Details of a Researcher - Kanai, Takanori

Papers - Kanai, Takanori

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Negative feedback regulation of colitogenic CD4⁺ T cells by increased granulopoiesis

Nemoto Yasuhiro, Kanai Takanori, Tohda Shuji, Totsuka Teruji, Okamoto Ryuichi, Tsuchiya Kiichiro, Nakamura Tetsuya, Sakamoto Naoya, Fukuda Tetsuya, Miura Osamu, Yagita Hideo, Watanabe Mamoru

Inflammatory Bowel Diseases 14 ( 11 ) 1491 - 1503 2008

ISSN 1078-0998

Background: Chronic inflammatory diseases are characterized by massive infiltration of innate and acquired immune cells in inflammatory sites. However, it remains unclear how these cells cooperate in the development of disease. Although bone marrow (BM) is a primary site for hematopoiesis of immune cells except T cells, BM recruits memory T cells from the periphery. We have recently demonstrated that colitogenic CD4⁺ memory T cells reside in BM of colitic CD4⁺CD45RB^high T-cell-transferred SCID mice. Based on this background we here investigate whether granulocytes promote or suppress the expansion of colitogenic CD4⁺ T cells. Methods: First, we show that Gr-1^highCD11b⁺ granulocytes were significantly increased in colitic BM along with a significant increase of peripheral granulocytes. Consistently, the colony-forming unit (CFU) assay revealed that granulocyte colony formation was dominantly induced by supernatants from anti-CD3-stimulated colitic BM CD4⁺ T cells. Results: Administration of granulocyte-depleting anti-Gr-1 mAb to colitic mice did not ameliorate the colitis, but exacerbated the wasting disease with an increased expansion of systemic, but not lamina propria, CD4⁺ T cells with activated phenotype. Conclusions: These results suggest that the increased granulopoiesis by colitogenic BM CD4⁺ T cells represent a negative feedback mechanism to control systemic inflammation. Copyright © 2008 Crohn's & Colitis Foundation of America, Inc.

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FTY720 suppresses the development of colitis in lymphoid-null mice by modulating the trafficking of colitogenic CD4⁺ T cells in bone marrow

Fujii Toshimitsu, Tomita Takayuki, Kanai Takanori, Nemoto Yasuhiro, Totsuka Teruji, Sakamoto Naoya, Nakamura Tetsuya, Tsuchiya Kiichiro, Okamoto Ryuichi, Watanabe Mamoru

European Journal of Immunology 38 ( 12 ) 3290 - 3303 2008

ISSN 0014-2980

2-Amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride (FTY720) suppresses T-cell egress from LN, thereby preventing pathogenic T cells from migrating toward disease sites. However, little is known about whether FTY720 could control the trafficking of T cells without the presence of lymphoid tissues. Here we demonstrate that FTY720 treatment suppresses the recirculation of CD4⁺ T cells in splenectomized (SPX) lymphotoxin-α^-/- (LT-α ^-/-) mice that lack LN and spleen, as shown by peripheral blood (PB) lymphopenia in FTY720-treated SPX LT-α ^-/- mice. In a short-term transfer experiment, the cell number of transferred Ly5.1⁺CD4⁺ T cells recovered from host FTY720-treated SPX LT-α^-/- mice (Ly5.2⁺) was markedly decreased in PB, but conversely increased in BM. Notably, FTY720 treatment prevented the development of colitis that is otherwise induced in untreated SPX LT-α ^-/- x RAG-2^-/- mice upon transfer of colitic lamina propria CD4⁺ T cells. In such mice, the number of CD4⁺ T cells in PB or lamina propria of FTY720-treated SPX LT-α^-/- x RAG-2^-/- recipients was significantly reduced, but that in the BM was significantly increased as compared with untreated control mice. Altogether, the present results indicate that FTY720 treatment may offer an additional role to direct trafficking of CD4⁺ T cells in BM, resulting in the prevention of colitis. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.

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Colitogenic CD4⁺ effector-memory T cells actively recirculate in chronic colitic mice

Tomita Takayuki, Kanai Takanori, Nemoto Yasuhiro, Fujii Toshimitsu, Nozaki Kengo, Okamoto Ryuichi, Tsuchiya Kiichiro, Nakamura Tetsuya, Sakamoto Naoya, Totsuka Teruji, Watanabe Mamoru

Inflammatory Bowel Diseases 14 ( 12 ) 1630 - 1640 2008

ISSN 1078-0998

Background: Although the clinical usefulness of leukocytapheresis for patients with inflammatory bowel disease (IBD) has been reported as a selective removal therapy targeting pathogenic immune cells in blood circulation, it remains unclear whether colitogenic CD4⁺ T cells continuously recirculate in peripheral blood during the chronic phase of colitis. Methods: To resolve this question we conducted a series of in vivo experiments using a murine chronic colitis model induced by adoptive transfer of CD4⁺CD45RB^high cells into SCID mice in combination with a parabiosis system. Results: In colitic SCID recipients, first, almost all CD4⁺ CD45RB^high donor cells were converted to CD4⁺CD44^highCD62L^- IL-7Rα ^high effector-memory T (T_EM) cells at 8 weeks after transfer and were distributed throughout the whole body, including colonic lamina propria, mesenteric lymph nodes, thoracic duct, peripheral blood, spleen, and bone marrow. Second, SCID mice retransferred with the colitic peripheral blood CD4⁺ T cells developed colitis that is identical to the original colitis. Third, CD4⁺ cells in parabionts between established colitic RAG-2^-/- mice induced by adoptive transfer of Ly5.1⁺ or Ly5.2⁺ CD4⁺CD45RB^high T cells were well mixed in almost equal proportions at various sites 2 weeks after parabiosis surgery, and the redistribution of Ly5.1⁺ and Ly5.2⁺ CD4⁺ T cells was significantly suppressed in FTY720-treated parabionts. Conclusions: Together, these findings indicate that colitogenic CD4⁺ TEM cells continuously recirculate in established colitic mice, suggesting that therapeutic approaches targeting systemic CD4⁺ T_EM cells, such as bone marrow transplantation, rather than those targeting only intestinal CD4⁺ T cells, may be feasible for the treatment of IBD. Copyright © 2008 Crohn's & Colitis Foundation of America, Inc.

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Treatment of inflammatory immunologic disease 1. Leukocytapheresis for inflammatory immunologic disease (tentative)

Watanabe Mamoru, Kubota Daisuke, Nagahori Masakazu, Kanai Takanori

Internal Medicine 46 ( 16 ) 1305 - 1306 2007.08

ISSN 0918-2918

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Intestinal lamina propria retaining CD4⁺CD25⁺ regulatory T cells is a suppressive site of intestinal inflammation

Makita Shin, Kanai Takanori, Nemoto Yasuhiro, Totsuka Teruji, Okamoto Ryuichi, Tsuchiya Kiichiro, Yamamoto Masafumi, Kiyono Hiroshi, Watanabe Mamoru

Journal of Immunology 178 ( 8 ) 4937 - 4946 2007.04

ISSN 0022-1767

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_REG) cells play an important role in the normal intestinal homeostasis, but also that its dysregulation of immune response leads to the development of inflammatory bowel disease. In this study, we demonstrate that murine CD4⁺CD25⁺ T cells residing in the intestinal lamina propria (LP) constitutively express CTLA-4, glucocorticoid-induced TNFR, and Foxp3 and suppress proliferation of responder CD4⁺ T cells in vitro. Furthermore, cotransfer of intestinal LP CD4₊CD25⁺ T cells prevents the development of chronic colitis induced by adoptive transfer of CD4⁺CD45RB^high T cells into SCID mice. When lymphotoxin (LT)α-deficient intercrossed Rag2 double knockout mice (LTα^-/- × Rag2^-/-), which lack mesenteric lymph nodes and Peyer's patches, are transferred with CD4⁺CD45RB ^high T cells, they develop severe wasting disease and chronic colitis despite the delayed kinetics as compared with the control LTα ^+/+ × Rag2^-/- mice transferred with CD4 ⁺CD45RB^high T cells. Of note, when a mixture of splenic CD4⁺CD25⁺ T_REG cells and CD4 ⁺CD45RB^high T cells are transferred into LTα^-/- × Rag2^-/- recipients, CD4 ⁺CD25⁺ T_REG cells migrate into the colon and prevent the development of colitis in LTα^-/- × Rag2 ^-/- recipients as well as in the control LTα^+/+ × Rag2^-/- recipients. These results suggest that the intestinal LP harboring CD4⁺CD25⁺ T_REG cells contributes to the intestinal immune suppression. Copyright © 2007 by The American Association of lmmunologists, Inc.

IL-7 is essential for the development and the persistence of chronic colitis

Totsuka Teruji, Kanai Takanori, Nemoto Yasuhiro, Makita Shin, Okamoto Ryuichi, Tsuchiya Kiichiro, Watanabe Mamoru

Journal of Immunology 178 ( 8 ) 4737 - 4748 2007.04

ISSN 0022-1767

Although IL-7 has recently emerged as a key cytokine involved in controlling the homeostatic turnover and the survival of peripheral resting memory CD4⁺ T cells, its potential to be sustained pathogenic CD4⁺ T cells in chronic immune diseases, such as inflammatory bowel diseases, still remains unclear. In this study, we demonstrate that IL-7 is essential for the development and the persistence of chronic colitis induced by adoptive transfer of normal CD4⁺CD45RB^high T cells or colitogeoic lamina propria (LP) CD4⁺ memory T cells into immunodeficient IL-7^+/+ x RAG-1^-/- and IL-7^-/- x RAG-1^-/- mice. Although EL-7^+/+ x RAG-1^-/- recipients transferred-with CD4⁺CD45RB^high splenocytes developed massive inflammation of the large intestinal mucosa concurrent with massive expansion of Th1 cells, IL-7^-/- x RAG-1^-/- recipients did not. Furthermore, IL-7^-/- x RAG-1^-/-, but not IL-7^+/+ x RAG-1^-/-, mice transferred with LP CD4 ⁺CD44^highCD62L^-IL-7Rα^high effector-memory T cells (T_EM) isolated from colitic CD4 ⁺CD45RB^high-transferred mice did not develop colitis. Although rapid proliferation of transferred colitogenic LP CD4⁺ T_EM cells was observed in the in IL-7^-/- x RAG-1 ^-/- mice to a similar extent of those in IL-7^-/- x RAG-1^-/- mice, Bcl-2 expression was significantly down-modulated in the transferred CD4⁺ T cells in IL-7^-/- x RAG-1 ^-/- mice compared with those in IL-7^+/+ x RAG-1 ^-/- mice. Taken together, IL-7 is essential for the development and the persistence of chronic colitis as a critical survival factor for colitogenic CD⁺ T_EM cells, suggesting that therapeutic approaches targeting IL-7/IL-7R signaling pathway may be feasible in the treatment of inflammatory bowel diseases. Copyright © 2007 by The American Association of Immunologists, Inc.

Extracorporeal elimination of TNF-α-producing CD14 ^dullCD16⁺ monocytes in leukocytapheresis therapy for ulcerative colitis

Kanai Takanori, Makita Shin, Kawamura Takahiro, Nemoto Yasuhiro, Kubota Daisuke, Nagayama Kazuyoshi, Totsuka Teruji, Watanabe Mamoru

Inflammatory Bowel Diseases 13 ( 3 ) 284 - 290 2007.03

ISSN 1078-0998

Background: In recent years leukocytapheresis using a leukocyte removal filter (known as lymphocytapheresis, LCAP) has been applied to the treatment of various autoimmune diseases including ulcerative colitis (UC). In the present study we aimed to clarify how LCAP therapy modifies inflammatory responses by modulating circulating TNF-α-producing monocytes. Methods: Mononuclear cells were obtained from blood before and after the first treatment, and the expression profiles of various immune cells (naive versus, memory, regulatory CD4⁺CD25^bright versus non-regulatory CD4 ⁺CD25^- T cells, and CD14⁺CD16^- versus CD14^dullCD16⁺ monocytes) were assessed. To evaluate immunological differences between CD14⁺CD16^- and CD14^dullCD16⁺ monocytes, the expression of TNF-α, IL-6, IL-12, IL-10, IL-18, surface toll-like receptor 2 (TLR2), TLR4, and other activation markers including HLA-DR, CD80 and CD86, as well as cytokine profiles, were analyzed. Results: LCAP treatment selectively removed CD14 ^dullCD16⁺ monocytes, which preferentially produce TNF-α and IL-12 and express HLA-DR, CD80, CD86, and TLR2, compared with the major fraction of CD14⁺CD16^- monocytes, which conversely produce a higher amount of IL-10. In addition, the CD4 ⁺CD45RO⁺CD62L^-/CD4⁺CD45RO ⁺CD62L⁺ ratio was significantly lower after LCAP therapy. However, the CD4⁺CD25^bright/total CD4⁺ ratio did not change. Conclusions: The present findings revealed the real target of proinflammatory CD14^dullCD16⁺ monocytes removed during LCAP treatment of UC and that LCAP might be used as an extracorporeal anti-TNF-α therapy, expanding the clinical applications of this procedure to include the treatment of Crohn's disease. Copyright © 2006 Crohn's & Colitis Foundation of America, Inc.

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A case of severe ulcerative colitis successfully with intravenous cyclosporine without high dose corticosteroid

Kubota Daisuke, Kanai Takanori, Yui Fumiro, Matsumoto Tomoko, Kawamura Takahiro, Itsui Yasuhiro, Okada Eriko, Chin Seishin, Ooka Shinya, Nagahori Masakazu, Tsuchiya Kiichiro, Araki Akihiro, Sakamoto Naoya, Miyata Tatsuya, Watanabe Mamoru

Japanese Journal of Gastroenterology 104 ( 1 ) 42 - 46 2007.01

ISSN 0446-6586

A 44-year-old women developed marked myopathy one year earlier, when she was treated with intravenous prednisolone for acute severe exacerbation of ulcerative colitis. When she was admitted to our hospital for another severe exacerbation, intravenous cyclosporine A was administered as monotherapy because she could not tolerate corticosteroid. The treatment was successful and she obtained complete remission. Cyclosporine A monotherapy is considered to be a valuable alternative to proctocolectomy for severe ulcerative colitis patients who cannot tolerate corticosteroid.

Reciprocal Targeting of Hath1 and β-Catenin by Wnt Glycogen Synthase Kinase 3β in Human Colon Cancer

Tsuchiya Kiichiro, Nakamura Tetsuya, Okamoto Ryuichi, Kanai Takanori, Watanabe Mamoru

Gastroenterology 132 ( 1 ) 208 - 220 2007.01

ISSN 0016-5085

Background & Aims: The transcription factor Hath1 plays a crucial role in the differentiation program of the human gut epithelium. The present study was conducted to investigate the molecular mechanism of Hath1 expression and its close association with β-catenin/glycogen synthase kinase 3β (GSK3β) under the Wnt pathway in human colonocytes. Methods: Tissue distribution of Hath1 messenger RNA in human tissues was examined by Northern blot. Stability of Hath1 protein was analyzed by expression of FLAG-tagged Hath1 in human cell lines. Targeting of Hath1 protein by GSK3β was determined by specific inhibition of GSK-3β function. Expression of Hath1 protein in colorectal cancers was examined by immunohistochemistry. Results: Hath1 messenger RNA expression was confined to the lower gastrointestinal tract in human adult tissues. In colon cancer cells, although Hath1 messenger RNA was also detected, Hath1 protein was positively degradated by proteasome-mediated proteolysis. Surprisingly, the GSK3β-dependent protein degradation was switched between Hath1 and β-catenin by Wnt signaling, leading to the dramatic alteration of cell status between proliferation and differentiation, respectively. Hath1 protein was detected exclusively in normal colon tissues but not in cancer tissues, where nuclear-localized β-catenin was present. Conclusions: The present study suggests a novel function of the canonical Wnt signaling in human colon cancer cells, regulating cell proliferation and differentiation by GSK3β-mediated, reciprocal degradation of β-catenin or Hath1, respectively, which further emphasizes the importance of aberrant Wnt signaling in colonocyte transformation. © 2007 AGA Institute.

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Bone Marrow Retaining Colitogenic CD4⁺ T Cells May Be a Pathogenic Reservoir for Chronic Colitis

Nemoto Yasuhiro, Kanai Takanori, Makita Shin, Okamoto Ryuichi, Totsuka Teruji, Takeda Kiyoshi, Watanabe Mamoru

Gastroenterology 132 ( 1 ) 176 - 189 2007.01

ISSN 0016-5085

Background & Aims: Although bone marrow (BM) is known as a primary lymphoid organ, it also is known to harbor memory T cells, suggesting that this compartment is a preferential site for migration and/or selective retention of memory T cells. We here report the existence and the potential ability to induce colitis of the colitogenic BM CD4⁺ memory T cells in murine colitis models. Methods: We isolated BM CD4⁺ T cells obtained from colitic severe combined immunodeficient mice induced by the adoptive transfer of CD4⁺CD45RB^high T cells and colitic interleukin (IL)-10^-/- mice that develop colitis spontaneously, and analyzed the surface phenotype, cytokine production, and potential activity to induce colitis. Furthermore, we assessed the role of IL-7 to maintain the colitogenic BM CD4⁺ T cells. Results: A high number of CD4⁺ T cells reside in the BM of colitic severe combined immunodeficient mice and diseased IL-10^-/- mice, and they retain significant potential to induce type-1 T helper-mediated colitis in an IL-7-dependent manner. These resident BM CD4⁺ T cells have an effector memory (T_EM; CD44^highCD62L^-IL-7R^high) phenotype and preferentially are attached to IL-7-producing BM cells. Furthermore, the accumulation of BM CD4⁺ T_EM cells was decreased significantly in IL-7-deficient recipients reconstituted with the colitogenic lamina propria CD4⁺ T_EM cells. Conclusions: Collectively, these findings suggest that BM-retaining colitogenic CD4⁺ memory T cells in colitic mice play a critical role as a reservoir for persisting lifelong colitis. © 2007 AGA Institute.

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Blockade of NKG2D signaling prevents the development of murine CD4 ⁺ T cell-mediated colitis

Ito Y., Kanai T., Totsuka T., Okamoto R., Tsuchiya K., Nemoto Y., Yoshioka A., Tomita T., Nagaishi T., Sakamoto N., Sakanishi T., Okumura K., Yagita H., Watanabe M.

American Journal of Physiology - Gastrointestinal and Liver Physiology 294 ( 1 ) 2007

ISSN 0193-1857

It has been recently demonstrated that NKG2D is an activating costimulatory receptor on natural killer (NK) cells, natural killer T (NKT) cells, activated CD8⁺ T cells, and γδ T cells, which respond to cellular stress, such as inflammation, transformation, and infection. Here we show that intestinal inflammation in colitic SCID mice induced by adoptive transfer of CD4⁺CD45RB^high T cells is characterized by significant increase of CD4⁺NKG2D⁺ T cells and constitutive expression of NKG2D ligands, such as H60, Mult-1, and Rae-1, by lamina propria CD11c ⁺ dendritic cells. Furthermore, treatment with nondepleting and neutralizing anti-NKG2D MAb after transfer of CD4⁺CD45RB ^high T cells into SCID mice significantly suppressed wasting disease with colitis, abrogated leukocyte infiltration, and reduced production of IFN-γ by lamina propria CD4⁺ T cells. These findings demonstrate that NKG2D signaling pathway is critically involved in CD4 ⁺ T cell-mediated disease progression and suggest a new therapeutic target for inflammatory bowel diseases. Copyright © 2008 the American Physiological Society.

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Leukocytapheresis for inflammatory immune diseases

Watanabe Mamoru, Kubota Taisuke, Nagahori Masakazu, Kanai Takanori

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 95 ( 9 ) 1775 - 1780 2006.09

ISSN 0021-5384

A case report

Kubota Daisuke, Takishima Chizuru, Ishii Ken Ichi, Kawamura Takahiro, Matsumoto Tomoko, Itsui Yasuhiro, Okada Eriko, Chin Seishin, Oooka Shinya, Tsuchiya Kiichiro, Araki Akihiro, Sakamoto Naoya, Miyata Tatsuya, Kanai Takanori, Watanabe Mamoru

Japanese Journal of Gastroenterology 103 ( 9 ) 1044 - 1049 2006.09

ISSN 0446-6586

A 23-year-old man was admitted for treatment of acute exacerbation of ileitis and perianal abscess caused by Crohn's disease. After incision and drainage of the abscess, coupled with antibiotic therapy, 6-mercaptopurine (6-MP) was commenced. His white blood cell (WBC) count on day 12 after initiation of 6-MP was not decreased. However, on day 24 he was re-admitted because of severe myelosuppression (WBC: 300/μl), which was complicated by the recurrence of the perianal abscess. Myelosuppression was prolonged and required the administration of granulocyte colony stimulating factor (G-CSF). G-CSF was continued for 17 days to achieve recovery of his WBC count to a normal level.

Naturally arising CD4⁺CD25⁺ regulatory T cells suppress the expansion of colitogenic CD4⁺CD44 ^highCD62L^- effector memory T cells

Kanai T., Tanimoto K., Nemoto Y., Fujii R., Makita S., Totsuka T., Watanabe M.

American Journal of Physiology - Gastrointestinal and Liver Physiology 290 ( 5 ) 2006.05

ISSN 0193-1857

Naturally arising CD4⁺CD25⁺ regulatory T (T _R) cells have been shown to prevent and cure murine T cell-mediated colitis. However, their exact mechanism of controlling colitogenic memory CD4⁺ T cells in in vivo systems excluding the initial process of naive T cell activation and differentiation has not been examined to date. Using the colitogenic effector memory (T_EM) CD4⁺ cell-mediated colitis model induced by adoptive transfer of colitogenic CD4 ⁺CD44^highCD62L^- lamina propria (LP) T cells obtained from colitic CD4⁺CD45RB^high T cell-transferred mice, we have shown in the present study that CD4⁺CD25⁺ T_R cells are able not only to suppress the development of colitis, Th1 cytokine production, and the expansion of colitogenic LP CD4⁺ T_EM cells but also to expand these cells by themselves extensively in vivo. An in vitro coculture assay revealed that CD4⁺CD25⁺ T_R cells proliferated in the presence of IL-2-producing colitogenic LP CD4⁺ T_EM cells at the early time point (48 h after culture), followed by the acquisition of suppressive activity at the late time point (96 h after culture). Collectively, these data suggest the distinct timing of the IL-2-dependent expansion of CD4⁺CD25⁺ T _R cells and the their suppressive activity on colitogenic LP CD4 ⁺ T_EM cells. Copyright © 2006 the American Physiological Society.

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The logics of leukocytapheresis as a natural biological therapy for inflammatory bowel disease

Kanai Takanori, Hibi Toshifumi, Watanabe Mamoru

Expert Opinion on Biological Therapy 6 ( 5 ) 453 - 466 2006.05

ISSN 1471-2598

Ulcerative colitis (UC) and Crohn's disease (CD) are debilitating idiopathic inflammatory bowel diseases (IBDs) with symptoms that impair ability to function and quality of life. The aetiology of IBD is inadequately understood and, therefore, drug therapy has been empirical instead of based on sound understanding of the disease mechanisms. This has been a major factor for poor drug efficacy and treatment-related side effects that often add to disease complications. The development of biologicals, notably infliximab, to block TNF-α reflects some progress, but there is major concern about their side effects and lack of long-term safety and efficacy profiles. However, IBD by its very nature is exacerbated and perpetuated by inflammatory cytokines, including TNF-α, IL-6 and IL-12, for which activated peripheral blood lymphocytes, monocytes/macrophages and granulocytes are major sources. Hence, activated leukocytes should be appropriate targets of therapy. At present, three strategies are available for removing excess and activated leukocytes by leukocytapheresis: centrifugation, Adacolumn® and Cellsorba™. Centrifugation can deplete lymphocytes or total leukocytes, whereas Adacolumn selectively adsorbs granulocytes and monocytes together with a smaller fraction of lymphocytes (FcγR- and complement receptor-bearing leukocytes), and Cellsorba non-selectively removes all three major leukocyte populations. Efficacy has ranged from 'none' to an impressive 93% together with excellent safety profiles and downmodulation of inflammation factors. Furthermore, leukocytapheresis has shown strong drug-sparing effects and reduced the number of patients requiring colectomy or exposure to unsafe immunosuppressants, such as cyclosporin A. Leukocytapheresis removes from the body cells that contribute to IBD and, therefore, unlike drugs, it is not expected to induce dependency or refractoriness. © 2006 Informa UK Ltd.

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Do fatty acids influence functions of intestinal dendritic cells?

Kanai Takanori, Watanabe Mamoru

Journal of Gastroenterology 41 ( 3 ) 288 - 289 2006.03

ISSN 0944-1174

T _H1/T _H2-mediated colitis induced by adoptive transfer of CD4 ⁺CD45RB ^high T lymphocytes into nude mice

Kanai Takanori, Kawamura Takahiro, Dohi Taeko, Makita Shin, Nemoto Yasuhiro, Totsuka Teruji, Watanabe Mamoru

Inflammatory Bowel Diseases 12 ( 2 ) 89 - 99 2006.02

ISSN 1078-0998

Background: Transfer of CD4 ⁺CD45RB ^high T cells from normal donors to SCID/Rag-1, 2-deficient mice, which lack T and B cells, leads to the development of a T _H1-mediated inflammatory bowel disease (IBD)-like syndrome characterized by extensive mononuclear cell infiltrates and epithelial cell hyperplasia. Because it is well known that B cells are also involved in a multitude of mechanistic pathways in human IBD, this study attempts to establish a new model of colitis in nude mice. Methods: We transferred CD4 ⁺CD45RB ^high T cells into athymic nude mice, which lack thymus-dependent T cells but retain normal B cells, to establish and investigate a B cell-involving chronic colitis model. As a control, CD4 ⁺CD25 ^- T cells were also used. Results: Mice reconstituted with CD4 ⁺CD45RB ^high but not CD4 ⁺CD25 ^- T cells developed a wasting disease, with severe infiltrates of B cell aggregates as well as T cells, macrophages, and dendritic cells into the colon and elevated levels of interferon-γ, tumor necrosis factor-α, interleukin (IL)-4, IL-5, and IL-10, by 7 weeks after T cell transfer. Furthermore, the infiltrated lamina propria B cells in colitic nude mice consisted predominantly of massive aggregated immunoglobulin (Ig) M- and scattered IgG-positive cells, but not IgA-positive cells. In contrast, mice reconstituted with CD4 ⁺CD45RB ^high and CD4 ⁺CD45RB ^low did not develop wasting disease or colitis. Conclusions: Collectively, the power of the colitis model induced by the adoptive transfer of CD4 ⁺CD45RB ^high T cells into nude mice is that one can investigate the roles of T _H2-type cells and B cells in a regulatory T cell-depleted condition. Copyright © 2006 by Lippincott Williams & Wilkins.

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FTY720 suppresses CD4⁺CD44^highCD62L^- effector memory T cell-mediated colitis

Fujii R., Kanai T., Nemoto Y., Makita S., Oshima S., Okamoto R., Tsuchiya K., Totsuka T., Watanabe M.

American Journal of Physiology - Gastrointestinal and Liver Physiology 291 ( 2 ) 2006

ISSN 0193-1857

FTY720, a sphingosine-derived immunomodulator, causes immunosuppression via enhancement of lymphocyte sequestration into secondary lymphoid organs, thereby preventing their antigen-activated T cell egress to sites of inflammation. FTY720 is highly effective in inhibiting autoimmunity in various animal models. However, there is little known about how FTY720 controls the migration property of memory T cells. Here, we demonstrated that FTY720 prevents the development of colitis induced by the adoptive transfer of lamina propria (LP) colitogenic effector memory CD4⁺ T cells (T_EM cells; CD45RB ^lowCD44^highCD62L^-) into severe combined immunodeficiency (SCID) mice and suppresses interferon-γ, interleukin-2, and tumor necrosis factor-α production by LP CD4⁺ T cells. The numbers of spleen, peripheral blood, mesenteric lymph node, and LP CD4 ⁺ T cells in FTY720-treated mice were significantly reduced compared with those in control mice. Notably, LP CD⁴ T_EM cells as well as splenic CD4⁺CD45RB^high T cells expressed several spingosine-1-phosphate receptors that are targets for FTY720. Furthermore, FTY720 also prevented the development of colitis induced by the adoptive transfer of splenic CD4⁺CD45RB^high T cells into SCID mice. Collectively, the present data indicate that FTY720 treatment may offer the potential not only to prevent the onset of disease but also to treat memory T cell-mediated autoimmune diseases including inflammatory bowel diseases. Copyright © 2006 the American Physiological Society.

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A case of sacroiliitis complicated by ulcerative colitis that was successfully treated with steroid

Kubota Daisuke, Kanai Takanori, Matsumoto Tomoko, Kawamura Takahiro, Itsui Yasuhiro, Okada Eriko, Chin Seishin, Ohoka Shinya, Tsuchiya Kiichiro, Araki Akihiro, Sakamoto Naoya, Miyata Tatsuya, Watanabe Mamoru

Japanese Journal of Gastroenterology 103 ( 8 ) 936 - 942 2006

ISSN 0446-6586

A 23-year-old woman was admitted in November, 2002, complaining pain of the left side and buttock. She had ulcerative colitis when she was 16 and received medical treatment. Based on physical examination and findings of magnetic resonance imaging and bone scintigrapy, as sacroiliitis complicated by ulcerative colitis, was diagnosed Reports on sacroiliitis and ankylosing spondylitis complicated by inflammatory bowel diseases (IBD) are relatively rare in Japan, whereas they are common complications of IBD in Western countries. The efficacy of steroids on pain relief of sacroiliitis and ankylosing spondylitis is unclear.

Ameliorating effect of saporin-conjugated anti-CD11b monoclonal antibody in a murine T-cell-mediated chronic colitis

Kanai Takanori, Uraushihara Koji, Totsuka Teruji, Nemoto Yasuhiro, Fujii Rei, Kawamura Takahiro, Makita Shin, Sawada Daisuke, Yagita Hideo, Okumura Ko, Watanabe Mamoru

Journal of Gastroenterology and Hepatology (Australia) 21 ( 7 ) 1136 - 1142 2006

ISSN 0815-9319

Background: Crohn's disease (CD) is an inflammatory bowel disease that is associated with several changes in the immune system, including an increased number of infiltrating macrophages. These macrophages release a variety of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) which are critically involved in the onset and the development of CD. The present study was performed to explore the initial involvement of macrophages in the development of T-cell-mediated chronic colitis. Methods: The effects were evaluated of saporin-conjugated anti-CD11b monoclonal antibody (mAb) on the development of chronic colitis in severe combined immunodeficiency (SCID) mice induced by adoptive transfer of CD4⁺CD45RB^high T cells as an animal model of CD. Results: Significantly increased CD11b-expressing macrophages as well as CD4⁺ T cells were found in inflamed colon from colitic mice. Administration of saporin-conjugated anti-CD11b mAb markedly ameliorated the clinical and histopathological disease. In vivo treatment with saporin-conjugated anti-CD11b mAb decreased CD4⁺ T-cell infiltration in the colon and suppressed inferferon-γ (IFN-γ) and TNF-α production by lamina propria CD4⁺ T cells. Conclusions: Collectively, the present results suggest an initial role of macrophages in the pathogenesis of T-cell-mediated chronic colitis. Furthermore, the macrophage-specific targeting may be a promising strategy for therapeutic intervention in CD. © 2006 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

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