Details of a Researcher - Kanai, Takanori

Papers - Kanai, Takanori

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Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract

Okamoto Ryuichi, Yajima Tomoharu, Yamazaki Motomi, Kanai Takanori, Mukai Makio, Okamoto Shinichiro, Ikeda Yasuo, Hibi Toshifumi, Inazawa Johji, Watanabe Mamoru

Nature Medicine 8 ( 9 ) 1011 - 1017 2002.09

ISSN 1078-8956

Studies have shown that bone marrow cells have the potential to differentiate into a variety of cell types. Here we show that bone marrow cells can repopulate the epithelia of the human gastrointestinal tract. Epithelial cells of male donor origin were distributed in every part of the gastrointestinal tract of female bone marrow transplant recipients. Donor-derived epithelial cells substantially repopulated the gastrointestinal tract during epithelial regeneration after graft-versus-host disease or ulcer formation. Regeneration of gastrointestinal epithelia with donor-derived cells in humans shows a potential clinical application of bone marrow-derived cells for repairing severely damaged epithelia, not only in the gastrointestinal tract but also in other tissues.

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Cytokine networks in the development of intestinal inflammation in Crohn's disease

Kanai Takanori, Watanabe Mamoru, Hibi Toshifumi

Folia Pharmacologica Japonica 120 ( 1 ) 39 - 45 2002

ISSN 0015-5691

Crohn's disease (CD) affects more than 400,000 individuals in the United States and more than 18,000 in Japan. Its incidence is CD, one of the chronic inflammatory bowel diseases (IBD), is debilitating disorder of unknown ethiology, characterized by a marked accumulation of activated T cells and monocytes/macrophages in the inflamed mucosa. Various proinflammatory cytokines, such as TNF-α, INF-γ, IL-6, IL-12, and IL-18, might be involved in its pathogenesis. In this review, we describe the role of various cytokines in the development of CD and the new therapeutic trials modulating cytokine networks for the treatment of CD.

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Characterization of structures with T-lymphocyte aggregates in ileal villi of Crohn's disease

Naganuma Makoto, Watanabe Mamoru, Kanai Takanori, Iwao Yasushi, Mukai Makio, Ishii Hiromasa, Hibi Toshifumi

American Journal of Gastroenterology 97 ( 7 ) 1741 - 1747 2002

ISSN 0002-9270

OBJECTIVES: Epithelioid granulomas with transmural inflammation are a characteristic histological feature in Crohn's disease (CD). However, these are not frequently detected by histopathological examination in the biopsy specimens. Here, we demonstrated unique structures with T-lymphocyte aggregates (TLAs) that were specifically found in ileal villi of CD. We characterized the histological and phenotypical features of these structures and assessed the diagnostic value of TLAs for CD. METHODS: Tissue samples were obtained from the inflamed and uninflamed areas of ileal and colonic mucosa of 32 patients with CD. For controls, mucosal samples were obtained from unaffected areas of 18 patients with colon cancer and inflamed and uninflamed areas of 12 patients with ulcerative colitis (UC). RESULTS: 1) In 21 of 32 cases of CD (66%), we found unique structures with lymphoid cell aggregates that were localized in villi of ileum. These structures were not detected in any normal or UC intestine. 2) These structures were composed mainly of T cells, and CD4+ CD45RO+ cells dominated. Neither B cells nor c-kit positive immature lymphocytes were found. Moreover, CD68 positive macrophages were demonstrated in these aggregates, and cells positive for interleukin 18, a pivotal cytokine for Th1 differentiation, were expressed. 3) The aggregates were detected in seven of 13 patients with CD in whom granuloma was not detected by precise histopathological examination. Furthermore, we detected TLAs even in the ilea of two of four CD patients (50%) whose affected lesions were limited to the colon. CONCLUSIONS: We demonstrated TLAs in intestinal villi that may contribute to the pathogenesis of CD. Detection of these lymphocyte aggregates is helpful for diagnosis of CD when granuloma is not found. © 2002 by Am. Coll. of Gastroenterology.

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Restricted V_H gene usage in lamina propria B cells producing anticolon antibody from patients with ulcerative colitis

Inoue Nagamu, Watanabe Mamoru, Sato Toshiro, Okazawa Akira, Yamazaki Motomi, Kanai Takanori, Ogata Haruhiko, Iwao Yasushi, Ishii Hiromasa, Hibi Toshifumi

Gastroenterology 121 ( 1 ) 15 - 23 2001

ISSN 0016-5085

Background & Aims: Autoimmune responses against colonic epithelium may play a role in the development of colonic inflammation associated with ulcerative colitis (UC). In this study, we established and characterized B-cell lines and clones that produced anticolon antibody from inflamed colonic mucosa of UC subjects. Methods: B-cell lines were generated through Epstein-Barr virus transformation of lamina propria lymphocytes (LPLs) from colonic mucosa and peripheral blood lymphocytes, and these lines were screened for the production of anticolon antibodies. B-cell lines were then cloned by limiting dilution culture, and messenger RNA expression of immunoglobulin heavy-chain variable region (V_H) was assessed. Results: V_H gene families used in B-cell lines established from LPLs of normal controls were diverse, and B-cell lines from UC LPLs expressed a restricted V_H3 family usage. All 15 clones from UC used a restricted V_H3 gene family, whereas diverse V_H gene families were used by 24 clones from normal controls. The analysis of nucleotide sequences indicated that these clones were derived from various germline gene segments. Conclusions: The restricted V_H gene usage in anticolon autoantibodies producing B-cell clones suggests that a particular antigenic stimulus contributes to the pathogenesis of UC.

Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease

Kanai Takanori, Watanabe Mamoru, Okazawa Akira, Sato Toshiro, Yamazaki Motomi, Okamoto Susumu, Ishii Hiromasa, Totsuka Teruji, Iiyama Ryoichi, Okamoto Ryuichi, Ikeda Masao, Kurimoto Masashi, Takeda Kiyoshi, Akira Shizuo, Hibi Toshifumi

Gastroenterology 121 ( 4 ) 875 - 888 2001

ISSN 0016-5085

Background & Aims: Crohn's disease (CD) is associated with an increased number of infiltrating macrophages, which release a variety of proinflammatory cytokines. Interleukin (IL)-18 has been implicated in the modulation of mucosal CD4 ⁺ T cells towards Th1 responses, which are implicated in the pathogenesis of CD. Here we assess the role of macrophages and of IL-18 in the murine model of intestinal inflammation that mimics the immunologic characteristics of human CD. Methods: Colitis was induced in C57BL/6 mice immunized with 2,4,6-trinitrobenzene sulfonic acid (TNBS) followed by rectal administration of TNBS in ethanol. Mice were treated with either an antibody directed against macrophages conjugated to the ribosome-inactivating protein saporin (anti-Mac-1-saporin) or with a neutralizing antibody against IL-18. In addition, we assessed whether an identical TNBS immunization/challenge protocol could induce colitis in IL-18 ^-/- mice. Results: The colonic mucosa of TNBS-treated mice was marked by infiltration of Mac-1-positive macrophages and up-regulation of IL-18. The administration of the anti-Mac-1-saporin antibody or the neutralizing anti-IL-18 antibody resulted in a dramatic attenuation of mucosal inflammation in this model. In addition, TNBS was unable to induce significant colitis in the IL-18 ^-/- mice. Conclusions: Our data underscore the pivotal role of macrophages, and the macrophage-derived IL-18, in the establishment of TNBS-induced colitis in mice. Our results highlight the potential use of therapy directed against IL-18 in the treatment of patients with CD.

Interleukin-18 and Crohn's disease

Kanai Takanori, Watanabe Mamoru, Okazawa Akira, Sato Toshiro, Hibi Toshifumi

Digestion 63 ( SUPPL. 1 ) 37 - 42 2001

ISSN 0012-2823

The etiology and pathogenesis of inflammatory bowel disease remains an area under intense investigation. Crohn's disease (CD) is characterized by a marked accumulation of activated Th1 type CD4+ T cells and macrophages in inflamed intestinal mucosa. IL-18 is a recently described cytokine that mainly exists in activated macrophages and shares biological activities with IL-12 in driving the development of Th1 type CD4+ T cells by inducing interferon-γ. To clarify the role of IL-18 in intestinal inflammation in CD, we assessed the functional role of IL-18 in regulating intestinal mucosal lymphocytes in human CD and murine CD model. Copyright © 2001 S. Karger AG, Basel.

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Circulating autoantibodies against purified colonic mucin in ulcerative colitis

Takaishi Hiromasa, Ohara Susumu, Hotta Kyoko, Yajima Tomoharu, Kanai Takanori, Inoue Nagamu, Iwao Yasushi, Watanabe Mamoru, Ishii Hiromasa, Hibi Toshifumi

Journal of Gastroenterology 35 ( 1 ) 20 - 27 2000.01

ISSN 0944-1174

To clarify the role of colonic mucin in the autoimmune process of ulcerative colitis, circulating antibodies against human colonic mucin were investigated. Purified colonic mucin, obtained from human colonic mucosa by gel filtration, using a Bio-Gel A-1.5-m column and CsCl equilibrium density gradient, was divided into soluble mucin (S-mucin) secreted extracellularly and membranous mucin (M-mucin) binding to cell membrane. Sodium dodecylsulfate polyacrylamide gel electrophoresis and Western blotting analysis showed that antibodies in the serum samples of some patients with ulcerative colitis recognized purified S- and M-mucin of >180-kD. By enzyme-linked immunosorbent assay (ELISA), anti-mucin antibodies were detected in 11 of 60 patients with ulcerative colitis (18). In contrast, the antibodies were not detected in 22 patients with Crohn's disease. The titers of anti-mucin antibodies against S-mucin and M-mucin were not different in each patient. By ELISA using mucin in which the sugar chains were destroyed by neuraminidase or NaIO₄ treatment, it was demonstrated that anti-mucin antibodies recognized the epitopes of either the sugar chain or the core protein exposed through destruction of the sugar chains. We then investigated the relationship between anti-mucin antibodies and the patients' clinical features. Anti-mucin antibodies were detected in 6 of 15 patients with chronic continuous type ulcerative colitis (40) and in 5 of 26 patients with relapsing-remitting type (19), but there was no anti-mucin antibody-positive serum in patients who had had only one attack without any relapse. These results suggest that anti-mucin antibodies could be a disease marker for ulcerative colitis and that immunological abnormalities in colonic mucin contribute to the persistence of colonic mucosal inflammation.

Regulatory effect of interleukin-4 and interleukin-13 on colon cancer cell adhesion

Kanai T., Watanabe M., Hayashi A., Nakazawa A., Yajima T., Okazawa A., Yamazaki M., Ishii H., Hibi T.

British Journal of Cancer 82 ( 10 ) 1717 - 1723 2000

ISSN 0007-0920

To assess the role of interleukin-4 (IL-4) and interleukin-13 (IL-13) in colon cancer cell-cell adhesion, we investigated the effect of both cytokines in human colon cancer cell line, colo205 cell-cell adhesion. IL-4 receptor was expressed on the cell surface of colo205, and recombinant IL-4 inhibited colo205 cell-cell adhesion in a dose-dependent fashion without inhibiting cell proliferation. Flow cytometric analysis revealed that monoclonal antibodies (mAbs) directed against E-cadherin and carcinoembryonic antigen (CEA) inhibited colo205 cell-cell adhesion and IL-4 significantly inhibited the expression of E-cadherin and CEA. IL-13 also inhibited colo205 cell-cell adhesion. These results indicated that IL-4 and IL-13 inhibited colon cancer cell-cell adhesion by down-regulation of E-cadherin and CEA molecules. We then investigated the expression of both cytokines from freshly isolated colon cancer tumour-infiltrating lymphocytes (TILs). With reverse transcription-polymerase chain reaction and flow cytometric analysis. we demonstrated that colon TILs expressed IL-4 and IL-13 mRNA and protein. These results suggest that Th 2 type cytokines IL-4 and IL-13 locally-produced from TILs may regulate colon cancer adhesion by down-regulation of adhesion molecules. (C) 2000 Cancer Research Campaign.

Analysis of clinical course and long-term prognosis of surgical and nonsurgical patients with intestinal Behcet's disease

Naganuma Makoto, Iwao Yasushi, Inoue Nagamu, Hisamatsu Tadakazu, Imaeda Hiroyuki, Ishii Hiromasa, Kanai Takanori, Watanabe Mamoru, Hibi Toshifumi

American Journal of Gastroenterology 95 ( 10 ) 2848 - 2851 2000

ISSN 0002-9270

OBJECTIVE: Much remains unknown about the pathogenesis of intestinal Behcet's disease. The majority of these patients are treated with surgical intervention, although it has been recently reported that a number of medical treatments are sometimes effective. Only few studies, however, have ever been undertaken to analyze the long-term prognosis of this disease. In this study, we analyzed the clinical course and the recurrences after initial therapy in patients with intestinal Behcet's disease. METHODS: We investigated 20 patients (surgical group, n = 8; nonsurgical group, n = 12) for whom the clinical courses were known for ≥2 yr (2-23 yr). RESULTS: The surgical group tended to have higher rates of complications such as ocular and ileal lesions than the nonsurgical group. In the surgical group, 75% of the patients recurred (and were readmitted) within 2 yr, and 37.5% of the patients required reoperation for intestinal obstruction because of ulcer at the anastomosis. The percentage of peripheral CD8 + DR + lymphocytes in the recurrent group (10.4% ± 2.5%) was significantly higher than that in the nonrecurrent group (4.3% ± 1.2%, p < 0.05). CONCLUSIONS: Our results indicate that more extensive disease involving the ileum and ocular lesions are markers of severity and progression to surgical crisis, and that patients requiring surgery suffer more frequent recurrences. Furthermore, an increased percentage of peripheral CD8 + DR + lymphocytes may be a risk factor for disease recurrence. (C) 2000 by Am. Coll. of Gastroenterology.

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Clinical usefulness of microsatellite instability for the prediction of gastric adenoma or adenocarcinoma in patients with chronic gastritis

Kashiwagi K., Watanabe M., Ezaki T., Kanai T., Ishii H., Mukai M., Hibi T.

British Journal of Cancer 82 ( 11 ) 1814 - 1818 2000

ISSN 0007-0920

To assess a role of microsatellite instability (MSI) in the development of gastric adenocarcinoma or adenoma from chronic gastritis, we analysed mutations of five microsatellite loci in gastritis, adenoma and adenocarcinoma retrospectively. Gastric mucosa was biopsied from the same area in each patient at different periods and examined for MSI. Only one of 55 patients with chronic gastritis revealed MSI-H phenotype and the other 54 patients showed microsatellite stable (MSS) phenotypes. In six of 17 patients with gastric adenoma or well-differentiated adenocarcinoma, MSI-positive phenotypes were demonstrated. Interestingly, all of six patients showing MSI, including three high-level MSI (MSI-H) cases and three low-level (MSH-L) cases, had already revealed MSI at the stage of chronic gastritis. In two of three MSI-H cases, the identical MSI patterns had been observed at the stage of gastritis 1.5-7 years before the final diagnosis of adenocarcinoma. The adjacent gastritis mucosa within 10 mm from the carcinoma demonstrated MSI as well. MSI was not found in any of 35 patients with Helicobacter pylori infection, but found in one of 30 patients without infection. Moreover, two of three cases of gastric adenoma or well-differentiated adenocarcinoma with MSI-H at the stage of chronic gastritis showed no evidence of Helicobacter pylori infection throughout the observation periods. These results indicate that MSI in biopsy specimens at the stage of chronic gastritis may predict the risk of the progression to adenoma and well-differentiated adenocarcinoma, and that Helicobacter pylori infection itself may not induce MSI directly in the gastric mucosa. (C) 2000 Cancer Research Campaign.

Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease

Kanai Takanori, Watanabe Mamoru, Okazawa Akira, Nakamaru Koichi, Okamoto Makiyo, Naganuma Makoto, Ishii Hiromasa, Ikeda Masao, Kurimoto Masashi, Hibi Toshifumi

Gastroenterology 119 ( 6 ) 1514 - 1523 2000

ISSN 0016-5085

Background & Aims: Crohn's disease (CD) is characterized by a marked accumulation of activated Th1 type CD4⁺ T cells and macrophages in inflamed intestinal mucosa. Interleukin (IL)-18 is a recently described cytokine that mainly exists in activated macrophages and shares biological activities with IL-12 in driving the development of Th1 type CD4⁺ T cells by inducing interferon gamma. To clarify the role of IL-18 in intestinal inflammation in CD, we assessed the functional role of IL-18 in regulating intestinal mucosal lymphocytes. Methods: Serum IL-18 concentration was measured by enzyme-linked immunosorbent assay. Expression of IL-18 and IL-18 receptor in human intestinal mucosa was determined using immunohistochemistry and flow cytometry. The functional activity of IL-18 was assessed by the use of recombinant IL-18 to stimulate both the growth of intestinal mucosal lymphocytes and IL-2 receptor induction activity. Results: The serum IL-18 concentration was significantly higher in patients with CD than normal controls. In the inflamed colonic mucosa of CD, many IL-18⁺CD68⁺ macrophages had infiltrated the lamina propria. Intestinal mucosal lymphocytes from CD expressed functional IL-18 receptors. Recombinant IL-18 induced significant proliferative responses in freshly isolated mucosal lymphocytes from CD patients, but not from normal controls. 1L-18 up-regulated IL-2 receptor expression in mucosal lymphocytes from patients with CD, but not from normal controls. Conclusions: These findings suggest that infiltrated macrophages in the inflamed intestinal mucosa in CD produce IL-18, and that macrophage-derived IL-18 may serve as a potent regulatory factor for intestinal mucosal lymphocytes, thereby contributing to chronic intestinal inflammation in CD.

The role of IL-18 on the pathogenesis of Crohn's disease

Hibi T., Kanai T., Watanabe M., Okazawa S., Sato T.

Nihon Rinshō Men'eki Gakkai kaishi = Japanese journal of clinical immunology 23 ( 6 ) 607 - 610 2000

ISSN 0911-4300

Interferon-inducible gene family 1-8U expression in colitis-associated colon cancer and severely inflamed mucosa in ulcerative colitis

Hisamatsu Tadakazu, Watanabe Mamoru, Ogata Haruhiko, Ezaki Toshihiko, Hozawa Shigenari, Ishii Hiromasa, Kanai Takanori, Hibi Toshifumi

Cancer Research 59 ( 23 ) 5927 - 5931 1999.12

ISSN 0008-5472

Persistent severe inflammation in colonic mucosa is thought to cause the development of colon cancer in patients with ulcerative colitis (UC). However, predisposing genetic abnormalities have not been identified in this sequence. Using differential display PCR, we isolated cDNA fragments corresponding to mRNAs that were differentially expressed in colitis- associated cancer tissues and mucosa with mild inflammation in the colon of five UC patients. This molecular screening approach identified 60 cDNA fragments, and we sequenced 34 fragments. One cDNA fragment, which is identical to IFN-inducible gene family 1-8U, was strongly expressed in all five UC-associated cancers. 1-8U was also expressed in sporadic colon cancer tissues and colon cancer cell lines, but not in normal mucosa. This gene was strongly expressed in severely inflamed colonic mucosa of UC without colitis- associated colon cancer, although 1-8U expression was not related to the extent and duration of the disease. However, 1-8U was expressed in the colonic mucosa of all patients with chronic, continuously severe inflammation. These results indicated that IFN-inducible gene family 1-8U expression in inflamed colonic mucosa might be used as a preferential marker of colitis-associated colon cancer in UC.

A case of well differentiated adenocarcinoma with ulcerative colitis resembling colitis cystica profunda

Naganuma Makoto, Iwao Yasushi, Miura Soichiro, Okamoto Ikuo, Ohkura Yasuo, Kanai Takanori, Watanabe Mamoru, Hibi Toshifumi, Ishii Hiromasa

Japanese Journal of Gastroenterology 96 ( 6 ) 658 - 663 1999.06

ISSN 0446-6586

Functional expression of costimulatory molecule CD86 on epithelial cells in the inflamed colonic mucosa

Nakazawa A., Watanabe M., Kanai T., Yajima T., Yamazaki M., Ogata H., Ishii H., Azuma M., Hibi T.

Gastroenterology 117 ( 3 ) 536 - 545 1999

ISSN 0016-5085

Background and Aims: Costimulatory signals are essential for T-cell activation. The aim of this study was to demonstrate expression of costimulatory molecules CD86 and CD80 in human colonic epithelial cells and assess their functional roles in the activation of T cells in inflamed colonic mucosa. Methods: CD86 and CD80 expression was assessed by immunohistochemistry of colonic mucosa, reverse-transcription polymerase chain reaction, and flow cytometric analysis of isolated colonic epithelial cells and cell lines. Costimulatory effect of CD86-expressing colonic epithelial cells on purified CD4⁺ T-cell proliferation was also assessed at suboptimal phytohemagglutinin stimulation. Results: CD86 and CD80 messenger RNA was detected in isolated colonic epithelial cells from normal and inflamed mucosa of patients with ulcerative colitis. Immunohistochemistry and flow cytometric analysis of colonic epithelial cells confirmed cell surface expression of CD86 protein in inflamed colonic mucosa. Cell surface expression of CD86 protein was increased in the colonic epithelial cell line HT29-18-N2 after interferon gamma stimulation. Purified CD4⁺ T cells proliferated in response to suboptimal phytohemagglutinin costimulated with interferon gamma-stimulated HT2918-N2, and these proliferative responses were efficiently inhibited by the addition of anti-CD86 monoclonal antibody. Costimulatory effect of CD86-expressing colonic epithelial cells isolated from inflamed mucosa of ulcerative colitis was also demonstrated at suboptimal phytohemagglutinin stimulation in CD4⁺ T cells. Conclusions: Colonic epithelial cells may act as antigen-presenting cells, and contribute to the activation of T cells through costimulatory molecule CD86 expression in inflamed colonic mucosa.

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Predictive factors of response to leukocytapheresis therapy for ulcerative colitis

Yajima Tomoharu, Takaishi Hiromasa, Kanai Takanori, Iwao Yasushi, Watanabe Mamoru, Ishii Hiromasa, Hibi Toshifumi

Therapeutic Apheresis 2 ( 2 ) 115 - 119 1998.05

ISSN 1091-6660

Leukocytapheresis (LCAP) using a leukocyte removal filter was performed for 8 patients with moderate to severe ulcerative colitis (UC). Significant clinical improvement was attained in 5 of 8 patients (62.5%). All of them had been suffering from moderately active colitis and received corticosteroid therapy. On the other hand, 3 patients with severely active disease and treated with little or no corticosteroid were resistant to LCAP. This result indicates that LCAP is an effective treatment for steroid-resistant cases of UC when combined with steroid therapy. LCAP alone, however, seems to have little efficacy for severely active UC.

Gastrointestinal endoscopy as a screening method for cytomegalovirus infection following allogeneic bone marrow transplantation

Yajima T., Iwao Y., Hisamatsu T., Okamato S., Ikeda Y., Sugiura H., Mukai M., Kanai T., Ogata H., Watanabe M., Hibi T., Ishii H.

Gastrointestinal Endoscopy 47 ( 4 ) 1998

ISSN 0016-5107

Background and Aim: Cytomegalovirus (CMV) infection is a serious complication following solid organ and bone marrow transplantation (BMT). CMV affects multiple organs and results in considerable morbidity and prolonged hospitalization. But the clinical feature of upper GI lesions in CMV infection after BMT remains unclear. Detection of CMV antigen in peripheral blood leukocytes with immunohistochemical technique (antigenemia) is the most reliable screening method for CMV infection. The antigenemia is, however, not sensitive enough in some cases. The aim of this study is to investigate the clinical significance of upper GI lesions in CMV infection. Patients and Methods: We performed endoscopic examination of the upper GI tract in 47 patients 20 to 70 days after allogeneic BMT from December 1992 to November 1997. Biopsy specimens, taken each from esophagus, stomach body and antrum, and duodenum, were assayed for CMV antigen with immunohistochemical technique. Results: CMV infection was revealed in the upper GI tract in 9 patients. The endoscopic findings of the affected lesions were characteristic erosions surrounded by redness in the stomach and duodenum, map-like redness in the duodenum, and ulcer in the esophagus. Stomach was involved in all cases (9/9, 100%), but duodenum (4/9, 44%) and esophagus (2/9, 22%) were less frequently infected. In 3 patients, CMV antigen was detected in the upper GI tract before antigenemia turned positive. Conclusion: The endoscopic examination of upper GI tract is a useful screening method for CMV infection following allogeneic BMT.

The serum factor from patients with ulcerative colitis that induces T cell proliferation in the mouse thymus is interleukin-7

Watanabe Mamoru, Watanabe Noriaki, Iwao Yasushi, Ogata Haruhiko, Kanai Takanori, Ueno Yoshitaka, Tsuchiya Masaharu, Ishii Hiromasa, Aiso Sadakazu, Habu Sonoko, Hibi Toshifumi

Journal of Clinical Immunology 17 ( 4 ) 282 - 292 1997

ISSN 0271-9142

The disturbance of immune regulatory T cells is related to the pathogenesis of ulcerative colitis. Here we demonstrated and characterized the serum factor from ulcerative colitis patients that induced proliferation of intrathymic T cells. The factor isolated from the patient sera by a combination of gel filtration and anion-exchange chromatography induced proliferation of CD4⁺CD8^- intrathymic T cells in the organ-cultured embryonic mouse thymus. Purification and amino acid sequence analysis of the serum factor demonstrated that the N-terminal 12 sequence was homologous to that of interleukin-7. SDS-PAGE and Western blot confirmed that purified serum factor was interleukin-7. Enzyme immunoassay demonstrated that the serum interleukin-7 concentration was significantly increased in the patients. PCR and Southern blot hybridization demonstrated that interleukin- 7 mRNA expression was increased in the thymus tissues from patients but decreased in the colonic mucosa. Since interleukin-7 is a crucial cytokine for proliferation and differentiation of T cells in the thymus, the present study indicates that interleukin-7 may contribute to the disturbance of immune regulatory T cells in ulcerative colitis.

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Carcinoembryonic antigen mediates in vitro cell aggregation induced by interferon-γ in a human colon cancer cell line

Kanai Takanori, Hibi Toshifumi, Hayashi Atsushi, Takashima Junya, Shiozawa Masahide, Aiso Sadakazu, Toda Kyoko, Iwao Yasushi, Watanabe Mamoru, Tsuchiya Masaharu

Cancer Letters 71 ( 1-3 ) 109 - 117 1993.07

ISSN 0304-3835

The homotypic cell aggregation of a carcinoembryonic antigen (CEA) positive colon cancer cell line (Colo 205) was induced in vitro by interferon-γ (IFN-γ) treatment. Divalent cations were required for this aggregation, as it was inhibited by EDTA. The partial inhibition by cytochalasin B and the complete inhibition by a mixture of sodium azide and 2-deoxyglucose suggests that the aggregation requires the integrity of cytoskeleton and active metabolism. The expression of CEA was increased in the cytoplasm and on the membrane of Colo 205 by IFN-γ treatment. Furthermore, this aggregation was inhibited completely by anti-CEA monoclonal antibody (mAb) and partially by mAb against intercellular adhesion molecule-1. This in vitro study suggests that CEA molecule participates in the IFN-γ induced homotypic adhesion of some CEA positive cancer cells and that IFN-γ has an important role in the regulation of cell-cell interaction mediated by CEA molecule. © 1993.

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Interleukin 2 and interferon-γ augment anticolon antibody dependent cellular cytotoxicity in ulcerative colitis

Hibi T., Ohara M., Watanabe M., Kanai T., Takaishi H., Hayashi A., Hosoda Y., Ogata H., Iwao Y., Aiso S., Watanabe N., Toda K., Tsuchiya M.

Gut 34 ( 6 ) 788 - 793 1993.06

ISSN 0017-5749

In vitro effects of cytokines and therapeutic drugs on antibody dependent cellular cytotoxicity (ADCC) mediated by anticolon antibody were investigated in serum samples from patients with ulcerative colitis. A ⁵¹Cr release assay was used to examine ADCC activity with the colon cancer cell line, colo 205, as the target and peripheral blood mononuclear cells as the effector. High ADCC activity was shown in 13 of 32 (41%) patients with ulcerative colitis. This ADCC activity was inhibited by protein A treatment of the serum samples. Interleukin 2 (IL2) activated effector cells could enhance ADCC activity, but interferon-γ (IFN-γ) or tumour necrosis factor-α (TNF-α) had no effect on the cytotoxic activity of effector cells. Treatment of target cells with IFN-γ increased the vulnerability of these cells to ADCC with a large increase of intercellular adhesion molecule-1 (ICAM-1) expression on their surface. Monoclonal antibodies to ICAM-1 inhibited this IFN-γ enhanced ADCC activity. Interestingly, prednisolone (PSL) reduced ADCC activity, but sulphasalazine (SASP) or 5-aminosalicylic acid (5-ASA) did not. These results suggest that IL2 and IFN-γ could enhance colonic epithelial cell injury mediated by the ADCC mechanism in ulcerative colitis and that ADCC enhanced by cytokines is restored by PSL treatment.

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