Details of a Researcher - Kanai, Takanori

Papers - Kanai, Takanori

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Endoscopic ultrasound-guided drainage for a mediastinal pancreatic pseudocyst

Sugimoto Shinya, Yamagishi Yoshiyuki, Higuchi Hajime, Kanai Takanori

Internal Medicine 53 ( 22 ) 2651 - 2652 2014

ISSN 0918-2918

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Risk and management of intra-abdominal abscess in crohn's disease treated with infliximab

Yoneno Kazuaki, Hisamatsu Tadakazu, Matsuoka Katsuyoshi, Okamoto Susumu, Takayama Tetsuro, Ichikawa Riko, Sujino Tomohisa, Miyoshi Jun, Takabayashi Kaoru, Mikami Yohei, Mizuno Shinta, Wada Yasuyo, Yajima Tomoharu, Naganuma Makoto, Inoue Nagamu, Iwao Yasushi, Ogata Haruhiko, Hasegawa Hirotoshi, Kitagawa Yuko, Hibi Toshifumi, Kanai Takanori

Digestion 89 ( 3 ) 201 - 208 2014

ISSN 0012-2823

Background and Aims: Infliximab (IFX) is a monoclonal antibody used to treat patients with Crohn's disease (CD). Intra-abdominal abscess formation is a major complication of CD with negative effects on patient prognosis. We have analyzed risk factors for abscess formation in CD patients treated with IFX. Methods: CD patients who received IFX between January 2000 and April 2011 at Keio University Hospital were analyzed retrospectively. Risk factors for abscess formation were assessed by univariate and multivariate logistic regression analyses. Results: Intra-abdominal abscess was seen in 15 of 258 patients. Univariate analyses showed serum C-reactive protein (CRP) concentration at 14 weeks after initiation of IFX (p = 0.021), serum albumin concentration at week 0 (p = 0.022) and week 14 (p = 0.004), the presence of anal lesions (p = 0.036), progression of intestine deformation (p = 0.015) and early loss of response to IFX (p < 0.0001) to be risk factors. Multivariate analysis showed that CRP concentration at 14 weeks [odds ratio (OR) 1.361] and loss of IFX response within 6 months (OR 5.361) were independent risk factors. Conclusions: Abscess formation should be suspected in patients with symptoms of CD recurrence during IFX therapy. Uncontrolled CRP concentration and early loss of response to IFX are risk factors. © 2014 S. Karger AG, Basel.

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Japan alcoholic hepatitis score can help management of patients with alcoholic hepatitis

Horie Yoshinori, Yamagishi Yoshiyuki, Ebinuma Hirotoshi, Kanai Takanori

Acta Hepatologica Japonica 55 ( 1 ) 22 - 32 2014

ISSN 0451-4203

Ability of a new scoring system for alcoholic hepatitis (AH) (Japan Alcoholic Hepatitis Score: J AS) to predict outcome was confirmed in the data of patients with AH in 2011. Twenty six hospitals provided full demographic data on 59 patients with AH (Moderate 26, Alive 22, Dead 4; Severe 33, Alive 16, Dead 17). There was no report of death in patients with mild AH (J AS score was 7 and less). Prevalence of renal failure, DIC and gastrointestinal bleeding was higher in patients who were died. Cr and PT (INR) were higher in severe AH patients who were died. These results suggest that JAS allows the stratification of the risk of death in AH, and can help the management of patients with AH. If there is any 3 points factor, intensive care such as corticosteroids, granulocytes/monocytes apheresis, plasma exchange and haemodialysis is recommended. © 2014 The Japan Society of Hepatology.

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Mucosal healing with oral tacrolimus is associated with favorable medium- and long-term prognosis in steroid-refractory/dependent ulcerative colitis patients

Miyoshi Jun, Matsuoka Katsuyoshi, Inoue Nagamu, Hisamatsu Tadakazu, Ichikawa Riko, Yajima Tomoharu, Okamoto Susumu, Naganuma Makoto, Sato Toshiro, Kanai Takanori, Ogata Haruhiko, Iwao Yasushi, Hibi Toshifumi

Journal of Crohn's and Colitis 7 ( 12 ) 2013.12

ISSN 1873-9946

Background: Oral administration of tacrolimus is an effective remission induction therapy for steroid-refractory/dependent ulcerative colitis (UC). Aim: This study aimed to evaluate the short- as well as medium- and long-term effectiveness of tacrolimus therapy. Methods: The medical records of 51 patients treated with tacrolimus for UC at our hospital between July 2009 and December 2011 were reviewed retrospectively. Clinical remission and improvement were defined as a Lichtiger score of 4 or less and as a Lichtiger score of ≤. 10 and a reduction in the score of ≥. 3 compared with the baseline score, respectively. Endoscopic findings were evaluated based on the endoscopic activity index and Mayo endoscopic score. Results: The clinical effectiveness combining clinical remission and improvement was observed in 62.7% of the patients at 3. months. Thirty-six patients underwent colonoscopy at 3. months, and 12 (33.3%) and 10 patients (27.8%) showed Mayo endoscopic scores of 0 and 1, respectively. On Kaplan-Meier analysis, the overall percentage of event-free survivors, who did not require colectomy nor switching to other induction therapy such as infliximab, was 73.0% at 6. months, 49.9% at 1. year, and 37.8% at 2. years. Patients with a Mayo endoscopic score of 0-1 at 3. months showed significantly better medium- and long-term prognosis than those with a score of 2-3 (p<. 0.01). All adverse events, including infections in 2 patients, were reversible. Conclusions: Tacrolimus therapy was effective for inducing clinical and endoscopic remission of steroid-refractory/dependent UC. Endoscopic improvement was associated with favorable medium- and long-term prognosis. © 2013 European Crohn's and Colitis Organisation.

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Mucosal CXCR4+ IgG plasma cells contribute to the pathogenesis of human ulcerative colitis through FcγR-mediated CD14 macrophage activation.

Uo M, Hisamatsu T, Miyoshi J, Kaito D, Yoneno K, Kitazume MT, Mori M, Sugita A, Koganei K, Matsuoka K, Kanai T, Hibi T.

1734 - 1744 2013.12

Joint Work, Accepted

BACKGROUND:

Chronic inflammation characterised by IgG-producing plasma cell infiltration of colonic mucosa is a histological hallmark of ulcerative colitis (UC); however, whether its function is pathogenic or protective remains unclear.

OBJECTIVE:

To explore the contribution of intestinal IgG plasma cells to UC pathogenesis.

METHODS:

We isolated lamina propria mononuclear cells (LPMCs) from intestinal mucosa of UC patients and analysed the characteristics of intestinal plasma cells (expression profiles of differentiation molecules and chemokine receptors). We investigated the involvement of IgG-immune complex (IC)-Fc gamma receptor (FcγR) signalling in intestinal inflammation by examining the cytokine production by LPMCs in response to IgG-IC stimulation.

RESULTS:

IgG plasma cells that were markedly increased in number in the inflamed mucosa of UC patients showed a distinct expression profile (CD19(+)CD27(low), CCR10(low)CXCR4(high)) compared with IgA plasma cells (CD19(+/-)CD27(high), CCR10(high)CXCR4(-/low)). In vitro IgG-IC stimulation activated intestinal CD14 macrophages that were increased in number in the inflamed mucosa of UC patients via FcγRI and FcγRII, and induced the extensive production of pro-inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin-1β (IL-1β), comparable to the effect of commensal bacteria stimulation. Co-stimulation with IgG-IC and commensal bacteria increased TNF and IL-1β production more than stimulation with the latter alone. Furthermore, IgG-IC notably up-regulated the expression of TL1A, whereas commensal bacteria specifically induced IL-23.

CONCLUSIONS:

Collectively, these results demonstrate a novel aspect of UC pathogenesis in which unique IgG plasma cells infiltrate the inflamed mucosa via CXCR4, and critically influence UC pathogenesis by exacerbating mucosal inflammation through the activation of 'pathogenic' intestinal CD14 macrophages via IgG-IC-FcγR signalling.

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Clinical strategies for the blockade of IL-18 in inflammatory bowel diseases.

Kanai Takanori, Kamada Nobuhiko, Hisamatsu Tadakazu

Current drug targets 14 ( 12 ) 1392 - 1399 2013.11

Interleukin 18 (IL-18) is an IL-1 super family cytokine that is involved in infection, inflammation and autoimmune diseases. Mounting evidence suggests that IL-18 exert a dual role in inflammation and homeostasis. IL-18 can act as a promoter of T cell immunities, such as type 1 and 17 helper T cell responses, and thus enhances T cell-mediated inflammation, whereas IL-18 increases the barrier function and regeneration of epithelial cells and protects the host from inflammatory stimuli. Although the functional role of IL-18 in regulation of inflammation remains controversial, accumulating evidence indicates the contribution of IL-18 to the pathogenesis of inflammatory bowel diseases (IBD). For example, levels of serum and/or mucosal IL-18 and IL-18 binding protein are elevated in the patients with IBD. Furthermore, polymorphisms in IL-18 and IL-18-related molecules, such as the IL-18 receptor and/or an IL-18 activator NLRP3, genes are found in the patients with IBD. Thus, these preclinical data imply that IL-18 can be a novel therapeutic target for the treatment of IBD. In this review, we focus on IL-18 biology and physiological roles in animal models and human IBD, to provide an outline for development of IL-18 blockade strategies.

IL-7 promotes long-term in vitro survival of unique long-lived memory subset generated from mucosal effector memory CD4⁺ T cells in chronic colitis mice

Takahara Masahiro, Nemoto Yasuhiro, Oshima Shigeru, Matsuzawa Yu, Kanai Takanori, Okamoto Ryuichi, Tsuchiya Kiichiro, Nakamura Tetsuya, Yamamoto Kazuhide, Watanabe Mamoru

Immunology Letters 156 ( 1-2 ) 82 - 93 2013.11

ISSN 0165-2478

Colitogenic memory CD4⁺ T cells are important in the pathogenesis of inflammatory bowel disease (IBD). Although memory stem cells with high survival and self-renewal capacity were recently identified in both mice and humans, it is unclear whether a similar subset is present in chronic colitis mice. We sought to identify and purify a long-lived subset of colitogenic memory CD4⁺ T cells, which may be targets for treatment of IBD. A long-lived subset of colitogenic memory CD4⁺ T cells was purified using a long-term culture system. The characteristics of these cells were assessed. Interleukin (IL)-7 promoted the in vitro survival for >8 weeks of lamina propria (LP) CD4⁺ T cells from colitic SCID mice previously injected with CD4⁺CD45RB^high T cells. These cells were in a quiescent state and divided a maximum of 5 times in 4 weeks. LP CD4⁺ T cells expressed higher levels of Bcl-2, integrin-α4β7, CXCR3 and CD25 after than before culture, as well as secreting high concentrations of IL-2 and low concentrations of IFN-γ and IL-17 in response to intestinal bacterial antigens. LP CD4⁺ T cells from colitic mice cultured with IL-7 for 8 weeks induced more severe colitis than LP CD4⁺ T cells cultured for 4 weeks. We developed a novel culture system to purify a long-lived, highly pathogenic memory subset from activated LP CD4⁺ T cells. IL-7 promoted long-term in vitro survival of this subset in a quiescent state. This subset will be a novel, effective target for the treatment of IBD. © 2013 Elsevier B.V.

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Establishment of novel prediction system of intestinal absorption in humans using human intestinal tissues

Miyake Masateru, Toguchi Hajime, Nishibayashi Toru, Higaki Kazutaka, Sugita Akira, Koganei Kazutaka, Kamada Nobuhiko, Kitazume Mina T., Hisamatsu Tadakazu, Sato Toshiro, Okamoto Susumu, Kanai Takanori, Hibi Toshifumi

Journal of Pharmaceutical Sciences 102 ( 8 ) 2564 - 2571 2013.08

ISSN 0022-3549

The objective of this study was to establish a novel prediction system of drug absorption in humans by utilizing human intestinal tissues. Based on the transport index (TI), a newly defined parameter, calculated by taking account of the change in drug concentrations because of precipitation on the apical side and the amounts accumulated in the tissue and transported to the basal side, the absorbability of drugs in rank order as well as the fraction of dose absorbed (Fa) in humans were estimated. Human intestinal tissues taken from ulcerative colitis or Crohn's disease patients were mounted in a mini-Ussing chamber and transport studies were performed to evaluate the permeation of drugs, including FD-4, a very low permeable marker, atenolol, a low permeable marker, and metoprolol, a high permeable marker. Although apparent permeability coefficients calculated by the conventional equation did not reflect human Fa values for FD-4, atenolol, and metoprolol, TI values were well correlated with Fa values, which are described by 100 · [1 - e ^{- f · (TI - α)}]. Based on this equation, Fa values in humans for other test drugs were predicted successfully, indicating that our new system utilizing human intestinal tissues would be valuable for predicting oral drug absorption in humans. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

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Gastric emptying rate in subjects with malocclusion examined by [¹³C] breath test

Koike S., Sujino T., Ohmori H., Shimazaki K., Fukuyama E., Kanai T., Hibi T., Ono T.

Journal of Oral Rehabilitation 40 ( 8 ) 574 - 581 2013.08

ISSN 0305-182X

Masticatory function is significantly lower in individuals with malocclusion than in those with normal occlusion. Although several studies suggest that masticatory function influences gastrointestinal digestive function, the relationship between malocclusion and gastrointestinal symptoms has not been studied extensively. We hypothesised that insufficient masticatory function would increase the functional burden of the stomach and have some influence on the gastrointestinal system. The purpose of this study was to investigate masticatory function and gastric emptying rate in subjects with malocclusion. Eleven healthy dentate female volunteers and eleven female patients with maloc-clusion underwent a ¹³C-acetate breath test with a liquid meal. Maximum ¹³CO₂ exhalation time (T_max) was compared statistically between both groups. Masticatory function was assessed by colour-changeable chewing gum. In addition, the frequency scale for the symptoms of gastroeso-phageal reflux disease (FSSG) and questionnaires on food intake were given to both groups. The mean T_max of the malocclusion group was significantly longer than that of the normal occlusion group (P = 0·007). Masticatory performance, measured by colour-changeable gum and questionnaires, was significantly lower in the malocclusion group than in the normal occlusion group (P = 0·023, P = 0·003). There was no significant difference in the FSSG results between the two groups (P = 0·262). This study suggested that there was a correlation between malocclusion and gastric emptying function in women. © 2013 John Wiley & Sons Ltd.

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Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4 memory T cells

Nemoto Yasuhiro, Kanai Takanori, Takahara Masahiro, Oshima Shigeru, Nakamura Tetsuya, Okamoto Ryuichi, Tsuchiya Kiichiro, Watanabe Mamoru

Gut 62 ( 8 ) 1142 - 1152 2013.08

ISSN 0017-5749

Objective Interleukin (IL)-7 is mainly produced in bone marrow (BM) that forms the niche for B cells. We previously demonstrated that BM also retains pathogenic memory CD4 T cells in murine models of inflammatory bowel disease (IBD). However, it remains unknown whether BM-derived IL-7 is sufficient for the development of IBD and which cells form the niche for colitogenic memory CD4 T cells in BM. Design To address these questions, we developed mice in which IL-7 expression was specific for BM, and identified colitis-associated IL-7-expressing mesenchymal stem cells (MSC) in the BM. Results IL-7-/-×RAG-1-/- mice injected with BM cells from IL-7+/+×RAG-1-/- mice, but not from IL-7-/-×RAG- 1-/- mice, expressed IL-7 in BM, but not in their colon, and developed colitis when injected with CD4+CD45RBhigh T cells. Cultured BM MSC stably expressed a higher level of IL-7 than that of primary BM cells. IL-7-sufficient, but not IL-7-deficient, BM MSC supported upregulation of Bcl-2 in, and homeostatic proliferation of, colitogenic memory CD4 T cells in vitro. Notably, IL-7-/-×RAG-1-/- mice transplanted with IL-7- sufficient, but not IL-7-deficient, BM MSC expressed IL-7 in BM, but not in their colon, and developed colitis when transplanted with CD4+CD45RBhigh T cells. Conclusions We demonstrate for the first time that BM MSC are a major source of IL-7 and play a pathological role in IBD by forming the niche for colitogenic CD4 memory T cells in BM.

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C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice

Chu Po sung, Nakamoto Nobuhiro, Ebinuma Hirotoshi, Usui Shingo, Saeki Keita, Matsumoto Atsuhiro, Mikami Yohei, Sugiyama Kazuo, Tomita Kengo, Kanai Takanori, Saito Hidetsugu, Hibi Toshifumi

Hepatology 58 ( 1 ) 337 - 350 2013.07

ISSN 0270-9139

Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. C-C motif chemokine receptor (CCR) 9⁺ macrophages are crucial in the pathogenesis of acute liver inflammation, but the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed that tumor necrosis factor alpha (TNF-α)-producing CCR9⁺ macrophages accumulated during the initiation of carbon tetrachloride (CCl₄)-induced liver injury, and CCR9 deficiency attenuated the degree of liver damage. Accumulation of CCR9⁺ macrophages persisted prominently during the process of liver fibrosis induced by repetitive CCl₄ or thioacetamide (TAA)/leptin administration. Increased CCR9 expression was also found on activated hepatic stellate cells (HSCs). Importantly, experimental liver fibrosis was significantly ameliorated in CCR9^-/- mice compared with wild-type (WT) mice, assessed by α-smooth muscle actin (α-SMA) immunostain, Sirius red staining, and messenger RNA (mRNA) expression levels of α-SMA, collagen 1α1, transforming growth factor (TGF)-β1, and tissue inhibitor of metalloproteinase (TIMP)-1. Accumulated CD11b⁺ macrophages in CCl₄-treated WT mice showed marked increases in TNF, NO synthase-2, and TGF-β1 mRNA expression compared with CCR9^-/- mice, implying proinflammatory and profibrogenic properties. Hepatic CD11b⁺ macrophages from CCl₄-treated WT mice (i.e., CCR9⁺ macrophages), but not CD8⁺ T lymphocytes or non-CD11b⁺ cells, significantly activated HSCs in vitro compared with those from CCR9^-/- mice. TNF-α or TGF-β1 antagonism attenuated CCR9⁺ macrophage-induced HSC activation. Furthermore, C-C motif chemokine ligand (CCL) 25 mediated migration and, to a lesser extent, activation of HSCs in vitro. Conclusion: Accumulated CD11b⁺ macrophages are critical for activating HSCs through the CCR9/CCL25 axis and therefore promote liver fibrosis. CCR9 antagonism might be a novel therapeutic target for liver fibrosis. © 2013 American Association for the Study of Liver Diseases.

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Th1/Th17-mediated interstitial pneumonia in chronic colitis mice independent of intestinal microbiota

Nemoto Yasuhiro, Kanai Takanori, Takahara Masahiro, Oshima Shigeru, Okamoto Ryuichi, Tsuchiya Kiichiro, Matsumoto Satoshi, Watanabe Mamoru

Journal of Immunology 190 ( 12 ) 6616 - 6625 2013.06

ISSN 0022-1767

Although intestinal microbiota are essential for the development of T cell-mediated colitis, it remains undetermined whether they enhance or suppress the chronic extraintestinal inflammation that often complicates inflammatory bowel diseases. In this study, we investigate the role of intestinal microbiota in the development of colitis and extraintestinal manifestations in a mouse model in which colitis was induced in SCID mice by adoptive transfer of CD4 ⁺CD45RB^high T cells. Under specific pathogen-free conditions, these mice developed both colitis and extraintestinal interstitial pneumonia, whereas mice given a mixture of antibiotics did not develop colitis, but, surprisingly, developed Th1/Th17-mediated IP. Irrespective of antibiotic treatment, cotransfer of CD4⁺CD25⁺ regulatory T cells suppressed the development of pneumonitis and colitis, with all local CD4 ⁺CD45RB^high T cell-derived cells converted to CD44 ^highCD62L^-IL-7Rα^high effector-memory T cells. Retransfer of CD4⁺ effector-memory T cells from the lungs of antibiotic-treated mice with IP not only induced IP in both antibiotic-treated and -untreated recipients but also induced colitis in the untreated recipients. In summary, we have established a unique model of Th1/Th17-mediated IP in microbiota-free and antibiotic-treated mice. This model may be valuable in investigating the immunological mechanisms underlying extraintestinal disorders in patients with inflammatory bowel disease. Copyright © 2013 by The American Association of Immunologists, Inc.

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A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice

Hayashi Atsushi, Sato Toshiro, Kamada Nobuhiko, Mikami Yohei, Matsuoka Katsuyoshi, Hisamatsu Tadakazu, Hibi Toshifumi, Roers Axel, Yagita Hideo, Ohteki Toshiaki, Yoshimura Akihiko, Kanai Takanori

Cell Host and Microbe 13 ( 6 ) 711 - 722 2013.06

ISSN 1931-3128

Imbalance in gut bacterial composition provokes host proinflammatory responses causing diseases such as colitis. Colonization with a mixture of Clostridium species from clusters IV and XIVa was shown to suppress colitis through the induction of IL-10-producing regulatory T (Treg) cells. We demonstrate that a distinct Clostridium strain from cluster I, Clostridium butyricum (CB), prevents acute experimental colitis in mice through induction of IL-10, an anti-inflammatory cytokine. However, while CB treatment had no effect on IL-10 production by T cells, IL-10-producing F4/80⁺CD11b ⁺CD11c^int macrophages accumulated in the inflamed mucosa after CB treatment. CB directly triggered IL-10 production by intestinal macrophages in inflamed mucosa via the TLR2/MyD88 pathway. The colitis-preventing effect of CB was negated in macrophage-specific IL-10-deficient mice, suggesting that induction of IL-10 by intestinal macrophages is crucial for the probiotic action of CB. Collectively, CB promotes IL-10 production by intestinal macrophages in inflamed mucosa, thereby preventing experimental colitis in mice. © 2013 Elsevier Inc.

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A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice.

Hayashi A, Sato T, Kamada N, Mikami Y, Matsuoka K, Hisamatsu T, Hibi T, Roers A, Yagita H, Ohteki T, Yoshimura A, Kanai T.

Cell Host Microbe 13 ( 6 ) 71 - 722 2013.06

Joint Work, Accepted

Abstract

Imbalance in gut bacterial composition provokes host proinflammatory responses causing diseases such as colitis. Colonization with a mixture of Clostridium species from clusters IV and XIVa was shown to suppress colitis through the induction of IL-10-producing regulatory T (Treg) cells. We demonstrate that a distinct Clostridium strain from cluster I, Clostridium butyricum (CB), prevents acute experimental colitis in mice through induction of IL-10, an anti-inflammatory cytokine. However, while CB treatment had no effect on IL-10 production by T cells, IL-10-producing F4/80(+)CD11b(+)CD11c(int) macrophages accumulated in the inflamed mucosa after CB treatment. CB directly triggered IL-10 production by intestinal macrophages in inflamed mucosa via the TLR2/MyD88 pathway. The colitis-preventing effect of CB was negated in macrophage-specific IL-10-deficient mice, suggesting that induction of IL-10 by intestinal macrophages is crucial for the probiotic action of CB. Collectively, CB promotes IL-10 production by intestinal macrophages in inflamed mucosa, thereby preventing experimental colitis in mice.

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Activated hepatic stellate cells mediate the differentiation of macrophages

Chang Jonathan, Hisamatsu Tadakazu, Shimamura Katsuyoshi, Yoneno Kazuaki, Adachi Masayuki, Naruse Hiroshi, Igarashi Toru, Higuchi Hajime, Matsuoka Katsuyoshi, Kitazume Mina T., Ando Setsu, Kamada Nobuhiko, Kanai Takanori, Hibi Toshifumi

Hepatology Research 43 ( 6 ) 658 - 669 2013.06

ISSN 1386-6346

Aim: Liver macrophages play integral roles in both the progression and resolution of hepatic inflammation and fibrosis, comprising opposing functions that largely coincide with the activation state of nearby hepatic stellate cells (HSC). While cross-talk between HSC and macrophages may be essential at various stages of inflammation and fibrogenesis, many facets of this interaction have yet to be thoroughly explored. Here, we examine the potential roles of HSC-derived signaling molecules as mediators of liver macrophage differentiation. Methods: Human peripheral blood mononuclear cells (PBMC) were differentiated to macrophages in the presence or absence of cultured HSC-derived conditioned media. The phenotype of resulting macrophages was characterized by examination of cell surface marker expression, antigen-presenting capabilities and cytokine secretion. Results: Conditioned media from activated human HSC promoted the differentiation of a unique set of macrophages that differed in morphology and function from both classical (M1) and alternative (M2) macrophages, expressing increased levels of CD14 and CD16, as well as a distinct interleukin (IL)-6^high/IL-10^low/transforming growth factor (TGF)-β^high expression profile. These macrophages expressed high levels of CD206, CD209, CD80 and human leukocyte antigen DR, though no significant increases in antigen presentation were apparent. HSC-derived macrophages exhibited specific activation of p38 mitogen-activated protein kinase, and inhibition of this activation by p38 inhibitors during differentiation effectively reversed increases in IL-6 and TGF-β. Conclusion: The present results suggest that HSC-derived signaling molecules promote differentiation of liver macrophages with both pro-inflammatory and profibrotic functions. Furthermore, these effects appear to be mediated, at least partially, in a p38-dependent manner. © 2012 The Japan Society of Hepatology.

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A case of acute pancreatitis induced by telaprevir in the anti-HCV treatment with peginterferon and ribavirin

Matsushita Misako, Ebinuma Hirotoshi, Fukuhara Seiichirou, Minami Kazushi, Minami Kazuhiro, Nakamoto Nobuhiro, Funakoshi Shinsuke, Kanai Takanori, Saito Hidetsugu, Hibi Toshifumi

Acta Hepatologica Japonica 54 ( 5 ) 340 - 346 2013.05

ISSN 0451-4203

A 61-years-old man started the combination treatment with telaprevir, peginterferon-alfa 2b, and ribavirin against chronic hepatitis C after the cure of hepatocellular carcinoma. Telaprevir was reduced to 1500 mgday due to renal dysfunction but the serum HCV-RNA was disappeared on the 15th day. On the 18th day, he visited our hospital with severe epigastralgia and a high fever. He was diagnosed acute pancreatitis by elevation of his serum amylase (2905 IUL) and diffuse swelling of pancreas. We suspected the drug-induced pancreatitis and stopped telaprevir. Although peginterferon and ribavirin were continued for the treating acute pancreatitis, his HCV-RNA became positive again. Therefore we restarted telaprevir with plenty of informed consent after recovery of the pancreatitis. On the 10th day after the resume of telaprevir, the recurrence of the pancreatitis occurred and we stopped any anti-HCV treatment. These twice pancreatitis were immediately improved by the suspension of telaprevir and the administration of antibiotics and gabexate mesilate. We here report this case of telaprevir induced acute pancreatitis confirmed by the re-administration of telaprevir. © 2013 The Japan Society of Hepatology.

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TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease

Yoneno Kazuaki, Hisamatsu Tadakazu, Shimamura Katsuyoshi, Kamada Nobuhiko, Ichikawa Riko, Kitazume Mina T., Mori Maiko, Uo Michihide, Namikawa Yuka, Matsuoka Katsuyoshi, Sato Toshiro, Koganei Kazutaka, Sugita Akira, Kanai Takanori, Hibi Toshifumi

Immunology 139 ( 1 ) 19 - 29 2013.05

ISSN 0019-2805

Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (Mφ{symbol}s) and dendritic cells. Mφ{symbol}s differentiated with macrophage colony-stimulating factor and interferon-γ (Mγ-Mφ{symbol}s), which are similar to the human intestinal lamina propria CD14⁺ Mφ{symbol}s that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated Mφ{symbol} and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-α production in Mγ-Mφ{symbol}s stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5-cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-κB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non-inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14⁺ intestinal Mφ{symbol}s from patients with CD expressed TGR5. In isolated intestinal CD14⁺ Mφ{symbol}s, a TGR5 agonist could inhibit tumour necrosis factor-α production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease. © 2013 Blackwell Publishing Ltd.

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IL-22-Producing RORγt-Dependent Innate Lymphoid Cells Play a Novel Protective Role in Murine Acute Hepatitis

Matsumoto Atsuhiro, Kanai Takanori, Mikami Yohei, Chu Po Sung, Nakamoto Nobuhiro, Ebinuma Hirotoshi, Saito Hidetsugu, Sato Toshiro, Yagita Hideo, Hibi Toshifumi

PLoS ONE 8 ( 4 ) 2013.04

Retinoid-related orphan receptor (ROR) γt is known to be related to the development and function of various immunological compartments in the liver, such as Th17 cells, natural killer T (NKT) cells, and innate lymphoid cells (ILCs). We evaluated the roles of RORγt-expressing cells in mouse acute hepatitis model using RORγt deficient (RORγt^-/-) mice and RAG-2 and RORγt double deficient (RAG-2^-/- × RORγt^-/-) mice. Acute hepatitis was induced in mice by injection with carbon tetrachloride (CCl₄), to investigate the regulation of liver inflammation by RORγt-expressing cells. We detected RORC expression in three compartments, CD4⁺ T cells, NKT cells, and lineage marker-negative SCA-1⁺Thy1^high ILCs, of the liver of wild type (WT) mice. CCl₄-treated RORγt^-/- mice developed liver damage in spite of lack of RORγt-dependent cells, but with reduced infiltration of macrophages compared with WT mice. In this regard, ILCs were significantly decreased in RAG-2^-/- × RORγt^-/- mice that lacked T and NKT cells. Surprisingly, RAG-2^-/- × RORγt^-/- mice developed significantly severer CCl₄-induced hepatitis compared with RAG-2^-/- mice, in accordance with the fact that hepatic ILCs failed to produce IL-22. Lastly, anti-Thy1 monoclonal antibody (mAb), but not anti-NK1.1 mAb or anti-asialo GM1 Ab administration exacerbated liver damage in RAG-2^-/- mice with the depletion of liver ILCs. Collectively, hepatic RORγt-dependent ILCs play a part of protective roles in hepatic immune response in mice. © 2013 Matsumoto et al.

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Long-term prognosis of patients with ulcerative colitis treated with cytapheresis therapy

Takayama Tetsuro, Kanai Takanaori, Matsuoka Katsuyoshi, Okamoto Susumu, Sujino Tomohisa, Mikami Yohei, Hisamatsu Tadakazu, Yajima Tomoharu, Iwao Yasushi, Ogata Haruhiko, Hibi Toshifumi

Journal of Crohn's and Colitis 7 ( 2 ) 2013.03

ISSN 1873-9946

Background: Although accumulating studies in Japan show that cytapheresis (CAP) therapy is safe and effective for the induction of remission of moderate or severe ulcerative colitis (UC), the long-term prognosis of UC patients treated with CAP is unknown. The aim of this study was to determine the long-term prognosis of UC patients treated with CAP. Methods: Ninety patients treated previously with CAP and followed for more than 3. years were evaluated. The rates of operation, readmission, and use or dose-up of corticosteroid were analyzed as long-term prognosis. Results: Following the first course of CAP treatment, 64% of patients showed clinical improvement (> 4-point decrease in the clinical activity index (CAI)), and 49% of patients achieved clinical remission (CAI ≤ 4). Longer disease duration and lower age at the first CAP treatment correlated significantly with the therapeutic effects of CAP (p= 0.003 and 0.035, respectively). The rates of operation and readmission were significantly lower in patients who showed previous clinical effects of CAP than in those who did not respond to CAP. The rates of operation and readmission were also significantly lower in patients whose treatment was combined with immunomodulators after the initiation of CAP than in patients who did not use immunomodulators. Importantly, the second course of CAP was also effective in most of the patients who showed a clinical response to the first CAP. Conclusions: Patients who achieve remission after the first CAP therapy may have a good long-term prognosis and a good response to a second CAP therapy even after relapse. © 2012 European Crohn's and Colitis Organisation.

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Epstein-barr virus-associated gastritis

Sujino Tomohisa, Ebinuma Hirotoshi, Hosoe Naoki, Okamoto Susumu, Imaeda Hiroyuki, Hayashi Yuuichirou, Mukai Makio, Ogata Haruhiko, Kanai Takanori, Hibi Toshifumi

Digestive Diseases and Sciences 58 ( 3 ) 883 - 886 2013.03

ISSN 0163-2116

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