研究者業績
基本情報
- 所属
- 千葉大学 大学院医学研究院耳鼻咽喉・頭頸部腫瘍学教室 助教
- 学位
- 医学博士(千葉大学)
- J-GLOBAL ID
- 201801013866893732
- researchmap会員ID
- B000311603
千葉大学医学部附属病院で耳鼻咽喉科医として働きながら、免疫、アレルギー、がんの研究を行っています。
委員歴
1-
2018年4月 - 現在
受賞
4-
2024年
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2023年
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2017年
論文
51-
The journal of allergy and clinical immunology. In practice 2024年7月4日 査読有りThe traditional healthcare model is focused on diseases (medicine and natural science) and does not acknowledge patients' resources and abilities to be experts in their own life based on their lived experiences. Improving healthcare safety, quality and coordination, as well as quality of life, are important aims in the care of patients with chronic conditions. Person-centred care needs to ensure that people's values and preferences guide clinical decisions. This paper reviews current knowledge to develop (i) digital care pathways for rhinitis and asthma multimorbidity and (ii) digitally-enabled person-centred care (1). It combines all relevant research evidence, including the so-called real-world evidence, with the ultimate goal to develop digitally-enabled, patient-centred care. The paper includes (i) Allergic Rhinitis and its Impact on Asthma (ARIA), a two-decade journey, (ii) Grading of Recommendations, Assessment, Development and Evaluation (GRADE), the evidence-based model of guidelines in airway diseases, (iii) mHealth impact on airway diseases, (iv) from guidelines to digital care pathways, (v) embedding Planetary Health, (vi) novel classification of rhinitis and asthma, (vi) embedding real-life data with population-based studies, (vii) the ARIA-EAACI strategy for the management of airway diseases using digital biomarkers, (viii) Artificial Intelligence, (ix) the development of digitally-enabled ARIA Person-Centred Care and (x) the political agenda. The ultimate goal is to propose ARIA 2024 guidelines centred around the patient in order to make them more applicable and sustainable.
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Arthritis research & therapy 26(1) 55-55 2024年2月20日 査読有りOBJECTIVES: IgG4-related disease (IgG4-RD) is a systemic autoimmune disease with an unknown etiology, affecting single/multiple organ(s). Pathological findings include the infiltration of IgG4-producing plasma cells, obliterative phlebitis, and storiform fibrosis. Although immunological studies have shed light on the dysregulation of lymphocytes in IgG4-RD pathogenesis, the role of non-immune cells remains unclear. This study aimed to investigate the demographics and characteristics of non-immune cells in IgG4-RD and explore potential biomarkers derived from non-immune cells in the sera. METHODS: We conducted single-cell RNA sequence (scRNA-seq) on non-immune cells isolated from submandibular glands of IgG4-RD patients. We focused on fibroblasts expressing collagen type XV and confirmed the presence of those fibroblasts using immunohistochemistry. Additionally, we measured the levels of collagen type XV in the sera of IgG4-RD patients. RESULTS: The scRNA-seq analysis revealed several distinct clusters consisting of fibroblasts, endothelial cells, ductal cells, and muscle cells. Differential gene expression analysis showed upregulation of COL15A1 in IgG4-RD fibroblasts compared to control subjects. Notably, COL15A1-positive fibroblasts exhibited a distinct transcriptome compared to COL15A1-negative counterparts. Immunohistochemical analysis confirmed a significant presence of collagen type XV-positive fibroblasts in IgG4-RD patients. Furthermore, immune-suppressive therapy in active IgG4-RD patients resulted in decreased serum levels of collagen type XV. CONCLUSIONS: Our findings suggest that collagen type XV-producing fibroblasts may represent a disease-characterizing non-immune cell population in IgG4-RD and hold potential as a disease-monitoring marker.
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Allergology international : official journal of the Japanese Society of Allergology 73(3) 436-444 2024年2月12日 査読有りBACKGROUND: This study aimed to clarify the diagnostic and predictive factors for perennial allergic rhinitis (PAR) onset in children by analyzing the results of the Chiba High-risk Birth Cohort for Allergy study, which examined newborns with a family history of allergies. METHODS: Overall, 306 pregnant women were recruited. Their newborns were examined by otolaryngologists and pediatric allergists at 1, 2, and 5 years of age. Participants with clinical and laboratory data available at all consultation points were considered eligible. RESULTS: Among 187 eligible participants, the prevalence rates of PAR were 2.1%, 4.3%, and 24.1% at 1, 2, and 5 years of age, respectively. AR-specific nasal local findings and eosinophils in nasal smear were observed in a substantial number of patients with PAR at 1 and 2 years of age. Factors present up to 2 years of age that were associated with PAR onset at 5 years of age, in descending order, were as follows: sensitization to house dust mites (HDM), nasal eosinophilia, and sensitization to cat dander. In 44 cases with HDM sensitization, nasal eosinophilia up to 2 years of age achieved a sensitivity of 76.0% and a specificity of 73.7% for predicting PAR onset at 5 years. CONCLUSIONS: Rhinitis findings and nasal eosinophilia are useful auxiliary diagnostic items for pediatric PAR. Sensitization to HDM and nasal eosinophilia were the most influential factors associated with future PAR onset. A combination of these factors may facilitate the prediction of PAR onset.
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Proceedings of the National Academy of Sciences of the United States of America 120(49) e2302903120 2023年12月5日 査読有りUncontrolled type 2 immunity by type 2 helper T (Th2) cells causes intractable allergic diseases; however, whether the interaction of CD4+ T cells shapes the pathophysiology of allergic diseases remains unclear. We identified a subset of Th2 cells that produced the serine proteases granzyme A and B early in differentiation. Granzymes cleave protease-activated receptor (Par)-1 and induce phosphorylation of p38 mitogen-activated protein kinase (MAPK), resulting in the enhanced production of IL-5 and IL-13 in both mouse and human Th2 cells. Ubiquitin-specific protease 7 (USP7) regulates IL-4-induced phosphorylation of STAT3, resulting in granzyme production during Th2 cell differentiation. Genetic deletion of Usp7 or Gzma and pharmacological blockade of granzyme B ameliorated allergic airway inflammation. Furthermore, PAR-1+ and granzyme+ Th2 cells were colocalized in nasal polyps from patients with eosinophilic chronic rhinosinusitis. Thus, the USP7-STAT3-granzymes-Par-1 pathway is a potential therapeutic target for intractable allergic diseases.
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Pharmacology & Therapeutics 247 108445-108445 2023年7月 査読有りAllergic diseases arise from a complex interplay between immune system and environmental factors. A link between the pathogenesis of allergic diseases and type 2 immune responses has become evident, with conventional and pathogenic type 2 helper T (Th2) cells involved in both. Recently, there has been a significant development in therapeutic agents for allergic diseases: IL-5 and IL-5 receptor antagonists, Janus kinase (JAK) inhibitors, and sublingual immunotherapy (SLIT). Mepolizumab, an IL-5, and Benralizumab, an IL-5 receptor antagonist, modulate eosinophilic inflammation mediated by IL-5-producing Th2 cells. Delgocitinib shows that JAK-associated signaling is essential for the inflammatory reaction in atopic dermatitis, one of the common allergic diseases. SLIT has a significant effect on allergic rhinitis by reducing pathogenic Th2 cell numbers. More recently, novel molecules that are involved in pathogenic Th2 cell-mediated allergic diseases have been identified. These include calcitonin gene-related peptide (CGRP), reactive oxygen species (ROS) scavenging machinery regulated by the Txnip-Nrf2-Blvrb axis, and myosin light chain 9 (Myl9), which interacts with CD69. This review provides an updated view of the recent research on treatment of allergic diseases and their cause: conventional and pathogenic Th2 cells.
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Acta Oto-Laryngologica Case Reports 8(1) 91-96 2023年6月19日 査読有り
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Clinical case reports 11(5) e7135 2023年5月Preoperative simulation using a three-dimensional printer is effective to perform safe surgery by knowing the range limit of drilling in the temporal bone. Moreover, simulations using models are thought to be useful for education of young surgeon.
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Allergology International 2023年5月 査読有り筆頭著者
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日本耳鼻咽喉科免疫アレルギー感染症学会誌 3(3) 101-107 2023年非結核性抗酸菌（NTM）によるリンパ節炎の多くは小児例であり，成人では免疫不全例以外での報告は少ない。今回，健康成人に発症したNTMによる耳前部リンパ節炎の1例を経験したので報告する。症例は41歳男性。右耳前部の腫瘤を主訴に近医耳鼻咽喉科を受診し，耳下腺腫瘍が疑われたため当科へ紹介となった。初診時，右耳前部皮下に20 mm大の可動性不良な硬結を触れ，超音波検査では右耳下腺上極の被膜付近から皮下組織へ広がる境界不明瞭・辺縁不整な腫瘤を認めた。MRI検査では被膜部分は造影されるが，内部は造影効果の少ない腫瘤性病変として描出された。穿刺吸引細胞診では悪性所見は認めず，炎症を伴う肉芽病変が示唆された。穿刺物の抗酸菌培養およびPCRは陰性であった。精査中に膿瘍形成後に自壊したため，膿汁を培養検査に提出したところ，質量分析法および遺伝子解析から起因菌は迅速発育抗酸菌であるMycobacterium mageritenseと同定された。感染症内科にコンサルトの上，sulfamethoxazole/trimethoprim合剤とlevofloxacinによる薬物療法を開始したが，2ヵ月間の抗菌薬投与でも改善が乏しかったため，局所麻酔下で外科的切除を行った。病理所見では乾酪壊死を伴う類上皮細胞肉芽腫を認め，NTMによるリンパ節炎として矛盾しない結果であった。迅速発育抗酸菌の治療方針は確立されておらず，患者の背景因子，病変の状態，および薬剤感受性などを考慮して，個々の症例に対応した治療を展開する必要がある。
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日本鼻科学会会誌 61(4) 640-647 2022年12月内視鏡下に鼻副鼻腔腫瘍を切除するにあたって,重要な点の一つにワーキングスペースの確保と明視下に腫瘍基部を同定することが挙げられる。鼻中隔の開窓による両側鼻腔アプローチは非常に有用な方法であり,大きなワーキングスペースを得ることができるが,術後に大きな鼻中隔穿孔を生じるリスクがある。今回,頭側後方茎の鼻中隔粘膜弁挙上による鼻中隔の開窓により,内視鏡下に切除可能であった鼻腔粘膜悪性黒色腫を経験した。症例は70歳代の男性であり,右下鼻甲介から発生したと考えられる悪性黒色腫が前鼻孔から上咽頭まで充満していた。手術は全過程を内視鏡下に行った。頭側後方茎の鼻中隔粘膜弁挙上による鼻中隔開窓とmedial maxillectomyを行うことで,内視鏡と手術器具を操作でき,更には腫瘍を外側に移動させ得るワーキングスペースを確保した。これにより,腫瘍基部を下鼻甲介の後方内側粘膜と同定し,下鼻甲介ごと一塊切除を行うことができた。鼻中隔の開窓時に患側鼻中隔粘膜は切除したが,鼻中隔粘膜弁の切開ラインを工夫したことで術後の鼻中隔穿孔は軽微にとどめられた。頭側後方茎の鼻中隔粘膜弁挙上による鼻中隔開窓は鼻腔悪性腫瘍の切除において有効な手法と考えられた。(著者抄録)
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Allergology International in press(2) 335-338 2022年12月 査読有り
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Pathogens (Basel, Switzerland) 11(11) 2022年11月1日 責任著者Sublingual immunotherapy for Japanese cedar pollinosis can improve the symptoms of allergic rhinitis and modify its natural course. However, sublingual immunotherapy requires a long treatment period and some patients do not respond to treatment. In this study, we aimed to identify biomarkers that could predict the efficacy of sublingual immunotherapy at an early stage. In this study, 40 patients from phase III trials were recruited and divided into good and poor response groups. Using peripheral blood mononuclear cells from before and two months after the start of medication, microarray, discriminant analysis, and real-time polymerase chain reaction were performed to extract candidate genes that could be biomarkers. Furthermore, these genes were validated in 30 patients in general clinical practice. Complement factor H was upregulated in the good response group and downregulated in the poor response group. Complement factor H may be a useful biomarker for predicting the efficacy of sublingual immunotherapy for Japanese cedar pollinosis at early time points after treatment initiation.
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Life (Basel, Switzerland) 12(11) 2022年10月24日 査読有りCarcinoma ex pleomorphic adenoma (CXPA) is a rare malignant salivary gland tumor, and its prognosis is determined by the histological progression beyond the adenoma capsule. However, a preoperative evaluation of the histological progression remains challenging, and there is no consensus regarding treatment strategies for CXPA. Herein, we aimed to predict the histological progression preoperatively and develop an appropriate treatment strategy for CXPA. We retrospectively reviewed 22 patients with parotid gland CXPA recorded at our hospital. The clinicopathological characteristics were assessed, and survival analysis was performed. T3≤ or N+ were common in widely invasive CXPA (WICXPA) (p < 0.05). A tumor diameter > 40 mm and the N+ status were associated with poor prognosis considering overall survival (OS) and locoregional recurrence rate (LRC) (p < 0.05). Patients with facial nerve paralysis exhibited better OS and LRC than those without facial nerve paralysis. More than 90% of patients with WICXPA experienced distant metastases. Meanwhile, there were no cases of recurrence or death due to intracapsular and minimally invasive CXPA. A preoperative advanced T stage or N+ status was suspected as WICXPA. Tumors > 40 mm in size and N+ status necessitate high-intensity local treatment. Facial nerve invasion can be controlled by nerve resection. Postoperative systemic therapy could control distant metastases.
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The Journal of allergy and clinical immunology 2022年7月18日 査読有り筆頭著者BACKGROUND: Allergic rhinitis is a growing problem worldwide. Currently, the only treatment that can modify the disease is antigen-specific immunotherapy; however, its mechanism(s) of action is not fully understood. OBJECTIVE: To comprehensively investigate the role and changes of antigen-specific T cells before and after sublingual immunotherapy (SLIT) for Japanese cedar pollinosis (JCP). METHODS: We cultured PBMCs obtained both before and at 1 year after initiating SLIT and used a combination of single-cell RNA sequence and repertoire sequencing. To investigate biomarkers, we used PBMCs from patients participating a phase II/III trial of SLIT tablets for JCP and PBMCs from good and poor responders in outpatients. RESULTS: Antigen-stimulated culturing after SLIT led to clonal expansion of Th2 and Treg cells, and most of these CD4+ T cells retained their CDR3 regions before and after treatment, indicating antigen-specific clonal responses and differentiation secondary to SLIT. However, SLIT reduced the number of clonal functional Th2 cells but increased the Trans-type Th2 cell population that expresses musculin (MSC), TGF-β, and IL-2. Trajectory analysis suggested that SLIT induced clonal differentiation of the Trans-type Th2 cells differentiated into Treg cells. Using real-time PCR, we found that the MSC levels increased in the active SLIT group and good responders after 1 year of treatment. CONCLUSION: The combination of single-cell RNA sequencing and repertoire analysis helped reveal a part of the underlying mechanism-that SLIT promotes the expression of MSC on pathogenic Th2 cells and suppresses their function; MSC may be a potential biomarker of SLIT for allergic rhinitis.
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The World Allergy Organization journal 15(3) 100636-100636 2022年3月 査読有りBackground: Complementary and alternative medicine, including Japanese traditional medicine (JTM), has been used for various allergic diseases, but the evidence is limited. Shoseiryuto (Xiao-Qing-Long-Tang), one of the representative JTM drugs, is frequently used to treat allergic rhinitis (AR). However, its efficacy for seasonal AR has not been fully established. Using an Environmental challenge chamber (ECC), we evaluated the therapeutic effects of shoseiryuto on AR induced by Japanese cedar pollen (JCP). Methods: A placebo-controlled double-blind crossover study with shoseiryuto was conducted using the ECC. The shoseiryuto or placebo was orally administered from 2 weeks before the exposure test. The pollen exposure test was conducted for 3 h, and the pollen concentration was set at 8000 pollen/m3. The primary endpoint of the study was the total nasal symptom score (TNSS) during pollen exposure. A physician certified by the Japanese Society of Oriental Medicine as a specialist checked each participant's "pattern", a comprehensive expression of signs obtained from individual patients' subjective symptoms and other personal findings. Blood samples collected just before the first pollen exposure were stimulated with cedar antigens and used for immunological studies. Results: The results of the 46 participants were analyzed, and no significant side effects were detected. There was no significant difference in TNSS during pollen exposure for 3 h in the ECC between the shoseiryuto and placebo groups. However, some symptoms were improved in the shoseiryuto group after leaving the ECC. There was no significant correlation between the "fluid retention pattern" and TNSS. In immunological studies, shoseiryuto did not inhibit Th2-type cytokine production and mRNA expression. Conclusions: Oral administration of shoseiryuto from 2 weeks before pollen exposure did not prevent or inhibit immediate symptoms of AR induced by JCP in the ECC. Further study is needed to reevaluate the shoseiryuto specific "pattern" in JTM.
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Allergology international : official journal of the Japanese Society of Allergology 71(1) 144-146 2022年1月 査読有り
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Clinical Case Reports 9(9) 2021年9月 査読有り
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頭頸部外科 31(1) 33-38 2021年6月 査読有り筆頭著者近年,検査機器の発達によって咽喉頭部でも表在がんが発見され,手術手技の革新により経口的に切除可能になった。今回,食道表在癌で用いられている拡大内視鏡を中心に,中下咽頭癌に対して後方視的にTransoral Surgery症例を検討した。2016年1月からの3年間で拡大内視鏡診断を確認し得た40症例,45病変について検討した。結果,拡大内視鏡診断におけるB2・B3病変と上皮下浸潤には強い関連を認め,術前の深達度診断として感度・特異度ともに高い結果となった。重度の術後合併症も散見する中で,術前に拡大内視鏡診断を確認できれば切除範囲の広さ・深さや合併症の懸念を持って手術に臨めるのではないかと思われた。(著者抄録)
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Allergy 2021年5月24日 査読有りAllergen exposure chambers (AECs) can be used for controlled exposure to allergenic and non-allergenic airborne particles in an enclosed environment, in order to (i) characterize the pathological features of respiratory diseases and (ii) contribute to and accelerate the clinical development of pharmacological treatments and allergen immunotherapy for allergic disease of the respiratory tract (such as allergic rhinitis, allergic rhinoconjunctivitis, and allergic asthma). In the guidelines of the European Medicines Agency for the clinical development of products for allergen immunotherapy (AIT), the role of AECs in determining primary endpoints in dose-finding Phase II trials is emphasized. Although methodologically insulated from the variability of natural pollen exposure, chamber models remain confined to supporting secondary, rather than primary, endpoints in Phase 3 registration trials. The need for further validation in comparison with field exposure is clearly mandated. On this basis the European Academy of Allergy and Clinical Immunology (EAACI) initiated a Task Force in 2015 charged to gain a better understanding of how AECs can generate knowledge about respiratory allergies and can contribute to the clinical development of treatments. Researchers working with AECs worldwide were asked to provide technical information in eight sections: (i) dimensions and structure of the AEC, (ii) AEC staff, (iii) air flow, air processing, and operating conditions, (iv) particle dispersal, (v) pollen/particle counting, (vi) safety and non-contamination measures, (vii) procedures for symptom assessments, (viii) tested allergens/substances and validation procedures. On this basis, a minimal set of technical requirements for AECs applied to the field of allergology is proposed.
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Allergologie select 2021年5月
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Allergy 2021年3月17日 査読有りBACKGROUND: Although there are many asymptomatic patients, one of the problems of COVID-19 is early recognition of the disease. COVID-19 symptoms are polymorphic and may include upper respiratory symptoms. However, COVID-19 symptoms may be mistaken withthe common cold or allergic rhinitis. An ARIA-EAACI study group attempted to differentiate upper respiratory symptoms betweenthe three diseases. METHODS: A modified Delphi process was used and ARIA members who were seeing COVID-19 patients were asked to fill in a questionnaire on the upper airway symptoms of COVID-19, common cold andallergic rhinitis. RESULTS: Among the 192 ARIA members who were invited to respond to the questionnaire, 89 responded. 87 questionnaires were analysed. The consensus was then reported.A two-way ANOVA analysis revealed significant differences inthe symptom intensity between the three diseases (p<0.001). CONCLUSIONS: This modified Delphi approach enabled thedifferentiationof upper respiratory symptoms betweenCOVID-19, common cold and allergic rhinitis. An electronic algorithm will be devised using the questionnaire.
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Allergy 76(1) 168-190 2021年1月 査読有りDigital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
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International journal of pediatric otorhinolaryngology 140 110503-110503 2021年1月 査読有りBACKGROUND: The influence of tonsillectomy on allergic airway diseases is not well known. OBJECTIVES: In the present study, the influence of tonsillectomy on perennial allergic rhinitis (PAR) and bronchial asthma (BA) among pediatric subjects was prospectively investigated. METHODS: The tonsillectomy (surgery group) and the age-matched non-surgical subjects (control group) were examined and followed prospectively. In addition, immunological analysis was conducted. RESULTS: After in vitro allergen stimulation, the production of a small number of allergen-specific Th2 cells was induced in the tonsillar cells, even in sensitized subjects. Flow cytometry analysis detected more effector regulatory T cells (Tregs) in the tonsils than in peripheral blood. Clinically, after surgery, the PAR and BA symptoms improved in the surgery group but not in the control group. The total IgE in the surgery group was significantly lower than in the control group; after surgery, IgE levels slightly increased but remained lower. The postoperative Dermatophagoides farina (Der f)-specific IgE level increased in the sensitized subjects but not in the non-sensitized subjects. CONCLUSION: Tonsillectomy did not improve the underlying mechanisms of the allergy, however the decreased risk of infection and upper airway obstruction could lead to improved symptoms of allergic airway diseases.
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Investigating Japanese cedar pollen-induced allergic rhinitis and related terms using Google Trends.Allergology international : official journal of the Japanese Society of Allergology 69(4) 616-618 2020年4月7日 査読有り筆頭著者
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Rhinology 2020年1月6日 査読有りBACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease, and its pathogenesis remains controversial. This study aimed to examine the involvement of fungi in CRSwNP pathogenesis. METHODS: We enrolled 29 controls and 111 CRSwNP patients. We analyzed fungi in the nasal secretions, serum fungus-specific immunoglobulin E (IgE) levels, and nasal polyp (NP) IgE levels. Moreover, we evaluated the correlation between patients' IgE levels and computed tomography (CT) scores. RESULTS: There was no difference in fungal detection rate between CRSwNP patients with and without asthma. Specific IgEs against various antigens were highly detectable in NPs of CRSwNP patients. In CRSwNP patients, fungus-specific IgE levels in NPs were correlated with CT scores. Serum fungus-specific IgEs became undetectable after operation in more than half of the CRSwNP patients without asthma but not in those with asthma. Other serum airborne antigen-specific IgEs did not become undetectable after operation. CONCLUSIONS: Fungus-specific IgEs were highly detectable in NPs of CRSwNP patients, and NPs comprised a major region of specific IgE production. Fungi may therefore play an important role in CRSwNP pathogenesis by inducing Th2 immune responses, including IgE synthesis.
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Cancer immunology, immunotherapy : CII 68(12) 1935-1947 2019年12月 査読有りBACKGROUND: Due to the strong tumoricidal activities of activated natural killer T (NKT) cells, invariant NKT cell-based immunotherapy has shown promising clinical efficacy. However, suppressive factors, such as regulatory T cells (Tregs), may be obstacles in the use of NKT cell-based cancer immunotherapy for advanced cancer patients. Here, we investigated the suppressive effects of Tregs on NKT cells and the underlying mechanisms with the aim to improve the antitumor activities of NKT cells. METHODS: Peripheral blood samples were obtained from healthy donors, patients with benign tumors, and patients with head and neck squamous cell carcinoma (HNSCC). NKT cells, induced with α-galactosylceramide (α-GalCer), and monocyte-derived dendritic cells (DCs) were co-cultured with naïve CD4+ T cell-derived Tregs to investigate the mechanism of the Treg suppressive effect on NKT cell cytotoxic function. The functions and phenotypes of NKT cells were evaluated with flow cytometry and cytometric bead array. RESULTS: Treg suppression on NKT cell function required cell-to-cell contact and was mediated via impaired DC maturation. NKT cells cultured under Treg-enriched conditions showed a decrease in CD4- NKT cell frequency, which exert strong tumoricidal responsiveness upon α-GalCer stimulation. The same results were observed in HNSCC patients with significantly increased effector Tregs. CONCLUSION: Tregs exert suppressive effects on NKT cell tumoricidal function by inducing more CD4- NKT cell anergy and less CD4+ NKT cell anergy. Both Treg depletion and NKT cell recovery from the anergy state may be important for improving the clinical efficacy of NKT cell-based immunotherapy in patients with advanced cancers.
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The Journal of allergy and clinical immunology 2019年10月 査読有り
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International Archives of Allergy and Immunology 2019年9月 査読有り
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Journal of thoracic disease 11(9) 4072-4084 2019年9月 査読有り
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Journal of thoracic disease 11(8) 3633-3642 2019年8月 査読有り
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Allergology international : official journal of the Japanese Society of Allergology 68(3) 352-362 2019年2月 査読有り
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International archives of allergy and immunology 180(4) 274-283 2019年 査読有りBACKGROUND: No comparative study of antihistamines that differ in structural system has been conducted in allergic rhinitis. OBJECTIVE: This was a randomized, double-blind, crossover comparative study to verify the efficacy of antihistamines that differ in structural system. METHODS: A total of 50 patients with moderate or more severe Japanese cedar pollen-induced allergic rhinitis were randomized to receive either placebo, desloratadine 5 mg (a tricyclic), or levocetirizine 5 mg (a piperazine). One dose of the study drug was orally administered at 9 pm on the day before a pollen exposure test, which was performed for 3 h (9 a.m. to 12 p.m.) to assess symptoms in an environmental challenge chamber (ECC). Nasal and ocular symptoms were compared at an airborne pollen level of 8,000 grains/m3. The primary endpoint was mean total nasal symptom score (TNSS) from 120 to 180 min in the ECC. Subjects with a difference of ≥1 in TNSS between 2 drugs were extracted to the relevant drug-responsive group. RESULTS: The difference in TNSS from placebo was -2.42 (p < 0.0001) with levocetirizine and -1.66 (p < 0.01) with desloratadine, showing that both drugs were significantly more effective than placebo in controlling symptoms, but with no statistically significant difference between the 2 drugs. There were 12 subjects in the desloratadine-responsive group and 24 subjects in the levocetirizine-responsive group, with no contributor to response was detected. CONCLUSION: Levocetirizine tended to control nasal symptoms more effectively than desloratadine. However, the response to each antihistamine varied among individuals and the predictors to the response are unknown. CLINICAL TRIAL REGISTRATION NUMBER: UMIN ID: UMIN000029653.
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Allergy 73(9) 1823-1832 2018年9月 査読有り
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International archives of allergy and immunology 1-10 2018年7月 査読有り
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Allergy: European Journal of Allergy and Clinical Immunology 73(2) 479-489 2018年2月1日 査読有り筆頭著者Background: Allergic rhinitis (AR) consists of three developmental stages that are based on the presence/absence of antigen-specific IgE and symptoms. The pathogenic Th2 (Tpath2) cells constitute a population of Th2 cells with additional potentially pathogenic characteristics. We examined the relationship between Tpath2 cells and the stages of allergic rhinitis by focusing on ST2, which is an IL-33 receptor. Methods: Patients with Japanese cedar pollen-induced AR (JCP-AR) and healthy volunteers were divided into “nonsensitized,” “asymptomatic sensitized (AS),” and “JCP-AR” groups. We analyzed the ST2 expression and the Th2 function of cultured CD4+ T cells. Next, we observed the progress of patients in the AS stage around the time of seasonal pollen dispersal, with the characteristics of Th2 cells. Results: The ST2 expression of T cells was only upregulated in the AR group. The production of IL-4 and IL-13 was found in CD4+ T cells obtained from AS by stimulation with JCP, but reactivity to IL-33 was not observed. Although IL-33 did not induce the elevation of IL-4 production in the JCP-AR group, IL-33 substantially increased the production of IL-5 and IL-13 in comparison with antigen stimulation alone. In newly afflicted patients, the increased expression of ST2 and elevated reactivity to IL-33 was observed, even before the pollen dispersal season. Conclusions: Our study demonstrated that the pathogenicity of memory Th2 cells is linked to sensitization and the stage of allergic rhinitis. Therefore, Tpath2 cells may provide useful insights into the mechanism of the onset and progression of allergic rhinitis.
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Annals of Allergy, Asthma and Immunology 120(2) 155-163 2018年2月1日 査読有りBackground: An allergic rhinitis (AR) diagnosis is based on typical nasal symptoms and allergen sensitization testing. However, it is sometimes difficult to distinguish AR from non-AR, and it is especially difficult to identify the causal allergen for immunotherapy of patients with AR. Objective: To identify differences among patients with AR, subjects with asymptomatic sensitization (AS), and subjects without sensitization (NS) that could facilitate the diagnosis of AR. Methods: We used RNA sequencing to examine differential gene expression in unstimulated and allergen-stimulated peripheral basophils from participants with NS, AS, and AR. We selected genes that were upregulated after allergen stimulation and showed differences in expression in patients with AR compared with subjects with AS and NS. Basophil surface expression of 1 gene product was examined by flow cytometry. The usefulness of gene expression in the diagnosis of AR was examined with receiver operating characteristic curves. Results: Expression of cytokine receptor-like factor 2 and its product, thymic stromal lymphopoietin receptor (TSLPR), was significantly increased in basophils of patients with AR after allergen stimulation. A significantly larger percentage of TSLPR-positive cells was observed after allergen-specific stimulation of basophils from patients with AR compared with subjects with AS. Basophil TSLPR expression was as good as or better than CD203c expression in discriminating between patients with AR and subjects with AS, as judged by receiver operating characteristic curves. Conclusion: Our data suggest that TSLPR expression on basophils was specifically upregulated by allergen stimulation and might be useful for the identification of the causative allergen in patients with AR.
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JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 141(2) AB205 2018年2月 査読有り
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ALLERGOLOGY INTERNATIONAL 66(3) 425-431 2017年7月 査読有りBackground: Complementary and alternative medicine (CAM) is extensively used in patients with allergic diseases worldwide. The purpose of this study was to investigate the actual situation of CAM practice in the treatment of allergic rhinitis. Methods: We distributed questionnaires to otolaryngologists at 114 facilities in Japan. The subjects who participated in this study included children <16 years of age and adults >= 16 years of age diagnosed with allergic rhinitis by otolaryngologists. The survey was performed in the period from September 2007 to August 2009. Furthermore, we performed the same investigation out of the hospital setting, such as during general health examinations. All questionnaires were returned to Chiba University and analyzed. Results: The proportions of patients who had ever experimented with CAM in the hospital survey were 7.1% (225/3170) and 19.2% (1416/7363) of children and adults, respectively. Approximately 36.2% of the adult patients thought that the treatments were effective. The main reasons for CAM use were safety, convenience and low price. However, the group who spent more than $1000 on CAM felt more dissatisfaction and anxiety related to treatment at the hospital. The situation of CAM practice was not consistent and was instead influenced by the backgrounds of the subjects. Conclusions: Many patients who receive CAM report feeling that the effects of treatment provided by hospitals are insufficient and have concerns about the side effects of such treatments. Information regarding standard treatments, as described in the guidelines, should become widely known and diffused, and strong communication with patients should be considered. Copyright (C) 2016, Japanese Society of Allergology. Production and hosting by Elsevier B.V.
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Allergology International 66(3) 425-431 2017年7月1日 査読有りBackground Complementary and alternative medicine (CAM) is extensively used in patients with allergic diseases worldwide. The purpose of this study was to investigate the actual situation of CAM practice in the treatment of allergic rhinitis. Methods We distributed questionnaires to otolaryngologists at 114 facilities in Japan. The subjects who participated in this study included children < 16 years of age and adults ≥16 years of age diagnosed with allergic rhinitis by otolaryngologists. The survey was performed in the period from September 2007 to August 2009. Furthermore, we performed the same investigation out of the hospital setting, such as during general health examinations. All questionnaires were returned to Chiba University and analyzed. Results The proportions of patients who had ever experimented with CAM in the hospital survey were 7.1% (225/3170) and 19.2% (1416/7363) of children and adults, respectively. Approximately 36.2% of the adult patients thought that the treatments were effective. The main reasons for CAM use were safety, convenience and low price. However, the group who spent more than $1000 on CAM felt more dissatisfaction and anxiety related to treatment at the hospital. The situation of CAM practice was not consistent and was instead influenced by the backgrounds of the subjects. Conclusions Many patients who receive CAM report feeling that the effects of treatment provided by hospitals are insufficient and have concerns about the side effects of such treatments. Information regarding standard treatments, as described in the guidelines, should become widely known and diffused, and strong communication with patients should be considered.
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RHINOLOGY 54(3) 221-230 2016年9月 査読有りBackground: Biomarkers that enable objective evaluation of the clinical effects of immunotherapy for allergic rhinitis have yet to be identified. Methods: This study included 40 patients who were enrolled in a large randomized, double-blind, placebo-controlled, multi-center study examining the efficacy of sublingual immunotherapy (SLIT) using Japanese cedar (JC) pollen extract during two consecutive pollen seasons from 2010 to 2012. Based on changes in total nasal symptom medication score, patients in the SLIT and placebo groups were subdivided into two subgroups: good responders and poor responders.The levels of JC pollen-specific IL-10(+)Foxp3(+) cells and specific Th2 cytokine-producing cells were measured and the association with the efficacy of SLIT was analysed. Results: The total nasal symptom medication score was significantly lower in the SLIT group compared with the placebo group. The number of JC pollen-specific Th2 cytokine-producing cells increased during the pollen season in the placebo group and in poor responders in the SLIT group; however, the increases were inhibited in the good responders in the SLIT group. The number of JC pollen-specific IL-10(+)Foxp3(+) cells increased only in these good responders. Conclusions: Changes in levels of allergen-specific Th2 cytokine-producing cells and IL-10(+)Foxp3(+) cells could be objective biomarkers for SLIT.
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Science Immunology 1(3) eaaf9154-eaaf9154 2016年9月 査読有り
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ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY 117(2) 150-157 2016年8月 査読有りBackground: Immediate- and late-phase reactions are associated with nasal symptoms of patients with allergic rhinitis. Objective: To examine the symptoms and mediators released after continuous allergen exposure in an environmental challenge chamber (ECC). Methods: Fifteen patients with Japanese cedar pollinosis were enrolled in this study and continuously exposed to cedar pollen at a concentration of 8,000 grains/m(3) for 3 hours in an ECC. Nasal function tests were performed, and nasal secretions were collected before pollen exposure (0 hour), immediately after exiting the ECC (3 hours), and 6 hours after exiting the ECC (9 hours). Symptom scores were recorded every 30 minutes in the ECC and every 3 hours after exiting the ECC. The frequency of sneezing and nose blowing also was monitored. Results: The severity of symptoms in the ECC peaked approximately 2 hours after the beginning of pollen exposure and continued more than 6 hours after leaving the ECC. Concentrations of histamine, tryptase, interleukins 5, 3, 33, and 31, and substance P increased over time, whereas that of nasal fractional exhaled nitric oxide decreased. Conclusion: Various mediators are released during continuous allergen exposure, which subsequently induce persistent nasal symptoms. Effective treatment is required to control the intense inflammation observed after allergen exposure. (C) 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 113(20) E2842-E2851 2016年5月 査読有りMemory CD4(+) T helper (Th) cells are central to long-term protection against pathogens, but they can also be pathogenic and drive chronic inflammatory disorders. How these pathogenic memory Th cells are maintained, particularly at sites of local inflammation, remains unclear. We found that ectopic lymphoid-like structures called inducible bronchus-associated lymphoid tissue (iBALT) are formed during chronic allergic inflammation in the lung, and that memory-type pathogenic Th2 (Tpath2) cells capable of driving allergic inflammation are maintained within the iBALT structures. The maintenance of memory Th2 cells within iBALT is supported by Thy1(+) IL-7-producing lymphatic endothelial cells (LECs). The Thy1(+) IL-7-producing LECs express IL-33 and T-cell-attracting chemokines CCL21 and CCL19. Moreover, ectopic lymphoid structures consisting of memory CD4(+) T cells and IL-7(+) IL-33(+) LECs were found in nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, Thy1(+) IL-7-producing LECs control chronic allergic airway inflammation by providing a survival niche for memory-type Tpath2 cells.
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ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY 114(4) 289-298 2015年4月 査読有り筆頭著者Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease of uncertain pathogenesis. Memory T cells acquire additional functions during the secondary response and play important roles in chronic inflammation. Objective: To investigate characteristics of tissue memory CD4(+) T cells obtained from patients with non-eosinophilic CRSwNP (NECRS) and eosinophilic CRSwNP (ECRS) by focusing on the influence of interleukin (IL)-25. Methods: Pro-allergic cytokines in tissue homogenates were measured using enzyme-linked immunosorbent assays. NP mononuclear cells and CD4(+) T cells were isolated from NPs from patients with CRSwNP. Cytokine expression and CD4(+) T-cell subpopulations were analyzed using enzyme-linked immunosorbent assay, flow cytometry, and real-time polymerase chain reaction. Results: The IL-25 level in NPs increased in patients with ECRS. IL-5 and IL-9 mRNA levels expressed by tissue CD4(+) T cells were significantly elevated in patients with ECRS. Most infiltrating CD4(+) T cells in ECRS and NECRS expressed CD45RO; however, regardless of the atopic status, high IL-17RB levels were detected in CD4(+) T cells from patients with ECRS. IL-17RB mRNA levels expressed by tissue CD4(+) T cells significantly correlated with the number of eosinophils in NPs. Elevation of IL-5 and IL-9 production was found in NP mononuclear cells from patients with ECRS, but not in those from patients with NECRS, by stimulation with IL-25 under T-cell receptor stimulation. Conclusion: Interleukin-25 and a subpopulation of tissue T-helper type 2 and 9 cells that express increased IL-17RB levels could contribute to infiltration of eosinophils in NPs and could have produced the pathologic difference between NECRS and ECRS. (C) 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
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IMMUNITY 42(2) 294-308 2015年2月 査読有りMemory CD4(+) T helper (Th) cells provide long-term protection against pathogens and are essential for the development of vaccines; however, some antigen-specific memory Th cells also drive immunerelated pathology, including asthma. The mechanisms regulating the pathogenicity of memory Th cells remain poorly understood. We found that interleukin-33 (IL-33)-ST2 signals selectively licensed memory Th2 cells to induce allergic airway inflammation via production of IL-5 and that the p38 MAP kinase pathway was a central downstream target of IL-33-ST2 in memory Th2 cells. In addition, we found that IL-33 induced upregulation of IL-5 by memory CD4(+) T cells isolated from nasal polyps of patients with eosinophilic chronic rhinosinusitis. Thus, IL-33ST2-p38 signaling appears to directly instruct pathogenic memory Th2 cells to produce IL-5 and induce eosinophilic inflammation.
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Clinical and experimental immunology 178(1) 65-74 2014年10月 査読有り
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ALLERGOLOGY INTERNATIONAL 63(1) 41-50 2014年3月 査読有りBackground: An environmental challenge chamber (ECC), which we refer to as the a-chamber, was built at Chiba University in 2008. The aim of this study was to validate the functionality of the ECC. Methods: The stability of the pollen distribution and concentration in the ECC and symptoms of patients with Japanese cedar pollinosis induced by cedar pollen exposure were examined. Carryover effects of symptoms induced by different exposure protocols and correlations between symptoms induced in the ECC and those in the natural cedar pollen season were also determined. All the studies using the a-chamber were conducted out of the cedar pollen season. Results: The severity of symptoms in the chamber reached a peak about 2 hours after the start of pollen exposure and plateaued thereafter. After subjects left the chamber, the symptoms persisted for several days. There was no significant difference between the severity of symptoms at exposure levels of 8000 and 12000 grains/m(3). The symptoms were significantly increased by exposure for 3 consecutive days; however, there were no carryover effects in a study performed with a two-week interval. The total nasal symptom score (TNSS) in the natural pollen season showed a weak correlation with the mean TNSS on the day of exposure and the following 3 days. Symptoms in the ECC also had weak correlations with those in the early natural pollen season. Conclusions: The ECC under well-controlled conditions is suitable for clinical studies and might accelerate development of treatment for seasonal allergic rhinitis. A complete evaluation requires inclusion of the persistent reaction after subjects leave the ECC.
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INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY 162(1) 71-78 2013年 査読有りBackground: The efficacy of prophylactic treatment before the start of pollen dispersal for prevention of aggravation of symptoms is unclear. The aim of the present study was to examine the efficacy of prophylactic treatment with an antihistamine for seasonal allergic rhinitis (SAR) using an environmental challenge chamber (ECC). Methods: The study was performed in a randomized double-blind manner with a 3-way crossover design. The subjects were 50 patients with SAR caused by Japanese cedar pollen who were randomized for treatment with levocetirizine hydrochloride 5 mg (Xyzal (R)) or placebo as follows: administration of placebo for 8 days (treatment A), single administration of levocetirizine on day 8 after placebo for 7 days (treatment B) or administration of levocetirizine for 8 days (treatment C). Efficacy in each treatment arm was evaluated based on cedar pollen exposure for 3 h on day 9 in an ECC, following 1-hour exposure on day 8. The primary endpoint was the total nasal symptom score for 12 h on day 9. Other nasal and ocular symptoms were secondary endpoints. Results: The evaluation was performed in 45 subjects. The total nasal symptom score on day 9 was significantly lower with treatment B compared with treatment A. Treatment C did not show superior efficacy compared with treatment B. Conclusions: Our results suggest that early intervention with levocetirizine soon after onset of symptoms may attenuate these symptoms as effectively as prophylactic treatment before pollen dispersal. These results are important from the perspective of patient convenience and reduction of medical costs. Copyright (C) 2013 S. Karger AG, Basel
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