研究者詳細 - 金井　隆典

論文 - 金井　隆典

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Immunological homeostasis for understanding inflammatory bowel diseases

Kanai Takanori, Watanabe Mamoru

Japan Medical Association Journal 48 （ 12 ） 593 - 600 2005年12月

ISSN 1346-8650

Inflammatory bowel diseases are thought to be caused by a complex interaction of genetic, immunological, and environmental factors. The involvement of immunological factors in the etiology of inflammatory bowel diseases is suggested by various facts, such as 1) the effectiveness of immunosuppressive agents, steroids, and anti-TNF-α antibody; 2) the presence of autoantibodies, and 3) the spontaneous development of chronic colitis in mice lacking a single immunity-related gene, e.g., IL-2 or TGF-β. In particular, the treatment of Crohn's disease using anti-TNF-α antibody has been applied to clinical practice with satisfactory clinical results all over the world. This article describes the immunological pathology of inflammatory bowel diseases as autoimmune diseases, and outlines prospective new treatment methods based on the nature of the disease.

A novel apoptosis-inducing monoclonal antibody (anti-LHK) against a cell surface antigen on colon cancer cells

Matsukawa Hidehiko, Kanai Takanori, Naganuma Makoto, Kamada Nobuhiko, Hisamatsu Tadakazu, Takaishi Hiromasa, Ogata Haruhiko, Mukai Makio, Ishii Hiromasa, Mimori Tsuneyo, Watanabe Mamoru, Hibi Toshifumi

Journal of Gastroenterology 40 （ 10 ） 945 - 955 2005年10月

ISSN 0944-1174

Background. Apoptosis is a crucial element in the behavior of mammalian cells in many different situations. We here report the establishment of a novel monoclonal antibody (anti-LHK mAb) that has apoptosis-inducing activity against colon cancer Colo205 cells. Methods. The mechanism of anti-LHK mAb-induced cell death was assessed by microscopic morphology, Annexin V/Hoechst 33528 staining, and detection of DNA fragmentation. The molecular weight of LHK antigen was determined by Western blotting. Growth inhibition of Colo205 cells induced by anti-LHK mAb was determined by in vitro and in vivo studies. Results. Anti-LHK reacted with a 70-kDa antigen and completely blocked the proliferation of Colo205 cells bearing LHK in vitro in a manner characteristic of apoptosis. Strikingly, anti-LHK mAb suppressed tumor growth in a murine peritoneal dissemination model. Conclusions. LHK antigen, which is restricted to epithelial cells, may be a novel death receptor that plays a critical role in controlling the growth, invasion, and metastasis of human colon cancer cells. © Springer-Verlag Tokyo 2005.

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New concept of cell therapy using regulatory T cells for the treatment of inflammatory bowel disease

Kanai Takanori, Watanabe Mamoru

Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology. 102 （ 9 ） 1132 - 1138 2005年09月

ISSN 0446-6586

Regulation of murine chronic colitis by CD4⁺CD25^- programmed death-1⁺ T cells

Totsuka Teruji, Kanai Takanori, Makita Shin, Fujii Rei, Nemoto Yasuhiro, Oshima Shigeru, Okamoto Ryuichi, Koyanagi Akemi, Akiba Hisaya, Okumura Ko, Yagita Hideo, Watanabe Mamoru

European Journal of Immunology 35 （ 6 ） 1773 - 1785 2005年06月

ISSN 0014-2980

Naturally arising CD4⁺CD25⁺ regulatory T (T_R) cells are engaged in the maintenance of self tolerance and prevention of autoimmune diseases. However, accumulating evidence suggests that a fraction of peripheral CD4⁺CD25^- T cells also possesses regulatory activity. Programmed death-1 (PD-1) is a new member of the CD28/CTLA-4 family, which has been implicated in the maintenance of peripheral self tolerance. Here, we identified a subpopulation of CD4⁺CD25^-PD-1⁺ T cells in the spleen of naive mice that constitutively expressed CTLA-4 and FoxP3 and was hypoproliferative in response to anti-CD3 antibody stimulation in vitro. However, the CD4⁺CD25^-PD-1⁺ T cells uniquely produced large amounts of IL-4 and IL-10 in response to anti-CD3 and anti-CD28 mAb stimulation, unlike the CD4⁺CD25⁺ T_R cells. The CD4⁺CD25^-PD-1⁺ T cells exhibited a suppressor activity against the proliferation of anti-CD3 antibody-stimulated CD4⁺CD25^-PD-1^- T cells in vitro, which was partially abrogated by anti-CTLA-4 mAb, but not by anti-IL-10 or anti-PD-1 mAb. Remarkably, the CD4⁺CD25^-PD-1⁺ T cells inhibited the development of colitis induced by adoptive transfer of CD4⁺CD45RB^high T cells into C.B17-scid/scid mice, albeit to a lesser extent than CD4⁺CD25⁺ T_R cells, in a CTLA-4-dependent manner. These results indicate that the CD4⁺CD25^-PD-1⁺ T cells contain substantial amounts of T_R cells that are involved in the maintenance of peripheral tolerance. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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Increase of bone marrow-derived secretory lineage epithelial cells during regeneration in the human intestine

Matsumoto Tomoko, Okamoto Ryuichi, Yajima Tomoharu, Mori Takehiko, Okamoto Shinichiro, Ikeda Yasuo, Mukai Makio, Yamazaki Motomi, Oshima Shigeru, Tsuchiya Kiichiro, Nakamura Tetsuya, Kanai Takanori, Okano Hideyuki, Inazawa Johji, Hibi Toshifumi, Watanabe Mamoru

Gastroenterology 128 （ 7 ） 1851 - 1867 2005年06月

ISSN 0016-5085

Background & Aims: We have previously reported that bone marrow (BM)-derived cells contribute to the regeneration of the human intestinal epithelium. To analyze further how these cells arise, proliferate, and differentiate as epithelial cells, histologic analysis was conducted using endoscopic specimens. Methods: Thirty biopsy specimens from 14 female, sex-mismatched BM-transplantation recipients were examined. BM-derived cells were identified by fluorescent in situ hybridization (FISH) for the Y chromosome and immunohistochemistry. Multicolor FISH was used to exclude cell fusion. These cells were further analyzed for various differentiation or proliferation markers. Results: No evidence of cell fusion was detected. BM-derived cells did not distribute within the crypt as stem cells and rarely expressed Musashi-1. However, BM-derived epithelial cells frequently expressed Ki-67, and some of these cells appeared as pairs of adjacent cells. These cells also expressed markers of all 4 lineages of terminally differentiated cells. During regeneration following graft-vs-host disease, the number of BM-derived cells was substantially increased within Ki-67-positive cells. Interestingly, the number of cells expressing markers for secretory lineage cells was significantly increased within BM-derived cells. This change was unique for BM-derived cells, resulting in a significantly increased proportion of BM-derived cells among secretory lineage cells. Conclusions: BM-derived epithelial cells arise via a mechanism other than cell fusion and rarely give rise to stem cells. However, a small proportion of these cells express proliferation markers, and a majority reside as terminally differentiated cells. During regeneration BM-derived cells increase as secretory lineage cells, thereby contributing to restore epithelial functions. © 2005 by the American Gastroenterological Association.

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IRF-1 mediates upregulation of LMP7 by IFN-γ and concerted expression of immunosubunits of the proteasome

Namiki Shin, Nakamura Tetsuya, Oshima Shigeru, Yamazaki Motomi, Sekine Yuko, Tsuchiya Kiichiro, Okamoto Ryuichi, Kanai Takanori, Watanabe Mamoru

FEBS Letters 579 （ 13 ） 2781 - 2787 2005年05月

ISSN 0014-5793

An immunoproteasome subunit low molecular weight protein 7 (LMP7) plays critical roles in major histocompatibility complex class I antigen processing; however, the mechanism for its expression has remained unclear. We demonstrate that interferon (IFN) regulatory factor-1 (IRF-1) has a pivotal role in IFN-γ-dependent LMP7 expression, as was shown for the other two immunosubunits. A tetracycline-inducible system for IRF-1 revealed its function in the LMP7 expression, and a genomic region functionally interacting with IRF-1 was also determined. Furthermore, the role of IRF-1 in IFN-γ-inducible LMP7 transcription was confirmed by employing small interfering RNA experiments and IRF-1-/- mice. These results suggest that IRF-1 acts as a master regulator for the concerted expression of immunoproteasome components. © 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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IL-7 exacerbates chronic colitis with expansion of memory IL-7R ^high CD4⁺ mucosal T cells in mice

Okada Eriko, Yamazaki Motomi, Tanabe Masanobu, Takeuchi Tsutomu, Nanno Masanobu, Oshima Shigeru, Okamoto Ryuichi, Tsuchiya Kiichiro, Nakamura Tetsuya, Kanai Takanori, Hibi Toshifumi, Watanabe Mamoru

American Journal of Physiology - Gastrointestinal and Liver Physiology 288 （ 4 51-4 ） 2005年04月

ISSN 0193-1857

We have previously demonstrated that mucosal CD4⁺ T cells expressing high levels of IL-7 receptor (IL-7R^high) are pathogenic cells responsible for chronic colitis. Here we investigate whether IL-7 is directly involved in the expansion of IL-7R^high memory CD4 ⁺ mucosal T cells and the exacerbation of colitis. We first showed that CD4⁺ lamina propria lymphocytes (LPLs) from wild-type, T cell receptor-α-deficient (TCR-α^-/-), and recombinase- activating gene (RAG)-2^-/--transferred mice with or without colitis showed phenotypes of memory cells, but only CD4⁺ LPLs from colitic mice showed IL-7R^high. In vitro stimulation by IL-7, but not by IL-15 and thymic stromal lymphopoietin, enhanced significant proliferative responses and survival of colitic CD4⁺, but not normal CD4⁺ LPLs. Importantly, in vivo administration of IL-7 mice accelerated the expansion of IL-7R^high memory CD4⁺ LPLs and thereby exacerbated chronic colitis in RAG-2^-/- mice transferred with CD4⁺ LPLs from colitic TCR-α^-/- mice. Conversely, the administration of anti-IL-7R monoclonal antibody significantly inhibited the development of TCR-α^-/- colitis with decreased expansion of CD4⁺ LPLs. Collectively, the present data indicate that IL-7 is essential for the expansion of pathogenic memory CD4⁺ T cells under pathological conditions. Therefore, therapeutic approaches targeting the IL-7R pathway may be feasible in the treatment of human inflammatory bowel disease. Copyright © 2005 the American Physiological Society.

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Clinical application of human CD4⁺CD25⁺ regulatory T cells for the treatment of inflammatory bowel diseases

Kanai Takanori, Watanabe Mamoru

Expert Opinion on Biological Therapy 5 （ 4 ） 451 - 462 2005年04月

ISSN 1471-2598

As our understanding of the immunological and genetic basis of inflammatory bowel disease (IBD) grows, potential therapeutic options are being developed at a rapid pace. Nevertheless, new drugs for IBD are needed because about half of all patients with severe ulcerative colitis (UC) eventually undergo colectomy, and a significant part of Crohn's disease (CD) patients do not respond to standard medical therapies, including immunosuppressants and TNF-α neutralising antibodies, or suffer from significant side effects. Finally, recurrence of disease activity following remission is frequent in both UC and CD, and there is an unmet need for effective maintenance strategies. It is well-known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only does active suppression by regulatory T (T_R) cells play an important role in the normal intestinal homeostasis, but also its dysregulation might lead to the development of IBD. T_R cells are functional subsets of T cells that downregulate adaptive immune responses by interfering with the activation of dendritic cells and proliferation of T cells. From experimental work it is now clear that T_R cells play a critical role in maintaining immune homeostasis, and several therapeutic approaches have been targeted at the induction of T _R cells in order to control mucosal inflammation. Before using T _R cells clinically as living immunosuppressants for the treatment of IBD, however, we have to pass many critical checkpoints, such as the in vitro expansion of T_R cells and the confirmation of their safety. This paper will discuss recently gained knowledge of human T_R cells and the possibility of their clinical usages as a new strategy for the treatment of IBD. © 2005 Ashley Publications Ltd.

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MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis

Araki Akihiro, Kanai Takanori, Ishikura Takahiro, Makita Shin, Uraushihara Koji, Iiyama Ryoichi, Totsuka Teruji, Takeda Kiyoshi, Akira Shizuo, Watanabe Mamoru

Journal of Gastroenterology 40 （ 1 ） 16 - 23 2005年01月

ISSN 0944-1174

Background: Gut commensal microbes affect the development and activation of the mucosal and systemic immune systems. However, the exact molecular mechanism of these microbes that is involved in the development of colitis remains unclear. Methods: The present study was conducted to determine the distinct role of the innate immune system in the development of a dextran sulfate sodium (DSS) colitis model in MyD88^-/- mice, because myeloid differentiation protein (MyD88) is a major adaptor molecule essential for signaling via Toll-like receptors (TLRs). To this end, MyD88^-/- and wild-type (WT) mice received sterile distilled water containing 1.2% DSS for 8 days. The survival rate, total clinical score (body weight loss, stool consistency, and rectal bleeding), colon length, and histological score were assessed. The expression of surface markers (F4/80 and CD4) on infiltrating lamina propria mononuclear cells was analyzed immunohistochemistrically. Results: MyD88^-/- mice exhibited increased susceptibility to DSS-induced colitis, as reflected by significantly higher lethality and higher clinical and histological scores, and more severe colonic shortening compared to WT mice. Immunohistochemical analysis revealed a significant increase of both F4/80⁺ macrophages and CD4⁺ T cells in the inflamed mucosa in DSS-fed MyD88^-/- mice compared to DSS-fed WT mice. Conclusions: These findings suggest that, via MyD88 signaling, the innate immune system in the gut plays an important protective role in colitis. © Springer-Verlag Tokyo 2005.

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Clinical significance of microsatellite instability in the inflamed mucosa for the prediction of colonic neoplasms in patients with ulcerative colitis

Tahara Toshiyuki, Inoue Nagamu, Hisamatsu Tadakazu, Kashiwagi Kazuhiro, Takaishi Hiromasa, Kanai Takanori, Watanabe Mamoru, Ishii Hiromasa, Hibi Toshifumi

Journal of Gastroenterology and Hepatology (Australia) 20 （ 5 ） 710 - 715 2005年

ISSN 0815-9319

Background and Aim: Although molecular mechanisms underlying ulcerative colitis (UC)-associated neoplasms have been studied for years, understanding of these mechanisms remains incomplete and no good predictable marker for development of colonic neoplasms in patients with UC has been established. The aim of this study was to assess if microsatellite instability (MSI) contributes to the development of colonic neoplasms in patients with UC. Methods: We have examined MSI in chronic inflamed and neoplastic colonic mucosa of UC patients. We have also obtained serial biopsied colonic tissues retrospectively 2-12 years before the final diagnosis from patients with high level MSI (MSI-H+) UC-associated neoplasms, and analyzed MSI using them at different periods. Results: Eight of 12 UC-associated colon cancers (67%), four of six UC-associated high grade dysplasias (67%), and two of six UC-associated low grade dysplasias (33%) revealed MSI-H+ phenotypes. In contrast, 15 of 59 lesions (25%) in inflamed UC mucosa without colonic neoplasm revealed MSI-H+. Interestingly, all four patients with MSI-H+ phenotypes at the final diagnosis of UC-associated colon cancer or dysplasia had already had MSI-H+ at the stage of chronic colitis, 2-12 years before the final diagnosis. Conclusion: These results support the notion that MSI contributes to the carcinogenesis of UC-associated neoplasms, and indicate that this analysis in inflamed colonic mucosa at surveillance colonoscopy is useful for identifying UC patients who have high risk for neoplastic progression. © 2005 Blackwell Publishing Asia Pty Ltd.

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Immune responses in intestinal mucosa

Kanai Takanori, Watanabe Mamoru

Nippon rinsho. Japanese journal of clinical medicine 63 Suppl 4 459 - 467 2005年

ISSN 0047-1852

CD4⁺CD25^bright T cells in human intestinal lamina propria as regulatory cells

Makita Shin, Kanai Takanori, Oshima Shigeru, Uraushihara Koji, Totsuka Teruji, Sawada Taisuke, Nakamura Tetsuya, Koganei Kazutaka, Fukushima Tsuneo, Watanabe Mamoru

Journal of Immunology 173 （ 5 ） 3119 - 3130 2004年09月

ISSN 0022-1767

It is well known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only active suppression by regulatory T cells plays an important role in the normal intestinal homeostasis, but also its dysregulation leads to the development of inflammatory bowel disease. In this study, we demonstrate that the CD4⁺CD25 ^bright T cells reside in the human intestinal lamina propria (LP) and functionally retain regulatory activities. All human LP CD4⁺ T cells regardless of CD25 expression constitutively expressed CTLA-4, glucocorticoid-induced TNFR family-related protein, and Foxp3 and proliferate poorly. Although LP CD4⁺CD25^- T cells showed an activated and anergic/memory phenotype, they did not retain regulatory activity. In LP CD4⁺CD25⁺ T cells, however, cells expressing CD25 at high levels (CD4⁺CD25^bright) suppressed the proliferation and various cytokine productions of CD4⁺CD25^- T cells. LP CD4⁺CD25^bright T cells by themselves produced fewer amounts of IL-2, IFN-γ, and IL-10. Interestingly, LP CD4 ⁺CD25^bright T cells with regulatory T activity were significantly increased in patients with active inflammatory bowel disease. These results suggest that CD4⁺CD25^bright T cells found in the normal and inflamed intestinal mucosa selectively inhibit the host immune response and therefore may contribute to the intestinal immune homeostasis.

T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction or Th1 mediated immunopathology in Crohn's disease

Matsuoka K., Inoue N., Sato T., Okamoto S., Hisamatsu T., Kishi Y., Sakuraba A., Hitotsumatsu O., Ogata H., Koganei K., Fukushima T., Kanai T., Watanabe M., Ishii H., Hibi T.

Gut 53 （ 9 ） 1303 - 1308 2004年09月

ISSN 0017-5749

Background and aims: Many lines of evidence suggest that T helper cell type 1 (Th1) immune responses predominate in Crohn's disease (CD). Recently, a novel transcription factor T-box expressed in T cells (T-bet) has been reported as the master regulator of Th1 development. This study was designed to investigate the role of T-bet and proinflammatory cytokines in Th1 mediated immunopathology in CD. Materials: CD4+ lamina propria mononuclear cells (LPMCs) were isolated from surgically resected specimens (CD, n = 10; ulcerative colitis (UC), n = 10; normal controls (NL), n = 5). Methods: (1) T-bet expression of CD4+ LPMCs was examined by quantitative real time polymerase chain reaction and western blotting. (2) T-bet expression of LPMCs stimulated by interleukin (IL)-12/IL-18 was analysed by western blotting. (3) Interferon γ (IFN-γ) production and T-bet expression of CD4+ peripheral blood mononuclear cells (PBMCs) were examined with or without stimulation by anti-CD3/CD28 monoclonal antibodies and/or IL-12. Results: (1) T-bet expression of CD4+ LPMCs was increased in CD compared with UC and NL. (2) Synergistically, augmentation of IFN-γ production by IL-12/IL-18 was independent of T-bet expression in LPMCs. (3) T-bet was induced by T cell receptor stimulation in CD4+ PBMCs. T-bet induction correlated with IFN-γ production and with augmentation of surface expressed IL-12 receptor β2. Conclusions: T-bet induction by antigenic stimulation and subsequent stimulation by macrophage derived IL-12/IL-18 are important for establishing Th1 mediated immunopathology in CD.

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Interferon regulatory factor 1 (IRF-1) and IRF-2 distinctively up-regulate gene expression and production of interleukin-7 in human intestinal epithelial cells

Oshima Shigeru, Nakamura Tetsuya, Namiki Shin, Okada Eriko, Tsuchiya Kiichiro, Okamoto Ryuichi, Yamazaki Motomi, Yokota Takanori, Aida Masatoshi, Yamaguchi Yuki, Kanai Takanori, Handa Hiroshi, Watanabe Mamoru

Molecular and Cellular Biology 24 （ 14 ） 6298 - 6310 2004年07月

ISSN 0270-7306

Intestinal epithelial cell-derived interleukin (IL)-7 functions as a pleiotropic and nonredundant cytokine in the human intestinal mucosa; however, the molecular basis of its production has remained totally unknown. We here showed that human intestinal epithelial cells both constitutively and when induced by gamma interferon (IFN-γ) produced IL-7, while several other factors we tested had no effect. Transcriptional regulation via an IFN regulatory factor element (IRF-E) on the 5′ flanking region, which lacks canonical core promoter sequences, was pivotal for both modes of IL-7 expression. IRF-1 and IRF-2, the latter of which is generally known as a transcriptional repressor, were shown to interact with IRF-E and transactivate IL-7 gene expression in an IFN-γ-inducible and constitutive manner, respectively. Indeed, tetracycline-inducible expression experiments revealed that both of these IRF proteins up-regulated IL-7 protein production, and their exclusive roles were further confirmed by small interfering RNA-mediated gene silencing systems. Moreover, these IRFs displayed distinct properties concerning the profile of IL-7 transcripts upon activation and expression patterns within human colonic epithelial tissues. These results suggest that the functional interplay between IRF-1 and IRF-2 serves as an elaborate and cooperative mechanism for timely as well as continuous regulation of IL-7 production that is essential for local immune regulation within human intestinal mucosa.

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Hepatitis C virus infection in human liver tissue engrafted in mice with an infectious molecular clone

Maeda Norio, Watanabe Mamoru, Okamoto Susumu, Kanai Takanori, Yamada Taketo, Hata Jun Ichi, Hozumi Nobumichi, Katsume Asao, Nuriya Hideko, Sandhu Jasbir, Ishii Hiromasa, Kohara Michinori, Hibi Toshifumi

Liver International 24 （ 3 ） 259 - 267 2004年06月

ISSN 1478-3223

Background/Aims: Recent advances in molecular cloning of hepatitis C virus (HCV) have enabled us to apply some available HCV molecular clones to experimental studies. However, these investigations have been restricted to chimpanzee models or 'isolated hepatocytes' from tree shrews. In this study, we engrafted 'human liver tissue' into immunodeficient mice and investigated HCV infection using an infectious molecular clone. Methods: Human liver tissues from normal (non-HCV-infected) liver were transplanted into non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. We then inoculated the mice with sera from HCV-infected patients or an infectious HCV molecular clone. HCV RNA was assessed using nested reverse-transcription polymerase chain reaction (PCR), real-time detection PCR and in situ PCR. Results: Without any growth support, normal human liver tissues survived in NOD/SCID mice while maintaining the original viable hepatic architecture. HCV RNA was detected in the mice serum until the fourth week after the inoculation. In situ PCR and immunohistochemistry clearly demonstrated positive signals for HCV in the cytoplasm of infected hepatocytes, while the engrafted human liver tissues showed no apparent morphological changes indicative of infection. Conclusion: Engraftment of human liver tissues into NOD/SCID mice and infection with HCV molecular clones could offer a reverse genetic strategy for HCV infection. Copyright © Blackwell Munksgaard 2004.

Ectopic CD40 Ligand Expression on B Cells Triggers Intestinal Inflammation

Kawamura Takahiro, Kanai Takanori, Dohi Taeko, Uraushihara Koji, Totsuka Teruji, Iiyama Ryoichi, Taneda Chikara, Yamazaki Motomi, Nakamura Tetsuya, Higuchi Tetsuya, Aiba Yuichi, Tsubata Takeshi, Watanabe Mamoru

Journal of Immunology 172 （ 10 ） 6388 - 6397 2004年05月

ISSN 0022-1767

Several studies indicate that CD4⁺ T cells, macrophages, and dendritic cells initially mediate intestinal inflammation in murine models of human inflammatory bowel disease. However, the initial role of B cells in the development of intestinal inflammation remains unclear. In this study we present evidence that B cells can trigger intestinal inflammation using transgenic (Tg) mice expressing CD40 ligand (CD40L) ectopically on B cells (CD40L/B Tg). We demonstrated that CD40L/B Tg mice spontaneously developed severe transmural intestinal inflammation in both colon and ileum at 8-15 wk of age. In contrast, CD40L/B TgxCD40^-/- double-mutant mice did not develop colitis, indicating the direct involvement of CD40-CD40L interaction in the development of intestinal inflammation. The inflammatory infiltrates consisted predominantly of massive aggregated, IgM-positive B cells. These mice were also characterized by the presence of anti-colon autoantibodies and elevated IFN-γ production. Furthermore, although mice transferred with CD4⁺ T cells alone or with both CD4⁺ T and B220 ⁺ B cells, but not B220⁺ cells alone, from diseased CD40L/B Tg mice, develop colitis, mice transferred with B220⁺ B cells from diseased CD40L/B Tg mice and CD4⁺ T cells from wild-type mice also develop colitis, indicating that the Tg B cells should be a trigger for this colitis model, whereas T cells are involved as effectors. As it has been demonstrated that CD40L is ectopically expressed on B cells in some autoimmune diseases, the present study suggests the possible contribution of B cells in triggering intestinal inflammation in human inflammatory bowel disease.

Human intestinal epithelial cell-derived interleukin (IL)-18, along with IL2, IL-7 and IL-15, is a potent synergistic factor for the proliferation of intraepithelial lymphocytes

Okazawa A., Kanai T., Nakamaru K., Sato T., Inoue N., Ogata H., Iwao Y., Ikeda M., Kawamura T., Makita S., Uraushihara K., Okamoto R., Yamazaki M., Kurimoto M., Ishii H., Watanabe M., Hibi T.

Clinical and Experimental Immunology 136 （ 2 ） 269 - 276 2004年05月

ISSN 0009-9104

Intestinal epithelial cell (IEC)-derived cytokines, such as stem cell factor (SCF), interleukin (IL)-7 and IL-15 are known to be required for the development of intestinal intraepithelial lymphocytes (IELs). A newly described cytokine, IL-18, has also been shown to be produced by intestinal epithelial cells. To demonstrate the functional effects of IL-18 on human IELs, we assessed IL-18/IL-18 receptor expression in IEC/IEL and proliferation following stimulation of intestinal IELs by IL-18. IL-18 transcripts were detected both in freshly isolated human colonie epithelial cells and in various colonie epithelial cell lines. IL-18 protein was also detected by ELISA and flow cytometric analysis using antihuman IL-18-specific monoclonal antibody (MoAb). Furthermore, IELs constitutively expressed the IL-18 receptor in addition to the IL-2 and IL-7 receptors. More importantly, IL-18 augmented significant proliferative responses of IEL in combination with IL-2, IL-7 and IL-15 both in the presence and in absence of anti-CD3 MoAb. These results suggest that IL-18 might play a crucial role in the proliferation and maintenance of intestinal IELs.

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Hyperexpression of Inducible Costimulator and Its Contribution on Lamina Propria T Cells in Inflammatory Bowel Disease

Sato Toshiro, Kanai Takanori, Watanabe Mamoru, Sakuraba Atsushi, Okamoto Susumu, Nakai Takaaki, Okazawa Akira, Inoue Nagamu, Totsuka Teruji, Yamazaki Motomi, Kroczek Richard A., Fukushima Tsuneo, Ishii Hiromasa, Hibi Toshifumi

Gastroenterology 126 （ 3 ） 829 - 839 2004年03月

ISSN 0016-5085

Background & Aims: To investigate the role of inducible costimulator (ICOS), a new member of the CD28 family involved in regulation of T-cell activation and chronic intestinal inflammation, we assessed its expression and functional role in patients with inflammatory bowel disease (IBD). Methods: Expression of ICOS, CD28, and cytotoxic T-lymphocyte antigen (CTLA) 4 on intestinal lamina propria mononuclear cells (LPMC) from patients with ulcerative colitis (UC), Crohn's disease (CD), and normal controls was determined using flow cytometry and immunohistochemistry. Expressions of the ICOS ligand, B7h, on lamina propria B cells, macrophages, and epithelial cells (EC) in the intestinal mucosa were also determined using flow cytometry. The functional costimulatory effect of ICOS on LPMC was assessed by the proliferative response and cytokine production. Results: CD4⁺ LPMC expressing ICOS was significantly increased in the inflamed mucosa of IBD patients but not in inflammatory or normal controls. B7h was also significantly up-regulated on B cells, macrophages, and EC in inflamed mucosa of IBD patients. Proliferative responses of anti-CD3/ICOS costimulation were significantly higher compared with those of anti-CD3 monoclonal antibody (mAb) alone. Anti-CD3/ICOS-stimulated-LPMC from UC secreted significantly increased amounts of interleukin (IL)-5 among the 3 groups. In contrast, anti-CD3/ICOS-stimulated-LPMC from CD secreted significantly increased amounts of interferon (IFN)-γ in the presence of IL-12. Conclusions: Highly expressed ICOS in activated CD4⁺ LPMC of IBD patients contributes to the dysregulated immune responses in IBD. Because ICOS hyperexpression was limited to inflammatory sites in IBD patients, ICOS would be a feasible therapeutic target for the treatment of IBD.

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Erratum

Uraushihara Koji, Kanai Takanori, Ko Kwibeom, Totsuka Teruji, Makita Shin, Iiyama Ryoichi, Nakamura Tetsuya, Watanabe Mamoru

Journal of Immunology 172 （ 1 ） 717 2004年01月

ISSN 0022-1767

Regulatory T cells and inflammatory bowel diseases

Kanai Takanori, Watanabe Mamoru

Nihon Rinshō Men'eki Gakkai kaishi = Japanese journal of clinical immunology 27 （ 5 ） 302 - 308 2004年

ISSN 0911-4300

Crohn's disease and ulcerative colitis are two major forms of human inflammatory bowel diseases (IBD). Their etiology is unknown, but increasing evidence indicate that immune mechanisms play an important role. It is well known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only active suppression by regulatory T (TR) cells plays an important role in the normal intestinal homeostasis, but also its dysregulation leads to the development of IBD. This article reviews the unique aspects of TR cells and discuss how these control the intestinal homeostasis.

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