Details of a Researcher - Kanai, Takanori

Papers - Kanai, Takanori

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Hyperexpression of inducible costimulator on lamina propria mononuclear cells in rat dextran sulfate sodium colitis

Ishii Kenichi, Kanai Takanori, Totsuka Teruji, Uraushihara Koji, Ishikura Takahiro, Yamazaki Motomi, Okamoto Ryoici, Araki Akihiro, Miyata Tatsuya, Tezuka Katsuaki, Nakamura Tetsuya, Watanabe Mamoru

Journal of Gastroenterology and Hepatology (Australia) 19 ( 2 ) 174 - 181 2004

ISSN 0815-9319

Background and Aims: The authors have previously shown that a third member of the CD28 family, inducible costimulator (ICOS), was increased in the inflamed intestinal mucosa of murine experimental colitis, and that the blockade of ICOS ameliorated the development of colitis. However, the role of ICOS in rat intestinal inflammation and its expression profile remains unclear. In the present study, the authors investigated the involvement of ICOS in the development of rat dextran sulfate sodium (DSS)-induced colitis, and the therapeutic potential of anti-ICOS monoclonal antibody (mAb) in colitis. Methods: The authors first examined expression of ICOS protein in normal rat by immunohistochemistry and flow cytometry. Sprague-Dawley rats were fed 3.0% DSS. The expression of ICOS on infiltrating lamina propria mononuclear cells and splenocytes were examined. The DSS-fed rats were then administered anti-ICOS mAb to test its effect on the development of colitis. Results: Unlike mice and human, ICOS was expressed on a part of CD4⁺ T-cells from the thymus, spleen, mesenteric lymph nodes and lamina propria. Levels of ICOS on CD4 ₊ T-cells from the spleen and colonic lamina propria were significantly upregulated after Concanavalin A (Con A) stimulation. In addition, ICOS was also upregulated on CD4⁺ T-cells from DSS-fed rats compared with those from non DSS-fed rats. However, anti-ICOS mAb did not ameliorate the development of both acute and chronic DSS colitis. Conclusion: These results suggest that the different expression of ICOS in rats plays a distinct role in rat intestinal inflammation. © 2004 Blackwell Publishing Asia Pty Ltd.

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Normal Development of the Gut-Associated Lymphoid Tissue Except Peyer's Patch in MyD88-Deficient Mice

Iiyama R., Kanai T., Uraushihara K., Ishikura T., Makita S., Totsuka T., Yamazaki M., Nakamura T., Miyata T., Yoshida H., Takeuchi O., Hoshino K., Takeda K., Ishikawa H., Akirat S., Watanabe M.

Scandinavian Journal of Immunology 58 ( 6 ) 620 - 627 2003.12

ISSN 0300-9475

MyD88 is a key adaptor molecule for signalling via Toll-like receptors (TLRs) and the response to gut commensal microbes. To investigate the role of TLRs/MyD88 pathway in the development of the gut-associated lymphoid tissue (GALT), we examined the development of Peyer's patches (PPs) and cryptopatch (CP), and also one of effector compartment, intraepithelial lymphocyte (IEL) in MyD88 ^-/-, TLR2 ^-/- and TLR4 ^-/- mice. In MyD88 ^-/- mice, the organogenesis of PPs was not disturbed. However, PPs in 2-week-old MyD88 ^-/- mice were significantly smaller than those in MyD88 ^+/- mice. Also, in 2-week-old TLR4 ^-/-, but not TLR2 ^-/- mice, PPs did not develop rapidly. The development of PPs in MyD88 ^-/- and TLR4 ^-/- mice was completely recovered in 10 weeks. PP cells from MyD88 ^-/- mice showed significant decrease in proliferation when stimulated with lipopolysaccharide. The development of CP and IEL was also normal in 10-week-old MyD88 ^-/- mice. These results suggest that the TLRs/MyD88 pathway might be involved in the development of PPs only at early postnatal stage, and TLRs/MyD88-independent signalling is critically involved in the development of GALT in adult mice.

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Blockade of B7-H1 suppresses the development of chronic intestinal inflammation

Kanai Takanori, Totsuka Teruji, Uraushihara Koji, Makita Shin, Nakamura Tetsuya, Koganei Kazutaka, Fukushima Tsuneo, Akiba Hisaya, Yagita Hideo, Okumura Ko, Machida Utako, Iwai Hideyuki, Azuma Miyuki, Chen Lieping, Watanabe Mamoru

Journal of Immunology 171 ( 8 ) 4156 - 4163 2003.10

ISSN 0022-1767

A newly identified costimulatory molecule, programmed death-1 (PD-1), provides a negative signal that is essential for immune homeostasis. However, it has been suggested that its ligands, B7-H1 (PD-L1) and B7-dendritic cells (B7-DC; PD-L2), could also costimulate T cell proliferation and cytokine secretion. Here we demonstrate the involvement of PD-1/B7-H1 and B7-DC interaction in the development of colitis. We first examined the expression profiles of PD-1 and its ligands in both human inflammatory bowel disease and a murine chronic colitis model induced by adoptive transfer of CD4 ⁺CD45RB^high T cells to SCID mice. Second, we assessed the therapeutic potential of neutralizing anti-B7-H1 and/or B7-DC mAbs using this colitis model. We found significantly increased expression of PD-1 on T cells and of B7-H1 on T, B, and macrophage/DCs in inflamed colon from both inflammatory bowel disease patients and colitic mice. Unexpectedly, the administration of anti-B7-H1, but not anti-B7-DC, mAb after transfer of CD4 ⁺CD45RB^high T cells suppressed wasting disease with colitis, abrogated leukocyte infiltration, and reduced the production of IFN-γ, IL-2, and TNF-α, but not IL-4 or IL-10, by lamina propria CD4⁺ T cells. These data suggest that the interaction of PD-1/B7-H1, but not PD-1/B7-DC, might be involved in intestinal mucosal inflammation and also show a possible role of interaction between B7-H1 and an as yet unidentified receptor for B7-H1 in inducing T cell activation.

The role of cryptopatch-derived intraepithelial lymphocytes in the development of chronic ileocecitis

Makita S., Kanai T., Matsumoto S., Iiyama R., Uraushihara K., Totsuka T., Yamazaki M., Nakamura T., Ishikawa H., Watanabe M.

Scandinavian Journal of Immunology 58 ( 4 ) 428 - 435 2003.10

ISSN 0300-9475

Lympho-haemopoietic progenitors residing in murine gut cryptopatches (CPs) have been shown to generate intestinal extrathymic intraepithelial lymphocytes (IELs). However, the role of CPs in the development of intestinal inflammation remains unclear. To investigate the role of CPs in the development of intestinal inflammation, we examined SAMP1/Yit mice, which spontaneously develop a chronic intestinal inflammation localized to the terminal ileum and cecum. Here, we showed the sharp correlation between the disease onset and the decreased number of CPs, resulting in decreased number of both thymus-independent IELs including T-cell receptor γδ⁺ (TCRγδ⁺) and CD8αα⁺TCRα β⁺ cells but not thymus-dependent CD8αβ ⁺TCRαβ⁺ and CD4⁺TCRαβ ⁺ cells in SAMP1/Yit mice. These data provide the first suggestion that thymus-independent IELs derived from CP might play protective role against the onset and the development of intestinal inflammation.

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Ameliorating effect of anti-Fas ligand MAb on wasting disease in murine model of chronic colitis

Dan N., Kanai T., Totsuka T., Iiyama R., Yamazaki M., Sawada T., Miyata T., Yagita H., Okumura K., Watanabe M.

American Journal of Physiology - Gastrointestinal and Liver Physiology 285 ( 4 48-4 ) 2003.10

ISSN 0193-1857

Fas/Fas ligand (FasL) interaction has been implicated in the pathogenesis of various diseases. To clarify the involvement of Fas/FasL in the pathogenesis of intestinal inflammation, we investigated the preventive and therapeutic effects of neutralizing anti-FasL monoclonal antibody (MAb) on the development of chronic colitis induced by adaptive transfer of CD4⁺CD45RB ^high T cells to SCID mice. Administration of anti-FasL MAb from 1 day after T cell transfer (prevention study) resulted in a significant improvement of clinical manifestations such as wasting and diarrhea. However, histological examination showed that mucosal inflammation in the colon, such as infiltration of T cells and macrophages, was not improved by the anti-FasL MAb treatment. In vitro studies showed that anti-FasL MAb did not inhibit IFN-γ production by anti-CD3/CD28-stimulated lamina propria CD4 ⁺ T cells but suppressed TNF-α and IL-1β production by lamina propria mononuclear cells. Therapeutic administration of anti-FasL MAb from 3 wk after T cell transfer also improved ongoing wasting disease but not intestinal inflammation. These results suggest that the Fas/FasL interaction plays a critical role in regulating systemic wasting disease but not local intestinal inflammation.

Mucosal T cells expressing high levels of IL-7 receptor are potential targets for treatment of chronic colitis

Yamazaki Motomi, Yajima Tomoharu, Tanabe Masanobu, Fukui Kazuto, Okada Eriko, Okamoto Ryuichi, Oshima Shigeru, Nakamura Tetsuya, Kanai Takanori, Uehira Masahiro, Takeuchi Tsutomu, Ishikawa Hiromichi, Hibi Toshifumi, Watanabe Mamoru

Journal of Immunology 171 ( 3 ) 1556 - 1563 2003.08

ISSN 0022-1767

The IL-7/IL-7R-dependent signaling pathway plays a crucial role in regulating the immune response in intestinal mucosa. Here we demonstrate the pivotal role of this pathway in the development and treatment of chronic colitis. T cells expressing high levels of IL-7R were substantially infiltrated in the chronic inflamed mucosa of TCR α-chain knockout mice and IL-7 transgenic mice. Transfer of mucosai T cells expressing high levels of IL-7R, but not T cells expressing low levels of IL-7R, from these mice into recombinase-activating gene-2^-/- mice induced chronic colitis. Selective elimination of T cells expressing high levels of IL-7R by administrating small amounts of toxin-conjugated anti-IL-7R Ab completely ameliorated established, ongoing colitis. These findings provide evidence that therapeutic approaches targeting mucosal T cells expressing high levels of IL-7R are effective in the treatment of chronic intestinal inflammation and may be feasible for use in the therapy of human inflammatory bowel disease.

Contrasting action of IL-12 and IL-18 in the development of dextran sodium sulphate colitis in mice

Takagi H., Kanai T., Okazawa A., Kishi Y., Sato T., Takaishi H., Inoue N., Ogata H., Iwao Y., Hoshino K., Takeda K., Akira S., Watanabe M., Ishii H., Hibi Toshifumi

Scandinavian Journal of Gastroenterology 38 ( 8 ) 837 - 844 2003.08

ISSN 0036-5521

Background: Interleukin (IL)-12 and IL-18 are major interferon (IFN)-γ-inducing factors that collaborate with each other. The present study was conducted to determine the distinct roles of IL-12 and IL-18 in the development of dextran sulphate sodium (DSS) colitis in mice. Methods: Colitis was induced in IL-12p35^-/-, IL-18^-/-, IL-18 receptor ^-/- and control mice with DSS. Clinical and histopathological analysis was conducted using survival rate, weight loss score, diarrhoea score, bloody stool score and histological score. In addition, cytokine production by lamina propria mononuclear cells (LPMCs) was examined using the specific enzyme-linked immunoassay. Results: IL-12p35^-/- mice developed only a mild disease associated with no lethality and few histopathological abnormalities. In contrast, IL-18^-/- and IL-18R^-/- mice developed more severe colitis associated with high lethality and more histopathological abnormalities compared with control mice. LPMCs from DSS-fed IL-18^-/- mice produced significantly higher amounts of IFN-γ, while LPMCs from DSS-fed IL-12^-/- mice produced lower amounts of IFN-γ and tumour necrosis factor (TNF)-α compared with control mice. Conclusion: These results suggest that IL-18 might function with manners different from IL-12 at some pathological conditions in the development of colitis.

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Interleukin-18 overproduction exacerbates the development of colitis with markedly infiltrated macrophages in interleukin-18 transgenic mice

Ishikura Takahiro, Kanai Takanori, Uraushihara Koji, Iiyama Ryoichi, Makita Shin, Totsuka Teruji, Yamazaki Motomi, Sawada Taisuke, Nakamura Tetsuya, Miyata Tatsuya, Kitahora Tetsuji, Hibi Toshifumi, Hoshino Tomoaki, Watanabe Mamoru

Journal of Gastroenterology and Hepatology (Australia) 18 ( 8 ) 960 - 969 2003.08

ISSN 0815-9319

Background and Aim: The authors have previously shown that production of interleukin (IL)-18 was increased in the inflamed mucosa of patients with Crohn's disease (CD) and blockade of IL-18 ameliorated the murine model of CD. This demonstrated that IL-18 plays a significant role during intestinal inflammation. However, the initial role of IL-18 during intestinal inflammation was unclear; therefore the susceptibility of IL-18 transgenic (Tg) mice to acute dextran sulfate sodium (DSS)-induced colitis was examined. Methods: Interleukin-18 Tg and wild-type (WT) mice were fed 2.0% of DSS for 8 days. The total clinical scores (bodyweight loss, stool consistency, and rectal bleeding), colon length and histological scores were assessed. The expressions of surface markers and IL-18 on infiltrating lamina propria mononuclear cells were analyzed immunohistochemistrically. Mesenteric lymph node (MLN) cells were isolated and the expressions of CD4⁺ T-cell activation markers (CD69, CD25 and IL18R) were analyzed by flow cytometry. Results: The IL-18 Tg mice exhibited an increased susceptibility to DSS-induced colitis, as shown by significantly increased clinical, histological scores, and more severe colonic shortening compared with WT mice. Immunohistochemical analysis revealed a significant increase of IL-18 production and CD11b⁺ macrophages but not CD4⁺T cells in the inflamed mucosa in DSS-fed IL-18 Tg compared with DSS-fed WT mice. Furthermore, MLN cells revealed no evidence of increased CD4⁺T-cell activation in DSS-fed IL-18 Tg. Conclusions: These findings suggest that IL-18 overproduction in the mucosa plays an important role in the marked infiltration of macrophages and exacerbates colitis in IL-18 Tg mice. © 2003 Blackwell Publishing Asia Pty Ltd.

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Regulation of murine inflammatory bowel disease by CD25⁺ and CD25^- CD4⁺ glucocorticoid-induced TNF receptor family-related gene⁺ regulatory T cells

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

Journal of Immunology 171 ( 2 ) 708 - 716 2003.07

ISSN 0022-1767

CD4⁺CD25⁺ regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance and prevention of autoimmune disease. However, accumulating evidence suggests that a fraction of the peripheral CD4⁺CD25^- T cell population also possesses regulatory activity in vivo. Recently, it has been shown glucocorticoid-induced TNFR family-related gene (GITR) is predominantly expressed on CD4⁺CD25⁺ regulatory T cells. In this study, we show evidence that CD4+GITR+ T cells, regardless of the CD25 expression, regulate the mucosal immune responses and intestinal inflammation. SCID mice restored with the CD4⁺GITR^- T cell population developed wasting disease and severe chronic colitis. Cotransfer of CD4⁺GITR⁺ population prevented the development of CD4⁺CD45RB^high T cell-transferred colitis. Administration of anti-GITR mAb-induced chronic colitis in mice restored both CD45RB^high and CD45RB^low CD4⁺ T cells. Interestingly, both CD4⁺CD25⁺ and CD4⁺CD25^- GITR⁺ T cells prevented wasting disease and colitis. Furthermore, in vitro studies revealed that CD4⁺CD25^-GITR⁺ T cells as well as CD4⁺CD25⁺GITR⁺ T cells expressed CTLA-4 intracellularly, showed anergic, suppressed T cell proliferation, and produced IL-10 and TGF-β. These data suggest that GITR can be used as a specific marker for regulatory T cells controlling mucosal inflammation and also as a target for treatment of inflammatory bowel disease.

The role of inducible co-stimulator (ICOS)/B7-related protein-1 (B7RP-1) interaction in the functional development of Peyer's patches

Iiyama R., Kanai T., Uraushihara K., Totsuka T., Nakamura T., Miyata T., Yagita H., Kushi A., Suzuki K., Tezuka K., Watanabe M.

Immunology Letters 88 ( 1 ) 63 - 70 2003.07

ISSN 0165-2478

T-cell co-stimulatory molecule, inducible co-stimulator (ICOS)/B7-related protein-1 (B7RP-1) interactions play an essential role of T-cell-dependent B-cell activation in peripheral lymphoid organs such as spleen and lymph nodes. Here, we investigate the role of ICOS/B7RP-1 interactions in the development of Peyer's patches (PPs). In ICOS^-/- mice, the number of PPs was not decreased, although PPs in ICOS^-/- mice were significantly reduced in size. Phenotypic analysis showed no obvious differences between ICOS^-/- and ICOS^+/- mice in the distribution of T-cells, B-cells, macrophages and dendritic cells. However, PNA⁺ cells characteristic of intestinal germinal centers were totally absent in ICOS^-/- mice. Moreover, production of IgA and IgG, but not IgM was significantly reduced in PPs in ICOS^-/- mice. These data suggest that ICOS/B7RP-1 interactions may not affect the organogenesis, but involve in the functional development of PPs. © 2003 Elsevier Science B.V. All rights reserved.

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A specific genetic alteration on chromosome 6 in ulcerative colitis-associated colorectal cancers

Ezaki Toshihiko, Watanabe Mamoru, Inoue Nagamu, Kanai Takanori, Ogata Haruhiko, Iwao Yasushi, Ishii Hiromasa, Hibi Toshifumi

Cancer Research 63 ( 13 ) 3747 - 3749 2003.07

ISSN 0008-5472

Various genetic alterations in ulcerative colitis (UC)-associated colorectal cancers (CRCs) have been reported. However, almost all studies have shown abnormalities of the known genes that have been demonstrated in sporadic CRCs. To identify novel genetic alterations, we selected unintentionally 35 microsatellite markers, and performed allelotype study in CRCs or dysplastic lesions from UC. High frequency of loss of heterozygosity (LOH; 62.5%) was detected on chromosome 6 (D6S468) but not on other chromosomes. With four additional microsatellite markers around the D6S468 locus, we determined the commonly deleted region between two loci, D6S1543 and D6S1580, in UC-associated CRCs and dysplasia. Interestingly, there was no LOH in this region in sporadic CRCs and severely inflamed lesions of longstanding and extensive UC without cancers. These results indicated the presence of novel tumor suppressor genes on chromosome 6 related to the carcinogenesis of UC but not to sporadic CSCs.

A case of chronic graft-versus-host disease (GVHD) colitis with multiple colon ulcers

Kubota Daisuke, Tozuka Teruji, Suzuki Shinji, Tamura Michiaki, Kanai Takanori, Dan Naoaki, Kurosaki Masayuki, Enomoto Nobuyuki, Miyata Tatsuya, Takizawa Toichiro, Okusa Toshifumi, Watanabe Mamoru

Gastroenterological Endoscopy 45 ( 6 ) 1044 - 1050 2003.06

ISSN 0387-1207

A rare case of chronic GVHD enterocolitis with multiple colon ulcers was reported. A 21-year-old man was admitted on May 2000, because of progressing diarrhea and abdominal pain. He had received allogenic bone marrow transplantation in August 1999. On admission, Colonoscopy showed multiple colon ulcers and mucosal edema. He was treated with antibiotics and virucide, but had no resolution both in clinically and endoscopically. We eventually diagnosed this case as chronic GVHD enterocolitis and treated with immunosuppressant. Endoscopic appearance was remarkably improved and diarrhea was disappeared.

Macrophage-derived IL-18 targeting for the treatment of Crohn's disease.

Kanai Takanori, Uraushihara Koji, Totsuka Teruji, Okazawa Akira, Hibi Toshifumi, Oshima Shigeru, Miyata Tatsuya, Nakamura Tetsuya, Watanabe Mamoru

Current drug targets. Inflammation and allergy 2 ( 2 ) 131 - 136 2003.06

ISSN 1568-010X

Crohn's disease is an inflammatory bowel disease associated with several changes in the immune system, including an increased number of infiltrating macrophages. These macrophages release a variety of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha, macrophage infiltrating factor (MIF), interleukin (IL)-6, IL-12 and IL-18, which are critically involved in the onset and the development of Crohn's disease. We here focus on the role of macrophages, especially macrophage-derived IL-18 in both patients with Crohn's disease and a murine model of Crohn's disease.

Therapeutic approaches to chronic intestinal inflammation by specific targeting of mucosal IL-7/IL-7R signal pathway.

Watanabe Mamoru, Yamazaki Motomi, Okamoto Ryuichi, Ohoka Shinya, Araki Akihiro, Nakamura Tetsuya, Kanai Takanori

Current drug targets. Inflammation and allergy 2 ( 2 ) 119 - 123 2003.06

ISSN 1568-010X

Inflammatory bowel disease is thought to result from inappropriate activation of mucosal immune responses. Intestinal epithelial cells produce interleukin (IL)-7 that serves as a regulatory factor for IL-7 receptor (IL-7R)(+) mucosal lymphocytes. The pivotal role of mucosal IL-7/IL-7R dependent signals in the activation of mucosal immune responses that lead to the development of chronic intestinal inflammation are demonstrated. Therapeutic approaches targeting IL-7/IL-7R signal pathway may be feasible in the treatment of inflammatory bowel disease.

Therapeutic effect of anti-OX40l and anti-TNF-α MAbs in a murine model of chronic colitis

Totsuka T., Kanai T., Uraushihara K., Iiyama R., Yamazaki M., Akiba H., Yagita H., Okumura K., Watanabe M.

American Journal of Physiology - Gastrointestinal and Liver Physiology 284 ( 4 47-4 ) 2003.04

ISSN 0193-1857

Interaction of OX40 (CD134) on T cells with its ligand (OX40L) on antigen-presenting cells has been implicated in pathogenic T cell activation. This study was performed to explore the involvement of OX40/OX40L in the development of T cell-mediated chronic colitis. We evaluated both the preventive and therapeutic effects of neutralizing anti-OX40L MAb on the development of chronic colitis in SCID mice induced by adoptive transfer of CD4⁺CD45RB^high T cells as an animal model of Crohn's disease. We also assessed the combination of anti-OX40L and anti-TNF-α MAbs to improve the therapeutic effect. Administration of anti-OX40L MAb markedly ameliorated the clinical and histopathological disease in preventive and therapeutic protocols. In vivo treatment with anti-OX40L MAb decreased CD4⁺ T cell infiltration in the colon and suppressed IFN-γ IL-2, and TNF-α production by lamina propria CD4⁺ T cells. The combination with anti-TNF-α MAb further improved the therapeutic effect by abolishing IFN-γ, IL-2, and TNF-α production by lamina propria CD4⁺ T cells. Our present results suggested a pivotal role of OX40/OX40L in the pathogenesis of T cell-mediated chronic colitis. The OX40L blockade, especially in combination with the TNF-α blockade, may be a promising strategy for therapeutic intervention of Crohn's disease.

Ameliorating effect of anti-inducible costimulator monoclonal antibody in a murine model of chronic colitis

Totsuka Teruji, Kanai Takanori, Iiyama Ryoichi, Uraushihara Koji, Yamazaki Motomi, Okamoto Ryuichi, Hibi Toshifumi, Tezuka Katsunari, Azuma Miyuki, Akiba Hisaya, Yagita Hideo, Okumura Ko, Watanabe Mamoru

Gastroenterology 124 ( 2 ) 410 - 421 2003.02

ISSN 0016-5085

Background & Aims: Inducible costimulator (ICOS)/B7RP-1 represents a newly described receptor/ligand pair involved in costimulation of T cells by antigen-presenting cells. We investigated the involvement of the ICOS/B7RP-1 interaction in the pathogenesis of colitis and the therapeutic potential of anti-ICOS monoclonal antibody (mAb) in experimental colitis. Methods: We administered anti-ICOS or anti-B7RP-1 mAb to mice with experimental colitis induced by transfer of CD4⁺CD45RB^high T cells from normal mice into SCID mice. The ability of CD4⁺CD45RB^high cells derived from ICOS-/- mice to induce colitis was assessed. Th2 cytokine production and apoptosis in infiltrating T cells was examined after administration of anti-ICOS mAb. Results: ICOS was strongly induced on CD4⁺ T cells, and B7RP-1 was expressed by macrophages in the inflamed mucosa of colitic mice. Anti-ICOS mAb, but not anti-B7RP-1, ameliorated chronic colitis when administered in prevention or therapeutic protocols. Transfer of CD4⁺CD45RB^high T cells from ICOS-/- mice induced colitis. Treatment with anti-ICOS mAb did not enhance the production of Th2 cytokines, but a single dose of anti-ICOS mAb induced massive apoptosis of infiltrating ICOS-expressing T cells. Conclusions: ICOS/B7RP-1 interactions are not required for the development of colitis. However, treatment with anti-ICOS mAb can prevent and reverse intestinal inflammation by inducing apoptosis of ICOS-expressing T lymphocytes.

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Mucosal T cells as a target for treatment of IBD

Watanabe Mamoru, Yamazaki Motomi, Kanai Takanori

Journal of Gastroenterology 38 ( SUPPL. 15 ) 48 - 50 2003

ISSN 0944-1174

Interleukin-7 (IL-7) is an indispensable cytokine for the development of lymphocyte lineage cells. However, the potential role of IL-7 in peripheral nonlymphoid tissues was unclear before our study. We have demonstrated that intestinal epithelial cells produce IL-7 and that IL-7 serves as a regulatory factor for proliferation of mucosal lymphocytes expressing IL-7 receptor (IL-7R). Recent studies demonstrated that intestinal epithelial cell-derived IL-7 plays a crucial role in the organization of mucosal lymphoid tissues and regulating the normal immune response in intestinal mucosa. In a previous study, we demonstrated that IL-7 transgenic mice developed chronic colitis. Here, we have demonstrated the essential role of mucosal IL-7/IL-7R-dependent signals in the development of chronic intestinal inflammation. Our results indicate that mucosal IL-7/IL-7R-dependent signals are involved in the development of chronic intestinal inflammation in both the mouse model and human disease of the intestinal mucosa. Therefore, current studies indicate that therapeutic approaches by specific targeting of IL-7R-expressing mucosal T cells may be feasible in the treatment of human ulcerative colitis.

Th1-mediated intestinal inflammation in Crohn's disease may be induced by activation of lamina propria lymphocytes through synergistic stimulation of interleukin-12 and interleukin-18 without T cell receptor engagement

Okazawa Akira, Kanai Takanori, Watanabe Mamoru, Yamazaki Motomi, Inoue Nagamu, Ikeda Masao, Kurimoto Masashi, Ishii Hiromasa, Hibi Toshifumi

American Journal of Gastroenterology 97 ( 12 ) 3108 - 3117 2002.12

ISSN 0002-9270

OBJECTIVE: The development of T helper type 1 (Th1) CD4+ T cells in the intestinal mucosa is driven by interleukin (IL)-12 produced from activated macrophages and IL-18 produced from activated macrophages and epithelial cells. Each of these two cytokines is important for the mucosal response during intestinal inflammation, but their synergistic effect is not fully understood. To characterize the synergistic effect of IL-12 and IL-18 with respect to human intestinal inflammation, we assessed the effect of IL-12 and IL-18 on lamina propria lymphocytes from normal control subjects (LPL-NL) and patients with Crohn's disease (LPL-CD). METHODS: Expression of IL-12 receptor (IL-12R) β1, β2, and IL-18Rα in LPLs was analyzed by flow cytometry. The functional activity of IL-12 and IL-18 was assessed by the effect of recombinant IL-12 and recombinant IL-18 on interferon-γ production, the proliferative response, and the induction of IL-2R, IL-12R, and IL-18R of LPLs. RESULTS: IL-12Rβ2 expression was significantly greater in LPL-CD compared with LPL-NL. LPL-NL demonstrated a proliferative response and a significant increase in interferon-γ production and IL-2Rα expression when exposed to both IL-12 and IL-18, but neither IL-12 nor IL-18 were able to induce this response on their own. However, IL-12 and IL-18 produced this response in LPL-CD when administered alone. Moreover, a more pronounced synergistic effect of IL-12 and IL-18 was observed in LPL-CD. The response normally observed after administration of IL-12 and IL-18 was significantly inhibited by anti-IL-2 and anti-IL-2Rα monoclonal antibody. Furthermore, IL-12 was observed to upregulate IL-18Rα expression in LPL-CD. CONCLUSIONS: These findings suggest that a combination of IL-12 and IL-18 in the absence of T cell receptor engagement may serve as a potent regulatory factor for LPL and contribute to the maintenance and enhancement of chronic inflammation in CD. © 2002 by Am. Coll. of Gastroenterology.

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Role of the innate immune system in the development of chronic colitis

Kanai Takanori, Iiyama Ryoichi, Ishikura Takahiro, Uraushihara Koji, Totsuka Teruji, Yamazaki Motomi, Nakamura Tetsuya, Watanabe Mamoru

Journal of Gastroenterology 37 ( SUPPL. 14 ) 38 - 42 2002.11

ISSN 0944-1174

Based on Pasteur's work on the microbial nature of fermentation, it was widely believed that the presence of bacteria in the intestine was essential for the life of the host. It has also been known for decades that gut commensal microbes effect the activation and development of the systemic immune system through gut-associated lymphoid tissues (GALT). Recent extensive studies have shown that recognition of microbes is mediated by a set of germline-encoded receptors, Toll-like receptors (TLRs), in mammals. This article reviews the role of the innate immunity system in the development of GALT and the pathogenesis of inflammatory bowel diseases (IBD).

ICOS costimulation in inflammatory bowel disease

Kanai Takanori, Totsuka Teruji, Tezuka Katsunari, Watanabe Mamoru

Journal of Gastroenterology 37 ( SUPPL. 14 ) 78 - 81 2002.11

ISSN 0944-1174

For years, medical researchers have striven to develop selective immunotherapies that could specifically ameliorate pathogenic immune responses without immunocompromising the patient. Blockade of many known receptors on T cells can inhibit the initiation of immune responses. However, this approach is problematic in that it is not possible to predict the onset of disease in patients. Current immunotherapies are unsatisfactory for the sporadic exacerbating type of diseases such as multiple sclerosis and inflammatory bowel disease (IBD), because they require either long-term treatment or acute treatment with high-dose immunosuppressants. With regard to this issue, the inducible and inflammatory site-specific molecule, inducible costimulator (ICOS), may be particularly useful as an ideal targeting molecule for the strategy of treatment of human IBD patients.

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