Details of a Researcher - NAKASE Hiroshi

Papers - NAKASE Hiroshi

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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

Journal of Crohn's & colitis ( ELSEVIER SCIENCE BV ) 8 ( 11 ) 1444 - 53 2014.11 [Refereed] [International journal]

BACKGROUND: The methods of evaluating endoscopic mucosal findings and the definition of mucosal healing in inflammatory bowel disease have not been standardized. AIM: To examine a third-party central review of colonic mucosal evaluations. METHODS: A double-blind, placebo-controlled, parallel-group trial was performed for 4weeks, which involved continuous administration of a 1-g mesalazine suppository to 129 patients with mild to moderate ulcerative colitis and active rectal inflammatory findings. Mucosal findings were evaluated by using a 4-grade score (0, 1, 2, 3). Reviews by attending physicians were considered the primary evaluations. Concurrently, a central review committee of 7 gastroenterologists served as the third party. RESULTS: The endoscopic remission induction rate from the attending physicians' evaluations was 82.8% in the mesalazine suppository group and 31.1% in the placebo suppository group, whereas the respective rates from the central review committee were 90.6% and 59.0%. However, there was a difference of 27.9 percentage points between the remission induction rates of the placebo group found by the two groups of raters. Differences in the evaluations of mucosal finding scores were also found among the third-party reviewers. CONCLUSIONS: The evaluations of the attending physicians were consistent with those of the central review committee in showing the effectiveness of mesalazine suppository through the index of mucosal healing. However, differences were observed among the raters in their evaluations of mucosal finding scores. Therefore, standardizing evaluation criteria and improving review methods for mucosal findings would enable the more effective use of third-party central reviews in clinical drug trials.

Role in calcineurin inhibitors for inflammatory bowel disease in the biologics era: when and how to use.

Hiroshi Nakase, Takuya Yoshino, Minoru Matsuura

Inflammatory bowel diseases ( LIPPINCOTT WILLIAMS & WILKINS ) 20 ( 11 ) 2151 - 6 2014.11 [Refereed] [International journal]

Ulcerative colitis and Crohn's disease, which is the 2 major forms of inflammatory bowel disease, are chronic relapsing and remitting inflammatory disorder of the gastrointestinal tract. During the last 30 years, the therapy for patients with refractory inflammatory bowel diseases is still challenging despite the fact that morbidity and mortality rates have been obviously reduced. The conventional management with corticosteroids has been modified by the introduction of calcineurin inhibitors and biologics. In this review, we focus on role in calcineurin inhibitors for patients with inflammatory bowel disease in the currently clinical practice.

感染性腸炎の診断と治療潰瘍性大腸炎に合併するサイトメガロウイルス再活性化症例の予後の検討

長沼誠, 仲瀬裕志, 鈴木康夫

日本大腸肛門病学会雑誌 ( (一社)日本大腸肛門病学会 ) 67 ( 9 ) 605 - 605 2014.09

Education and Imaging. Gastroenterology: mesenteric lymphoma with chylous ascites.

Soichi Arasawa, Hiroshi Nakase, Naoki Minami

Journal of gastroenterology and hepatology ( WILEY-BLACKWELL ) 29 ( 8 ) 1570 - 1570 2014.08 [Refereed] [International journal]

Therapeutic effect of intensive granulocyte and monocyte adsorption apheresis combined with thiopurines for steroid- and biologics-naïve Japanese patients with early-diagnosed Crohn's disease.

Takumi Fukuchi, Hiroshi Nakase, Satoshi Ubukata, Minoru Matsuura, Takuya Yoshino, Takahiko Toyonaga, Keiji Shimazu, Hideaki Koga, Hiroshi Yamashita, Dai Ito, Kiyoshi Ashida

BMC gastroenterology ( BIOMED CENTRAL LTD ) 13 124 - 124 2014.07 [Refereed] [International journal]

BACKGROUND: Early induction with biologics can reduce complications in patients with Crohn's disease (CD) and improve their quality of life. The safety of biologics, however, is uncertain. Granulocyte and monocyte adsorptive apheresis (GMAA) is a natural biologic therapy that selectively removes granulocytes and monocytes/macrophages and has few severe adverse effects. The effects of GMAA on patients with early-diagnosed CD are unclear. We investigated the effects of GMAA combined with thiopurines on patients with early-diagnosed CD. METHODS: Twenty-two corticosteroid- and biologic-naïve patients with active early-diagnosed CD were treated with intensive GMAA (twice per week) combined with thiopurines administration. Active early-diagnosed CD was defined as follows: (i) within 2years after diagnosis of CD, (ii) with no history of both surgical treatment and endoscopic dilation therapy, and (iii) Crohn's Disease Activity Index (CDAI) was higher than 200. We investigated the ratios of clinical remission defined as CDAI was less than or equal to 150 at 2, 4, 6 and 52weeks and mucosal healing defined as a Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD) as 0 at 6 and 52weeks. Adverse events were recorded at each visit. RESULTS: The ratios of clinical remission at 2, 4, and 6 weeks were 6 of 22 (27.2%), 12 of 22 (54.5%), and 17 of 22 (77.2%), respectively. At 52 weeks, 18 of 21 patients (81.8%) were in clinical remission. The ratios of mucosal healing at 6 and 52 weeks were 5 of 22 (22.7%) and 11 of 22 (50%), respectively. The difference in the mucosal healing ratio was significant between 6 and 52 weeks (p = 0.044). No serious adverse effects were observed during this study. CONCLUSIONS: Combination therapy with intensive GMAA and thiopurines administration rapidly induced high remission in patients with active early-diagnosed CD without serious adverse effect. Mucosal healing was observed in 50.0% of enrolled patients. This combination therapy might be a rational option for patients with early-diagnosed CD.

Pulmonary Mycobacterium avium Infection in a Patient with Crohn's Disease under Azathioprine Treatment.

Tomonori Hirano, Minoru Matsuura, Hiroshi Nakase

Case reports in gastroenterology 8 ( 2 ) 182 - 5 2014.05 [Refereed] [International journal]

Anti-tumor necrosis factor alpha therapy is known as a risk factor of non-tuberculous mycobacteria (NTM) infection. However, there are few reports of NTM infection under treatment with thiopurine agents. We herein report a first case of pulmonary infection caused by Mycobacterium avium complex (MAC) in a patient with Crohn's disease under treatment with thiopurine. After starting antibiotics therapy for NTM including clarithromycin, rifampicin, ethambutol and streptomycin, MAC infection was well controlled, and she kept clinical remission even without azathioprine. In conclusion, our case emphasizes the importance of considering NTM infection in respiratory complications of inflammatory bowel disease patients under immunosuppressive therapies.

Long-term efficacy of infliximab for refractory ulcerative colitis: results from a single center experience.

Satoshi Yamada, Takuya Yoshino, Minoru Matsuura, Naoki Minami, Takahiko Toyonaga, Yusuke Honzawa, Yoshihisa Tsuji, Hiroshi Nakase

BMC gastroenterology ( BIOMED CENTRAL LTD ) 14 80 - 80 2014.04 [Refereed] [International journal]

BACKGROUND: The long-term efficacy of infliximab (IFX) for patients with refractory ulcerative colitis (UC) is unclear. The aim of this study was to assess the long-term outcomes of IFX treatment in patients with refractory UC. METHODS: Thirty-three patients with refractory UC who received IFX treatment at Kyoto University Hospital between 2003 and 2013 were retrospectively evaluated. IFX intensification was defined as a dose escalation (up to 10 mg/kg) and/or shorter intervals between infusions (every 4-6 weeks). RESULTS: Of the 33 patients who received scheduled infusions of IFX, 24 (72.7%) achieved clinical remission within 8 weeks after initiating IFX treatment. Of these 24 responders, 17 (70.8%) experienced a relapse of UC and required IFX intensification, and 16 (66.7%) eventually maintained clinical remission with IFX treatment, including IFX intensification. Of the 33 patients, 6 (18.2%) underwent colectomy during IFX treatment. Multivariate regression analysis showed that a serum C-reactive protein (CRP) concentration <5 mg/L two weeks after starting IFX was a predictor of a positive clinical response to IFX induction therapy. No severe adverse events occurred in UC patients treated with IFX. CONCLUSION: IFX intensification was necessary for long-term maintenance of remission and to prevent colectomy in patients with refractory UC.

Unique endoscopic findings of colitis-associated colorectal cancer in a patient with ulcerative colitis and Lynch syndrome.

Naoki Minami, Takuya Yoshino, Hiroshi Nakase

Journal of Crohn's & colitis ( ELSEVIER SCIENCE BV ) 8 ( 4 ) 336 - 7 2014.04 [Refereed] [International journal]

Efficacy and safety of granulocyte and monocyte adsorption apheresis for ulcerative colitis: a meta-analysis.

Takuya Yoshino, Hiroshi Nakase, Naoki Minami, Satoshi Yamada, Minoru Matsuura, Shujiro Yazumi, Tsutomu Chiba

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver ( ELSEVIER SCIENCE INC ) 46 ( 3 ) 219 - 26 2014.03 [Refereed] [International journal]

BACKGROUND: Safe and effective treatments are required for patients with ulcerative colitis. It was suggested that granulocyte and monocyte adsorption apheresis might play an important role for ulcerative colitis. Therefore, a meta-analysis was performed. METHODS: Medline and the Cochrane controlled trials register were used to identify randomized controlled trials comparing granulocyte and monocyte adsorption apheresis with corticosteroids, and comparing intensive with conventional apheresis in patients with ulcerative colitis. RESULTS: Nine randomized trials were eligible for inclusion criteria. According to pooled data, granulocyte and monocyte adsorption apheresis is effective for inducing clinical remission in patients with ulcerative colitis compared with corticosteroids (odds ratio, 2.23; 95% confidence interval: 1.38-3.60). However, the efficacy of granulocyte and monocyte adsorption apheresis was not dependent on the number of apheresis sessions. The intensive apheresis (≥2 sessions per week) is more effective for inducing clinical remission than weekly apheresis (odds ratio, 2.10; 95% confidence interval: 1.12-3.93). The rate of adverse events by apheresis was significantly lower than that by corticosteroids (odds ratio, 0.24; 95% confidence interval: 0.15-0.37). CONCLUSION: Our meta-analysis reveals that intensive granulocyte and monocyte adsorption apheresis is a safe and effective treatment with higher rates of clinical remission and response for ulcerative colitis compared with corticosteroids.

Diagnosis and treatment of ulcerative colitis with cytomegalovirus infection: importance of controlling mucosal inflammation to prevent cytomegalovirus reactivation.

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

Intestinal research 12 ( 1 ) 5 - 11 2014.01 [Refereed] [International journal]

Human cytomegalovirus (HCMV) is a member of the herpesvirus family. HCMV infection persists throughout the host lifespan in a latent state following primary infection. The ability of HCMV to escape control by the host immune system and its resulting reactivation suggests the importance of ongoing immune surveillance in the prevention of HCMV reactivation. HCMV is a common cause of opportunistic infection that causes severe and fatal disease in immune-compromised individuals. In inflammatory bowel disease patients, particularly those with ulcerative colitis (UC), HCMV is often reactivated because these patients are frequently treated with immunosuppressive agents. This reactivation exacerbates colitis. Additionally, HCMV infection can induce severe colitis, even in patients with UC who have never been treated with immunosuppressive agents. However, the role of HCMV in colonic inflammation in patients with UC remains unclear. Here, we present previous and current clinical data on the diagnosis and treatment of HCMV infection in UC. Additionally, our experimental data from a newly established mouse model mimicking UC with concomitant CMV infection clearly demonstrate that inflammation could result in the exacerbation of UC disease activity with induction of HCMV reactivation. In summary, optimal control of colonic inflammation should be achieved in UC patients who are refractory to conventional immunosuppressive therapies and are positive for HCMV.

Use of capsule endoscopy in patients with Crohn's disease in Japan: A multicenter survey

Motohiro Esaki, Takayuki Matsumoto, Kenji Watanabe, Tetsuo Arakawa, Yuji Naito, Minoru Matsuura, Hiroshi Nakase, Toshifumi Hibi, Takayuki Matsumoto, Sadaharu Nouda, Kazuhide Higuchi, Naoki Ohmiya, Hidemi Goto, Sei Kurokawa, Satoshi Motoya, Mamoru Watanabe

Journal of Gastroenterology and Hepatology (Australia) 29 ( 1 ) 96 - 101 2014.01 [Refereed]

Background and Aim: Until the approval of patency capsule, capsule endoscopy (CE) has not been routinely applied for the diagnosis of Crohn's disease (CD) in Japan. We aimed to survey current situation of CE use for patients with CD in Japan. Methods: The nationwide survey of 40 Japanese institutions identified 94 patients with established CD (eCD) and 80 patients with suspected CD (sCD), who were examined by CE. Types and positive rates of mucosal injury under CE and capsule retention rate were investigated. In sCD, final diagnosis after CE was also analyzed. Results: Patients with eCD comprised 82 patients of ileitis or ileocolitis type, while 12 patients had CD of colitis type. CE identified mucosal injuries in 83 of 94 patients. Eight of 12 patients with eCD of colitis type had ileal lesions under CE, thereby being reclassified as ileocolitis type. In patients with sCD, CE detected mucosal injuries in 58 patients. Linear ulceration and cobblestone appearance were depicted in 22 and 3 patients, respectively, thereby resulting in established diagnosis of CD in 23 patients. Mucosal lesion was not found in 22 patients with sCD, who were diagnosed as not having CD. Capsule retention rate was not statistically different between patients with eCD and those with sCD (7.4% vs 6.3%, P=1.0). Conclusions: CE is useful for the evaluation of small bowel mucosal injuries in Japanese patients with sCD and eCD. Possible intestinal stricture needs to be carefully evaluated before CE even in patients with sCD. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Use of capsule endoscopy in patients with Crohn's disease in Japan: a multicenter survey.

Motohiro Esaki, Takayuki Matsumoto, Kenji Watanabe, Tetsuo Arakawa, Yuji Naito, Minoru Matsuura, Hiroshi Nakase, Toshifumi Hibi, Takayuki Matsumoto, Sadaharu Nouda, Kazuhide Higuchi, Naoki Ohmiya, Hidemi Goto, Sei Kurokawa, Satoshi Motoya, Mamoru Watanabe

Journal of gastroenterology and hepatology ( WILEY-BLACKWELL ) 29 ( 1 ) 96 - 101 2014.01 [Refereed] [International journal]

BACKGROUND AND AIM: Until the approval of patency capsule, capsule endoscopy (CE) has not been routinely applied for the diagnosis of Crohn's disease (CD) in Japan. We aimed to survey current situation of CE use for patients with CD in Japan. METHODS: The nationwide survey of 40 Japanese institutions identified 94 patients with established CD (eCD) and 80 patients with suspected CD (sCD), who were examined by CE. Types and positive rates of mucosal injury under CE and capsule retention rate were investigated. In sCD, final diagnosis after CE was also analyzed. RESULTS: Patients with eCD comprised 82 patients of ileitis or ileocolitis type, while 12 patients had CD of colitis type. CE identified mucosal injuries in 83 of 94 patients. Eight of 12 patients with eCD of colitis type had ileal lesions under CE, thereby being reclassified as ileocolitis type. In patients with sCD, CE detected mucosal injuries in 58 patients. Linear ulceration and cobblestone appearance were depicted in 22 and 3 patients, respectively, thereby resulting in established diagnosis of CD in 23 patients. Mucosal lesion was not found in 22 patients with sCD, who were diagnosed as not having CD. Capsule retention rate was not statistically different between patients with eCD and those with sCD (7.4% vs 6.3%, P = 1.0). CONCLUSIONS: CE is useful for the evaluation of small bowel mucosal injuries in Japanese patients with sCD and eCD. Possible intestinal stricture needs to be carefully evaluated before CE even in patients with sCD.

Development and function of cortical thymic epithelial cells.

Kensuke Takada, Izumi Ohigashi, Michiyuki Kasai, Hiroshi Nakase, Yousuke Takahama

Current topics in microbiology and immunology 373 1 - 17 2014 [Refereed] [International journal]

The thymic cortex provides a microenvironment that supports the generation and T cell antigen receptor (TCR)-mediated selection of CD4(+)CD8(+)TCRαβ(+) thymocytes. Cortical thymic epithelial cells (cTECs) are the essential component that forms the architecture of the thymic cortex and induces the generation as well as the selection of newly generated T cells. Here we summarize current knowledge on the development, function, and heterogeneity of cTECs, focusing on the expression and function of β5t, a cTEC-specific subunit of the thymoproteasome.

Bifid tail of the pancreas with localized acute pancreatitis.

Sho Koyasu, Hiroyoshi Isoda, Hiroshi Nakase, Yuzo Kodama, Tsutomu Chiba, Kaori Togashi

Magnetic resonance in medical sciences : MRMS : an official journal of Japan Society of Magnetic Resonance in Medicine ( JPN SOC MAGNETIC RESONANCE IN MEDICINE ) 12 ( 4 ) 315 - 8 2013.12 [Refereed] [Domestic journal]

Bifid tail of the pancreas is an extremely rare developmental anomaly, and its clinical importance is not well known. We report the case of a 28-year-old man with acute pancreatitis limited to one side of a bifid tail with no otherwise detectable parenchymal edema on magnetic resonance (MR) imaging. Neither was there evidence of other anatomical ductal abnormalities that could have contributed to the patient's pancreatitis. To the best of our knowledge, this is the first report to suggest that bifid tail of the pancreas might cause acute pancreatitis.

Tacrolimus therapy for patients with ulcerative colitis

Hiroshi Nakase

Journal of Japanese Society of Gastroenterology 110 ( 11 ) 1916 - 1921 2013.11 [Refereed]

Effect of intensive granulocyte and monocyte adsorptive apheresis in patients with ulcerative colitis positive for cytomegalovirus.

Takumi Fukuchi, Hiroshi Nakase, Minoru Matsuura, Takuya Yoshino, Takahiko Toyonaga, Katsuyuki Ohmori, Satoshi Ubukata, Aya Ueda, Takaaki Eguchi, Hiroshi Yamashita, Dai Ito, Kiyoshi Ashida

Journal of Crohn's & colitis ( ELSEVIER SCIENCE BV ) 7 ( 10 ) 803 - 11 2013.11 [Refereed] [International journal]

BACKGROUND AND AIM: Cytomegalovirus (CMV) exacerbates ulcerative colitis (UC) refractory to immunosuppressive therapies. The conditions under which CMV reactivation occurs in patients with UC, however, is unclear. In addition, the diagnostic and treatment strategies for UC positive for CMV have not been established. Granulocyte and monocyte adsorptive apheresis (GMAA) is natural biological therapy for UC in which the granulocytes/macrophages producing inflammatory cytokines are removed. We investigated the rate of colonic CMV reactivation and the efficacy of GMAA in active UC patients positive for CMV without concomitant corticosteroid (CS) therapy. METHODS: Fifty-one active UC patients without concomitant CS therapy were enrolled. Colonic CMV reactivation was examined by real-time polymerase chain reaction (PCR) using biopsy specimen and/or histological examination. All patients were treated with intensive GMAA (twice per week). Rates of clinical remission and mucosal healing were compared between UC patients positive and negative for CMV. RESULTS: Of 51 patients, 15 (29.4%) were diagnosed as CMV positive. The clinical remission rates following intensive GMAA did not differ between UC patients positive and negative for CMV (73.3% vs 69.4%, p=0.781). Proportion of patients achieving mucosal healing was also similar between these two groups. CMV-DNA became negative in all UC patients positive for CMV who achieved clinical remission 1 week after completion of intensive GMAA. CONCLUSIONS: Intestinal inflammation might trigger CMV reactivation in a subpopulation of active UC patients without CS treatment. GMAA could be a promising option for active UC positive for CMV.

DOI PubMed CiNii

Human CD1c⁺ myeloid dendritic cells acquire a high level of retinoic acid-producing capacity in response to vitamin D₃.

Takayuki Sato, Toshio Kitawaki, Haruyuki Fujita, Makoto Iwata, Tomonori Iyoda, Kayo Inaba, Toshiaki Ohteki, Suguru Hasegawa, Kenji Kawada, Yoshiharu Sakai, Hiroki Ikeuchi, Hiroshi Nakase, Akira Niwa, Akifumi Takaori-Kondo, Norimitsu Kadowaki

Journal of immunology (Baltimore, Md. : 1950) 191 ( 6 ) 3152 - 60 2013.09 [Refereed] [International journal]

All-trans-retinoic acid (RA) plays a critical role in maintaining immune homeostasis. Mouse intestinal CD103⁺ dendritic cells (DCs) produce a high level of RA by highly expressing retinal dehydrogenase (RALDH)2, an enzyme that converts retinal to RA, and induce gut-homing T cells. However, it has not been identified which subset of human DCs produce a high level of RA. In this study, we show that CD1c⁺ blood myeloid DCs (mDCs) but not CD141(high) mDCs or plasmacytoid DCs exhibited a high level of RALDH2 mRNA and aldehyde dehydrogenase (ALDH) activity in an RA- and p38-dependent manner when stimulated with 1α,25-dihydroxyvitamin D₃ (VD₃) in the presence of GM-CSF. The ALDH activity was abrogated by TLR ligands or TNF. CD103⁻ rather than CD103⁺ human mesenteric lymph node mDCs gained ALDH activity in response to VD₃. Furthermore, unlike in humans, mouse conventional DCs in the spleen and mesenteric lymph nodes gained ALDH activity in response to GM-CSF alone. RALDH2(high) CD1c⁺ mDCs stimulated naive CD4⁺ T cells to express gut-homing molecules and to produce Th2 cytokines in an RA-dependent manner. This study suggests that CD1c⁺ mDCs are a major human DC subset that produces RA in response to VD₃ in the steady state. The "vitamin D-CD1c⁺mDC-RA" axis may constitute an important immune component for maintaining tissue homeostasis in humans.

Prior use of immunomodulatory drugs improves the clinical outcome of endoscopic balloon dilation for intestinal stricture in patients with Crohn's disease.

Yusuke Honzawa, Hiroshi Nakase, Minoru Matsuura, Hirokazu Higuchi, Takahiko Toyonaga, Kayoko Matsumura, Takuya Yoshino, Kazuichi Okazaki, Tsutomu Chiba

Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society ( WILEY-BLACKWELL ) 25 ( 5 ) 535 - 43 2013.09 [Refereed] [International journal]

BACKGROUND: Endoscopic balloon dilation is a promising procedure to improve symptoms of intestinal stricture in patients with Crohn's disease (CD). However, the long-term efficacy of endoscopic balloon dilation combined with immunomodulatory drugs remains unclear. The aim of the present study is to investigate whether prior use of immunomodulatory drugs affects the clinical outcome of endoscopic balloon dilation for intestinal stricture in CD. PATIENTS AND METHODS: Between January 2004 and December 2011, 83 dilations were carried out in 25 patients with CD. Median follow-up period was 46 months. Patients were categorized into two groups based on their medications at the first endoscopic balloon dilation: early immunomodulatory drug-induction group (early IM-induction group) in which patients were already treated with immunomodulatory drugs before the dilation; and post-immunomodulatory drug-induction group (post-IM-induction group) in which patients were not yet treated withimmunomodulatory drugs before dilation. We compared the long-term cumulative non-surgical rate and the mean number of dilation procedures per patient between early and post-IM-induction groups to clarify the influence of prior use of immunomodulatory drugs on the clinical outcome of endoscopic balloon dilation. RESULTS: There was a significant difference in the mean number of dilation procedures per patient between the early IM-induction and post-IM-induction groups (P = 0.04), although no significant difference in the cumulative non-surgical rate was observed between the two groups (P = 0.14). CONCLUSION: Prior use of immunomodulatory drugs may improve the clinical outcome of endoscopic balloon dilation for intestinal stricture in CD.

DOI PubMed J-GLOBAL

Heparan sulfate on intestinal epithelial cells plays a critical role in intestinal crypt homeostasis via Wnt/β-catenin signaling.

Shuji Yamamoto, Hiroshi Nakase, Minoru Matsuura, Yusuke Honzawa, Kayoko Matsumura, Norimitsu Uza, Yu Yamaguchi, Emiko Mizoguchi, Tsutomu Chiba

American journal of physiology. Gastrointestinal and liver physiology 305 ( 3 ) G241-9 2013.08 [Refereed] [International journal]

Heparan sulfate (HS), a constituent of HS proteoglycans (HSPGs), is a linear polysaccharide present on the cell surface. HSPGs modulate functions of several growth factors and signaling molecules. We examined whether small intestinal epithelial HS plays some roles in crypt homeostasis using intestinal epithelium cell (IEC)-specific HS-deficient C57Bl/6 mice. Survival rate after total body irradiation was significantly reduced in HS-deficient mice due to profound intestinal injury. HS-deficient IECs exhibited Wnt/β-catenin pathway disruption, decreased levels of β-catenin nuclear localization, and reduced expression of Wnt target genes, including Lgr5 during crypt regeneration. Moreover, epithelial HS increased Wnt binding affinity of IECs, promoted phosphorylation of Wnt coreceptor LRP6, and enhanced Wnt/β-catenin signaling following ex vivo stimulation with Wnt3a, whereas activation of canonical Wnt signaling following direct inhibition of glycogen synthase kinase-3β by lithium chloride was similar between HS-deficient and wild-type mice. Thus HS influences the binding affinity of IECs to Wnt, thereby promoting activation of canonical Wnt signaling and facilitating regeneration of small intestinal crypts after epithelial injury.

Establishment of a novel mouse model of ulcerative colitis with concomitant cytomegalovirus infection: in vivo identification of cytomegalovirus persistent infected cells.

Kayoko Matsumura, Hiroshi Nakase, Isao Kosugi, Yusuke Honzawa, Takuya Yoshino, Minoru Matsuura, Hideya Kawasaki, Yoshifumi Arai, Toshihide Iwashita, Takashi Nagasawa, Tsutomu Chiba

Inflammatory bowel diseases ( LIPPINCOTT WILLIAMS & WILKINS ) 19 ( 9 ) 1951 - 63 2013.08 [Refereed] [International journal]

BACKGROUND: Human cytomegalovirus (HCMV) infection is considered to be an exacerbating factor in patients with ulcerative colitis (UC). However, the pathogenicity of HCMV in the exacerbation of UC remains unclear. The lack of a model mimicking UC with HCMV infection has posed a challenge for research into the pathogenic mechanism of HCMV in flare of UC. Therefore, the aim of our study was to establish a new mouse model of UC with HCMV infection. METHODS: We established latent murine CMV (MCMV) infection in T-cell receptor α knockout (TCR-α KO) mice at an early age by adjustment of viral dose. Next, we performed immunohistochemical analysis in various organs of infected adult TCR-α KO mice to prove the correlation between MCMV infection and development of colitis. We then assessed colitis histologically and cytokine expression in the colon of infected and uninfected TCR-α KO mice. Finally, the types of MCMV-infected cells in the inflamed colon were examined by immunohistochemical analysis. RESULTS: MCMV antigen-positive cells reappeared predominantly in the inflamed colon of TCR-α KO mice. Severe colitis developed in the infected TCR-α KO mice compared with uninfected mice, and Th1/Th17 and Th2 responses were strongly induced. MCMV-infected cells were mainly perivascular stromal cells including pericytes, expressing platelet-derived growth factor receptor-beta (PDGFR-β) and CXC chemokine ligand 12 (CXCL12). CONCLUSIONS: In this study, we established, to our knowledge, the first mouse model of UC with HCMV infection. This model is an excellent tool for clarifying the detailed pathogenicity of HCMV in the exacerbation of UC and developing new treatment strategy for active UC with HCMV infection.

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