研究者詳細 - 仲瀬　裕志

論文 - 仲瀬　裕志

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IL-7 produced by thymic epithelial cells plays a major role in the development of thymocytes and TCRγδ+ intraepithelial lymphocytes.

Soichiro Shitara, Takahiro Hara, Bingfei Liang, Keisuke Wagatsuma, Saulius Zuklys, Georg A Holländer, Hiroshi Nakase, Tsutomu Chiba, Shizue Tani-ichi, Koichi Ikuta

Journal of immunology (Baltimore, Md. : 1950) ( AMER ASSOC IMMUNOLOGISTS ) 190 ( 12 ) 6173 - 9 2013年06月 [査読有り] [国際誌]

IL-7 is a cytokine essential for T cell development and survival. However, the local function of IL-7 produced by thymic epithelial cells (TECs) is poorly understood. To address this question, we generated IL-7-floxed mice and crossed them with FoxN1 promoter-driven Cre (FoxN1-Cre) mice to establish knockout mice conditionally deficient for the expression of IL-7 by TECs. We found that αβ and γδ T cells were significantly reduced in the thymus of IL-7(f/f) FoxN1-Cre mice. Proportion of mature single-positive thymocytes was increased. In lymph nodes and the spleen, the numbers of T cells were partially restored in IL-7(f/f) FoxN1-Cre mice. In addition, γδ T cells were absent from the fetal thymus and epidermis of IL-7(f/f) FoxN1-Cre mice. Furthermore, TCRγδ(+) intraepithelial lymphocytes (IELs) were significantly decreased in the small intestines of IL-7(f/f) FoxN1-Cre mice. To evaluate the function of IL-7 produced in the intestine, we crossed the IL-7(f/f) mice with villin promoter-driven Cre (Vil-Cre) mice to obtain the mice deficient in IL-7 production from intestinal epithelial cells. We observed that αβ and γδ IELs of IL-7(f/f) Vil-Cre mice were comparable to control mice. Collectively, our results suggest that TEC-derived IL-7 plays a major role in proliferation, survival, and maturation of thymocytes and is indispensable for γδ T cell development. This study also demonstrates that IL-7 produced in the thymus is essential for the development of γδ IELs and indicates the thymic origin of γδ IELs.

DOI PubMed

Erratum: The challenge of acute rejection in intestinal transplantation (Pediatric Surgery International (2012) 28 (855-859) DOI: 10.1007/s00383-012- 3110-x)

E. Y. Yoshitoshi, A. Yoshizawa, E. Ogawa, M. Kaneshiro, N. Takada, S. Okamoto, Y. Fujimoto, S. Sakamoto, S. Masuda, M. Matsuura, H. Nakase, T. Chiba, T. Tsuruyama, H. Haga, S. Uemoto

Pediatric Surgery International 29 ( 6 ) 663 2013年06月 [査読有り]

DOI

Effect of infliximab on inflammatory bowel disease with Takayasu arteritis: case series and review of the literature.

Naoki Minami, Hiroshi Nakase, Takuya Yoshino, Satoshi Yamada, Takahiko Toyonaga, Yusuke Honzawa, Minoru Matsuura, Tsutomu Chiba

Clinical journal of gastroenterology 6 ( 3 ) 226 - 30 2013年06月 [査読有り] [国内誌]

Takayasu arteritis (TA) and inflammatory bowel disease (IBD) are chronic inflammatory disorders. The mechanisms underlying these diseases are not precisely known, but tumor necrosis factor alpha (TNF-α) is considered to have an important role in the pathophysiology of both TA and IBD. Simultaneous occurrence of both TA and IBD is rare. Our first case was a 42-year-old woman with TA and inflammatory bowel disease unclassified. The patient was refractory to treatment with an immunomodulator, and infliximab (IFX) was started. After starting IFX, clinical remission was achieved and maintained for 2 years. The second case was a 34-year-old woman with TA accompanied by Crohn's disease. Because her abdominal symptoms relapsed despite treatment with an immunomodulator, IFX was started. Both diseases were well controlled for 2 years by scheduled maintenance therapy with IFX. Relapse of the TA required increased doses of IFX at shorter intervals, which relieved her symptoms. Overall, we identified nine cases for which IFX was effective, including our 2 cases. They may demonstrate the efficacy of IFX for IBD with TA and emphasize the role of TNF-α in the pathophysiology.

DOI PubMed

Histology of intestinal allografts: lymphocyte apoptosis and phagocytosis of lymphocytic apoptotic bodies are diagnostic findings of acute rejection in addition to crypt apoptosis.

Tatsuaki Tsuruyama, Shinya Okamoto, Yasuhiro Fujimoto, Atsushi Yoshizawa, Elena Yoshitoshi, Hiroto Egawa, Hiroshi Nakase, Wulamujiang Aini, Masashi Miyao, Keiji Tamaki, Hirohiko Yamabe, Hironori Haga, Shinji Uemoto

The American journal of surgical pathology 37 ( 2 ) 178 - 84 2013年02月 [査読有り] [国際誌]

Acute rejection of a small-bowel transplant is often difficult to diagnose due to complicated immune responses. The present study aimed to elucidate the specific immune responses involved in intestinal transplant rejection. We correlated immunohistologic findings with an increase in crypt apoptosis, which has been commonly accepted as a criterion for the diagnosis of acute cellular rejection (ACR). Of 8 patients who received an intestinal allograft at Kyoto University Hospital, biopsy specimens from 7 patients were assessed immunohistologically with antibodies against 20 types of lymphocytic antigens including CD3, CD4, CD8, CD79a, CD20, IgG, and T-cell receptor, along with assessment of the patients' clinical courses. It was revealed that, in addition to apoptotic crypts, T-lymphocyte apoptosis and phagocytosis of apoptotic bodies in the lamina propria of villi were findings of ACR; both were observed in all cases. Immunostaining of the Fas ligand, one of the apoptosis-inducing molecules, was useful for the identification of the apoptotic bodies in the lamina propria of villi. Apoptotic body phagocytosis may be a surrogate diagnostic finding of grafts undergoing ACR.

DOI PubMed J-GLOBAL

Refractoriness of intestinal Behçet's disease with myelodysplastic syndrome involving trisomy 8 to medical therapies - our case experience and review of the literature.

Toyonaga T, Nakase H, Matsuura M, Minami N, Yamada S, Honzawa Y, Hukata N, Yoshino T, Chiba T, Okazaki K

Digestion ( KARGER ) 88 ( 4 ) 217 - 21 2013年 [査読有り] [国際誌]

BACKGROUND/AIMS: Gastrointestinal lesions of Behçet's disease (BD) are often refractory to medical therapy and sometimes result in serious comorbidities such as gastrointestinal perforation and massive bleeding. There are several reports of patients with BD comorbid with myelodysplastic syndrome (MDS) involving trisomy 8 that frequently have intestinal lesions refractory to conventional medical therapy. Little is known about the efficacy of infliximab (IFX) for these intestinal lesions. METHODS: We present 2 cases of intestinal BD with MDS involving trisomy 8 who did not respond to IFX, and review previous reports of BD with MDS involving trisomy 8 concerning their responsiveness to conventional medical therapy. RESULTS: Among 31 previously reported cases that received medical treatment for BD, 19 (61.3%) showed temporary improvement of the BD symptoms, 9 (29.0%) deteriorated, and 3 (9.7%) showed no change. All of the 9 cases that showed deterioration had intestinal lesions. Our 2 cases failed to respond to IFX, resulting in a poor prognosis. CONCLUSIONS: IFX might not be effective for improving intestinal BD comorbid with MDS involving trisomy 8. Trisomy 8 is associated with the BD prognosis and refractoriness to conventional medical therapy.

DOI PubMed

Mediterranean mimicker.

Soichi Arasawa, Hiroshi Nakase, Yoshinao Ozaki, Norimitsu Uza, Minoru Matsuura, Tsutomu Chiba

Lancet (London, England) ( ELSEVIER SCIENCE INC ) 380 ( 9858 ) 2052 - 2052 2012年12月 [査読有り] [国際誌]

DOI PubMed

Gastric ulcer and gastroenteritis caused by Epstein-Barr virus during immunosuppressive therapy for a child with systemic juvenile idiopathic arthritis.

Eitaro Hiejima, Takahiro Yasumi, Hirohito Kubota, Katsuyuki Ohmori, Koichi Ohshima, Ryuta Nishikomori, Hiroshi Nakase, Tsutomu Chiba, Toshio Heike

Rheumatology (Oxford, England) ( OXFORD UNIV PRESS ) 51 ( 11 ) 2107 - 9 2012年11月 [査読有り] [国際誌]

DOI PubMed

Letter: mucosal PCR for cytomegalovirus in refractory ulcerative colitis

T. Yoshino, H. Nakase, M. Matsuura

ALIMENTARY PHARMACOLOGY & THERAPEUTICS ( WILEY-BLACKWELL ) 36 ( 8 ) 811 - 812 2012年10月 [査読有り]

DOI

Esophageal foreign body causing sustained stridor in an infant.

Eitaro Hiejima, Hiroshi Nakase, Shinji Uemoto, Toshio Heike

Clinical journal of gastroenterology 5 ( 2 ) 146 - 9 2012年04月 [査読有り] [国内誌]

The patient was an 8-month-old boy with a 2-month history of stridor. Initially, he had been diagnosed with bronchitis and/or asthma and treated with antibiotics, a β-antagonist and a leukotriene antagonist, but his symptoms were not relieved. An enhanced computed tomography scan showed a gas filled mass and tracheal compression above the level of the aortic arch, and barium swallow revealed an approximately 3 cm mass with irregular surface. Endoscopic examination showed a yellow foreign body (FB) with surrounding granulation tissue. The FB was removed surgically. Postoperative bronchoscopy showed improvement of tracheal compression. The patient had an uneventful recovery with disappearance of his stridor.

DOI PubMed

The role of Hes genes in intestinal development, homeostasis and tumor formation.

Taro Ueo, Itaru Imayoshi, Taeko Kobayashi, Toshiyuki Ohtsuka, Hiroshi Seno, Hiroshi Nakase, Tsutomu Chiba, Ryoichiro Kageyama

Development (Cambridge, England) ( COMPANY OF BIOLOGISTS LTD ) 139 ( 6 ) 1071 - 82 2012年03月 [査読有り] [国際誌]

Notch signaling regulates intestinal development, homeostasis and tumorigenesis, but its precise downstream mechanism remains largely unknown. Here we found that inactivation of the Notch effectors Hes1, Hes3 and Hes5, but not Hes1 alone, led to reduced cell proliferation, increased secretory cell formation and altered intestinal structures in adult mice. However, in Apc mutation-induced intestinal tumors, inactivation of Hes1 alone was sufficient for reducing tumor cell proliferation and inducing differentiation of tumor cells into all types of intestinal epithelial cells, but without affecting the homeostasis of normal crypts owing to genetic redundancy. These results indicated that Hes genes cooperatively regulate intestinal development and homeostasis and raised the possibility that Hes1 is a promising target to induce the differentiation of tumor cells.

DOI PubMed

Targeting activation-induced cytidine deaminase prevents colon cancer development despite persistent colonic inflammation

A. Takai, H. Marusawa, Y. Minaki, T. Watanabe, H. Nakase, K. Kinoshita, G. Tsujimoto, T. Chiba

ONCOGENE ( NATURE PUBLISHING GROUP ) 31 ( 13 ) 1733 - 1742 2012年03月 [査読有り]

Inflammatory bowel disease (IBD) is an important etiologic factor in the development of colorectal cancer. However, the mechanism underlying carcinogenesis through chronic inflammation is still unknown. Activation-induced cytidine deaminase (AID) is induced by the inflammation and involved in various human carcinogenesis via its mutagenic activity. In the current study, we investigated whether the inflammation/AID axis plays an integral role in the development of colitis-associated cancers. Inflammation in the cecum was more severe than that in other colonic regions, and endogenous AID expression was enhanced most prominently in the inflamed cecal mucosa of interleukin (IL)-10(-/-) mice. Blockade of tumor necrosis factor (TNF)-alpha and IL-12 significantly suppressed AID expression. Although proinflammatory cytokine expression was comparable between IL-10(-/-) AID(+/+) and IL-10(-/-) AID(-/-) mice, sequencing analyses revealed a significantly lower incidence of somatic mutations in Trp53 gene in the colonic mucosa of IL-10(-/-) AID(-/-) than IL-10(-/-) AID(+/+) mice. Colon cancers spontaneously developed in the cecum in 6 of 22 (27.2%) IL-10(-/-) AID(+/+) mice. In contrast, none of the IL-10(-/-) AID(-/-) mice developed cancers except only one case of neoplasia in the distal colon. These findings suggest that the proinflammatory cytokine-induced aberrant production of AID links colonic inflammation to an enhanced genetic susceptibility to oncogenic mutagenesis. Targeting AID could be a novel strategy to prevent colitis-associated colon carcinogenesis irrespective of ongoing colonic inflammation. Oncogene (2012) 31, 1733-1742; doi:10.1038/onc.2011.352; published online 15 August 2011

DOI PubMed

Successful treatment with infliximab for inflammatory colitis in a patient with X-linked anhidrotic ectodermal dysplasia with immunodeficiency.

Tomoyuki Mizukami, Megumi Obara, Ryuta Nishikomori, Tomoki Kawai, Yoshihiro Tahara, Naoki Sameshima, Kousuke Marutsuka, Hiroshi Nakase, Nobuhiro Kimura, Toshio Heike, Hiroyuki Nunoi

Journal of clinical immunology ( SPRINGER/PLENUM PUBLISHERS ) 32 ( 1 ) 39 - 49 2012年02月 [査読有り] [国際誌]

X-linked anhidrotic ectodermal dysplasia with immunodeficiency (X-EDA-ID) is caused by hypomorphic mutations in the gene encoding nuclear factor-κB essential modulator protein (NEMO). Patients are susceptibile to diverse pathogens due to insufficient cytokine and frequently show severe chronic colitis. An 11-year-old boy with X-EDA-ID was hospitalized with autoimmune symptoms and severe chronic colitis which had been refractory to immunosuppressive drugs. Since tumor necrosis factor (TNF) α is responsible for the pathogenesis of NEMO colitis according to intestinal NEMO and additional TNFR1 knockout mice studies, and high levels of TNFα-producing mononuclear cells were detected in the patient due to the unexpected gene reversion mosaicism of NEMO, an anti-TNFα monoclonal antibody was administered to ameliorate his abdominal symptoms. Repeated administrations improved his colonoscopic findings as well as his dry skin along with a reduction of TNFα-expressing T cells. These findings suggest TNF blockade therapy is of value for refractory NEMO colitis with gene reversion.

DOI PubMed J-GLOBAL

[Effect of immunosuppressants on inflammatory bowel disease: tacrolimus and cyclosporine].

Hiroshi Nakase, Minoru Matsuura, Tsutomu Chiba

Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 1 324 - 8 2012年02月 [査読有り] [国内誌]

PubMed

Technology of drug delivery system for gastroenterologists

Hiroshi Nakase, Minoru Matsuura

Drug Delivery System 27 ( 4 ) 267 - 274 2012年 [査読有り]

Many gastroenterologists have performed various treatments on several diseases such as inflammatory diseases and neoplastic diseases. Therefore, in the field of Gastroenterology, drug delivery system (DDS) is absolutely required for avoidance of drug-induced side effects. Development of DDS with polymeric materials such as biodegradable microspheres, etc., which could carry drugs and cytokines to targeted gastrointestinal tracts and liver, would contribute to future therapeutic strategy for gastrointestinal diseases. © 2012, THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM. All rights reserved.

DOI

SR-PSOX/CXCL16 plays a critical role in the progression of colonic inflammation.

Norimitsu Uza, Hiroshi Nakase, Shuji Yamamoto, Takuya Yoshino, Yasuhiro Takeda, Satoru Ueno, Satoko Inoue, Sakae Mikami, Minoru Matsuura, Takeshi Shimaoka, Noriaki Kume, Manabu Minami, Shin Yonehara, Hiroki Ikeuchi, Tsutomu Chiba

Gut ( B M J PUBLISHING GROUP ) 60 ( 11 ) 1494 - 505 2011年11月 [査読有り] [国際誌]

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is initiated and perpetuated by a dysregulated immune response to unknown environmental antigens such as luminal bacteria in genetically susceptible hosts. SR-PSOX/CXCL16, a scavenger receptor that binds phosphatidylserine and oxidised lipoprotein, has both phagocytic activity and chemotactic properties. The aim of this study was to investigate the role of SR-PSOX/CXCL16 in patients with IBD and experimental murine colitis. METHODS: The serum levels of SR-PSOX/CXCL16 were measured in patients with IBD. The roles of SR-PSOX/CXCL16 in phagocytosis of bacterial components and cytokine production by macrophages from wild-type (WT) and SR-PSOX/CXCL16 knockout (KO) mice were assessed. Colitis was induced by administering dextran sulfate sodium (DSS) to WT and SR-PSOX/CXCL16 KO mice. Colonic inflammation was analysed by clinical, histological and immunological parameters. Finally, the effect of a monoclonal antibody (mAb) to SR-PSOX/CXCL16 on DSS-induced colitis and trinitrobenzene sulfonic acid-induced colitis models was evaluated. RESULTS: Serum levels of SR-PSOX/CXCL16 correlated significantly with the disease activity of patients with IBD. Ex vivo experiments showed that SR-PSOX/CXCL16 was involved in both phagocytosis of bacterial antigens and the T helper 1 immune response through the production of interleukin 12 and interferon γ. In vivo murine experiments demonstrated the upregulated gene expression of SR-PSOX/CXCL16 in inflamed colonic tissues and the predominant expression of SR-PSOX/CXCL16 on macrophages. SR-PSOX/CXCL16 KO mice were less susceptible to colonic inflammation than were their WT littermates. Administration of SR-PSOX/CXCL16 mAb ameliorated the condition in the two different experimental colitis models. CONCLUSIONS: SR-PSOX/CXCL16 plays a critical role in colonic inflammation and could be a potential therapeutic target for patients with IBD.

DOI PubMed CiNii

Involvement of mycobacterium avium subspecies paratuberculosis in TNF-α production from macrophage: possible link between MAP and immune response in Crohn's disease.

Hiroshi Nakase, Hiroyuki Tamaki, Minoru Matsuura, Tsutomu Chiba, Kazuichi Okazaki

Inflammatory bowel diseases ( WILEY-BLACKWELL ) 17 ( 11 ) E140-2 - E142 2011年11月 [査読有り] [国際誌]

DOI PubMed

Importance of CXCL16 as a biomarker for granulocytapheresis in patients with Crohn's disease.

Hiroshi Nakase, Norimitsu Uza, Minoru Matsuura, Tsutomu Chiba

Inflammatory bowel diseases ( WILEY-BLACKWELL ) 17 ( 10 ) 2211 - 2 2011年10月 [査読有り] [国際誌]

DOI PubMed

Rapid induction of mucosal healing by intensive granulocyte and monocyte adsorptive aphaeresis in active ulcerative colitis patients without concomitant corticosteroid therapy

T. Fukuchi, H. Nakase, D. Ito, H. Yamashita, M. Matsuura, Y. Nagatani, H. Koga, K. Senda, T. Eguchi, S. Ubukata, S. Kawaguchi, A. Ueda, T. Tanaka, R. Ohashi, M. Otzuka, K. Ashida

ALIMENTARY PHARMACOLOGY & THERAPEUTICS ( WILEY-BLACKWELL ) 34 ( 5 ) 583 - 585 2011年09月 [査読有り]

DOI

Tacrolimus therapy as an alternative to thiopurines for maintaining remission in patients with refractory ulcerative colitis.

Shuji Yamamoto, Hiroshi Nakase, Minoru Matsuura, Satohiro Masuda, Ken-ichi Inui, Tsutomu Chiba

Journal of clinical gastroenterology ( LIPPINCOTT WILLIAMS & WILKINS ) 45 ( 6 ) 526 - 30 2011年07月 [査読有り] [国際誌]

BACKGROUND: Although the efficacy of tacrolimus for inducing remission of refractory ulcerative colitis (UC) is established, its efficacy for maintaining remission of UC has not been evaluated. AIM: The aim of this study was to evaluate the efficacy of tacrolimus compared with thiopurines for maintaining remission in patients with refractory UC. METHODS: Twenty-four UC patients treated with tacrolimus and 34 treated with thiopurines to maintain remission were enrolled as the tacrolimus group and the thiopurine group, respectively. In the tacrolimus group, 82.8% of the patients were treated with tacrolimus for induction of the remission, whereas 70% of the patients in the thiopurine group were induced remission with either corticosteroid or cytapheresis. Proportions of patients who kept steroid-free remission between the tacrolimus and the thiopurine groups were compared. Maintenance of remission using tacrolimus or thiopurines was defined as no need for other therapies other than aminosalicylates without relapse for at least 3 months. Secondarily, to determine whether the response to thiopurines affects the long-term efficacy of tacrolimus maintenance therapy, the overall cumulative relapse-free survival based on the Kaplan-Meier method was estimated in thiopurine-naive or thiopurine-intolerant patients and thiopurine-refractory ones in the tacrolimus group. RESULTS: Remission was successfully maintained in 17 patients (70.8%) of the tacrolimus group, and 28 patients (82.4%) of the thiopurine group. The overall cumulative relapse-free survival of thiopurine-naive or thiopurine-intolerant patients in the tacrolimus group was similar to that in the thiopurine group, and significantly higher than that of thiopurine-refractory patients in the tacrolimus group. CONCLUSION: Maintenance therapy with tacrolimus for patients with UC could be considered an alternative to thiopurine therapy.

DOI PubMed

Tacrolimus suppresses IL-12/IL23 p40 in Crohn's disease and heals fistulae refractory to anti-TNF-alpha therapy

H. Nakase, M. Matsuura, N. Uza, T. Chiba

ALIMENTARY PHARMACOLOGY & THERAPEUTICS ( WILEY-BLACKWELL ) 33 ( 8 ) 979 - 980 2011年04月 [査読有り]

DOI

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