Acta Medica Okayama11912012Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17.285295ENHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakanoriTeshimaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHarukoSugiyamaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKoichiroKobayashiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoshikoYamasujiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesSachiyoKadohisaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesHidetakaUryuDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesKengoTakeuchiDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTakehiroTanakaDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesTadashiYoshinoDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesYoichiroIwakuraDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesMitsuneTanimotoDepartment of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-γ-deficient and IL-17-deficient mice as donors. Infusion of IFN-γ(-/-) or IL-17(-/-) T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF-β expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD.No potential conflict of interest relevant to this article was reported.Elsevier ScienceActa Medica Okayama0925-571010562017Predictors of vasovagal reactions during preoperative autologous blood donation: a single-institution analysis812818ENHisakazuNishimoriDepartment of Transfusion Medicine, Okayama University HospitalNobuharuFujii Department of Transfusion Medicine, Okayama University HospitalKeikoFujii Department of Transfusion Medicine, Okayama University HospitalTohruIkeda Department of Transfusion Medicine, Okayama University HospitalNaomiAsano Department of Transfusion Medicine, Okayama University HospitalHiroakiOgo Department of Transfusion Medicine, Okayama University HospitalMiwaYamakawaDepartment of Nursing, Okayama University HospitalNaoeTakagiDepartment of Nursing, Okayama University HospitalFumioOtsukaDepartment of Transfusion Medicine, Okayama University HospitalKazumaIkedaDepartment of Transfusion Medicine, Okayama University Hospital Studies examining risk factors associated with vasovagal reactions (VVRs) during autologous blood donations, especially in younger subjects, have been limited. The aim of the present study was to define risk factors for VVRs during preoperative autologous blood donation in patients, including those younger than 18 years old. We retrospectively analyzed 4192 autologous, preoperative blood donations between 2007 and 2015 at Okayama University Hospital. Eighty-seven (2.08%) of the patients experienced VVRs. VVRs occurred approximately three times as often in patients 0-17 years old (16/320, 5.0%) than in patients 18 years and older (71/3872, 1.8%). In particular, VVRs occurred more frequently in those 10-13 years old, and decreased with older age (P = 0.006). In a univariate analysis, younger age, lower body mass index, lower systolic blood pressure, lower body weight, lower total blood volume, female gender, first-time collection, and higher heart rate were associated with a higher incidence of VVRs. In a multivariate analysis, lower systolic blood pressure (P < 0.001), higher heart rate (P = 0.007), and first-time collection (P = 0.015), remained independent predictors of VVRs. These results emphasize the need for careful attention during blood collection.No potential conflict of interest relevant to this article was reported.BioMed CentralActa Medica Okayama1471-24071712017Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study314322ENT.YokotaDivision of Gastrointestinal Oncology, Shizuoka Cancer CenterT.OgawaDepartment of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of MedicineS.TakahashiDepartment of Medical Oncology, The Cancer Institute Hospital of JFCRK.OkamiDepartment of Otolaryngology, Center of Head and Neck Surgery, Tokai UniversityT.FujiiDepartment of Otolaryngology, Head and Neck Surgery, Osaka Medical Center for Cancer and Cardiovascular DiseasesK.TanakaDepartment of Medical Oncology, Kindai University Faculty of MedicineS.IwaeDepartment of Head and Neck Cancer, Hyogo Cancer CenterI.OtaDepartment of Otolaryngology-Head and Neck Surgery, Nara Medical UniversityT.UedaDepartment of Otorhinolaryngology-Head and Neck Surgery, Hiroshima University HospitalN.MondenDepartment of Head and Neck Surgery, Shikoku Cancer CenterK.MatsuuraDepartment of Head and Neck Surgery, Miyagi Cancer CenterH.KojimaDepartment of Otorhinolaryngology, Jikei University School of MedicineS.Ueda Medical Oncology, Nara Hospital, Kindai University School of MedicineK.SasakiHead and Neck, Chiba Cancer CenterY.FujimotoDepartment of Otorhinolaryngology, Nagoya University, Graduate School of MedicineY.HasegawaDepartment of Head and Neck Surgery, Aichi Cancer Center Hospital and Research InstituteT.BeppuDivision of Head and Neck Surgery, Saitama Cancer CenterHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalS.HiranoDepartment of Otolaryngology-Head and Neck Surgery, Kyoto University HospitalY.Naka Headquarters of New Product Evaluation and Development, Otsuka Pharmaceutical Co., Ltd.Y.Matsushima Headquarters of New Product Evaluation and Development, Otsuka Pharmaceutical Co., Ltd.M.FujiiDepartment of Otolaryngology, Eiju General HospitalM.TaharaDepartment of Head and Neck Medical Oncology, National Cancer Center Hospital EastBACKGROUND:
Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II study assessed the clinical benefit of rebamipide in reducing the incidence of severe chemoradiotherapy-induced oral mucositis in patients with head and neck cancer (HNC).
METHODS:
Patients aged 20-75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo. The primary endpoint was the incidence of grade ≥ 3 oral mucositis determined by clinical examination and assessed by central review according to the Common Terminology Criteria of Adverse Events version 3.0. Secondary endpoints were the time to onset of grade ≥ 3 oral mucositis and the incidence of functional impairment (grade ≥ 3) based on the evaluation by the Oral Mucositis Evaluation Committee.
RESULTS:
From April 2014 to August 2015, 97 patients with HNC were enrolled, of whom 94 received treatment. The incidence of grade ≥ 3 oral mucositis was 29% and 25% in the rebamipide 2% and 4% groups, respectively, compared with 39% in the placebo group. The proportion of patients who did not develop grade ≥ 3 oral mucositis by day 50 of treatment was 57.9% in the placebo group, whereas the proportion was 68.0% in the rebamipide 2% group and 71.3% in the rebamipide 4% group. The incidences of adverse events potentially related to the study drug were 16%, 26%, and 13% in the placebo, rebamipide 2%, and rebamipide 4% groups, respectively. There was no significant difference in treatment compliance among the groups.
CONCLUSIONS:
The present phase II study suggests that mouth washing with rebamipide may be effective and safe for patients with HNC receiving chemoradiotherapy, and 4% liquid is the optimal dose of rebamipide.
TRIAL REGISTRATION:
ClinicalTrials.gov under the identifier NCT02085460 (the date of trial registration: March 11, 2014).No potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X7052016An Open-labeled, Multicenter Phase II Study of Tamibarotene in Patients with Steroid-refractory Chronic Graft-versus-Host Disease409412ENYoshinobuMaedaDepartment of Hematology and Oncology, Okayama University HospitalHisakazuNishimoriDepartment of Hematology and Oncology, Okayama University HospitalYoshihiroInamotoDepartment of Hematopoietic Stem Cell Transplantation, National Cancer Center HospitalHirohisaNakamaeDepartment of Hematology, Osaka City University HospitalMasashiSawaDepartment of Hematology and Oncology, Anjo Kosei HospitalYasuoMoriDepartment of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical SciencesKazuteruOhashiHematology Division, Tokyo Metropolitan Cancer and Infectious Diseases CenterShin-ichiroFujiwaraDivision of Hematology, Department of Medicine, Jichi Medical UniversityMitsuneTanimotoDepartment of Hematology and Oncology, Okayama University HospitalClinical Study Protocols10.18926/AMO/54603Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HSCT). Retinoic acid (tamibarotene) exerts multiple effects on cell differentiation and is clinically used for the treatment of acute promyelocytic leukemia. Tamibarotene down-regulates both Th1 and Th17 differentiation in donor T cells after allogeneic HSCT, resulting in attenuation of experimental chronic GVHD. Based on preclinical data, we have launched a phase II study of tamibarotene in patients with steroid-refractory chronic GVHD. This study will clarify whether tamibarotene can exert beneficial effects in patients with steroid-refractory chronic GVHD.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812722015慢性移植片対宿主病に対するタミバロテン（AM80G）の医師主導臨床第U相試験133137ENHisakazuNishimoriYoshinobuMaedaNo potential conflict of interest relevant to this article was reported.Acta Medica Okayama1083-87912022014Mammalian Target of Rapamycin Inhibitors Permit Regulatory T Cell Reconstitution and Inhibit Experimental Chronic Graft-versus-Host Disease183191ENHarukoSugiyamaYoshinobuMaedaHisakazuNishimoriYoshikoYamasujiKen-ichiMatsuokaNobuharuFujiiEiseiKondoKatsujiShinagawaTakehiroTanakaKengoTakeuchiTakanoriTeshimaMitsuneTanimotoChronic graft-versus-host disease (GVHD) remains a major late complication of allogeneic bone marrow transplantation (BMT). In a previous study, impaired thymic negative selection of the recipients permitted the emergence of pathogenic T cells that cause chronic GVHD using MHC class II-deficient (H2-Ab1 KO) B6 into OH model and CD4(+) T cells isolated from chronic GVHD mice caused chronic GVHD when administered into the secondary recipients. In this study, we evaluated the kinetics of regulatory T cell (Treg) reconstitution in wild type B6 into C3H model. After myeloablative conditioning, host Tregs disappeared rapidly, followed by expansion of Tregs derived from the donor splenic T cell inoculum. However, the donor splenic T cell derived Treg pool contracted gradually and was almost completely replaced by newly generated donor bone marrow (BM)-derived Tregs in the late post-transplantation period. Next, we compared the effects of cyclosporine (CSA) and mammalian target of rapamycin (mTOR) inhibitors on Treg reconstitution. Administration of CSA significantly impaired Treg reconstitution in the spleen and thymus. In contrast, BM-derived Treg reconstitution was not impaired in mTOR inhibitor-treated mice. Histopathological examination indicated that mice treated with GSA, but not mTOR inhibitors, showed pathogenic features of chronic GVHD on day 120. Mice treated with CSA until day 60, but not mTOR inhibitors, developed severe chronic GVHD followed by adoptive transfer of the pathogenic CD4(+) T cells isolated from H2-Ab1 KO into C3H model. These findings indicated that long-term use of CSA impairs reconstitution of BM-derived Tregs and increases the liability to chronic GVHD. The choice of immunosuppression, such as calcineurin inhibitor-free GVHD prophylaxis with mTOR inhibitor, may have important implications for the control of chronic GVHD after BMT.No potential conflict of interest relevant to this article was reported.Biomed Central LtdActa Medica Okayama1465-993X142013IL-17A is essential to the development of elastase-induced pulmonary inflammation and emphysema in miceENEtsukoKurimotoNobuakiMiyaharaArihikoKanehiroKoichiWasedaAkihikoTaniguchiGenyoIkedaHikariKogaHisakazuNishimoriYasushiTanimotoMikioKataokaYoichiroIwakuraErwin W.GelfandMitsuneTanimotoBackground: Pulmonary emphysema is characterized by alveolar destruction and persistent inflammation of the airways. Although IL-17A contributes to many chronic inflammatory diseases, it's role in the inflammatory response of elastase-induced emphysema remains unclear.
Methods: In a model of elastase-induced pulmonary emphysema we examined the response of IL-17A-deficient mice, monitoring airway inflammation, static compliance, lung histology and levels of neutrophil-related chemokine and pro-inflammatory cytokines in bronchoalveolar lavage (BAL) fluid.
Results: Wild-type mice developed emphysematous changes in the lung tissue on day 21 after elastase treatment, whereas emphysematous changes were decreased in IL-17A-deficient mice compared to wild-type mice. Neutrophilia in BAL fluid, seen in elastase-treated wild-type mice, was reduced in elastase-treated IL-17A-deficient mice on day 4, associated with decreased levels of KC, MIP-2 and IL-1 beta. Elastase-treated wild-type mice showed increased IL-17A levels as well as increased numbers of IL-17A+ CD4 T cells in the lung in the initial period following elastase treatment.
Conclusions: These data identify the important contribution of IL-17A in the development of elastase-induced pulmonary inflammation and emphysema. Targeting IL-17A in emphysema may be a potential therapeutic strategy for delaying disease progression.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812612014糖尿病の腎臓においてcholecystokininはマクロファージに対する抗炎症作用を介した新規の保護効果を発揮する16ENSatoshiMiyamotoKenichiShikataKyokoMiyasakaShinichiOkadaMotofumiSasakiRyoKoderaDaishoHirotaNobuoKajitaniTetsuharuTakatsukaHitomiKataoka UsuiShingoNishishitaChikageHoriguchi SatoAkihiroFunakoshiHisakazuNishimoriHaruhito AdamUchidaDaisukeOgawaHirofumiMakinoNo potential conflict of interest relevant to this article was reported.Okayama University Medical SchoolActa Medica Okayama0386-300X6712013Chronic Graft-versus-Host Disease: Disease Biology and Novel Therapeutic Strategies18ENHisakazuNishimoriYoshinobuMaedaMitsuneTanimotoReview10.18926/AMO/49251Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Chronic GVHD often presents with clinical manifestations that resemble those observed in autoimmune diseases. Standard treatment is 1-2mg/kg/day of prednisone or an equivalent dose of methylprednisolone, with continued administration of a calcineurin inhibitor for steroid sparing. However, the prognosis of steroid-refractory chronic GVHD remains poor. Classically, chronic GVHD was said to involve predominantly Th2 responses. We are now faced with a more complex picture, involving possible roles for thymic dysfunction, transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF), B cells and autoantibodies, and Th1/Th2/Th17 cytokines, as well as regulatory T cells (Tregs), in chronic GVHD. More detailed research on the pathophysiology of chronic GVHD may facilitate the establishment of novel strategies for its prevention and treatment.No potential conflict of interest relevant to this article was reported.岡山医学会Acta Medica Okayama0030-155812432012合成レチノイドAm80はTh1とTh17を抑制することにより慢性移植片対宿主病を改善する197201ENHisakazuNishimoriYoshinobuMaedaMitsuneTanimotoNo potential conflict of interest relevant to this article was reported.