, Makino A, Takasato Y, Sugiura S, Ito K

Allergy ( Allergy: European Journal of Allergy and Clinical Immunology )    2022年07月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Spontaneous pulmonary emphysema in mice lacking all three nitric oxide synthase isoforms.

Kato K, Tsutsui M, Noguchi S, Iha Y, Naito K, Ogoshi T, Nishida C, Tahara M, Yamashita H, Wang KY, Toyohira Y, Yanagihara N, Masuzaki H, Shimokawa H, Tanimoto A, Yatera K

Scientific reports ( Scientific Reports )  11 ( 1 ) 22088 - 22088   2021年11月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

The roles of endogenous nitric oxide (NO) derived from the entire NO synthases (NOSs) system have yet to be fully elucidated. We addressed this issue in mice in which all three NOS isoforms were deleted. Under basal conditions, the triple n/i/eNOSs-/- mice displayed significantly longer mean alveolar linear intercept length, increased alveolar destructive index, reduced lung elastic fiber content, lower lung field computed tomographic value, and greater end-expiratory lung volume as compared with wild-type (WT) mice. None of single NOS-/- or double NOSs-/- genotypes showed such features. These findings were observed in the triple n/i/eNOSs-/- mice as early as 4 weeks after birth. Cyclopaedic and quantitative comparisons of mRNA expression levels between the lungs of WT and triple n/i/eNOSs-/- mice by cap analysis of gene expression (CAGE) revealed that mRNA expression levels of three Wnt ligands and ten Wnt/β-catenin signaling components were significantly reduced in the lungs of triple n/i/eNOSs-/- mice. These results provide the first direct evidence that complete disruption of all three NOS genes results in spontaneous pulmonary emphysema in juvenile mice in vivo possibly through down-regulation of the Wnt/β-catenin signaling pathway, demonstrating a novel preventive role of the endogenous NO/NOS system in the occurrence of pulmonary emphysema.

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Impact of orally-administered oligosaccharides in a murine model of food allergy: Impact of oligosaccharides on food allergy

Yamashita H.

Journal of Functional Foods ( Journal of Functional Foods )  85   2021年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

Food allergy is a refractory condition for which there are no standard effective therapies. Prebiotic supplementation such as oligosaccharides in infants was found to be associated with decreased risk of allergic diseases. Raffinose and stachyose are the major oligosaccharides identified in beans; these oligosaccharides have properties of regulating homeostasis. In this study, we explored the use of oligosaccharides as a means to prevent food allergy using an ovalbumin (OVA) sensitization and challenge model in which reductions in body temperature and diarrhea were evaluated. Raffinose and stachyose were administered ad libitum in drinking water for five weeks from one week prior the first sensitization through the final oral administration of OVA. Among our findings, treatment with stachyose suppressed allergic diarrhea and prevented elevations in OVA-specific immunoglobulin (Ig)G1. We hypothesize that suppression of these responses was associated with the actions of regulatory T cells and promoted by utilization of the oligosaccharides by intestinal microbiota. Taken together, our findings suggest that daily ingestion of oligosaccharides might be effective for the prevention of food allergy.

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Staphylococcal Phage in Combination with Staphylococcus Epidermidis as a Potential Treatment for Staphylococcus Aureus-Associated Atopic Dermatitis and Suppressor of Phage-Resistant Mutants.

Shimamori Y, Mitsunaka S, Yamashita H, Suzuki T, Kitao T, Kubori T, Nagai H, Takeda S, Ando H

Viruses ( Viruses )  13 ( 1 )   2020年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Atopic dermatitis is accompanied by the abnormal overgrowth of Staphylococcus aureus, a common cause of skin infections and an opportunistic pathogen. Although administration of antibiotics is effective against S. aureus, the resulting reduction in healthy microbiota and the emergence of drug-resistant bacteria are of concern. We propose that phage therapy can be an effective strategy to treat atopic dermatitis without perturbing the microbiota structure. In this study, we examined whether the S. aureus phage SaGU1 could be a tool to counteract the atopic exacerbation induced by S. aureus using an atopic mouse model. Administration of SaGU1 to the back skin of mice reduced both S. aureus counts and the disease exacerbation caused by S. aureus. Furthermore, the S. aureus-mediated exacerbation of atopic dermatitis with respect to IgE plasma concentration and histopathological findings was ameliorated by the application of SaGU1. We also found that Staphylococcus epidermidis, a typical epidermal symbiont in healthy skin, significantly attenuated the emergence of SaGU1-resistant S. aureus under co-culture with S. aureus and S. epidermidis in liquid culture infection experiments. Our results suggest that phage therapy using SaGU1 could be a promising clinical treatment for atopic dermatitis.

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Convenient preparation of an antigenic oligosaccharide from white kidney bean powder: A useful plant oligosaccharide for synthesis of immunoactive glycopolymer.

Kimura M, Ogura M, Akamatsu M, Sugimoto K, Maeda M, Nitoda T, Nagasawa-Fujimori H, Yamashita H, Kimura Y

International journal of biological macromolecules   153   1016 - 1023   2020年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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Plant glycoproteins, especially allergenic glycoproteins such as pollen allergens, often carry antigenic N-glycans with α1-3 fucose and/or β1-2 xylose residue(s) on the trimannosyl core structure. We previously reported that one of such antigenic free-form N-glycans, Man3Xyl1Fuc1GlcNAc2 (M3FX) suppressed IL-4 production from Th2 cells of pollinosis patients. For the molecular-level analysis of this immunoactivity, an effective and convenient procedure for large scale preparation of the immunoactive free-form N-glycan and a synthesis of glycopolymers bearing multivalent M3FX has been required. During the preparation of prebiotic oligosaccharides from several edible beans, we found that the free-form M3FX accumulates in relatively large amounts in white kidney beans. In this report, we describe a new procedure for preparation of M3FX from white kidney bean powders by a combination of ion-exchange method, gel-filtration, and hydrophilic partitioning. The high-purity of M3FX prepared by this procedure was confirmed by MS-analysis and 1H-NMR, suggesting that the free-form M3FX can be used for the synthesis of neoglycopolymer. Using this new procedure, the immunoactive oligosaccharide can be prepared without the chemical method such as hydrazinolysis and other purification steps required to exclude other type of N-glycans.

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疫学と病態・PFAS グルテンの経口投与は種々の加水分解コムギによる経皮感作マウスにアナフィラキシー様症状を誘導する

徳満 大樹, 大日方 翔太朗, 佐々木 和実, 中村 政志, 山下 弘高, 松永 佳世子, 稲垣 直樹, 田中 宏幸

アレルギー ( (一社)日本アレルギー学会 )  68 ( 4-5 ) 492 - 492   2019年05月 [ 査読有り ]

掲載種別: 研究論文（その他学術会議資料等）

疫学と病態・PFAS ペプチドスクリーニングを可能とする魚アレルギーマウスモデルの確立

末吉 賢也, 下條 尚志, 中村 政志, 山下 弘高, 稲垣 直樹, 矢上 晶子, 松永 佳世子, 田中 宏幸

アレルギー ( (一社)日本アレルギー学会 )  68 ( 4-5 ) 492 - 492   2019年05月 [ 査読有り ]

掲載種別: 研究論文（その他学術会議資料等）

Food allergy is linked to season of birth, sun exposure, and vitamin D deficiency.

Matsui T, Tanaka K, Yamashita H, Saneyasu KI, Tanaka H, Takasato Y, Sugiura S, Inagaki N, Ito K

Allergology international : official journal of the Japanese Society of Allergology   68 ( 2 ) 172 - 177   2019年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

The season of birth and ultraviolet B exposure have been related to the occurrence of food allergy. The levels of vitamin D produced from skin by ultraviolet B exposure might reflect this relationship. Vitamin D is known to induce antimicrobial peptides, protect intestinal flora, enhance the gut epithelial barrier, suppress mast cell activation and IgE synthesis from B cells, and increase the number of tolerogenic dendritic cells and IL-10-producing regulatory T cells. Vitamin D deficiency has been shown to exacerbate sensitization and allergic symptoms in a murine model of food allergy. However, in clinical situations, contradictory observations have been reported regarding the relationship between food allergy and vitamin D deficiency/supplementation. In this review, we have explored the links between food allergy and vitamin D levels. One explanation for the discrepant findings is confounding factors such as race, age, residency, skin color, and epigenetic changes that contribute to vitamin D levels. In addition, the season of birth influences the development of atopic dermatitis, which could lead to food sensitization. Finally, ultraviolet radiation could lead to regulatory T cell expansion and immunosuppression, irrespective of vitamin D status. Based on our current understanding, we believe that correction of vitamin D deficiency by supplementation, appropriate skin care, and sufficient ultraviolet radiation exposure could alter the prognosis of food allergy. To identify potential treatment strategies for food allergy, it is essential to gain a better understanding of the appropriate levels of vitamin D and ultraviolet radiation exposure.

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グルテンの経口投与は種々の加水分解コムギ末による経皮感作マウスにアレルギー反応を誘導する

徳満 大樹, 大日方 翔太朗, 佐々木 和美, 中村 政志, 山下 弘高, 松永 佳世子, 稲垣 直樹, 田中 宏幸

日本薬学会年会要旨集 ( (公社)日本薬学会 )  139年会 ( 3 ) 71 - 71   2019年03月 [ 査読有り ]

掲載種別: 研究論文（その他学術会議資料等）

ペプチド免疫療法剤の開発を目的とした魚アレルギースクリーニングモデルの確立

末吉 賢也, 下條 尚志, 中村 政志, 山下 弘高, 稲垣 直樹, 矢上 晶子, 松永 佳世子, 田中 宏幸

日本薬学会年会要旨集 ( (公社)日本薬学会 )  139年会 ( 3 ) 62 - 62   2019年03月 [ 査読有り ]

掲載種別: 研究論文（その他学術会議資料等）

特集2　経口免疫寛容 経口免疫寛容の誘導における食品添加物の影響

山下 弘高

臨床免疫・アレルギー科   71(2)   146 - 152   2019年

掲載種別: 研究論文（学術雑誌）

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Immune suppression of food allergy by maternal IgG in murine models.

Yamashita H, Hayashi T, Saneyasu K, Matsuhara H, Matsui T, Tanaka H, Inagaki N

Allergology international : official journal of the Japanese Society of Allergology ( Japanese Society of Allergology )  67 ( 4 ) 506 - 514   2018年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

Background: Most of the patients develop food allergy early in life. The factors related to parental immune condition might be one of the conceivable causes. Methods: We reported murine models of food allergy and oral OVA tolerance. To investigate the influence of parental immune condition on infant food allergy, female and male mice with food allergy or oral tolerance were mated with each other. Results: Food allergy was suppressed by decreased IgE production in the offspring of mice with food allergy. On the contrary, anaphylaxis for OVA was induced in the offspring of mice with oral tolerance. The suppression of food allergy being dependent on a maternal factor was revealed in the offspring after cross-mating mice with food allergy and oral tolerance. Because OVA-specific IgG, presumed to be from the allergic mother, was detected in the serum of naïve infants from mothers allergic to food, we assumed that the suppression was dependent on a specific IgG. The serum IgG purified by a G-protein column was administered before OVA sensitization in the food allergy model, and OVA-specific IgE production was found to be diminished in the administered mice. However, OVA-specific monoclonal IgG1 and IgG2a administration could not suppress food allergy. Because we detected OVA-IgG immune complex in the serum of mothers allergic to food, it might be a cause of maternal immune suppression. Conclusions: We demonstrated that maternal specific IgG conjugated food antigen is an important factor related to the development of food allergy and acquiring tolerance.

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Vitamin D deficiency exacerbates sensitization and allergic diarrhea in a murine food allergy model.

Matsui T, Yamashita H, Saneyasu KI, Tanaka H, Ito K, Inagaki N

Allergology international : official journal of the Japanese Society of Allergology ( Japanese Society of Allergology )  67 ( 2 ) 289 - 291   2018年04月 [ 査読有り ]

掲載種別: 研究論文（その他学術会議資料等）

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Histamine-releasing factor enhances food allergy.

Ando T, Kashiwakura JI, Itoh-Nagato N, Yamashita H, Baba M, Kawakami Y, Tsai SH, Inagaki N, Takeda K, Iwata T, Shimojo N, Fujisawa T, Nagao M, Matsumoto K, Kawakami Y, Kawakami T

The Journal of clinical investigation ( AMER SOC CLINICAL INVESTIGATION INC )  127 ( 12 ) 4541 - 4553   2017年12月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

Food allergy occurs due to IgE- and mast cell-dependent intestinal inflammation. Previously, we showed that histamine-releasing factor (HRF), a multifunctional protein secreted during allergy, interacts with a subset of IgE molecules and that the HRF dimer activates mast cells in an HRF-reactive IgE-dependent manner. In this study, we investigated whether HRF plays any role in food allergy. Specifically, we determined that prophylactic and therapeutic administration of HRF inhibitors that block HRF-IgE interactions reduces the incidence of diarrhea and mastocytosis in a murine model of food allergy. Food allergy-associated intestinal inflammation was accompanied by increased secretion of the HRF dimer into the intestine in response to proinflammatory, Th2, and epithelial-derived cytokines and HRF-reactive IgE levels at the elicitation phase. Consistent with these data, patients with egg allergy had higher blood levels of HRF-reactive IgE compared with individuals that were not hypersensitive. Successful oral immunotherapy in egg-allergy patients and food-allergic mice reduced HRF-reactive IgE levels, thereby suggesting a pathological role for HRF in food allergy. Together, these results suggest that antigen and HRF dimer amplify intestinal inflammation by synergistically activating mast cells and indicate that HRF has potential as a therapeutic target in food allergy.

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Artificial sweeteners and mixture of food additives cause to break oral tolerance and induce food allergy in murine oral tolerance model for food allergy

H. Yamashita, H. Matsuhara, S. Miotani, Y. Sako, T. Matsui, H. Tanaka, N. Inagaki

CLINICAL AND EXPERIMENTAL ALLERGY ( WILEY )  47 ( 9 ) 1204 - 1213   2017年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

Background: Processed foods are part of daily life. Almost all processed foods contain food additives such as sweeteners, preservatives and colourants. From childhood, it is difficult to avoid consuming food additives. It is thought that oral tolerance for food antigens is acquired during early life. If tolerance fails, adverse immune responses to food proteins may occur. Objective: We hypothesized that food additives prevent acquisition of oral tolerance and aimed to verify the safety of food additives. Methods: We induced experimental oral tolerance in mice for ovalbumin (OVA), a food antigen, by previous oral treatment with OVA before sensitization with OVA injections. Food additives were administered at the induction of oral tolerance, and food allergy was induced by repeated administration of OVA. Symptoms of food allergy were defined as a change in body temperature and allergic diarrhoea. Results: Saccharin sodium and a mixture of food additives inhibited acquisition of oral tolerance. Hypothermia and allergic diarrhoea with elevation of OVA-specific IgE were induced in the murine model of oral tolerance. Analyses of antigen-presenting cells in mesenteric lymph nodes showed that food additives affected their manner of migration. Additionally, food additives decreased the proportion of CD25(hi) regulatory T cells among CD4(+) T cells in the mesenteric lymph nodes. Conclusions and Clinical Relevance: A large amount of food additives may prevent acquisition of oral tolerance. Intake of food additives in early life may increase the risk of food allergies.

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Analyses for failure of acquiring oral tolerance by intakes of food additives to use murine food allergy model

Yamashita Hirotaka, Matsuhara Hiroki, Miotani Sho, Matsui Teruaki, Tanaka Hiroyuki, Inagaki Naoki

JOURNAL OF PHARMACOLOGICAL SCIENCES   133 ( 3 ) S124   2017年03月 [ 査読有り ]

掲載種別: 研究論文（その他学術会議資料等）

Eppikajutsuto Protects against Food Allergy Induced by Ovalbumin in a Murine Model.

Matsui T, Yamashita H, Mori M, Tanaka H, Inagaki N

International archives of allergy and immunology ( KARGER )  173 ( 2 ) 71 - 83   2017年 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

　概要を見る

Background: Currently, there are no efficient medications available for the prevention and treatment of food allergy (FA). Herbal medicines, including traditional Japanese Kampo medicines (TJKMs), are promising therapeutic drugs. Methods: We screened 18 TJKMs for treatment of FA symptoms in a mouse FA model induced by ovalbumin (OVA). BALB/c mice were sensitized intraperitoneally by an OVA/aluminum hydroxide gel mixture followed by 4 booster doses of oral OVA and FA symptom induction by 50 mg of OVA. TJKMs were orally administered for 28 days from the day of sensitization to the day before FA symptom induction. Evaluated FA symptoms included a decrease in body temperature and allergic diarrhea. Allergic sensitization was determined by plasma OVA-specific IgE levels. Cytokine mRNA levels in mesenteric lymph nodes, plasma mouse mast cell protease-1, and the number of mast cells in the small and large intestines were analyzed. Additionally, the therapeutic effect of the TJKM eppikajutsuto (EJT) on mast cell degranulation was determined in active anaphylaxis and passive cutaneous anaphylaxis models. Results: EJT effectively prevented FA symptoms. Although OVA-specific IgE levels and the intestinal mast cell numbers were not different between the EJT-treated and untreated FA mice, plasma mMcpt1 and IL-4 levels were lower in EJT-treated FA mice than untreated FA mice. EJT could alleviate symptoms in both active and passive anaphylaxis models. Conclusion: EJT prevented OVA-induced FA symptoms in a mouse model, suggesting that EJT might exert its therapeutic activity via IL-4 suppression and the inhibition of mucosal mast cell degranulation. (C) 2017 S. Karger AG, Basel

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Epithelial barrier function and innate immunity - their involvement in the pathophysiology of allergy and the therapeutic targets.

Tanaka H, Yamashita H, Inagaki N

Nihon yakurigaku zasshi. Folia pharmacologica Japonica ( 日本薬理学会 )  149 ( 5 ) 235 - 239   2017年 [ 査読有り ]

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Immune tolerance in maternal immunity using murine food allergy model

Yamashita Hirotaka, Hayashi Tadamasa, Tanaka Hiroyuki, Inagaki Naoki

JOURNAL OF PHARMACOLOGICAL SCIENCES   130 ( 3 ) S121   2016年03月 [ 査読有り ]

掲載種別: 研究論文（その他学術会議資料等）