Publications by authors named "Tomohisa Iinuma"

21 Publications

  • Page 1 of 1

The influence of tonsillectomy on allergic diseases in pediatric patients.

Int J Pediatr Otorhinolaryngol 2021 Jan 17;140:110503. Epub 2020 Nov 17.

Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan; Chiba Rosai Hospital, Chiba, Japan. Electronic address:

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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http://dx.doi.org/10.1016/j.ijporl.2020.110503DOI Listing
January 2021

[Application of iPS Cell-Derived NKT Cells to Cancer Immunotherapy].

Gan To Kagaku Ryoho 2020 Oct;47(10):1411-1414

Dept. of Medical Immunology, Graduate School of Medicine, Chiba University.

NKT cells are innate lymphocytes that express an invariant T cell receptor. Since activated NKT cells exert strong anti-tumor responses, NKT cells have been intensively studied for the purpose of their application to cancer immunotherapeutic approaches. Although human peripheral blood contained a very low fraction of NKT cells, and decreased number of NKT cells was also demonstrated in cancer-bearing patients, peripheral blood NKT cells can be activated by ligand-pulsed antigen presenting cells, and can produce a large amount of interferon-γ upon activation. The clinical trials of adoptive transfer of autologous NKT cells were already performed in patients with non-small cell lung cancer, and with head and neck cancer at Chiba University to show its effectiveness and limitation. Meanwhile, RIKEN reported NKT cell regeneration using iPS cell technology in mice, and subsequently established a protocol for regenerating NKT cells from human peripheral blood NKT cells using iPS cell technology. It was confirmed that the iPS cell-derived NKT cells (iPS-NKT) have sufficient expansion c apacity and potent direct and indirect cytotoxic activity in the humanized mice models, which suggests their therapeutic competence. We are currently planning an investigator-initiated clinical trial of allogeneic iPS-NKT cell therapy for head and neck cancer.
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October 2020

ARIA digital anamorphosis: Digital transformation of health and care in airway diseases from research to practice.

Authors:
Jean Bousquet Josep M Anto Claus Bachert Tari Haahtela Torsten Zuberbier Wienczyslawa Czarlewski Anna Bedbrook Sinthia Bosnic-Anticevich G Walter Canonica Victoria Cardona Elisio Costa Alvaro A Cruz Marina Erhola Wytske J Fokkens Joao A Fonseca Maddalena Illario Juan-Carlos Ivancevich Marek Jutel Ludger Klimek Piotr Kuna Violeta Kvedariene Ltt Le Désirée E Larenas-Linnemann Daniel Laune Olga M Lourenço Erik Melén Joaquim Mullol Marek Niedoszytko Mikaëla Odemyr Yoshitaka Okamoto Nikos G Papadopoulos Vincenzo Patella Oliver Pfaar Nhân Pham-Thi Christine Rolland Boleslaw Samolinski Aziz Sheikh Mikhail Sofiev Charlotte Suppli Ulrik Ana Todo-Bom Peter-Valentin Tomazic Sanna Toppila-Salmi Ioanna Tsiligianni Arunas Valiulis Erkka Valovirta Maria-Teresa Ventura Samantha Walker Sian Williams Arzu Yorgancioglu Ioana Agache Cezmi A Akdis Rute Almeida Ignacio J Ansotegui Isabella Annesi-Maesano Sylvie Arnavielhe Xavier Basagaña Eric D Bateman Annabelle Bédard Martin Bedolla-Barajas Sven Becker Kazi S Bennoor Samuel Benveniste Karl C Bergmann Michael Bewick Slawomir Bialek Nils E Billo Carsten Bindslev-Jensen Leif Bjermer Hubert Blain Matteo Bonini Philippe Bonniaud Isabelle Bosse Jacques Bouchard Louis-Philippe Boulet Rodolphe Bourret Koen Boussery Fluvio Braido Vitalis Briedis Andrew Briggs Christopher E Brightling Jan Brozek Guy Brusselle Luisa Brussino Roland Buhl Roland Buonaiuto Moises A Calderon Paulo Camargos Thierry Camuzat Luis Caraballo Ana-Maria Carriazo Warner Carr Christine Cartier Thomas Casale Lorenzo Cecchi Alfonso M Cepeda Sarabia Niels H Chavannes Ekaterine Chkhartishvili Derek K Chu Cemal Cingi Jaime Correia de Sousa David J Costa Anne-Lise Courbis Adnan Custovic Biljana Cvetkosvki Gennaro D'Amato Jane da Silva Carina Dantas Dejan Dokic Yves Dauvilliers Giulia De Feo Govert De Vries Philippe Devillier Stefania Di Capua Gerard Dray Ruta Dubakiene Stephen R Durham Mark Dykewicz Motohiro Ebisawa Mina Gaga Yehia El-Gamal Enrico Heffler Regina Emuzyte John Farrell Jean-Luc Fauquert Alessandro Fiocchi Antje Fink-Wagner Jean-François Fontaine José M Fuentes Perez Bilun Gemicioğlu Amiran Gamkrelidze Judith Garcia-Aymerich Philippe Gevaert René Maximiliano Gomez Sandra González Diaz Maia Gotua Nick A Guldemond Maria-Antonieta Guzmán Jawad Hajjam Yunuen R Huerta Villalobos Marc Humbert Guido Iaccarino Despo Ierodiakonou Tomohisa Iinuma Ewa Jassem Guy Joos Ki-Suck Jung Igor Kaidashev Omer Kalayci Przemyslaw Kardas Thomas Keil Musa Khaitov Nikolai Khaltaev Jorg Kleine-Tebbe Rostislav Kouznetsov Marek L Kowalski Vicky Kritikos Inger Kull Stefania La Grutta Lisa Leonardini Henrik Ljungberg Philip Lieberman Brian Lipworth Karin C Lodrup Carlsen Catarina Lopes-Pereira Claudia C Loureiro Renaud Louis Alpana Mair Bassam Mahboub Michaël Makris Joao Malva Patrick Manning Gailen D Marshall Mohamed R Masjedi Jorge F Maspero Pedro Carreiro-Martins Mika Makela Eve Mathieu-Dupas Marcus Maurer Esteban De Manuel Keenoy Elisabete Melo-Gomes Eli O Meltzer Enrica Menditto Jacques Mercier Yann Micheli Neven Miculinic Florin Mihaltan Branislava Milenkovic Dimitirios I Mitsias Giuliana Moda Maria-Dolores Mogica-Martinez Yousser Mohammad Steve Montefort Ricardo Monti Mario Morais-Almeida Ralph Mösges Lars Münter Antonella Muraro Ruth Murray Robert Naclerio Luigi Napoli Leyla Namazova-Baranova Hugo Neffen Kristoff Nekam Angelo Neou Björn Nordlund Ettore Novellino Dieudonné Nyembue Robyn O'Hehir Ken Ohta Kimi Okubo Gabrielle L Onorato Valentina Orlando Solange Ouedraogo Julia Palamarchuk Isabella Pali-Schöll Peter Panzner Hae-Sim Park Gianni Passalacqua Jean-Louis Pépin Ema Paulino Ruby Pawankar Jim Phillips Robert Picard Hilary Pinnock Davor Plavec Todor A Popov Fabienne Portejoie David Price Emmanuel P Prokopakis Fotis Psarros Benoit Pugin Francesca Puggioni Pablo Quinones-Delgado Filip Raciborski Rojin Rajabian-Söderlund Frederico S Regateiro Sietze Reitsma Daniela Rivero-Yeverino Graham Roberts Nicolas Roche Erendira Rodriguez-Zagal Christine Rolland Regina E Roller-Wirnsberger Nelson Rosario Antonino Romano Menachem Rottem Dermot Ryan Johanna Salimäki Mario M Sanchez-Borges Joaquin Sastre Glenis K Scadding Sophie Scheire Peter Schmid-Grendelmeier Holger J Schünemann Faradiba Sarquis Serpa Mohamed Shamji Juan-Carlos Sisul Mikhail Sofiev Dirceu Solé David Somekh Talant Sooronbaev Milan Sova François Spertini Otto Spranger Cristiana Stellato Rafael Stelmach Michel Thibaudon Teresa To Mondher Toumi Omar Usmani Antonio A Valero Rudolph Valenta Marylin Valentin-Rostan Marilyn Urrutia Pereira Rianne van der Kleij Michiel Van Eerd Olivier Vandenplas Tuula Vasankari Antonio Vaz Carneiro Giorgio Vezzani Frédéric Viart Giovanni Viegi Dana Wallace Martin Wagenmann De Yun Wang Susan Waserman Magnus Wickman Dennis M Williams Gary Wong Piotr Wroczynski Panayiotis K Yiallouros Osman M Yusuf Heather J Zar Stéphane Zeng Mario E Zernotti Luo Zhang Nan Shan Zhong Mihaela Zidarn

Allergy 2021 01 23;76(1):168-190. Epub 2020 Oct 23.

University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.

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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http://dx.doi.org/10.1111/all.14422DOI Listing
January 2021

Investigating Japanese cedar pollen-induced allergic rhinitis and related terms using Google Trends.

Allergol Int 2020 Oct 8;69(4):616-618. Epub 2020 Apr 8.

Department of Otorhinolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.alit.2020.03.006DOI Listing
October 2020

Next-generation care pathways for allergic rhinitis and asthma multimorbidity: a model for multimorbid non-communicable diseases-Meeting Report (Part 2).

J Thorac Dis 2019 Sep;11(9):4072-4084

Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Uniersität zu Berlin and Berlin Institute of Health, Comprehensive Allergy-Centre, Department of Dermatology and Allergy, Member of GA2LEN, Berlin, Germany.

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http://dx.doi.org/10.21037/jtd.2019.09.38DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790426PMC
September 2019

Regulatory T cells induce CD4 NKT cell anergy and suppress NKT cell cytotoxic function.

Cancer Immunol Immunother 2019 Dec 22;68(12):1935-1947. Epub 2019 Oct 22.

Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

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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http://dx.doi.org/10.1007/s00262-019-02417-6DOI Listing
December 2019

Next-generation Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines for allergic rhinitis based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) and real-world evidence.

Authors:
Jean Bousquet Holger J Schünemann Akdis Togias Claus Bachert Martina Erhola Peter W Hellings Ludger Klimek Oliver Pfaar Dana Wallace Ignacio Ansotegui Ioana Agache Anna Bedbrook Karl-Christian Bergmann Mike Bewick Philippe Bonniaud Sinthia Bosnic-Anticevich Isabelle Bossé Jacques Bouchard Louis-Philippe Boulet Jan Brozek Guy Brusselle Moises A Calderon Walter G Canonica Luis Caraballo Vicky Cardona Thomas Casale Lorenzo Cecchi Derek K Chu Elisio M Costa Alvaro A Cruz Wienczyslawa Czarlewski Gennaro D'Amato Philippe Devillier Mark Dykewicz Motohiro Ebisawa Jean-Louis Fauquert Wytske J Fokkens Joao A Fonseca Jean-François Fontaine Bilun Gemicioglu Roy Gerth van Wijk Tari Haahtela Susanne Halken Despo Ierodiakonou Tomohisa Iinuma Juan-Carlos Ivancevich Marek Jutel Igor Kaidashev Musa Khaitov Omer Kalayci Jorg Kleine Tebbe Marek L Kowalski Piotr Kuna Violeta Kvedariene Stefania La Grutta Désirée Larenas-Linnemann Susanne Lau Daniel Laune Lan Le Philipp Lieberman Karin C Lodrup Carlsen Olga Lourenço Gert Marien Pedro Carreiro-Martins Erik Melén Enrica Menditto Hugo Neffen Gregoire Mercier Ralph Mosgues Joaquim Mullol Antonella Muraro Leyla Namazova Ettore Novellino Robyn O'Hehir Yoshitaka Okamoto Ken Ohta Hae Sim Park Petr Panzner Giovanni Passalacqua Nhan Pham-Thi David Price Graham Roberts Nicolas Roche Christine Rolland Nelson Rosario Dermot Ryan Boleslaw Samolinski Mario Sanchez-Borges Glenis K Scadding Mohamed H Shamji Aziz Sheikh Ana-Maria Todo Bom Sanna Toppila-Salmi Ioana Tsiligianni Marylin Valentin-Rostan Arunas Valiulis Erkka Valovirta Maria-Teresa Ventura Samantha Walker Susan Waserman Arzu Yorgancioglu Torsten Zuberbier

J Allergy Clin Immunol 2020 01 15;145(1):70-80.e3. Epub 2019 Oct 15.

Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Uniersität zu Berlin and Berlin Institute of Health, Comprehensive Allergy-Centre, Department of Dermatology and Allergy, member of GA(2)LEN, Berlin, Germany.

The selection of pharmacotherapy for patients with allergic rhinitis aims to control the disease and depends on many factors. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines have considerably improved the treatment of allergic rhinitis. However, there is an increasing trend toward use of real-world evidence to inform clinical practice, especially because randomized controlled trials are often limited with regard to the applicability of results. The Contre les Maladies Chroniques pour un Vieillissement Actif (MACVIA) algorithm has proposed an allergic rhinitis treatment by a consensus group. This simple algorithm can be used to step up or step down allergic rhinitis treatment. Next-generation guidelines for the pharmacologic treatment of allergic rhinitis were developed by using existing GRADE-based guidelines for the disease, real-world evidence provided by mobile technology, and additive studies (allergen chamber studies) to refine the MACVIA algorithm.
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http://dx.doi.org/10.1016/j.jaci.2019.06.049DOI Listing
January 2020

Efficacy of Desloratadine and Levocetirizine in Patients with Cedar Pollen-Induced Allergic Rhinitis: A Randomized, Double-Blind Study.

Int Arch Allergy Immunol 2019 16;180(4):274-283. Epub 2019 Oct 16.

Biostatistics Section, Clinical Research Center, Chiba University Hospital, Chiba, Japan.

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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http://dx.doi.org/10.1159/000503065DOI Listing
December 2019

Next-generation care pathways for allergic rhinitis and asthma multimorbidity: a model for multimorbid non-communicable diseases-Meeting Report (Part 1).

J Thorac Dis 2019 Aug;11(8):3633-3642

Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Uniersität zu Berlin and Berlin Institute of Health, Comprehensive Allergy-Centre, Department of Dermatology and Allergy, Member of GA2LEN, Berlin, Germany.

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http://dx.doi.org/10.21037/jtd.2019.08.64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753463PMC
August 2019

2019 ARIA Care pathways for allergen immunotherapy.

Authors:
Jean Bousquet Oliver Pfaar Alkis Togias Holger J Schünemann Ignacio Ansotegui Nikolaos G Papadopoulos Ioanna Tsiligianni Ioana Agache Josep M Anto Claus Bachert Anna Bedbrook Karl-Christian Bergmann Sinthia Bosnic-Anticevich Isabelle Bosse Jan Brozek Moises A Calderon Giorgio W Canonica Luigi Caraballo Victoria Cardona Thomas Casale Lorenzo Cecchi Derek Chu Elisio Costa Alvaro A Cruz Wienczyslawa Czarlewski Stephen R Durham George Du Toit Mark Dykewicz Motohiro Ebisawa Jean Luc Fauquert Montserrat Fernandez-Rivas Wytske J Fokkens João Fonseca Jean-François Fontaine Roy Gerth van Wijk Tari Haahtela Susanne Halken Peter W Hellings Despo Ierodiakonou Tomohisa Iinuma Juan Carlos Ivancevich Lars Jacobsen Marek Jutel Igor Kaidashev Musa Khaitov Omer Kalayci Jörg Kleine Tebbe Ludger Klimek Marek L Kowalski Piotr Kuna Violeta Kvedariene Stefania La Grutta Désirée Larenas-Linemann Susanne Lau Daniel Laune Lan Le Karin Lodrup Carlsen Olga Lourenço Hans-Jørgen Malling Gert Marien Enrica Menditto Gregoire Mercier Joaquim Mullol Antonella Muraro Robyn O'Hehir Yoshitaka Okamoto Giovanni B Pajno Hae-Sim Park Petr Panzner Giovanni Passalacqua Nhan Pham-Thi Graham Roberts Ruby Pawankar Christine Rolland Nelson Rosario Dermot Ryan Bolesław Samolinski Mario Sanchez-Borges Glenis Scadding Mohamed H Shamji Aziz Sheikh Gunter J Sturm Ana Todo Bom Sanna Toppila-Salmi Maryline Valentin-Rostan Arunas Valiulis Erkka Valovirta Maria-Teresa Ventura Ulrich Wahn Samantha Walker Dana Wallace Susan Waserman Arzu Yorgancioglu Torsten Zuberbier

Allergy 2019 11 15;74(11):2087-2102. Epub 2019 Jul 15.

Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Comprehensive Allergy Centre, Member of GA2LEN, Humboldt-Uniersität zu Berlin, Berlin, Germany.

Allergen immunotherapy (AIT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence-based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including healthcare professionals. The decision to prescribe AIT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as the availability of good-quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomarkers that can predict AIT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate pharmacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow-up of patients.
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http://dx.doi.org/10.1111/all.13805DOI Listing
November 2019

Sublingual administration of liposomes enclosing alpha-galactosylceramide as an effective adjuvant of allergen immunotherapy in a murine model of allergic rhinitis.

Allergol Int 2019 Jul 22;68(3):352-362. Epub 2019 Feb 22.

Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan. Electronic address:

Background: Sublingual immunotherapy (SLIT) is an established efficacious approach for the treatment of allergic rhinitis (AR). However, SLIT requires a long administration period to establish stable and adequate responses. This study investigated the efficacy of the sublingual administration of an allergen with liposomes enclosing α-GalCer (α-GC-liposome) as a potential adjuvant in mice with AR.

Methods: Mice with AR induced by OVA received the sublingual administration of OVA, α-GC-liposomes, or OVA plus α-GC-liposomes for 7 days. After nasal re-challenge with OVA, nasal symptoms were evaluated. The serum levels of OVA-specific Ig, the cytokine production of CD4 T cells in the cultures of cervical lymph node (CLN) cells, and the gene expression of CLNs were analyzed.

Results: Although IL-4, IL-5 and IL-13 production from CD4 T cells in CLN cells was significantly inhibited by the sublingual administration of OVA alone in mice with AR induced by OVA, their nasal symptoms were not significantly diminished. However, the combined sublingual administration of α-GC-liposomes and OVA completely suppressed nasal symptoms, downregulated Th2 and Th17 type cytokine production in CD4 T cells as well as Th2 and Th17 gene expressions, and upregulated Th1 type cytokine production as well as Th1 gene expressions in CLN cells. Additionally, the serum levels of specific IgG2a were promoted, and specific IgE and IgG1 were inhibited.

Conclusions: Our findings suggest that the sublingual administration of an allergen with α-GC-liposomes as an adjuvant might increase the therapeutic efficacy and effectiveness of this treatment method.
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http://dx.doi.org/10.1016/j.alit.2019.02.003DOI Listing
July 2019

The Relationship of Pollen Dispersal with Allergy Symptoms and Immunotherapy: Allergen Immunotherapy Improves Symptoms in the Late Period of Japanese Cedar Pollen Dispersal.

Int Arch Allergy Immunol 2018;177(3):245-254. Epub 2018 Jul 18.

Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: The severity of symptoms of pollen-induced allergic rhinitis is affected by the amount of scattered pollen. However, the relationships between the pollen dispersal pattern, symptom severity, and treatment efficacy are not clear.

Methods: Between 2007 and 2012, we performed 4 randomized, placebo-controlled studies of sublingual immunotherapy (SLIT) on patients with Japanese cedar-induced allergic rhinitis who lived in or around Chiba, Japan. The participants were asked to avoid using rescue medicines during the cedar pollen season as much as possible and to record their nasal symptoms in allergy diaries. The amount of pollen dispersed daily was quantified using the Durham method, and the season was divided into early and late periods based on the pollen count.

Results: A total of 721 patients were enrolled in the 4 studies during the 6-year study period. In the placebo group (n = 349), a correlation was observed between the amount of pollen dispersed and the severity of symptoms in the early but not late period of pollen dispersal. Treatment with SLIT (n = 372) significantly improved symptom severity in the late but not early period.

Conclusion: For patients with Japanese cedar pollen-induced allergic rhinitis, the fluctuation of daily pollen dispersal had a minimal effect on the severity of symptoms during the late period. SLIT was remarkably effective in alleviating symptoms during this period but not in the early period.
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http://dx.doi.org/10.1159/000490314DOI Listing
December 2018

Basophils from allergic rhinitis patients show allergen-specific upregulation of thymic stromal lymphopoietin receptor.

Ann Allergy Asthma Immunol 2018 02;120(2):155-163

Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan. Electronic address:

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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http://dx.doi.org/10.1016/j.anai.2017.12.005DOI Listing
February 2018

Myosin light chains 9 and 12 are functional ligands for CD69 that regulate airway inflammation.

Sci Immunol 2016 Sep 16;1(3):eaaf9154. Epub 2016 Sep 16.

Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.

Recent decades have witnessed a rapid worldwide increase in chronic inflammatory disorders such as asthma. CD4 T helper 2 cells play critical roles in the pathogenesis of allergic airway inflammation, and CD69 expression on activated CD4 T cells is required to induce allergic inflammation in tissues. However, how CD69 mechanistically controls allergic inflammation remains poorly defined. In lymphoid tissues, CD69 regulates cellular retention through inhibition of S1P1 expression and requires no specific ligands to function. In contrast, we show herein that myosin light chain (Myl) 9 and Myl12 are new functional ligands for CD69. Blockade of CD69-Myl9/12 interaction ameliorates allergic airway inflammation in ovalbumin-induced and house dust mite-induced mouse models of asthma. Within the inflamed mouse airways, we found that the expression of Myl9/12 was increased and that platelet-derived Myl9/12 localized to the luminal surface of blood vessels and formed intravascular net-like structures. Analysis of nasal polyps of eosinophilic chronic rhinosinusitis patients revealed that Myl9/12 expression was increased in inflammatory lesions and was distributed within net-like structures in the intravascular space. In addition, we detected Myl9/12 in perivascular spaces where many CD69 cells were positioned within Myl9/12 structures. Thus, CD69-Myl9/12 interaction is a key event in the recruitment of activated CD69 T cells to inflamed tissues and could be a therapeutic target for intractable airway inflammatory diseases.
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http://dx.doi.org/10.1126/sciimmunol.aaf9154DOI Listing
September 2016

Complementary and alternative medicine for allergic rhinitis in Japan.

Allergol Int 2017 Jul 21;66(3):425-431. Epub 2016 Nov 21.

Department of Otorhinolaryngology, Nippon Medical School, Tokyo, Japan.

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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http://dx.doi.org/10.1016/j.alit.2016.10.006DOI Listing
July 2017

Persistent nasal symptoms and mediator release after continuous pollen exposure in an environmental challenge chamber.

Ann Allergy Asthma Immunol 2016 08 1;117(2):150-7. Epub 2016 Jun 1.

Department of Otolaryngology, Head and Neck Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

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.
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http://dx.doi.org/10.1016/j.anai.2016.05.015DOI Listing
August 2016

Thy1+IL-7+ lymphatic endothelial cells in iBALT provide a survival niche for memory T-helper cells in allergic airway inflammation.

Proc Natl Acad Sci U S A 2016 May 2;113(20):E2842-51. Epub 2016 May 2.

Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; AMED-CREST, AMED, Chiba 260-8670, Japan

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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http://dx.doi.org/10.1073/pnas.1512600113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878506PMC
May 2016

Interleukin-25 and mucosal T cells in noneosinophilic and eosinophilic chronic rhinosinusitis.

Ann Allergy Asthma Immunol 2015 Apr 19;114(4):289-98. Epub 2015 Feb 19.

Department of Immunology, Chiba University Graduate School of Medicine, Chiba, Japan.

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 noneosinophilic 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.
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http://dx.doi.org/10.1016/j.anai.2015.01.013DOI Listing
April 2015

The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway.

Immunity 2015 Feb;42(2):294-308

Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan; CREST, Japan Science and Technology Agency, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan. Electronic address:

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 immune-related 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-33-ST2-p38 signaling appears to directly instruct pathogenic memory Th2 cells to produce IL-5 and induce eosinophilic inflammation.
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http://dx.doi.org/10.1016/j.immuni.2015.01.016DOI Listing
February 2015

Characteristics of the Chiba environmental challenge chamber.

Allergol Int 2014 Mar 25;63(1):41-50. Epub 2013 Dec 25.

Weather Service Corporation, Chiba, Japan.

Background: An environmental challenge chamber (ECC), which we refer to as the α-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 α-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/m3. 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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http://dx.doi.org/10.2332/allergolint.13-OA-0578DOI Listing
March 2014

Randomized double-blind study of prophylactic treatment with an antihistamine for seasonal allergic rhinitis.

Int Arch Allergy Immunol 2013 26;162(1):71-8. Epub 2013 Jun 26.

Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.

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®) 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.
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http://dx.doi.org/10.1159/000350926DOI Listing
November 2013