Details of a Researcher - Kanai, Takanori

Papers - Kanai, Takanori

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Immune aspects of the pathogenesis of inflammatory bowel disease

Hisamatsu Tadakazu, Kanai Takanori, Mikami Yohei, Yoneno Kazuaki, Matsuoka Katsuyoshi, Hibi Toshifumi

Pharmacology and Therapeutics 137 ( 3 ) 283 - 297 2013.03

ISSN 0163-7258

Although the precise etiologies of inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) remain obscure, several reports have indicated that dysfunction of the mucosal immune system plays an important role in its pathogenesis. Recent progress with genome-wide association studies has identified many IBD susceptibility genes. In individuals with genetic risk, abnormal interactions between the host immune system and gut flora, and dysregulation of cellular responses such as autophagy and ER stress, induce an abnormal host immune response in the gut resulting in intestinal inflammation. Research progress animal models in IBD, and in human IBD, has identified several key molecules in IBD pathogenesis such as TNFα and adhesion molecules, and molecular targeting therapies based on these molecules have been developed. Here, we review immunological aspects in IBD pathogenesis and the development of immunoregulatory therapy. © 2012 Elsevier Inc.

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Dendritic cells administered intrarectally penetrate the intestinal barrier to break intestinal tolerance via Th2-medeiated colitis in mice

Handa Tango, Kanai Takanori, Sato Toshiro, Mikami Yohei, Sujino Tomohisa, Hayashi Atsushi, Mizuno Shinta, Matsumoto Atsuhiro, Hisamatsu Tadakazu, Hibi Toshifumi

Immunology Letters 150 ( 1-2 ) 123 - 129 2013.02

ISSN 0165-2478

Intestinal lamina propria dendritic cells (LPDCs) in mice are known to extend dendrites between the intestinal epithelia and the luminal side when processing luminal antigens. We conducted intrarectal cell transfer experiments of bone marrow-derived dendritic cells (BMDCs) in mice to assess dendritic cell penetration of the intestine. Intrarectally administered GFP⁺ BMDCs localized in the colonic LP within 3h and the spleen within 12h after administration. 72h after administration, recipient C57BL/6 mice showed acute diarrhea, and administration of BMDCs (once weekly for 3 weeks) induced intestinal inflammation with increased numbers of recipient macrophages and CD4⁺ T cells exhibiting a Th2-mediated immune response. These results demonstrate that DCs actively communicate across the intestinal barrier, and highlight a potential technique for controlling colonic immune tolerance. © 2013 Elsevier B.V.

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Suppression of myeloid cell leukemia-1 (Mcl-1) enhances chemotherapy-associated apoptosis in gastric cancer cells

Akagi Hideko, Higuchi Hajime, Sumimoto Hidetoshi, Igarashi Toru, Kabashima Ayano, Mizuguchi Hiroyuki, Izumiya Motoko, Sakai Gen, Adachi Masayuki, Funakoshi Shinsuke, Nakamura Shoko, Hamamoto Yasuo, Kanai Takanori, Takaishi Hiromasa, Kawakami Yutaka, Hibi Toshifumi

Gastric Cancer 16 ( 1 ) 100 - 110 2013.01

ISSN 1436-3291

Background: Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that regulates apoptosis sensitivity in a variety of cell types. Here we evaluate the roles of Mcl-1 in chemotherapy-associated apoptosis in gastric cancer cells. In addition, our study examined whether Mcl-1 contributed to apoptosis resistance in so-called cancer stem cell (CSC)-like populations in gastric cancer. Methods: Seven gastric cancer cell lines were used. The expression of Mcl-1 was assessed by either real-time polymerase chain reaction or Western blot analysis. Apoptosis was quantitated by morphological observation and caspase activity measurement. Adenovirus-mediated RNA interference (RNAi) technology was used to knockdown the expression of Mcl-1. The release of cytochrome c was evaluated by subcellular fractionation and immunoblot analysis. To identify and isolate the CSC-like populations, we used the CSC-associated cell surface marker CD44 and flow cytometry. Results: Six out of the 7 gastric cancer cell lines overexpressed Mcl-1 protein. These Mcl-1-expressing cell lines were relatively resistant to chemotherapeutic agents such as 5-fluorouracil (5-FU) and cisplatin (CDDP). Depletion of Mcl-1 protein by RNAi technology effectively sensitized the cells to anticancer drug-induced mitochondrial cytochrome c release, caspase activation, and apoptosis. In addition, vast amounts of Mcl-1 mRNA were expressed in CD44-positive CSC-like cells. Mcl-1 suppression enhanced the apoptosis in CD44-positive cells to a level equivalent to that in CD44-negative cells, suggesting that Mcl-1 mediates chemotherapy resistance in CSC-like populations. Conclusion: These results suggest that Mcl-1 mediates the resistance to apoptosis in gastric cancer cells by blocking the mitochondrial pathway of cell death. Mcl-1 depletion appears to be an attractive strategy to overcome chemotherapy resistance in gastric cancer cells. © 2012 The International Gastric Cancer Association and The Japanese Gastric Cancer Association.

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Spur cell anemia associated with alcoholic cirrhosis

Sugimoto Shinya, Yamagishi Yoshiyuki, Ebinuma Hirotoshi, Kanai Takanori

Internal Medicine 52 ( 24 ) 2831 2013

ISSN 0918-2918

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Mechanism and therapeutic strategy of secondary failure to anti-tumor necrosis factor-α monoclonal antibody treatment for crohn's disease

Matsuoka Katsuyoshi, Kanai Takanori

Digestion 88 ( 1 ) 17 - 19 2013

ISSN 0012-2823

It is not too much to say that infliximab has revolutionized the treatment of Crohn's disease. However, there is the problem of 'secondary failure' wherein the effect may diminish during treatment. This is a much-discussed topic. For example, not all patients with secondary failure can maintain remission with dose intensification to 10 mg/kg. It is also important to make the appropriate drug selection and to clarify the optimal timing of dose intensification for achieving long-term maintenance of remission, including discussion of the first priority use of adalimumab.

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Applicability of second-generation colon capsule endoscope to ulcerative colitis

Hosoe Naoki, Matsuoka Katsuyoshi, Naganuma Makoto, Ida Yosuke, Ishibashi Yuka, Kimura Kayoko, Yoneno Kazuaki, Usui Shingo, Kashiwagi Kazuhiro, Hisamatsu Tadakazu, Inoue Nagamu, Kanai Takanori, Imaeda Hiroyuki, Ogata Haruhiko, Hibi Toshifumi

Journal of Gastroenterology and Hepatology (Australia) 28 ( 7 ) 1174 - 1179 2013

ISSN 0815-9319

Background and Aim: Colon capsule endoscopy has already been used for colon visualization and detection of polyps but its applicability to inflammatory bowel disease is still unconfirmed. The aim of this study was to assess the feasibility of evaluating the severity of mucosal inflammation in patients with ulcerative colitis (UC) using a second-generation colon capsule endoscope (CCE-2). Methods: Forty patients with histological confirmed diagnosis of UC were enrolled. Low-volume (2L) polyethylene glycol solution with prokinetics (mosapride citrate and metoclopramide) regimen was used for the bowel preparation. In Phase 1, consisting of 10 patients, to confirm appropriate CCE-2 bowel preparation for UC. In Phase 2, consisting of 30 patients, CCE-2 was performed with a fixed bowel preparation regimen. CCE-2 findings were recorded for 8h starting from capsule ingestion and conventional colonoscopy was subsequently performed on the same day. CCE-2 procedure completion rate and the colon cleansing level with a 4-point grading scale (poor, fair, good, and excellent) were evaluated in Phase 2. Correlations between Matts endoscopic scores as judged by CCE-2 and conventional colonoscopy were calculated. Results: CCE-2 procedure was completed within 8h in 69% of the patients. The proportion of patients with good or excellent cleansing level was below 50%. However, Matts endoscopic scores determined by CCE-2 showed a strong correlation with scores obtained by conventional colonoscopy (average ρ=0.797). Conclusions: Although modifications in bowel preparation are needed, CCE-2 might be feasible for assessing the severity of mucosal inflammation in patients with UC. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

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CCR2 knockout exacerbates cerulein-induced chronic pancreatitis with hyperglycemia via decreased GLP-1 receptor expression and insulin secretion

Nakamura Yuji, Kanai Takanori, Saeki Keita, Takabe Miho, Irie Junichiro, Miyoshi Jun, Mikami Yohei, Teratani Toshiaki, Suzuki Takahiro, Miyata Naoteru, Hisamatsu Tadakazu, Nakamoto Nobuhiro, Yamagishi Yoshiyuki, Higuchi Hajime, Ebinuma Hirotoshi, Hozawa Shigenari, Saito Hidetsugu, Itoh Hiroshi, Hibi Toshifumi

American Journal of Physiology - Gastrointestinal and Liver Physiology 304 ( 8 ) 2013

ISSN 0193-1857

Glucagonlike peptide-1 (GLP-1) promotes insulin release; however, the relationship between the GLP-1 signal and chronic pancreatitis is not well understood. Here we focus on chemokine (C-C motif) ligand 2 (CCL2) and its receptor (CCR2) axis, which regulates various immune cells, including macrophages, to clarify the mechanism of GLP-1-mediated insulin secretion in chronic pancreatitis in mice. One and multiple series of repetitive cerulein administrations were used to induce acute and chronic cerulein pancreatitis, respectively. Acute cerulein-administered CCR2-knockout (KO) mice showed suppressed infiltration of CD11b⁺Gr-1^low macrophages and pancreatic inflammation and significantly upregulated insulin secretion compared with paired wild-type (WT) mice. However, chronic cerulein-administered CCR2-KO mice showed significantly increased infiltration of CD11b⁺/ Gr-1 ^-and CD11b⁺/Gr-1^high cells, but not CD11b⁺/Gr-1^low cells, in pancreas with severe inflammation and significantly decreased insulin secretion compared with their WT counterparts. Furthermore, although serum GLP-1 levels in chronic cerulein-administered WT and CCR2-KO mice were comparably upregulated after cerulein administrations, GLP-1 receptor levels in pancreases of chronic ceruleinadministered CCR2-KO mice were significantly lower than in paired WT mice. Nevertheless, a significantly higher hyperglycemia level in chronic cerulein-administered CCR2-KO mice was markedly restored by treatment with a GLP-1 analog to a level comparable to the paired WT mice. Collectively, the CCR2/CCL2 axis-mediated CD11b⁺-cell migration to the pancreas is critically involved in chronic pancreatitismediated hyperglycemia through the modulation of GLP-1 receptor expression and insulin secretion. © 2013 the American Physiological Society.

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Progressive liver failure induced by everolimus for renal cell carcinoma in a 58-year-old male hepatitis B virus carrier

Mizuno Shinta, Yamagishi Yoshiyuki, Ebinuma Hirotoshi, Nakamoto Nobuhiro, Katahira Mai, Sasaki Aya, Sakamoto Michiie, Suzuki Hidekazu, Kanai Takanori, Hibi Toshifumi

Clinical Journal of Gastroenterology 6 ( 2 ) 188 - 192 2013

ISSN 1865-7257

A 58-year-old man was diagnosed as a hepatitis B virus (HBV) carrier approximately 30 years ago. He was diagnosed with renal cell carcinoma when he was 57 years old. Radical nephrectomy was performed, and everolimus was administered to treat his lung metastasis. After beginning the everolimus, intermittent fever, general fatigue, and jaundice developed. He was admitted under a diagnosis of flare (acute exacerbation) of chronic B hepatitis due to HBV reactivation. Despite intensive care, he died of hepatic failure and fungus infection. The autopsy findings were compatible with hepatic failure due to HBV reactivation by everolimus. Antiviral prophylaxis must be taken into consideration before beginning immunosuppressive therapy such as everolimus in HBV carriers. © The Author(s) 2013.

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MyD88-dependent interleukin-10 production from regulatory CD11b+Gr-1high cells suppresses development of acute cerulein pancreatitis in mice

Koike Yuji, Kanai Takanori, Saeki Keita, Nakamura Yuji, Nakano Masaru, Mikami Yohei, Yamagishi Yoshiyuki, Nakamoto Nobuhiro, Ebinuma Hirotoshi, Hibi Toshifumi

Immunology Letters 148 ( 2 ) 172 - 177 2012.12

ISSN 0165-2478

We explored the role of the MyD88 signaling pathway. This pathway mediates the recognition of pathogen-associated molecular patterns and damage-associated molecular patterns via Toll-like receptors (TLRs) and/or IL-1/IL-18 via each cytokine receptor in a murine model of acute pancreatitis induced by cerulein administration. Our analysis revealed that: various TLRs and MyD88 molecules were constitutively expressed in the pancreas of cerulein-treated and untreated wild-type (WT) mice. MyD88^-/- mice administered cerulein developed severe pancreatitis as compared with MyD88^+/+ WT mice. The number of IL-10-expressing CD11b⁺Gr-1^high cells in cerulein-administered MyD88^-/- mice was significantly decreased. This was in accordance with a reciprocal increase in the infiltration of CD4⁺ T cells as compared with that in control MyD88^+/+ mice. WT mice pretreated with antibiotics and administered cerulein developed milder pancreatitis as compared with control cerulein-administered mice without antibiotic treatment. The MyD88 signaling pathway contributes to the induction of regulatory IL-10-producing macrophages/myeloid-derived suppressor cells, possibly in response to non-bacterial components in the damaged pancreas. These results provide a new concept for therapeutic strategies against acute pancreatitis. © 2012 Elsevier B.V.

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Anticoagulation therapy dramatically improved severe sigmoiditis with findings resembling inflammatory bowel disease, which was caused by mesenteric venous thrombosis

Mikami Yohei, Kanai Takanori, Iwasaki Eisuke, Naganuma Makoto, Yamagishi Yoshiyuki, Shimoda Masayuki, Matsuoka Katsuyoshi, Hisamatsu Tadakazu, Iwao Yasushi, Ogata Haruhiko, Nakatsuka Seishi, Mukai Makio, Hibi Toshifumi

Clinical Journal of Gastroenterology 5 ( 6 ) 377 - 382 2012.12

ISSN 1865-7257

Mesenteric venous thrombosis is an insidious disease, with a high mortality rate typically attributed to the long delay in diagnosis. Rapid diagnosis and treatment are important. Here, we present a patient with idiopathic inferior mesenteric venous (IMV) thrombosis. A 65-year-old man presented with constant abdominal pain associated with fever and bloody diarrhea. He was diagnosed with severe ulcerative colitis and was treated with mesalazine and prednisolone. The prednisolone was tapered because of liver dysfunction, and he received total parenteral nutrition for a month. His abdominal pain and bloody diarrhea worsened, and he lost 5 kg of weight. He was then transferred to our institute. Computed tomography showed thickening of the left colon. Colonoscopy showed diffuse colitis with multiple ulcers, large edematous folds, congested mucosa, and stenosis of the sigmoid colon, with sparing of the rectum, raising the possibility of IMV thrombosis. Angiography confirmed IMV thrombosis. Anticoagulation therapy was initiated with intravenous heparin followed by oral warfarin. His abdominal pain and diarrhea resolved, and he was discharged from hospital. Six months later, he remained asymptomatic with normal colonoscopic findings. © 2012 Springer Japan.

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Dysregulated balance of retinoid-related orphan receptor γt-dependent innate lymphoid cells is involved in the pathogenesis of chronic DSS-induced colitis

Kimura Kayoko, Kanai Takanori, Hayashi Atsushi, Mikami Yohei, Sujino Tomohisa, Mizuno Shinta, Handa Tango, Matsuoka Katsuyoshi, Hisamatsu Tadakazu, Sato Toshiro, Hibi Toshifumi

Biochemical and Biophysical Research Communications 427 ( 4 ) 694 - 700 2012.11

ISSN 0006-291X

Retinoid-related orphan receptor (ROR) γt-expressing and IL-22-producing NKp46⁺ innate lymphoid (ILC22) cells reside in the lamina propria of the intestine in mice, suggesting that ILC22 cells contribute to host defense during intestinal damage in models of colitis in mice. Nevertheless, another set of pathological interferon (IFN)-γ and/or IL-17A-producing innate lymphoid cells (ILC1 and ICL17) may participate in the pathogenesis in different models of colitis. We here showed that RORγt⁺IL-22⁺ ILC22 cells were localized in Thy-1^highSCA-1^high and/or Thy-1^highSCA-1^low subpopulations of the intestine in normal and dextran sodium sulfate (DSS)-induced colitic RORγt-sufficient Rag-2^-/- mice. RORγt-deficient Rag-2^-/- mice developed more severe DSS-induced colitis accompanied with lower expression of REG3β and REG3γ in the colon, but with a lower ratio and absolute number of IFN-γ-producing ILC1 cells as compared to control RORγt-sufficient Rag-2^-/- mice. Collectively, not only the presence of ILC22 cells but also the balance of protective and pathogenic ILCs may be involved in the prevention of colitis. © 2012 Elsevier Inc.

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T-helper 17 and interleukin-17-producing lymphoid tissue inducer-like cells make different contributions to colitis in mice

Ono Yuichi, Kanai Takanori, Sujino Tomohisa, Nemoto Yasuhiro, Kanai Yasumasa, Mikami Yohei, Hayashi Atsushi, Matsumoto Atsuhiro, Takaishi Hiromasa, Ogata Haruhiko, Matsuoka Katsuyoshi, Hisamatsu Tadakazu, Watanabe Mamoru, Hibi Toshifumi

Gastroenterology 143 ( 5 ) 1288 - 1297 2012.11

ISSN 0016-5085

Background & Aims: T helper (Th) 17 cells that express the retinoid-related orphan receptor (ROR) γt contribute to the development of colitis in mice, yet are found in normal and inflamed intestine. We investigated their development and functions in intestines of mice. Methods: We analyzed intestinal Th17 cells in healthy and inflamed intestinal tissues of mice. We analyzed expression of lymphotoxin (LT)α by Th17 cells and lymphoid tissue inducer-like cells. Results: LTα^-/- and RORγt^-/- mice had significantly lower percentages of naturally occurring Th17 cells in the small intestine than wild-type mice. Numbers of CD3^-CD4^+/-interleukin-7Rα⁺c-kit ⁺CCR6⁺NKp46^- lymphoid tissue inducer-like cells that produce interleukin-17A were increased in LTα^-/- and LTα^-/-×recombination activating gene (RAG)-2 ^-/- mice, compared with wild-type mice, but were absent from RORγt^-/- mice. Parabiosis of wild-type and LTα ^-/- mice and bone marrow transplant experiments revealed that LTα-dependent gut-associated lymphoid tissue structures are required for generation of naturally occurring Th17 cells. However, when wild-type or LTα^-/- CD4⁺CD45RB^high T cells were transferred to RAG-2^-/- or LTα^-/-×RAG-2 ^-/- mice, all groups, irrespective of the presence or absence of LTα on the donor or recipient cells, developed colitis and generated Th1, Th17, and Th17/Th1 cells. RAG-2^-/- mice that received a second round of transplantation, with colitogenic but not naturally occurring Th17 cells, developed intestinal inflammation. The presence of naturally occurring Th17 cells in the colons of mice inhibited development of colitis after transfer of CD4⁺CD45RB^high T cells and increased the numbers of Foxp3⁺ cells derived from CD4⁺CD45RB^high T cells. Conclusions: Gut-associated lymphoid tissue structures are required to generate naturally occurring Th17 cells that have regulatory activities in normal intestines of mice, but not for colitogenic Th17 and Th17/Th1 cells during inflammation. © 2012 AGA Institute.

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P53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice

Tomita Kengo, Teratani Toshiaki, Suzuki Takahiro, Oshikawa Tetsuya, Yokoyama Hirokazu, Shimamura Katsuyoshi, Nishiyama Kiyoshi, Mataki Norikazu, Irie Rie, Minamino Tohru, Okada Yoshikiyo, Kurihara Chie, Ebinuma Hirotoshi, Saito Hidetsugu, Shimizu Ippei, Yoshida Yohko, Hokari Ryota, Sugiyama Kazuo, Hatsuse Kazuo, Yamamoto Junji, Kanai Takanori, Miura Soichiro, Hibi Toshifumi

Journal of Hepatology 57 ( 4 ) 837 - 843 2012.10

ISSN 0168-8278

Background & Aims: The tumor suppressor p53 is a primary sensor of stressful stimuli, controlling a number of biologic processes. The aim of our study was to examine the roles of p53 in non-alcoholic steatohepatitis (NASH). Methods: Male wild type and p53-deficient mice were fed a methionine- and choline-deficient diet for 8 weeks to induce nutritional steatohepatitis. mRNA expression profiles in normal liver samples and liver samples from patients with non-alcoholic liver disease (NAFLD) were also evaluated. Results: Hepatic p53 and p66Shc signaling was enhanced in the mouse NASH model. p53 deficiency suppressed the enhanced p66Shc signaling, decreased hepatic lipid peroxidation and the number of apoptotic hepatocytes, and ameliorated progression of nutritional steatohepatitis. In primary cultured hepatocytes, transforming growth factor (TGF)-β treatment increased p53 and p66Shc signaling, leading to exaggerated reactive oxygen species (ROS) accumulation and apoptosis. Deficient p53 signaling inhibited TGF-β-induced p66Shc signaling, ROS accumulation, and hepatocyte apoptosis. Furthermore, expression levels of p53, p21, and p66Shc were significantly elevated in human NAFLD liver samples, compared with results obtained with normal liver samples. Among NAFLD patients, those with NASH had significantly higher hepatic expression levels of p53, p21, and p66Shc compared with the group with simple steatosis. A significant correlation between expression levels of p53 and p66Shc was observed. Conclusions: p53 in hepatocytes regulates steatohepatitis progression by controlling p66Shc signaling, ROS levels, and apoptosis, all of which may be regulated by TGF-β. Moreover, p53/p66Shc signaling in the liver appears to be a promising target for the treatment of NASH. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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Disadvantages of peginterferon and ribavirin treatment in older patients with chronic hepatitis C

Ebinuma Hirotoshi, Saito Hidetsugu, Tada Shinichiro, Nakamoto Nobuhiro, Ohishi Tazuko, Tsunematsu Satoshi, Kumagai Naoki, Tsuchimoto Kanji, Tsukada Nobuhiro, Inagaki Yasutaka, Horie Yoshinori, Takahashi Masahiko, Atsukawa Kazuhiro, Okamura Yukishige, Kanai Takanori, Hibi Toshifumi

Hepatology International 6 ( 4 ) 744 - 752 2012.10

ISSN 1936-0533

Purpose Peginterferon (PEG-IFN) and ribavirin (RBV) combination treatment for patients with chronic hepatitis C (CHC), infected by genotype-1 hepatitis C virus with high viral loads, results in a sustained viral response (SVR) in 50%. However, a trend of decreasing SVR in the older patients has been reported. In the present study, we verified this trend of treatment efficacy in older patients using the propensity score (PS). Methods We conducted a survey of 327 patients with CHC (genotype 1 and high viral loads) who were treated with PEG-IFN and RBV for 48 weeks. The SVR rate was compared between patients =60 and <60 years of age. Because backgrounds of these patients differed considerably, we verified this efficacy between the older (n = 102) and younger (n = 102) patients matched for gender, body weight, platelets (PLT), and red blood cell (RBC) counts using PS. Results The total SVR rate was 42.9% (161/327); this rate decreased with increasing age and was lower in the older patients (C60 years: 41.5%, <60 years: 54.3%, P = 0.0245). Moreover, younger age was a significant factor for SVR. After correction by PS, the SVR in older patients remained significantly lower (C60 years: 43.1%, <60 years: 57.8%, P = 0.0497). In addition, RBC counts and hemoglobin (Hgb) concentrations, as well as RBV adherence in the older patients, decreased with this treatment, although there were no significant differences in pretreatment RBC and Hgb levels. Conclusions The analysis using PS indicated that RBV adherence in the older patients decreased even if they did not have lower pretreatment RBC and Hgb levels. © Asian Pacific Association for the Study of the Liver 2011.

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IgA plasma cells express the negative regulatory co-stimulatory molecule programmed cell death 1 ligand and have a potential tolerogenic role in the intestine

Doi Tomomitsu, Kanai Takanori, Mikami Yohei, Sujino Tomohisa, Jun Li, Ono Yuichi, Hayashi Atsushi, Hibi Toshifumi

Biochemical and Biophysical Research Communications 425 ( 4 ) 918 - 923 2012.09

ISSN 0006-291X

To maintain immune homeostasis in the intestine, the intestinal immune system has evolved several tolerogenic mechanisms toward intestinal microflora and food antigens. Although programmed cell death-1 (PD-1) protein has been implicated in immunological tolerance in the intestine and gut-associated lymphoid tissues (GALTs), distribution of its ligands PD-L1 and PD-L2 in the small intestine lamina propria (LP) are unknown. We investigated PD-L1 expression in intestinal LP and found that IgA plasma cells (PCs) were major PD-L1 expressing cells. PD-L1 expression levels on IgA PCs were higher than that on IgG PCs in peripheral lymphoid tissues. IgA PCs expressed antigen-presenting molecule MHC class II and co-stimulatory molecules CD80, CD86, and PD-L2. IgA PCs isolated from intestinal LP exhibited antigen presentation activity, and in the presence of TGF-β induced FoxP3⁺ regulatory T cells, but not IFN-γ⁺ Th1 cells, from naïve T cells. Thus, IgA PCs in the intestine may be involved in an immune regulatory role in the intestinal immune system. © 2012 Elsevier Inc.

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CCR9⁺ macrophages are required for eradication of peritoneal bacterial infections and prevention of polymicrobial sepsis

Mizukami Takahiro, Kanai Takanori, Mikami Yohei, Hayashi Atsushi, Doi Tomomitsu, Handa Tango, Matsumoto Atsuhiro, Jun Li, Matsuoka Katsuyoshi, Sato Toshiro, Hisamatsu Tadakazu, Hibi Toshifumi

Immunology Letters 147 ( 1-2 ) 75 - 79 2012.09

ISSN 0165-2478

Sepsis is a systemic inflammatory response to infection associated with multiple organ dysfunction syndrome and a high mortality rate. In septic shock induced by severe peritonitis, early response of peritoneal macrophages against infected microbes is vital in preventing the spread of infection. We found that the mucosal homing receptor CCR9, is induced in peritoneal macrophages in response to inflammatory stimulation. We used a cecal ligation and puncture (CLP) model of sepsis to determine the role of CCR9 with respect to peritoneal macrophages, and controlling peritoneal infection and systemic inflammation. CCR9^-/- mice showed aggravated septic shock with higher mortality rates compared with wild-type (WT) mice. Six hours after CLP, CCR9^-/- mice demonstrated a greater inflammatory response. This was associated with higher production of inflammatory cytokines, such as IL-6, TNF and IP-10 in peritoneal lavage compared with WT mice. Although the numbers of peritoneal bacteria were elevated in CCR9^-/- mice subjected to CLP compared with WT mice, this was normalized in CCR9^-/- mice subjected to CLP through the adoptive transfer of WT peritoneal macrophages. We conclude that CCR9 is required for recruitment of peritoneal macrophages in the steady state to control systemic sepsis during early phases of peritoneal infection. © 2012 Elsevier B.V.

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Colon neoplastic cells do not originate from bone marrow-derived cells after sex-mismatched bone marrow transplantation

Sakai Gen, Yajima Tomoharu, Takaishi Hiromasa, Mori Takehiko, Higuchi Hajime, Nakamura Shoko, Funakoshi Shinsuke, Adachi Masayuki, Izumiya Motoko, Akagi Hideko, Hamamoto Yasuo, Kanai Takanori, Mukai Makio, Okamoto Shinichiro, Hibi Toshifumi

Anticancer Research 32 ( 9 ) 4097 - 4103 2012.09

ISSN 0250-7005

Background: Although previous studies indicate that gastrointestinal (GI) cancer may originate from cells recruited from bone marrow (BM) in mice, whether similar phenomena occur in humans is controversial. In the current study, we evaluated two female patients who developed colonic adenocarcinoma more than 10 years after gender-mismatched BM transplantation, and followingly underwent successful endoscopic mucosal resection. Materials and Methods: Fluorescent in situ hybridization (FISH) analysis was used to determine whether the tumours contained donor-derived BM cells. Results: Approximately 1.2% of the tumour cells contained Y-chromosome-positive signals, and a comparable percentage of normal colonic epithelial cells close to the tumour also contained Y-chromosome-positive signals. Conclusion: These results do not support the concept that GI cancer can originate from BM-derived cells.

Anti-high mobility group box 1 and box 2 non-histone chromosomal proteins (HMGB1/HMGB2) antibodies and anti-Saccharomyces cerevisiae antibodies (ASCA)

Takaishi Hiromasa, Kanai Takanori, Nakazawa Atsushi, Sugata Fumihiko, Nikai Akira, Yoshizawa Shigeo, Hamamoto Yasuo, Funakoshi Shinsuke, Yajima Tomoharu, Iwao Yasushi, Takemura Masao, Ozaki Shoichi, Hibi Toshifumi

Journal of Gastroenterology 47 ( 9 ) 969 - 977 2012.09

ISSN 0944-1174

Background The development of a supportive diagnostic method has long been required to differentially diagnose ulcerative colitis (UC) and Crohn's disease (CD). Several antibodies circulate in the sera of patients with inflammatory bowel disease. We previously identified the high mobility group box 1 and box 2 non-histone chromosomal proteins (HMGB1 and HMGB2) as novel antigens of perinuclear type anti-neutrophil cytoplasmic antibodies (pANCA) and discovered anti-HMGB1/HMGB2 antibodies in sera from patients with UC. Here, we evaluated the ability of anti-HMGB1/HMGB2 antibodies combined with anti-Saccharomyces cerevisiae antibodies (ASCA) to differentially diagnose UC and CD. Methods We measured titers of anti-HMGB1/HMGB2 antibodies and ASCA in the sera of 213 patients with UC and 93 with CD, using enzyme-linked immunosorbent assays. Results Among the patients with UC, 26.8% were positive for anti-HMGB1/HMGB2 antibodies, with 85.0% specificity towards CD and a positive predictive value of 80.3%. Corticosteroids significantly suppressed the titer of anti- HMGB1/HMGB2 antibodies. Among the patients with CD, 24.7% were positive for ASCA, with 96.2% specificity towards UC and a positive predictive value of 74.2%. Interestingly, the positivity rate of anti-HMGB/HMGB2 antibodies was higher (35.7%) in patients with the ileitis type ofCDthan in patients withCDin the colon (6.2%; significant difference, P0.01). The specificity of anti-HMGB1/ HMGB2 antibodies in UC for CD in the colon was 93.8%. Conclusions CD in the colon and UC can be differentially diagnosed using anti-HMGB/HMGB2 antibodies combined with ASCA. © 2012 Springer.

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CCR9⁺ plasmacytoid dendritic cells in the small intestine suppress development of intestinal inflammation in mice

Mizuno Shinta, Kanai Takanori, Mikami Yohei, Sujino Tomohisa, Ono Yuichi, Hayashi Atsushi, Handa Tango, Matsumoto Atsuhiro, Nakamoto Nobuhiro, Matsuoka Katsuyoshi, Hisamatsu Tadakazu, Takaishi Hiromasa, Hibi Toshifumi

Immunology Letters 146 ( 1-2 ) 64 - 69 2012.08

ISSN 0165-2478

Almost all mice lacking specific molecules associated with regulatory T cells or barrier function develop intestinal inflammation in the colon, but not in the small intestine (SI). Therefore, intestinal homeostasis of the SI may be tightly controlled by other mechanisms. To determine the role of CCR9⁺ plasmacytoid dendritic cells (pDCs) in intestinal homeostasis of the SI we transferred CD4⁺CD45RB^high T cells into ccr9^-/-×rag-2^-/- mice. We showed that CCL25, a counterpart chemokine for CCR9, is constitutively expressed in the SI but not the colon and spleen of rag-2^-/- or ccr9^-/-×rag-2^-/- mice before or after transfer of CD4⁺CD45RB^high T cells. The ccr9^-/-×rag-2^-/- mice did not develop spontaneous intestinal inflammation in the SI and colon. Mice of both genotype where CD4⁺CD45RB^high T cells were transferred developed colitis. However, the ccr9^-/-×rag-2^-/- mice also developed ileitis with marked infiltration of Th1 cells. These results suggest that CCR9⁺ pDCs are possibly small, regulatory, antigen-presenting cells of the intestine that suppress intestinal inflammation. © 2012 Elsevier B.V.

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Effects of the oral administration of mosapride citrate on capsule endoscopy completion rate

Ida Yosuke, Hosoe Naoki, Imaeda Hiroyuki, Bessho Rieko, Ichikawa Riko, Naganuma Makoto, Kanai Takanori, Hibi Toshifumi, Ogata Haruhiko

Gut and Liver 6 ( 3 ) 339 - 343 2012.07

ISSN 1976-2283

Background/Aims: In capsule endoscopy (CE), the capsule does not always reach the cecum within its battery life, which may reduce its diagnostic yield. We evaluated the effect of mosapride citrate, a 5-hydroxytryptamine-4 agonist that increases gastrointestinal motility, on CE completion. Methods: In a retrospective study, we performed univariate and multivariate analyses for 232 CE procedures performed at our hospital. To identify factors that affect CE completion, the following data were systematically collected: gender, age, gastric transit time (GTT), nonsteroidal anti-inflammatory drug administration, previous abdominal surgery, hospitalization, use of a polyethylene glycol solution, use of mosapride citrate (10 mg), body mass index (BMI), and total recording time. Results: The univariate analysis showed that oral mosapride citrate, GTT, and BMI were associated with improved CE completion. Multivariate analyses showed that oral mosapride citrate (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.01 to 3.91) and GTT (OR, 2.34; 95% CI, 1.13 to 4.87) were significant factors for improving the CE completion. Oral mosapride citrate significantly shortened the GTT and small bowel transit time (SBTT). Conclusions: Oral mosapride citrate reduced the GTT and SBTT during CE and improved the CE completion rate.

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