研究者詳細 - 仲瀬　裕志

論文 - 仲瀬　裕志

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Ileal follicular lymphoma with atypical endoscopic findings.

Satoshi Yamada, Yorimitsu Koshikawa, Naoki Minami, Yusuke Honzawa, Minoru Matsuura, Hiroshi Nakase

Endoscopy international open 4 ( 3 ) E323-5 - 5 2016年03月 [査読有り] [国際誌]

A 72-year-old woman presented with symptomatic anemia without abdominal symptoms. She had no history of abdominal surgery or use of non-steroidal anti-inflammatory drugs. Enhanced computed tomography of the abdomen revealed swelling of multiple intraperitoneal lymph nodes and a high density of mesenteric adipose tissue. Fluorodeoxyglucose (FDG-) positron emission tomography showed high FDG accumulation at the intraperitoneal lymph nodes. Double-balloon enteroscopy detected severe stenosis with an annular ulcer in the lower ileum. She was diagnosed with ileal follicular lymphoma based on histologic examination and fluorescence in situ hybridization analysis of the biopsy specimen. The ileal ulcer was successfully treated by chemotherapy with rituximab and bendamustine for 1 year. We strongly recommend consideration of gastrointestinal follicular lymphoma in the differential diagnosis of annular ulcers in the small intestine.

Efficacy of probiotic treatment with Bifidobacterium longum 536 for induction of remission in active ulcerative colitis: A randomized, double-blinded, placebo-controlled multicenter trial.

Hiroyuki Tamaki, Hiroshi Nakase, Satoko Inoue, Chiharu Kawanami, Toshinao Itani, Masaya Ohana, Toshihiro Kusaka, Suguru Uose, Hiroshi Hisatsune, Masahide Tojo, Teruyo Noda, Souichi Arasawa, Masako Izuta, Atsushi Kubo, Chikara Ogawa, Toshihiro Matsunaka, Mitsushige Shibatouge

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society ( WILEY-BLACKWELL ) 28 ( 1 ) 67 - 74 2016年01月 [査読有り] [国際誌]

BACKGROUND AND AIM: We conducted a randomized, double-blinded, placebo-controlled trial to investigate the efficacy of Bifidobacterium longum 536 (BB536) supplementation for induction of remission in Japanese patients with active ulcerative colitis (UC). METHODS: Fifty-six patients with mild to moderate UC were enrolled. Three patients had pancolitis, 36 had left-sided colitis, and 17 had proctitis. Patients were randomly treated with 2-3 × 10(11) freeze-dried viable BB536 (28 patients) or placebo (28 patients) for 8 weeks. RESULTS: In total, 63% of patients receiving BB536 showed clinical remission (UC disease activity index [UCDAI] ≤2) at week 8 compared to 52% of those receiving placebo (P = 0.395). We observed a significant decrease of UCDAI scores (3.8 ± 0.4 at baseline to 2.6 ± 0.4 at week 8) in the BB536 group (P < 0.01), whereas there was no significant decrease in the placebo group (P = 0.88). There was also a significant decrease in the Rachmilewitz endoscopic index (EI) and the Mayo subscore at week 8 in the BB536 group, whereas there was no significant decrease in the placebo group. A single patient in the BB536 group complained of a mild side-effect, but no other adverse effects were observed. CONCLUSION: Supplementation with BB536 was well tolerated and reduced UCDAI scores, EI and Mayo subscores after 8 weeks in Japanese patients with mild to moderately active UC.

Ischemic enteritis with intestinal stenosis.

Yorimitsu Koshikawa, Hiroshi Nakase, Minoru Matsuura, Takuya Yoshino, Yusuke Honzawa, Naoki Minami, Satoshi Yamada, Yumiko Yasuhara, Shigehiko Fujii, Toshihiro Kusaka, Dai Manaka, Hiroyuki Kokuryu

Intestinal research 14 ( 1 ) 89 - 95 2016年01月 [査読有り] [国際誌]

A 75-year-old man was admitted to our hospital with sudden onset of vomiting and abdominal distension. The patient was taking medication for arrhythmia. Computed tomography showed stenosis of the ileum and a small bowel dilatation on the oral side from the region of stenosis. A transnasal ileus tube was placed. Enteroclysis using contrast medium revealed an approximately 6-cm afferent tubular stenosis 10 cm from the terminal ileum and thumbprinting in the proximal bowel. Transanal double-balloon enteroscopy showed a circumferential shallow ulcer with a smooth margin and edema of the surrounding mucosa. The stenosis was so extensive that we could not perform endoscopic balloon dilation therapy. During hospitalization, the patient's nutritional status deteriorated. In response, we surgically resected the region of stenosis. Histologic examination revealed disappearance of the mucosal layer and transmural ulceration with marked fibrosis, especially in the submucosal layer. Hemosiderin staining revealed sideroferous cells in the submucosal layers. Based on the pathologic findings, the patient was diagnosed with ischemic enteritis. The patient's postoperative course was uneventful.

The development of drug delivery system for regulating mucosal immune system for future therapy of inflammatory bowel disease

Hiroshi Nakase, Tomoya Iida, Kei Onodera

Drug Delivery System ( Japan Society of Drug Delivery System ) 31 ( 3 ) 194 - 200 2016年 [査読有り]

TET1 Depletion Induces Aberrant CpG Methylation in Colorectal Cancer Cells.

Masahiro Kai, Takeshi Niinuma, Hiroshi Kitajima, Eiichiro Yamamoto, Taku Harada, Hironori Aoki, Reo Maruyama, Mutsumi Toyota, Yasushi Sasaki, Tamotsu Sugai, Takashi Tokino, Hiroshi Nakase, Hiromu Suzuki

PloS one ( PUBLIC LIBRARY SCIENCE ) 11 ( 12 ) e0168281 2016年 [査読有り] [国際誌]

Aberrant DNA methylation is commonly observed in colorectal cancer (CRC), but the underlying mechanism is not fully understood. 5-hydroxymethylcytosine levels and TET1 expression are both reduced in CRC, while epigenetic silencing of TET1 is reportedly associated with the CpG island methylator phenotype. In the present study, we aimed to clarify the relationship between loss of TET1 and aberrant DNA methylation in CRC. Stable TET1 knockdown clones were established using Colo320DM cells, which express high levels of TET1, and HCT116 cells, which express TET1 at a level similar to that in normal colonic tissue. Infinium HumanMethylation450 BeadChip assays revealed increased levels of 5-methylcytosine at more than 10,000 CpG sites in TET1-depleted Colo320DM cells. Changes in DNA methylation were observed at various positions within the genome, including promoters, gene bodies and intergenic regions, and the altered methylation affected expression of a subset of genes. By contrast, TET1 knockdown did not significantly affect DNA methylation in HCT116 cells. However, TET1 depletion was associated with attenuated effects of 5-aza-2'-deoxycytidine on gene expression profiles in both cell lines. These results suggest that loss of TET1 may induce aberrant DNA methylation and may attenuate the effect of 5-aza-2'-deoxycytidine in CRC cells.

Risk factors for developing colorectal cancer in Japanese patients with ulcerative colitis: a retrospective observational study-CAPITAL (Cohort and Practice for IBD total management in Kyoto-Shiga Links) study I.

Takuya Yoshino, Hiroshi Nakase, Tomohisa Takagi, Shigeki Bamba, Yusuke Okuyama, Takuji Kawamura, Teruki Oki, Hirozumi Obata, Chiharu Kawanami, Shinji Katsushima, Toshihiro Kusaka, Tomoyuki Tsujikawa, Yuji Naito, Akira Andoh, Takafumi Kogawa

BMJ open gastroenterology 3 ( 1 ) e000122 2016年 [査読有り] [国際誌]

BACKGROUND AND AIMS: Patients with ulcerative colitis (UC) are at risk for developing colorectal cancer (CRC), despite the development of new therapeutic agents. Stratification of the individual UC-patient's risk would be helpful to validate the risk factors for CRC. The aim of this study was to evaluate the risk factors for the development of CRC in a large cohort of patients with UC. METHODS: Data were obtained from 12 hospitals in the Kyoto-Shiga region during 2003-2013. We performed a retrospective cohort study of 2137 patients with UC. RESULTS: In total, 60 lesions of CRC were detected in 43 (2.0%) of 2137 patients. 30 of the 43 patients were male. The median age was 53 years. The median duration of disease was 13 years, and 67.4% of these patients had a disease duration >10 years. Of the 43 patients, 34 (79.1%) had extensive colitis. Primary sclerosing cholangitis was detected in 2 patients (4.7%). The median corticosteroids (CS) dose was 6.4 g, and 4 patients were treated with a total of more than 10 g of CS. 18 of these patients underwent more than 1 year CS treatment. Of all 60 CRC lesions, 43 (71.7%) were located in the distal colon and 35 (58.3%) were of the superficial type. Moreover, the stage of CRC was stage 0 or I in 55.8% of the 43 patients with CRC. Multivariate analysis suggested that extensive colitis could be a risk factor for the development of advanced CRC in patients with UC. CONCLUSIONS: Our findings indicated that male, extensive colitis, long-term duration of UC and family history of CRC, but not concomitant primary sclerosing cholangitis, are important factors for predicting CRC in Japanese patients with UC. Moreover, long-standing extensive colitis might contribute to the progression of CRC. Further studies are required to establish CRC surveillance in Japanese patients with UC.

Association of colorectal carcinogenesis pathway with life style and intestinal microbiome based on the genome and epigenome abnormalities.

Katsuhiko Nosho, Yasutaka Sukawa, Hiroshi Nakase

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 113 ( 11 ) 1878 - 1886 2016年 [査読有り] [国内誌]

Reply: To PMID 25946569.

Eitaro Hiejima, Hiroshi Nakase, Toshio Heike

Inflammatory bowel diseases 21 ( 12 ) E30-1 - 1 2015年12月 [査読有り] [国際誌]

An open-label prospective randomized multicenter study of intensive versus weekly granulocyte and monocyte apheresis in active crohn's disease.

Naoki Yoshimura, Yoko Yokoyama, Katsuyoshi Matsuoka, Hiroki Takahashi, Ryuichi Iwakiri, Takayuki Yamamoto, Tomoo Nakagawa, Takumi Fukuchi, Satoshi Motoya, Reiko Kunisaki, Shingo Kato, Fumihito Hirai, Yoh Ishiguro, Satoshi Tanida, Sakiko Hiraoka, Keiichi Mitsuyama, Shunji Ishihara, Shinji Tanaka, Michiro Otaka, Taro Osada, Takashi Kagaya, Yasuo Suzuki, Hiroshi Nakase, Hiroyuki Hanai, Kenji Watanabe, Nobuhito Kashiwagi, Toshifumi Hibi

BMC gastroenterology ( BIOMED CENTRAL LTD ) 15 163 - 163 2015年11月 [査読有り] [国際誌]

BACKGROUND: Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active Crohn's disease (CD). However, with routine weekly therapy, it may take several weeks to achieve remission. This study was performed to assess clinical efficacy and safety of intensive GMA in patients with active CD. METHODS: In an open-label, prospective, randomized multicentre setting, 104 patients with CD activity index (CDAI) of 200 to 450 received intensive GMA, at two sessions per week (n = 55) or one session per week (n = 49). Clinical remission was defined as a CDAI score <150. Patients in each arm could receive up to 10 GMA sessions. However, GMA treatment could be discontinued when CDAI decreased to <150 (clinical remission level). RESULTS: Of the 104 patients, 99 were available for efficacy evaluation as per protocol, 45 in the weekly GMA group, and 54 in the intensive GMA group. Remission was achieved in 16 of 45 patients (35.6 %) in the weekly GMA and in 19 of 54 (35.2 %) in the intensive GMA (NS). Further, the mean time to remission was 35.4 ± 5.3 days in the weekly GMA and 21.7 ± 2.7 days in the intensive GMA (P = 0.0373). Elevated leucocytes and erythrocyte sedimentation rate were significantly improved by intensive GMA, from 8005/μL to 6950/μL (P = 0.0461) and from 54.5 mm/hr to 30.0 mm/hr (P = 0.0059), respectively. In both arms, GMA was well tolerated and was without safety concern. CONCLUSIONS: In this study, with respect to remission rate, intensive GMA was not superior to weekly GMA, but the time to remission was significantly shorter in the former without increasing the incidence of side effects. UMIN registration # 000003666.

Efficacy and Safety of Long-Term Thiopurine Maintenance Treatment in Japanese Patients With Ulcerative Colitis.

Satoshi Yamada, Takuya Yoshino, Minoru Matsuura, Masamichi Kimura, Yorimitsu Koshikawa, Naoki Minami, Takahiko Toyonaga, Yusuke Honzawa, Hiroshi Nakase

Intestinal research 13 ( 3 ) 250 - 8 2015年07月 [査読有り] [国際誌]

BACKGROUND/AIMS: The long-term clinical outcomes of patients with bio-naive ulcerative colitis (UC) who maintain remission with thiopurine are unclear. The aim of this study was to assess the long-term efficacy and safety of maintenance treatment with thiopurine in UC patients. METHODS: This was a retrospective observational cohort analysis conducted at a single center. Between December 1998 and August 2013, 59 of 87 patients with bio-naive UC who achieved remission after induction with treatments other than biologics were enrolled. Remission maintenance with thiopurine was defined as no concomitant treatment needed other than 5-aminosalicylate without relapse. We assessed the remission-maintenance rate, mucosal healing rate, colectomy-free rate, and treatment safety in UC patients who received thiopurine as maintenance treatment. RESULTS: The 84-month cumulative remission-maintenance and colectomy-free survival rates in the UC patients who were receiving maintenance treatment with thiopurine and 5-aminosalicylate were 43.9% and 88.0%, respectively. Of the 38 patients who underwent colonoscopy during thiopurine maintenance treatment, 23 (60.5%) achieved mucosal healing. Of the 59 patients who achieved clinical remission with thiopurine, 6 patients (10.2%) discontinued the thiopurine therapy because of adverse events. CONCLUSIONS: Our study demonstrates the long-term efficacy and safety of thiopurine treatment in patients with bio-naive UC.

Efficacy of Thiopurines in Biologic-Naive Japanese Patients With Crohn's Disease: A Single-Center Experience.

Takuya Yoshino, Minoru Matsuura, Naoki Minami, Satoshi Yamada, Yusuke Honzawa, Masamichi Kimura, Yorimitsu Koshikawa, Ali Madian, Takahiko Toyonaga, Hiroshi Nakase

Intestinal research 13 ( 3 ) 266 - 73 2015年07月 [査読有り] [国際誌]

BACKGROUND/AIMS: Early use of biologics in patients with Crohn's disease (CD) improves quality of life. However, the effects of the early use of immunomodulators on long-term outcomes remain unclear. This study aimed to evaluate the effects of immunomodulators in patients with CD. METHODS: Between January 2004 and December 2011, 47 biologic-naive CD patients treated with thiopurines alone for remission maintenance were analyzed. The patients were classified into 2 groups depending on the presence or absence of digestive complications. We evaluated the efficacy of and predictive factors for thiopurine use for remission maintenance. RESULTS: The cumulative relapse rates at 24 and 60 months were 13.7% and 35.4%, respectively. Regarding patient characteristics, there was a significant difference in patient history of surgery between the non-relapse and relapse groups (P=0.021). The cumulative relapse rate was lower in patients without a history of surgery than in those with such a history (27.2% and 52.9% at 60.0 months, respectively). Multivariate analysis suggested that the prevalence of stricturing and penetrating complications is an independent factor for relapse. The cumulative relapse rate in patients without a history of surgery was significantly lower in the non-stricturing and non-penetrating group than in the stricturing and penetrating group (11.8% at 85.0 months vs. 58.5% at 69.0 months; P=0.036). CONCLUSIONS: Thiopurine use might be beneficial for the long-term maintenance of remission in biologic-naive Crohn's disease patients without digestive complications and a history of surgery.

Reduced Numbers and Proapoptotic Features of Mucosal-associated Invariant T Cells as a Characteristic Finding in Patients with Inflammatory Bowel Disease.

Eitaro Hiejima, Tomoki Kawai, Hiroshi Nakase, Tatsuaki Tsuruyama, Takeshi Morimoto, Takahiro Yasumi, Takashi Taga, Hirokazu Kanegane, Masayuki Hori, Katsuyuki Ohmori, Takeshi Higuchi, Minoru Matsuura, Takuya Yoshino, Hiroki Ikeuchi, Kenji Kawada, Yoshiharu Sakai, Mina T Kitazume, Tadakazu Hisamatsu, Tsutomu Chiba, Ryuta Nishikomori, Toshio Heike

Inflamm. Bowel Dis. 21 ( 7 ) 1529 - 1540 2015年07月 [査読有り]

Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in the homeostasis of mucosal immunity; however, their role in inflammatory bowel disease (IBD) is unclear.
Flow cytometry was used to enumerate peripheral blood MAIT cells in 88 patients with ulcerative colitis (UC), 68 with Crohn's disease (CD), and in 57 healthy controls. Immunohistochemistry identified MAIT cells in intestinal tissue samples from patients with UC (n = 5) and CD (n = 10), and in control colon (n = 5) and small intestine (n = 9) samples. In addition, expression of activated caspases by MAIT cells in the peripheral blood of 14 patients with UC and 15 patients with CD, and 16 healthy controls was examined.
Peripheral blood analysis revealed that patients with IBD had significantly fewer MAIT cells than healthy controls (P < 0.0001). The number of MAIT cells in the inflamed intestinal mucosae of patients with UC and CD was also lower than that in control mucosae (P = 0.0079 and 0.041, respectively). The number of activated caspase-expressing MAIT cells in the peripheral blood of patients with UC and CD was higher than that in healthy controls (P = 0.0061 and 0.0075, respectively), suggestin

Reduced Numbers and Proapoptotic Features of Mucosal-associated Invariant T Cells as a Characteristic Finding in Patients with Inflammatory Bowel Disease.

Eitaro Hiejima, Tomoki Kawai, Hiroshi Nakase, Tatsuaki Tsuruyama, Takeshi Morimoto, Takahiro Yasumi, Takashi Taga, Hirokazu Kanegane, Masayuki Hori, Katsuyuki Ohmori, Takeshi Higuchi, Minoru Matsuura, Takuya Yoshino, Hiroki Ikeuchi, Kenji Kawada, Yoshiharu Sakai, Mina T Kitazume, Tadakazu Hisamatsu, Tsutomu Chiba, Ryuta Nishikomori, Toshio Heike

Inflammatory bowel diseases ( LIPPINCOTT WILLIAMS & WILKINS ) 21 ( 7 ) 1529 - 40 2015年07月 [査読有り] [国際誌]

BACKGROUND: Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in the homeostasis of mucosal immunity; however, their role in inflammatory bowel disease (IBD) is unclear. METHODS: Flow cytometry was used to enumerate peripheral blood MAIT cells in 88 patients with ulcerative colitis (UC), 68 with Crohn's disease (CD), and in 57 healthy controls. Immunohistochemistry identified MAIT cells in intestinal tissue samples from patients with UC (n = 5) and CD (n = 10), and in control colon (n = 5) and small intestine (n = 9) samples. In addition, expression of activated caspases by MAIT cells in the peripheral blood of 14 patients with UC and 15 patients with CD, and 16 healthy controls was examined. RESULTS: Peripheral blood analysis revealed that patients with IBD had significantly fewer MAIT cells than healthy controls (P < 0.0001). The number of MAIT cells in the inflamed intestinal mucosae of patients with UC and CD was also lower than that in control mucosae (P = 0.0079 and 0.041, respectively). The number of activated caspase-expressing MAIT cells in the peripheral blood of patients with UC and CD was higher than that in healthy controls (P = 0.0061 and 0.0075, respectively), suggesting that the reduced MAIT cell numbers in IBD are associated with an increased level of apoptosis among these cells. CONCLUSIONS: The number of MAIT cells in the peripheral blood and inflamed mucosae of patients with UC and CD was lower than that in non-IBD controls. Also, MAIT cells from patients with IBD exhibited proapoptotic features. These data suggest the pathological involvement and the potential for therapeutic manipulation of these cells in patients with IBD.

Factors associated with treatment outcome, and long-term prognosis of patients with ulcerative colitis undergoing selective depletion of myeloid lineage leucocytes: a prospective multicenter study.

Yokoyama Y, Watanabe K, Ito H, Nishishita M, Sawada K, Okuyama Y, Okazaki K, Fujii H, Nakase H, Masuda T, Fukunaga K, Andoh A, Nakamura S

Cytotherapy ( ELSEVIER SCI LTD ) 17 ( 5 ) 680 - 8 2015年05月 [査読有り] [国際誌]

BACKGROUND: Patients with ulcerative colitis (UC) have elevated/activated myeloid lineage leucocytes and may respond favorably to adsorptive granulocyte/monocyte apheresis (GMA). However, there are patients who respond well to GMA, and patients who do not benefit. Therefore, predictive factors of GMA efficacy need to be defined. METHODS: In a prospective multicenter setting, 200 UC patients at 32 institutes received one GMA session per week over 10 weeks. Patients who achieved remission were followed for 12 months. The Clinical Activity Index (CAI) ≤3 meant remission, and response meant CAI decreased by ≥3. Quality of life was evaluated by the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: After final GMA, remission, response and no response rates were 67.0%, 15.0% and 18%, respectively. The remission group had a significant decrease in myeloid leucocytes and platelets. Corticosteroid dose decreased (P < 0.001); 49 of 97 patients on corticosteroids became steroid-free. Baseline CAI was lower in the remission group versus non-remission (P < 0.01), whereas IBDQ was higher in the remission group versus non-remission (P < 0.05). After 12 months, 52 of 134 patients had maintained remission. Disease duration was longer in the relapsed group versus maintained remission group (P = 0.041). Male gender, first UC episode and corticosteroid responder were significant factors for maintaining remission, whereas corticosteroid dependent UC was associating with relapse. DISCUSSION: Selective myeloid leucocyte depletion was effective for remission induction and improving patients' quality of life. Baseline demographics such as disease activity level, duration and corticosteroid dependency appear to predict response to GMA. Additionally, patients with a first UC episode who were drug naive responded well to GMA and achieved a favorable long-term disease course by avoiding pharmacologics from an early stage of their inflammatory bowel disease. These findings should help to end unnecessary use of medical resources by targeting GMA to patients who may respond well.

Usefulness of Adalimumab for Treating a Case of Intestinal Behçet's Disease With Trisomy 8 Myelodysplastic Syndrome.

Kimura M, Tsuji Y, Iwai M, Inagaki M, Madian A, Yoshino T, Matsuura M, Nakase H

Intestinal research 13 ( 2 ) 166 - 9 2015年04月 [査読有り] [国際誌]

Behçet's disease (BD) is a systemic vasculitis, while myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematologic disorders characterized by ineffective hematopoiesis. Some studies suggest a relationship between MDS and BD, especially intestinal BD, and trisomy 8 seems to play an important role in both diseases. There are several reports on patients with BD comorbid with MDS involving trisomy 8 that frequently have intestinal lesions refractory to conventional medical therapies. Tumor necrosis factor (TNF)-α is strongly involved in the pathophysiology of several autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and BD. In addition, TNF-α plays an important role in the pathophysiology of MDS by inhibiting normal hematopoiesis and inducing the programmed cell death of normal total bone marrow cells and normal CD34+ cells. Recent clinical reports demonstrate the favorable effect of TNF-α antagonists in patients with refractory intestinal BD and in those with MDS. We present the case of a patient with intestinal BD and MDS involving trisomy 8 who was successfully treated with adalimumab.

Autocrine pathways involving S100A8 and/or S100A9 that are postulated to regulate the immunological functions of macrophages in rats.

Kohki Okada, Satoshi Arai, Hiroshi Nakase, Hisashi Kohno, Fumihiko Nakamura, Mayu Takeda, Yoshinobu Toda, Hiroshi Itoh, Souichi Adachi, Masaki Ikemoto

Biochemical and biophysical research communications ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 456 ( 1 ) 415 - 20 2015年01月 [査読有り] [国際誌]

The development of ulcerative colitis (UC) is closely associated with abnormally functioning macrophages. Rat S100A8 (r-S100A8) and r-S100A9 (S100 proteins) is abundantly expressed in immune cells of myeloid origin, macrophages; however, it remains unclear why r-S100A9 is dominantly expressed in the macrophages of UC rats (UCR). The purpose of this study was to verify the immunological roles of S100 proteins in UCR. We observed the distribution of S100 protein-positive macrophages in the large colons of UCR using a fluorescent immunological staining method, so that S100 protein-positive macrophages were restricted to the rectal tissues of the UCR, and that the mRNA levels of r-S100A8 and r-S100A9 were up-regulated by stimulation with recombinant rat S100A8 (rr-S100A8) alone and rr-S100A9 alone, respectively. When the changes in the mRNA levels of r-S100A8 and r-S100A9 in macrophages were examined in in vitro study by PCR and real-time PCR, the mRNA levels of anti-inflammatory and inflammatory cytokines increased selectively after stimulation with rr-S100A8 alone and rr-S100A9 alone, respectively. These results suggest that autocrine signal transduction pathways involving S100 proteins regulate the immunological functions of macrophages to maintain homeostasis in the gastrointestinal tract. This may be depended on expression balance of S100 proteins in macrophages. It is strongly suggested that in UCR the immune functions of macrophages are regulated in a complex manner by r-S100A8 and/or r-S100A9 through undefined autocrine pathways on the cells.

Osteopontin Deficiency Accelerates Spontaneous Colitis in Mice with Disrupted Gut Microbiota and Macrophage Phagocytic Activity.

Takahiko Toyonaga, Hiroshi Nakase, Satoru Ueno, Minoru Matsuura, Takuya Yoshino, Yusuke Honzawa, Ayako Itou, Kazuyoshi Namba, Naoki Minami, Satoshi Yamada, Yorimitsu Koshikawa, Toshimitsu Uede, Tsutomu Chiba, Kazuichi Okazaki

PloS one 10 ( 8 ) e0135552 2015年 [査読有り] [国際誌]

BACKGROUND: Osteopontin (OPN) is a multifunctional protein expressed in a variety of tissues and cells. Recent studies revealed increased OPN expression in the inflamed intestinal tissues of patients with inflammatory bowel disease (IBD). The role of OPN in the pathophysiology of IBD, however, remains unclear. AIMS: To investigate the role of OPN in the development of intestinal inflammation using a murine model of IBD, interleukin-10 knock out (IL-10 KO) mice. METHODS: We compared the development of colitis between IL-10 KO and OPN/IL-10 double KO (DKO) mice. OPN expression in the colonic tissues of IL-10 KO mice was examined by fluorescence in situ hybridization (FISH) analysis. Enteric microbiota were compared between IL-10 KO and OPN/IL-10 DKO mice by terminal restriction fragment length polymorphism analysis. The effect of OPN on macrophage phagocytic function was evaluated by phagocytosis assay. RESULTS: OPN/IL-10 DKO mice had an accelerated onset of colitis compared to IL-10 KO mice. FISH analysis revealed enhanced OPN synthesis in the colonic epithelial cells of IL-10 KO mice. OPN/IL-10 DKO mice had a distinctly different enteric bacterial profile with a significantly lower abundance of Clostridium subcluster XIVa and a greater abundance of Clostridium cluster XVIII compared to IL-10 KO mice. Intracellular OPN deletion in macrophages impaired phagocytosis of fluorescence particle-conjugated Escherichia coli in vitro. Exogenous OPN enhanced phagocytosis by OPN-deleted macrophages when administered at doses of 1 to 100 ng/ml, but not 1000 ng/ml. CONCLUSIONS: OPN deficiency accelerated the spontaneous development of colitis in mice with disrupted gut microbiota and macrophage phagocytic activity.

Tacrolimus or infliximab for severe ulcerative colitis: short-term and long-term data from a retrospective observational study.

Naoki Minami, Takuya Yoshino, Minoru Matsuura, Yorimitsu Koshikawa, Satoshi Yamada, Takahiko Toyonaga, Ali Madian, Yusuke Honzawa, Hiroshi Nakase

BMJ open gastroenterology 2 ( 1 ) e000021 2015年 [査読有り] [国際誌]

OBJECTIVE: Treatment of severe ulcerative colitis (UC) is challenging. Although the efficacy of tacrolimus (TAC) and infliximab (IFX) have been evaluated in patients with severe UC, the safety and efficacy levels of sequential therapies (TAC→IFX/IFX→TAC) in these patients remain unclear. The aim of this study was to assess short-term and long-term outcomes in patients with severe UC treated with TAC and IFX. METHODS: From October 2001 to February 2014, 29 patients with consecutive severe UC treated with TAC or IFX were retrospectively evaluated. Median follow-up duration was 27 months (range 0.5-118 months). The primary end point was short-term outcomes at 8 weeks after induction of TAC (TAC group, n=22) or IFX (IFX group, n=7). The secondary end point included long-term outcomes and colectomy-free survival. The clinical response was evaluated based on a partial Mayo score. RESULTS: The clinical remission (CR) rate at 8 weeks in the TAC and IFX groups was 63.6% and 71.4%, respectively. In 13 of the 29 patients (10 in the TAC group, 3 in the IFX group), sequential therapies were used in their clinical courses. In 9 of these 13 patients (6 in the TAC group, 3 in the IFX group), CR was achieved and maintained by sequential therapies. Overall cumulative colectomy-free survival was 79.3% at 118 months. CONCLUSIONS: TAC and IFX had similar effects on remission induction in patients with severely active UC. Sequential therapies could rescue patients with UC who failed initial treatment with TAC or IFX. In clinical practice, sequential therapies might be deliberately performed.

Involvement of interleukin-17A-induced expression of heat shock protein 47 in intestinal fibrosis in Crohn's disease.

Yusuke Honzawa, Hiroshi Nakase, Masahiro Shiokawa, Takuya Yoshino, Hirotsugu Imaeda, Minoru Matsuura, Yuzo Kodama, Hiroki Ikeuchi, Akira Andoh, Yoshiharu Sakai, Kazuhiro Nagata, Tsutomu Chiba

Gut ( BMJ PUBLISHING GROUP ) 63 ( 12 ) 1902 - 12 2014年12月 [査読有り] [国際誌]

OBJECTIVE: Intestinal fibrosis is a clinically important issue in Crohn's disease (CD). Heat shock protein (HSP) 47 is a collagen-specific molecular chaperone involved in fibrotic diseases. The molecular mechanisms of HSP47 induction in intestinal fibrosis related to CD, however, remain unclear. Here we investigated the role of interleukin (IL)-17A-induced HSP47 expression in intestinal fibrosis in CD. DESIGN: Expressions of HSP47 and IL-17A in the intestinal tissues of patients with IBD were determined. HSP47 and collagen I expressions were assessed in intestinal subepithelial myofibroblasts (ISEMFs) isolated from patients with IBD and CCD-18Co cells treated with IL-17A. We examined the role of HSP47 in IL-17A-induced collagen I expression by administration of short hairpin RNA (shRNA) to HSP47 and investigated signalling pathways of IL-17A-induced HSP47 expression using specific inhibitors in CCD-18Co cells. RESULTS: Gene expressions of HSP47 and IL-17A were significantly elevated in the intestinal tissues of patients with active CD. Immunohistochemistry revealed HSP47 was expressed in α-smooth muscle actin (α-SMA)-positive cells and the number of HSP47-positive cells was significantly increased in the intestinal tissues of patients with active CD. IL-17A enhanced HSP47 and collagen I expressions in ISEMFs and CCD-18Co cells. Knockdown of HSP47 in these cells resulted in the inhibition of IL-17A-induced collagen I expression, and analysis of IL-17A signalling pathways revealed the involvement of c-Jun N-terminal kinase in IL-17A-induced HSP47 expression. CONCLUSIONS: IL-17A-induced HSP47 expression is involved in collagen I expression in ISEMFs, which might contribute to intestinal fibrosis in CD.

A randomized clinical trial of mesalazine suppository: The usefulness and problems of central review of evaluations of colonic mucosal findings.

Kiyonori Kobayashi, Fumihito Hirai, Makoto Naganuma, Kenji Watanabe, Takafumi Ando, Hiroshi Nakase, Katsuyoshi Matsuoka, Mamoru Watanabe

J Crohns Colitis 8 ( 11 ) 1444 - 1453 2014年11月 [査読有り]

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