Details of a Researcher - Kanai, Takanori

Papers - Kanai, Takanori

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Ectopic expression of blood type antigens in inflamed mucosa with higher incidence of FUT2 secretor status in colonic Crohn's disease

Miyoshi Jun, Yajima Tomoharu, Okamoto Susumu, Matsuoka Katsuyoshi, Inoue Nagamu, Hisamatsu Tadakazu, Shimamura Katsuyoshi, Nakazawa Atsushi, Kanai Takanori, Ogata Haruhiko, Iwao Yasushi, Mukai Makio, Hibi Toshifumi

Journal of Gastroenterology 46 ( 9 ) 1056 - 1063 2011.09

ISSN 0944-1174

Background Host-intestinal microbial interaction plays an important role in the pathogenesis of inflammatory bowel diseases (IBDs). The surface molecules of the intestinal epithelium act as receptors for bacterial adhesion and regulate the intestinal bacteria. Some known receptors are the mucosal blood type antigens, which are regulated by the fucosyltransferase2 (FUT2) gene, and individuals who express these antigens in the gastrointestinal tract are called secretors. Recent research has revealed that the FUT2 gene is associated with Crohn's disease (CD) in western populations. Methods To clarify the contribution of mucosal blood type antigens in IBD, we determined the incidence of five previously reported single-nucleotide polymorphisms of the FUT2 gene in Japanese patients. We also used immunohistochemistry to investigate the antigen expression in mucosal specimens from IBD patients and animal models. Results Genetic analysis revealed that all of the patients with colonic CD were secretors, whereas the incidence of secretors was 80, 80, 67, and 80%, respectively, for the control, ileocolonic CD, ileal CD, and ulcerative colitis groups (P = 0.036). Abnormal expression of blood type antigens was observed only in colonic CD. Interleukin- 10 ^-/- mice, but not dextran sulfate sodium colitis mice, had enhanced colonic expression of blood type antigens, and the expression of these antigens preceded the development of colitis in the interleukin-10 ^-/- mice. Conclusions FUT2 secretor status was associated with colonic-type CD. This finding, taken together with the immunohistochemistry data, suggests that the abnormal expression of blood type antigens in the colon may be a unique and essential factor for colonic CD. © Springer 2011.

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Dramatic changes in the technology of diagnostic imaging and management of Crohn's disease

Takazoe Masakazu, Hatada Yasumasa, Kanai Takanori

Gastroenterological Endoscopy 53 ( 9 ) 3000 - 3013 2011.09

ISSN 0387-1207

The appropriate therapy for Crohn's disease (CD) cannot be achieved until the extent of disease and its anatomical importance are taken into consideration. Therefore, information from imaging tests is essential to establish a diagnosis. A single gold standard for the diagnosis of CD is not available. The diagnosis should be made by clinical evaluation and a combination of endoscopic, histological, radiological, and/or biochemical investigations. In the case of patients with suspected CD in whom stenosis is not confirmed, if ileocolonoscopy and radiological examination/cross-sectional imaging show no lesion or they are difficult to conduct, small bowel capsule endoscopy is applicable. Radiological examination, especially, double-contrast imaging of the small intestine is one of the best tools for the evaluation of mucosal and transmural lesions and this technique is thought to be necessary to understand the past and present disease status. Double balloon enteroscopy should be reserved for specific situations in which biopsy samples from suspected involved areas are important for diagnosis or in which a dilatation of stricture is reasonable.

A case of beef tapeworm (Taenia saginata) infection observed by using video capsule endoscopy and radiography (with videos)

Hosoe Naoki, Imaeda Hiroyuki, Okamoto Susumu, Bessho Rieko, Saito Riko, Ida Yosuke, Kobayashi Seiki, Kanai Takanori, Hibi Toshifumi, Ogata Haruhiko

Gastrointestinal Endoscopy 74 ( 3 ) 690 - 691 2011.09

ISSN 0016-5107

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Intracellular bacteria recognition contributes to maximal interleukin (IL)-12 production by IL-10-deficient macrophages

Naruse H., Hisamatsu T., Yamauchi Y., Chang J. E., Matsuoka K., Kitazume M. T., Arai K., Ando S., Kanai T., Kamada N., Hibi T.

Clinical and Experimental Immunology 164 ( 1 ) 137 - 144 2011.04

ISSN 0009-9104

Interleukin (IL)-12 is a key factor that induces T helper cell type 1-mediated immunity and inflammatory diseases. In some colitis models, such as IL-10 knock-out (KO) mice, IL-12 triggers intestinal inflammation. An abundant amount of IL-12 is produced by intestinal macrophages in response to stimulation by commensal bacteria in IL-10 KO mice. Intact bacteria are more potent inducers of macrophage IL-12 production than cell surface components in this model. This suggested that cell surface receptor signalling and intracellular pathogen recognition mechanisms are important for the induction of IL-12. We addressed the importance of intracellular recognition mechanisms and demonstrated that signal transducers and activator of transcription 1 (STAT1) signalling activated bacterial phagocytosis and was involved in the induction of abnormal IL-12 production. In IL-10 KO mouse bone marrow-derived (BM) macrophages, Escherichia coli stimulation induced increased IL-12p70 production compared to lipopolysaccharide combined with interferon (IFN)-γ treatment. Significant repression of IL-12 production was achieved by inhibition of phagocytosis with cytochalasin D, and inhibition of de novo protein synthesis with cycloheximide. Induction of IFN regulatory factors-1 and -8, downstream molecules of STAT1 and the key transcription factors for IK-12 transcription, following E. coli stimulation, were mediated by phagocytosis. Interestingly, STAT1 was activated after stimulation with E. coli in IL-10 KO BM macrophages, although IFN-γ could not be detected. These data suggest that molecules other than IFN-γ are involved in hyper-production mechanisms of IL-12 induced by E. coli stimulation. In conclusion, enteric bacteria stimulate excessive IL-12p70 production in IL-10 KO BM macrophages via phagocytosis-dependent signalling. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.

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Upregulated IL-7 receptor a expression on colitogenic memory CD4 ⁺ T cells may participate in the development and persistence of chronic colitis

Shinohara Tamako, Nemoto Yasuhiro, Kanai Takanori, Kameyama Kaori, Okamoto Ryuichi, Tsuchiya Kiichiro, Nakamura Tetsuya, Totsuka Teruji, Ikuta Koichi, Watanabe Mamoru

Journal of Immunology 186 ( 4 ) 2623 - 2632 2011.02

ISSN 0022-1767

We have previously demonstrated that IL-7 is essential for the persistence of colitis as a survival factor of colitogenic IL-7Rα-expressing memory CD4⁺ T cells. Because IL-7Rα is broadly expressed on various immune cells, it is possible that the persistence of colitogenic CD4⁺ T cells is affected by other IL-7Rα-expressing non-T cells. To test this hypothesis, we conducted two adoptive transfer colitis experiments using IL-7Rα^-/- CD4⁺CD25^- donor cells and IL-7Rα^-/- x RAG-2^-/- recipient mice, respectively. First, IL-7Rα expression on colitic lamina propria (LP) CD4⁺ T cells was significantly higher than on normal LP CD4⁺ T cells, whereas expression on other colitic LP immune cells, (e.g., NK cells, macrophages, myeloid dendritic cells) was conversely lower than that of paired LP cells in normal mice, resulting in predominantly higher expression of IL-7Rα on colitogenic LP CD4⁺ cells, which allows them to exclusively use IL-7. Furthermore, RAG-2^-/- mice transferred with IL-7Rα^-/- CD4⁺CD25^- T cells did not develop colitis, although LP CD4⁺ T cells from mice transferred with IL-7Rα^-/- CD4⁺CD25^- T cells were differentiated to CD4⁺ CD44^highCD62L^- effector-memory T cells. Finally, IL-7Rα^-/- x RAG-2 ^-/- mice transferred with CD4⁺CD25^- T cells developed colitis similar to RAG-2^-/- mice transferred with CD4 ⁺CD25^- T cells. These results suggest that IL-7Rα expression on colitogenic CD4⁺ T cells, but not on other cells, is essential for the development of chronic colitis. Therefore, therapeutic approaches targeting the IL-7/IL-7R signaling pathway in colitogenic CD4 ⁺ T cells may be feasible for the treatment of inflammatory bowel diseases. Copyright©2011 by The American Association of Immunologists, Inc.

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Evaluation of liver fibrosis by transient elastography using acoustic radiation force impulse

Ebinuma Hirotoshi, Saito Hidetsugu, Komuta Mina, Ojiro Keisuke, Wakabayashi Kanji, Usui Shingo, Chu Po sung, Umeda Rumiko, Ishibashi Yuka, Takayama Tetsurou, Kikuchi Masahiro, Nakamoto Nobuhiro, Yamagishi Yoshiyuki, Kanai Takanori, Ohkuma Kiyoshi, Sakamoto Michiie, Hibi Toshifumi

Journal of Gastroenterology 1 - 11 2011

ISSN 0944-1174

Background: Accurate evaluation of liver fibrosis in patients with chronic liver damage is required to determine the appropriate treatment. Various approaches, including laboratory tests and transient elastography, have been used to evaluate liver fibrosis. Recently, transient elastography with acoustic radiation force impulse (ARFI) has been developed and applied with conventional ultrasonography. The aim of this study was to evaluate the clinical utility of transient elastography with ARFI and to compare the results with this method and those of the Fibroscan^® procedure. Methods: One hundred and thirty-one patients with liver damage, who underwent liver biopsy at our department, were enrolled prospectively in this study. Elastography with ARFI (applied with ACUSON S2000^®), and Fibroscan^® was performed at the same time as liver biopsy. These measurements were compared with histological findings in liver biopsy specimens, and measurement accuracy was evaluated by receiver-operating characteristic analysis. Results: Elastography values with both procedures were significantly correlated with the stages of liver fibrosis and there was little difference in the results obtained using the 2 procedures. The accuracy of differential diagnosis between no fibrosis at F0 and more than F1 stage was insufficient with ARFI, but this procedure was sufficient for diagnosing advanced fibrosis. The accuracy of ARFI was almost equivalent to that of the Fibroscan^® method. Moreover, both ARFI and Fibroscan^® values increased in proportion to the severity of hepatic inflammation when fibrosis stage is low, but not in proportion to the severity of steatosis. Conclusions: Transient elastography with ARFI is simple, non-invasive and useful for diagnosing the stage of fibrosis in chronic liver disease. The utility of ARFI was almost equivalent to that of the Fibroscan^® method. © 2011 Springer.

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Evaluation of small-intestinal abnormalities in adult patients with HenochSchönlein purpura using video capsule

Ichikawa R., Hosoe N., Imaeda H., Takabayashi K., Bessho R., Ida Y., Naganuma M., Hisamatsu T., Inoue N., Kanai T., Iwao Y., Mukai M., Hibi T., Ogata H.

Endoscopy 43 ( SUPPL. 2 ) 2011

ISSN 0013-726X

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Correlation between endocytoscopy and conventional histopathology in microstructural features of ulcerative colitis

Bessho Rieko, Kanai Takanori, Hosoe Naoki, Kobayashi Taku, Takayama Tetsuro, Inoue Nagamu, Mukai Makio, Ogata Haruhiko, Hibi Toshifumi

Journal of Gastroenterology 1 - 6 2011

ISSN 0944-1174

Background: Routine diagnosis of the histopathological activity of ulcerative colitis (UC) requires multiple biopsy samples, and an endocytoscopy system (ECS) provides real-time ultra-magnifying microscopic imaging in vivo. Methods: We have established an ECS score (ECSS) to determine a histopathological activity index of UC. Fifty-five UC patients (mean age 40.7 years; 67% men) were enrolled. A super-magnifying ECS with magnification 450× was used, and sample biopsies were obtained. Matts' histopathological grade was determined, to evaluate disease severity, by two pathologists, with consensus. The ECSS of UC was independently determined by at least two investigators, with consensus. In total, 76 pairs of ECSS and Matts' histopathological grades were independently acquired. To validate the ECSS, inter-observer agreement between three endoscopists, with consensus, and another endoscopist, was calculated as the kappa value. We also evaluated the correlation between the ECSS and Matts' histopathological grade, and between the conventional Matts' endoscopic grade and Matts' histopathological grade. Results: The ECSS of UC intestinal mucosa, i.e., the sum of the indices for shape (0-3) and distance between crypts (0-2), and the visibility of superficial microvessels (0-1), showed a strong correlation with Matts' histopathological grades (ρ = 0.713, P < 0.001); as well, there was a strong correlation between the conventional Matts' endoscopic grade and Matts' histopathological grade (ρ = 0.694, P < 0.001). Furthermore, the ECSS showed high reproducibility (κ = 0.79, 95% confidence interval [CI] 0.71-0.87). Conclusions: Our novel ECSS has good predictive value for the histopathological activity of UC. © 2011 Springer.

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Imbalance of NKp44⁺NKp46^- and NKp44 ^-NKp46⁺ natural killer cells in the intestinal mucosa of patients with Crohn's disease

Takayama Tetsuro, Kamada Nobuhiko, Chinen Hiroshi, Okamoto Susumu, Kitazume Mina T., Chang Jonathan, Matuzaki Yumi, Suzuki Sadafumi, Sugita Akira, Koganei Kazutaka, Hisamatsu Tadakazu, Kanai Takanori, Hibi Toshifumi

Gastroenterology 139 ( 3 ) 2010.09

ISSN 0016-5085

Background & Aims: Mucosal natural killer (NK) cells that produce interleukin (IL)-22 mediate intestinal homeostasis and inflammation in mice. However, their role in the pathogenesis of human inflammatory bowel diseases (IBDs) is not known. We investigated intestinal NK cells in intestinal mucosa samples of patients with Crohn's disease (CD). Methods: We isolated lamina propria NK cells from intestinal mucosal samples of patients with IBD and subjects without IBD (controls) and analyzed expression patterns of cell surface molecules and cytokine production. Interactions between lamina propria NK cells and intestinal macrophages were examined. Results: In intestinal mucosa samples from controls, NKp44 and NKp46 were expressed differentially on CD3 ^-CD56⁺ NK cells, NKp44⁺NKp46^- (NKp44⁺) NK cells expressed CD127 and the transcription factor retinoic acid-related orphan receptor C (RORC) and produced IL-22 whereas NKp44^-NKp46⁺ (NKp46⁺) NK cells did not express CD127 or RORC and produced interferon (IFN)-γ. NKp46⁺ NK cells were predominant in intestinal mucosa of patients with CD compared with controls or patients with ulcerative colitis. Upon interaction with intestinal inflammatory macrophages NKp46⁺, NK cells from patients with CD were activated via IL-23 and produced IFN-γ; this activation required cell-to-cell contact. Conclusions: The balance of NKp44⁺/NKp46 ⁺ NK cells is disrupted in intestinal mucosa of patients with CD. NKp46⁺ NK cells might mediate the pathogenesis of CD by producing IFN-γ. © 2010 by the AGA Institute.

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Novel endoscopic activity index is useful for choosing treatment in severe active ulcerative colitis patients

Naganuma Makoto, Ichikawa Hitoshi, Inoue Nagamu, Kobayashi Taku, Okamoto Susumu, Hisamatsu Tadakazu, Kanai Takanori, Ogata Haruhiko, Iwao Yasushi, Hibi Toshifumi

Journal of Gastroenterology 45 ( 9 ) 936 - 943 2010.09

ISSN 0944-1174

Aim: Clinical symptoms are the most important factors used by physicians to evaluate the severity and extent of ulcerative colitis (UC). In this context, colonoscopy is also a useful diagnostic tool. We have recently developed an endoscopic activity index (EAI) to assess the severity of UC. Here, we assess the correlations among the EAI, other endoscopic indices, and clinical scores. The usefulness of the EAI for choosing treatment options, such as intravenous corticosteroid or cyclosporine A (CsA), in severe UC patients was also evaluated. Methods: Clinical symptoms and endoscopic finding were evaluated in 396 patients with UC (454 colonoscopies). The EAI was scored using the following six items: ulcer size, ulcer depth, redness, bleeding, edema, and mucus exudates. The patients were also scored using Matts' grade, Rachmilewitz's endoscopic index, and the Lichtiger index. Results: Our results showed that (1) the EAI scores were closely correlated with those of the Lichtiger index, Matts' grade, and Rachmilewitz's endoscopic index; (2) the EAI scores significantly decreased in patients who responded to treatment, while Matts' grade did not change in some responders treated with intravenous CsA and steroid; (3) patients with a higher EAI (14-16) tended to be refractory to corticosteroid therapy (responders 19%) compared to CsA (77%), while steroid treatment was effective in 58% of patients with EAI scores of 11-13. Conclusions: The EAI is equivalent to other endoscopic indices and relatively more useful in choosing a treatment for patients with severe UC. © 2010 Springer.

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MyD88-dependent pathway accelerates the liver damage of Concanavalin A-induced hepatitis

Ojiro Keisuke, Ebinuma Hirotoshi, Nakamoto Nobuhiro, Wakabayashi Kanji, Mikami Yohei, Ono Yuichi, Po-Sung Chu, Usui Shingo, Umeda Rumiko, Takaishi Hiromasa, Yamagishi Yoshiyuki, Saito Hidetsugu, Kanai Takanori, Hibi Toshifumi

Biochemical and Biophysical Research Communications 399 ( 4 ) 744 - 749 2010.09

ISSN 0006-291X

We have explored the pathological role of the MyD88 signaling pathway via Toll-like receptors (TLRs) that mediate the recognition of pathogen-associated molecular patterns (PAMPs) in a murine model of autoimmune hepatitis induced by administering Concanavalin A (ConA). We first found that various TLRs and MyD88 molecules were expressed in liver of Con A-treated and untreated wild-type (WT) mice including liver macrophages. Flowcytometric analysis revealed that liver CD11b⁺CD11c^- and CD11b⁺CD11c⁺ antigen-presenting cells express TLR2, although NK and NKT cells did not. When WT and MyD88^-/- mice were intravenously administered with Con A, the severity of hepatitis was significantly lower in Con A-injected MyD88^-/- mice than in WT mice in terms of the histopathology, the levels of serum transaminase and pro-inflammatory cytokines (TNF-α, IFN-γ, and IL-6), and upregulation of CD80/CD86 and TNF-α on/in liver macrophages. The results provide evidence of a possible contribution of the TLRs-MyD88 signaling pathway in activating TLR-expressing liver macrophages in the autoimmune hepatitis model, and thus indicate that the strategy of blockade of pathological pathogens via the intestinal lumen may be feasible for the treatment of the disease. © 2010 Elsevier Inc.

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In vivo visualization of trophozoites in patients with amoebic colitis by using a newly developed endocytoscope

Hosoe Naoki, Kobayashi Taku, Kanai Takanori, Bessho Rieko, Takayama Tetsuro, Inoue Nagamu, Imaeda Hiroyuki, Iwao Yasushi, Kobayashi Seiki, Mukai Makio, Ogata Haruhiko, Hibi Toshifumi

Gastrointestinal Endoscopy 72 ( 3 ) 643 - 646 2010.09

ISSN 0016-5107

Background: The endocytoscopy system (ECS) is a new method to provide real-time super-magnifying microscopic imaging in vivo. Routine diagnosis of amebic colitis requires multiple tests that are both time consuming and costly. Objective: To determine the feasibility of ECS to directly detect the amebic parasites in vivo. Design: Prospective, single-center, pilot study. Setting: Tertiary-care university hospital. Patients: This study involved 5 patients who were suspected to have amebic colitis by conventional colonoscopy in our institute. Interventions: A super-magnifying ECS with 450 × magnification. Main Outcome Measurements: We compared ECS findings with those of conventional methodsserum antibody tests and histology of colon biopsy specimens. Results: We successfully visualized the amebic trophozoites in all 5 cases. In contrast, 3 specimens had positive results on serology, and 3 had positive histology results on hematoxylin and eosin staining. Limitations: Pilot study with a limited number of patients. Findings were compared only with serology and histology findings. Conclusions: ECS would be a useful tool for the prompt diagnosis of amebic colitis via the real-time in vivo visualization of amebic trophozoites. © 2010 American Society for Gastrointestinal Endoscopy.

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TL1A produced by lamina propria macrophages induces Th1 and Th17 immune responses in cooperation with IL-23 in patients with Crohn's disease

Kamada Nobuhiko, Hisamatsu Tadakazu, Honda Haruki, Kobayashi Taku, Chinen Hiroshi, Takayama Tetsuro, Kitazume Mina T., Okamoto Susumu, Koganei Kazutaka, Sugita Akira, Kanai Takanori, Hibi Toshifumi

Inflammatory Bowel Diseases 16 ( 4 ) 568 - 575 2010.04

ISSN 1078-0998

Background: Tumor necrosis factor (TNF)-like protein 1A (TL1A) is a member of the TNF superfamily and contributes to the pathogenesis of Crohn's disease (CD) by stimulating T-helper (Th) 1 cells. In addition to Th1, recent studies have focused on the role of Th17 cells in the pathogenesis of CD. Here we tried to clarify the role of TL1A in Th1 and Th17 immunity in CD. Methods: TL1A expression was assessed by quantitative reverse-transcription polymerase chain reaction (RT-PCR) in lamina propria (LP) macrophages (LP-Mφs) from normal controls (NC) and patients with CD or ulcerative colitis (UC). Purified LP CD4⁺ T cells were stimulated with TL1A and/or IL-23 and interferon gamma (IFN-γ) and interleukin (IL)-17 levels were analyzed. We also examined the effect of TL1A on naïve CD4⁺ Tcell differentiation. Results: We found that LP-Mφs are a major producer of TL1A. TL1A expression was markedly enhanced in LP-Mφs from CD patients compared with NC or UC patients. IL-23, in addition to TL1A, was induced in LP-Mφs by commensal bacteria stimulation. TL1A and IL-23 synergistically promoted the production of IFN-γ and IL-17 by LP T cells, while TL1A alone did not induce cytokine production. Furthermore, TL1A promoted Th17 differentiation from naïve T cells by LP-Mφs; however, IL-23 did not show any synergistic effects on Th17 differentiation. Conclusions: TL1A expressed in LP-Mφs might play an important role in the pathogenesis of CD by inducing Th1 and Th17 immunity. IL-23 differentially regulated these functions of TL1A on memory and naïve T cells. Copyright © 2009 Crohn's & Colitis Foundation of America, Inc.

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Monocyte chemoattractant protein-1 contributes to gut homeostasis and intestinal inflammation by composition of IL-10-producing regulatory macrophage subset

Takada Yasuhiro, Hisamatsu Tadakazu, Kamada Nobuhiko, Kitazume Mina T., Honda Haruki, Oshima Yosuke, Saito Riko, Takayama Tetsuro, Kobayashi Taku, Chinen Hiroshi, Mikami Yohei, Kanai Takanori, Okamoto Susumu, Hibi Toshifumi

Journal of Immunology 184 ( 5 ) 2671 - 2676 2010.03

ISSN 0022-1767

Lamina propria macrophages (LPMφs) spontaneously produce large amounts of anti-inflammatory IL-10 and play a central role in regulation of immune responses against commensal bacteria. MCP-1 is a chemokine that plays an important role in recruitment of monocytes and macrophages to inflamed tissues. We demonstrated that, in addition to IL-10, LPMφs produced large amounts of MCP-1, even in a steady state. MCP-1 deficiency caused impaired IL-10 production by LPMφs and led to exacerbation of dextran sulfate sodium-induced acute colitis. As an explanation of this impaired IL-10 production by LPMφs, we found that LPMφs could be separated into two subsets with distinct side-scattered properties, namely LPMφ1 (CD11b⁺F4/80 ⁺CD11c^-SSC^hi) and LPMf2 (CD11b ⁺F4/80⁺CD11c^-SSC^lo). Unlike LPMφ1, the LPMφ2 subset migrated in response to MCP-1 and produced a larger amount of IL-10 in response to commensal bacteria. LPMφs isolated from MCP-1-deficient mice produced less IL-10 as a consequence of the lack of the MCP-1-dependent LPMφ2 population. This imbalanced composition in LPMφ population may be involved in the susceptibility to DSS-induced colitis in MCP-1-deficient mice. Our results suggest that endogenous MCP-1 contributes to the composition of resident LPMφ subsets in the intestine. Moreover, MCP-1-dependent LPMφ2 subset may play an important role in maintenance of gut homeostasis in the steady state, and in the termination of excess inflammatory responses in the intestine, by producing IL-10. Copyright © 2010 by The American Association of Immunologists, Inc.

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Competition between colitogenic Th1 and Th17 cells contributes to the amelioration of colitis

Mikami Yohei, Kanai Takanori, Sujino Tomohisa, Ono Yuichi, Hayashi Atsushi, Okazawa Akira, Kamada Nobuhiko, Matsuoka Katsuyoshi, Hisamatsu Tadakazu, Okamoto Susumu, Takaishi Hiromasa, Inoue Nagamu, Ogata Haruhiko, Hibi Toshifumi

European Journal of Immunology 40 ( 9 ) 2409 - 2422 2010

ISSN 0014-2980

Th17 cells and Th1 cells coordinate to play a critical role in the formation of inflammatory bowel diseases. To examine how Th17 and Th1 cells are regulated at inflammatory sites, we used Th1-dominant CD4⁺CD45RB ^high T cell-transferred RAG-2^-/- and Th1/Th17-mixed IL-10^-/- mice. Interestingly, not only did colitic RAG-2 ^-/- mice that were parabiosed with WT mice show significant amelioration of colitis, but amelioration of disease was also observed in those parabiosed with colitic IL-10^-/- mice. To assess the interference between Th1 and Th17 colitogenic T cells, we co-transferred colitogenic CD4 ⁺ T cells from the lamina propria (LP) of CD4⁺CD45RB ^high T cell-transferred RAG-2^-/- mice and IL-10 ^-/- mice into RAG-2^-/- mice. Surprisingly, the co-transferred RAG-2^-/- mice showed a vast cellular infiltration of LP CD4⁺ T cells similar to that seen in RAG-2^-/- mice re-transferred with the cells from colitic RAG-2^-/- mice alone, but the co-transferred RAG-2^-/- mice did not have the wasting symptoms, which are also absent in RAG-2^-/- mice transferred with cells from colitic IL-10^-/- mice alone. Furthermore, the percentages of Th1 and Th17 cells originating from IL-10^-/- mice and those of Th1 cells originating from colitic RAG-2^-/- mice were all significantly decreased in the co-transferred mice as compared with the singly-transferred paired RAG-2^-/- mice, suggesting that Th1 and Th17 cells are in competition, and that their orchestration results in a merged clinical phenotype of the two types of murine colitis. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

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IL-2 is positively involved in the development of colitogenic CD4 ⁺ IL-7Rα^high memory T cells in chronic colitis

Kameyama Kaori, Nemoto Yasuhiro, Kanai Takanori, Shinohara Tamako, Okamoto Ryuichi, Tsuchiya Kiichiro, Nakamura Tetsuya, Sakamoto Naoya, Totsuka Teruji, Hibi Toshifumi, Watanabe Mamoru

European Journal of Immunology 40 ( 9 ) 2423 - 2436 2010

ISSN 0014-2980

IL-2 and IL-7 share a common γ-chain receptor and are critical for T-cell homeostasis. We aimed to clarify the reciprocal roles of IL-2 and IL-7 in the development and persistence of chronic colitis. We performed a series of adoptive transfers of IL-2^-/- CD4⁺CD45RB^high T cells into RAG-2^-/- mice and assessed the role of IL-2 in the induction of IL-7Rα on colitogenic CD4⁺ T cells and the development of chronic colitis. RAG-2^-/- mice transferred with WT but not with IL-2^-/- CD4⁺CD45RB^high T cells developed Th1/Th17-mediated colitis. Consistently, re-expression of IL-7Rα was severely impaired on IL-2^-/- but not on WT CD4⁺ T cells from the transferred mice. To exclude a contribution of the preclinical autoimmunity of IL-2^-/-mice, WT Ly5.1⁺ or IL-2 ^-/- Ly5.2⁺ CD4⁺CD45RB^high T cells from GFP mice previously transplanted with the same number of WT and IL-2 ^-/- BM cells were transferred into RAG-2^-/- mice. RAG-2^-/- mice transferred with IL-2^-/--derived CD4 ⁺ CD45RB^high T cells did not develop colitis, but their splenic CD4⁺ T cells changed from effector-memory to central-memory type. These results show that IL-2 is critically involved in the establishment and maintenance of IL-7-dependent colitogenic memory CD4⁺IL- 7Rα^high T cells. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

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A case of IgA-related enteropathy complicated with gastrointestinal bleeding and progressive IgA nephropathy

Nakamura Shoko, Hisamatsu Tadakazu, Kikuchi Jun, Adachi Masayuki, Yamagishi Yoshiyuki, Imaeda Hiroyuki, Hosoe Naoki, Naganuma Makoto, Ebinuma Hirotoshi, Okamoto Susumu, Kanai Takanori, Ogata Haruhiko, Hanaoka Hironari, Furuya Yoshiaki, Kawano Yoshinaga, Bokuda Kanako, Sasamura Hiroyuki, Uchida Hiroshi, Endo Takashi, Hashiguchi Akinori, Kameyama Kaori, Mukai Makio, Hibi Toshifumi

Internal Medicine 49 ( 16 ) 1755 - 1761 2010

ISSN 0918-2918

Here, we report an adult patient with IgA-related enteropathy complicated with massive intestinal bleeding and acute renal failure, but without skin lesions. Surgical resection of the small intestine and steroid pulse therapy was performed. Histopathology revealed significant deposition of IgA and C3 in the small vessels of the intestine and the kidney mesangium. Although skin purpura was absent, the histopathology and clinical manifestations suggested that the pathophysiology was similar to Henoch-Schönlein purpura (HSP), implying IgA-related enteropathy as a subclass of HSP. Retrospective analysis indicates that terminal ileum lesions may be a poor prognostic indicator. © 2010 The Japanese Society of Internal Medicine.

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Systemically circulating colitogenic memory CD4⁺ T cells may be an ideal target for the treatment of inflammatory bowel diseases

Kanai Takanori, Watanabe Mamoru, Hibi Toshifumi

Keio Journal of Medicine 58 ( 4 ) 203 - 209 2009.12

ISSN 0022-9717

Inflammatory bowel diseases (IBD) are thought to be caused by a complex interaction of genetic, immunological, and environmental factors. Why is it that once an IBD develops it lasts a long time? Considering this simple question, we propose that coliotogenic memory CD4⁺T cells that remember the prototype of the disease in each patient are formed in IBD at the onset, and, perceiving them as "benign T-cell leukemia"-like lifelong memory CD4⁺T cells that hematogenously spread throughout the body, we thus propose that systemic circulating colitogenic memory CD4⁺T cells would be an ideal target for the treatment of IBD. Accordingly, selective depletion of colitogenic memory CD4⁺T cells by leukocytapheresis and blockade of circulation of colitogenic memory CD4⁺T cells by a newly developed immunosuppressant, FTY720, may be associated with dramatic efficacy and a marked reduction of inflammatory cytokines produced by activated leucocytes. We here describe the immunological pathogenesis focusing on the generation of circulating colitogenic memory CD4⁺T cells and the possible logics of leukocytapheresis and FTY720 for the treatment of IBD.

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Long-lived colitogenic CD4⁺ memory T cells residing outside the intestine participate in the perpetuation of chronic colitis

Nemoto Yasuhiro, Kanai Takanori, Kameyama Kaori, Shinohara Tamako, Sakamoto Naoya, Totsuka Teruji, Okamoto Ryuichi, Tsuchiya Kiichiro, Nakamura Tetsuya, Sudo Tetsuo, Matsumoto Satoshi, Watanabe Mamoru

Journal of Immunology 183 ( 8 ) 5059 - 5068 2009.10

ISSN 0022-1767

To understand the perpetuation of inflammatory bowel disease (IBD), it is important to clarify whether the colitogenic CD4⁺ T cells are self-limited effector or long-lived memory T cells. We here investigate the latency of colitogenic CD4⁺ T cells in the remission stage of colitis under germfree (GF) conditions. We isolated splenic (SP) CD4⁺ T cells from colitic CD4⁺CD45RB^high T cell-injected SCID mice maintained under specific pathogen-free (SPF) conditions and transferred them into SPF or GF SCID mice. Donor colitic SP CD4⁺ T cells have a characteristic CD44^highCD62L^-IL-7Rα^high effector-memory T-type phenotype. Six weeks after transfer of cells to GF SCID mice, one group of mice was continued in GF conditions (GF→GF), and the other was transferred into SPF conditions (GF→SPF). GF→SPF but not GF→GF SCID mice developed colitis with elevated production of Th1 and Th17 cytokines at 4 wk after transfer. Surprisingly, a large number of CD4 ⁺ effector-memory T cells and a small but substantial number of central-memory T cells remained resident in SP and bone marrow, but not in lamina propria, of the GF→GF SCID recipients. Consistent with this, GF3SPF but not GF→GF SCID mice rapidly developed colitis. Taken together, these findings suggest that long-lived colitogenic memory CD4⁺ cells can be established even in the presence of commensal Ags, reside outside the intestine in the absence of commensal bacteria, and participate in the perpetuation of colitis. Thus, blocking a stimulus of colitogenic memory CD4⁺ cells such as IL-7 may have therapeutic benefit for treatment of inflammatory bowel disease. Copyright © 2009 by The American Association of Immunologists, Inc.

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IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4+ memory T cells in chronic colitis

Tomita Takayuki, Kanai Takanori, Totsuka Teruji, Nemoto Yasuhiro, Okamoto Ryuichi, Tsuchiya Kiichiro, Sakamoto Naoya, Ohteki Toshiaki, Hibi Toshifumi, Watanabe Mamoru

European Journal of Immunology 39 ( 10 ) 2737 - 2747 2009.10

ISSN 0014-2980

We previously demonstrated that IL-7 is essential for the persistence of T-cell-mediated colitis, by showing that adoptive transfer of CD4 ⁺CD45RB^high T cells into IL-7^-/- x RAG-1 ^+/+ mice did not induce colitis; and that intestinal IL-7 is not essential for this colitis model, by showing that IL-7^-/- x RAG-1^-/- mice parabiosed with colitic CD4⁺CD45RB ^high T-cell-transferred RAG-1^-/- mice developed colitis. Here, we investigated the role of IL-7 in the maintenance of colitogenic CD4⁺ T cells by surgically separating these parabionts. Surprisingly, the separated IL-7^-/- x RAG-1^-/- mice were consistently diseased after separation, although no IL-7 mRNA was detected in the tissues of separated IL-7^-/- x RAG-1^-/- partners. CD4⁺ T cells isolated from the separated RAG-1^-/- or IL-7^-/- x RAG-1^-/- mice were then transferred into new RAG-1^-/- or IL-7^-/- x RAG-1^-/- mice. Regardless of the source of donor cells, RAG-1^-/- recipients developed colitis, whereas IL-7 ^-/- x RAG-1^-/- recipients did not. Collectively, these results demonstrate that IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4⁺ T cells rather than the maintenance of those cells in established colitic mice. They also provide a basis for the timing of IL-7/IL-7R blockade for the treatment of inflammatory bowel diseases. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

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