研究者詳細 - 竹内　勤

論文 - 竹内　勤

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Quantitative analysis of lacrimal gland function, apoptotic figures, Fas and Fas ligand expression of lacrimal glands in dry eye patients

竹内勤

Experimental Eye Research 76 （ 2 ） 233 - 240 2003年02月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0014-4835

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Pathogenic roles of IL-6 and IL-6 blocking therapy on rheumatoid arthritis

竹内勤

Arthritis Research and Therapy 5 S42 2003年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1478-6354

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Rapid proliferation of a different clone early after autologous peripheral blood stem cell transplantation for non-hodgkin's lymphoma

Mori Takehiko, Tamaru Junichi, Tokuhira Michihide, Mori Shigehisa, Suzuki Hiroshi, Abe Toru, Takeuchi Tsutomu

International Journal of Hematology 76 （ 3 ） 287 - 289 2002年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0925-5710

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Rapid proliferation of a different clone early after autologous peripheral blood stem cell transplantation for non-Hodgkin's lymphoma

竹内勤

International Journal of Hematology 76 （ 3 ） 287 - 289 2002年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0925-5710

Successful non-surgical treatment of brain abscess and necrotizing fasciitis caused by Bacillus cereus

Mori Takehiko, Tokuhira Michihide, Takae Yujiro, Mori Shigehisa, Suzuki Hirosi, Abe Toru, Takeuchi Tsutomu

Internal Medicine 41 （ 8 ） 671 - 673 2002年08月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0918-2918

Musculoskeletal and central nervous system infections caused by Bacillus cereus are very rare. Only a few cases have been reported, whose clinical courses strongly suggested that surgical procedures combined with appropriate antimicrobial therapy are necessary to cure these infections. A 60-year-old man with severe neutropenia due to myelodysplastic syndrome, developing necrotizing fasciitis and brain abscess caused by Bacillus cereus is reported. Without performing any surgical procedures, the patient was successfully treated with systemic antimicrobial therapy combined with granulocyte colony stimulating factor, which contributed to the increase in the neutrophil count.

CD30 and the NPM-ALK fusion protein (p80) are differentially expressed between peripheral blood and bone marrow in primary small cell variant of anaplastic large cell lymphoma

竹内勤

American Journal of Hematology 69 （ 3 ） 200 - 204 2002年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0361-8609

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T-cell receptor ζ mRNA with an alternatively spliced 3′ untranslated region is generated predominantly in the peripheral blood T cells of systemic lupus erythematosus patients

Tsuzaka Kensei, Onoda Natsuko, Yoshimoto Keiko, Setoyama Yumiko, Suzuki Katsuya, Pang Ming, Abe Tohru, Takeuchi Tsutomu

Modern Rheumatology 12 （ 2 ） 167 - 173 2002年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1439-7595

To investigate the mechanism of the downregulation of T-cell receptor ζ chain (TCRζ) expression in the peripheral blood T cells (PBTs) of systemic lupus erythematosus (SLE) patients, we analyzed the 3′ untranslated region (3′UTR) of TCRζ mRNA, because the 3′UTR in mRNA is responsible for posttranscriptional regulation. Use of the reverse transcriptase polymerase chain reaction (RT-PCR) to amplify the 917bp TCRζ 3′UTR cDNA demonstrated that the short variant cDNA (355bp), expressed as an alternatively spliced 3′UTR with 562-bp deletion, was predominated in the PBTs of 11 of 14 SLE patients, whereas mainly the wild-form cDNA (917bp) was detected in the PBTs of seven negative controls (two systemic sclerosis patients, five normal controls) and in two T-cell line hybridomas. Semiquantitative PCR also revealed the predominant expression of the TCRζ mRNA with alternatively spliced 3′UTR (TCRζ mRNA/as-3′UTR), and a decreased expression of TCRζ mRNA with the wild form 3′UTR (TCRζ mRNA/w-3′UTR) in SLE T cells. However, there was no difference in the expression of the open reading frame (ORF) TCRζ mRNA between the negative controls and SLE patients. The TCRζ protein expression level according to Western blot analysis correlated well with that of TCRζ mRNA/w-3′UTR (r = 0.931) and reversibly with TCRζ mRNA/as-3′UTR (r = -0.614), but not with ORF TCRζ mRNA (r = -0.296). It can be concluded that the reduced expression of TCRζ mRNA/w-3′UTR and the pre-dominant expression of TCRζ mRNA/as-3′UTR lead to downregulation of the TCRζ protein in SLE T cells.

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Abnormal expression and function of Fas ligand of lachrymal glands and peripheral blood in Sjögren's syndrome patients with enlarged exocrine glands

Tsubota K., Fujita H., Tadano K., Onoda N., Tsuzaka K., Takeuchi T.

Clinical and Experimental Immunology 129 （ 1 ） 177 - 182 2002年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-9104

The objective of our study was to investigate the possibility of Fas ligand protein abnormalities in certain types of Sjögren's syndrome patients with enlarged exocrine glands. Fas ligand expression by lymphocytes infiltrating the lachrymal glands and by peripheral blood monocytes in Sjögren's syndrome patients with enlarged exocrine glands was assessed immunohistologically and by immunoblotting. Cytotoxicity of peripheral blood monocytes and sensitivity to steroids in Sjögren's syndrome patients with enlarged exocrine glands were studied by functional assay. Minimal Fas ligand expression was detected in the lymphocytes of the lachrymal glands and a decreased level of Fas ligand was found in peripheral blood monocytes as assessed by immunoblotting. Functional assay confirmed the decreased cytotoxicity of lymphocytes in Sjögren's syndrome patients with enlarged exocrine glands, and that it is not affected by anti-Fas ligand antibody. By contrast, the sensitivity of lymphocytes in Sjögren's syndrome patients with enlarged exocrine glands to steroids was increased. These observations suggest that abnormal expression and function of Fas ligand occurs in Sjögren's syndrome patients with enlarged exocrine glands.

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Defective expression and tyrosine phosphorylation of the T cell receptor zeta chain in peripheral blood T cells from systemic lupus erythematosus patients

Pang M., Setoyama Y., Tsuzaka K., Yoshimoto K., Amano K., Abe T., Takeuchi T.

Clinical and Experimental Immunology 129 （ 1 ） 160 - 168 2002年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0009-9104

We have reported that tyrosine phosphorylation and expression of the T cell receptor zeta chain (TCR ζ) was decreased in two systemic lupus erythematosus (SLE) patients with an abnormal TCR ζ lacking exon-7. To examine further the TCR ζ defect and any possible relationship with specific clinical features, we studied the expression of TCR ζ in peripheral blood T cells from 44 patients with SLE, 53 with other rheumatic diseases (30 rheumatoid arthritis (RA), 11 systemic sclerosis (SSc) and 12 primary Sjögren's syndrome(SjS)) and 39 healthy individuals. Flow cytometric analysis demonstrated a significant decrease in the expression of TCR ζ in SLE (P < 0.001), but not in the other rheumatic diseases. Immunoprecipitation experiments confirmed that the expression of TCR ζ in SLE T cells was decreased dramatically (normal: 111.4 ± 22.6%, SLE: 51.6 ± 37.4%,P < 0.0001). The decrease in TCR ζ did not correlate with disease activity, or with the dose of prednisolone (PSL). There were, however, three SLE patients in whom the level of TCR ζ expression normalized after treatment, suggesting that mechanisms responsible for the TCR ζ defect appear to be heterogeneous. These results confirm the defective expression and altered tyrosine phosphorylation of TCR ζ in a large proportion of SLE patients, suggesting that it may play an important role in T cell dysfunction in SLE.

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A functional polymorphism in Fas (CD95/APO-1) gene promoter associated with systemic lupus erythematosus

Kanemitsu Satomi, Ihara Kenji, Saifddin Ahmed, Otsuka Takeshi, Takeuchi Tsutomu, Nagayama Jun, Kuwano Michihiko, Hara Toshiro

Journal of Rheumatology 29 （ 6 ） 1183 - 1188 2002年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0315-162X

Objective. To investigate whether Fas promoter polymorphisms show a genetic contribution to the development of systemic lupus erythematosus (SLE) in a Japanese population, and to study the functional difference in promoter activity of the polymorphisms. Methods. In 109 SLE patients and 140 controls, the frequencies of A/G polymorphisms at -670 nucleotide position and G/A at -1377 nucleotide position were determined by allele-specific polymerase chain reaction (PCR) or PCR-single strand conformation polymorphism analysis. The functional significance of the -670A/G polymorphism in the Fas gene was evaluated by a combination of Fas transcriptional activity in the reporter gene assay and binding activity of signal transducer and activator of transcription (STAT)1 protein in the electrophoretic mobility shift assay. Results. SLE patients exhibited significantly higher frequency of A allele at nucleotide position -670 (p = 0.004). There was no significant difference in the nucleotide position -1377 in Fas promoter gene between SLE patients and controls. The electrophoretic mobility shift assay demonstrated that the oligonucleotide with -670A in the Fas promoter had a higher binding ability to a GAS binding protein, STAT1, than that with -670G, although there was no statistically significant difference in the reporter gene assay. Conclusion. Fas promoter -670A/G polymorphism was significantly associated with SLE, suggesting a possibility that Fas promoter contributes, at least in part, to the pathogenesis of SLE.

Diagnostic significance of serum soluble transferrin receptors in various anemic diseases

Matsuda Akira, Besso Masami, Mori Shigehisa, Takeuchi Tsutomu, Abe Tohru, Yawata Yoshihito, Mori Hiraku, Omine Mitsuhiro, Nakamura Yuichi, Furusawa Shinpei, Maeda Teiryo, Haginosita Susumu, Hirasawa Yoshihei, Kinugasa Eriko, Akizawa Tadao, Kawakami Naohito, Nagata Atsuo, Hirashima Kunitake

Haematologia 32 （ 3 ） 225 - 238 2002年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0017-6559

Serum soluble transferrin receptor (sTfR) has been reported to be higher in patients with iron deficiency or with elevated erythropoiesis. In the present study, serum sTfR was measured in various anemic diseases and their clinical significance was examined in a multi-institutional joint study. Serum sTfRs in patients with the following anemic diseases were markedly higher than those in normal healthy adults: non-treated iron deficiency anemia (IDA) (9.13 ± 7.04 mg/l, n = 52, p <0.0001), anemia of chronic disorders (ACD) (3.45 ± 1.38 mg/l, n = 20, p <0.0001), hemolytic anemia (HA) (5.57 ± 3.26 mg/l, n = 17, p <0.0001), and myelodysplastic syndrome (MDS) (4.03 ± 2.83 mg/l, n = 20, p <0.0001). There were significant differences between IDA and ACD (p <0.0001), between aplastic anemia (AA) (1.58 ± 1.26 mg/l, n = 16) and MDS (p <0.001), and between AA and MDS with refractory anemia (MDS-RA) (4.16 ± 3.40 mg/l, n = 9) (p <0.02). In patients with chronic renal failure (CRF), serum sTfR levels and serum sTfR/log serum ferritin ratios (sTfR/F index) were compared in the two classified groups according to Muirhead's criteria, as IDA and non-IDA groups with or without recombinant human erythropoietin (rHuEPO) treatment. Significantly high levels of both serum sTfR (p <0.0001) and the sTfR/F index (p <0.0001) were observed in IDA without rHuEPO treatment. Especially in CRF with rHuEPO treatment, the sTfR/F index showed marked elevation in the IDA group (p <0.0001) compared with serum sTfR (p <0.001), indicating more diagnostic efficacy of the sTfR/F index for CRF with IDA. In conclusion, the serum sTfR concentration is a useful diagnostic tool for discrimination between IDA and ACD, and between AA and MDS-RA, and for the detection of iron deficiency in CRF patients in the Japanese population.

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Primary natural killer cell lymphoma of the lacrimal sac

竹内勤

Annals of Hematology 80 （ 10 ） 607 - 610 2001年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0939-5555

Expression of Gab1 lacking the pleckstrin homology domain is associated with neoplastic progression

竹内勤

Molecular and Cellular Biology 21 （ 20 ） 6895 - 6905 2001年10月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0270-7306

Successful treatment of embryo implantation failure in patients with the Sjogren syndrome with low-dose prednisolone

竹内勤

Fertility and Sterility 75 （ 3 ） 640 - 641 2001年03月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0015-0282

Improvement of lacrimal function by topical application of CyA in murine models of Sjögren's syndrome

Tsubota K., Fujita H., Tadano K., Takeuchi T., Murakami T., Saito I., Hayashi Y.

Investigative Ophthalmology and Visual Science 42 （ 1 ） 101 - 110 2001年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0146-0404

PURPOSE. The object of this study was to evaluate improvement of lacrimal gland (LG) function after topical cyclosporin A (CyA). METHODS. Topical CyA (0.01% and 0.1%) was applied to two mouse models of Sjögren's syndrome, the NFS/sld after thymectomy and the nonobese diabetic (NOD) mouse, and the functional integrity of the lacrimal gland was evaluated by measuring basal and stimulated tear secretion and its histologic integrity by examining it for apoptosis and lymphocyte invasion. RESULTS. After treatment with CyA 0.1% in the NFS/sld mice, tear function increased, and there was a decrease in lymphocyte infiltration of the LG and a decrease in apoptotic figures among the acinar cells. In the NOD mice, tear function also improved, but there was no associated decrease in lymphocyte infiltration. However, the expression of Fas ligand (FasL) in NOD mice by infiltrating lymphocytes was suppressed with 0.1% CyA eye drops. CONCLUSIONS. CyA appears to improve tear secretion in mouse models of Sjögren's syndrome by preventing lymphocyte-induced apoptosis of acinar cells in one model this was achieved by preventing lymphocyte infiltration and in the other by reducing expression of FasL expression on infiltrating lymphocytes.

Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still's disease

Kawashima Masanori, Yamamura Masahiro, Taniai Madoka, Yamauchi Hiroshi, Tanimoto Tadao, Kurimoto Masashi, Miyawaki Shoji, Amano Tetsuki, Takeuchi Tsutomu, Makino Hirofumi

Arthritis and Rheumatism 44 （ 3 ） 550 - 560 2001年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0004-3591

Objective. Interleukin-18 (IL-18) is a proinflammatory cytokine that is involved in immunologically mediated tissue damage, but its bioactivity is regulated in vivo by its soluble decoy receptor, IL-18 binding protein (IL-18BP). This study was undertaken to determine levels of IL-18 and IL-18 binding inhibition in the blood of patients with adult-onset Still's disease (ASD). Methods. Serum concentrations of IL-18 in ASD patients were compared by enzyme-linked immunosorbent assay (ELISA) with those in patients with other systemic rheumatic diseases and healthy controls. The biologically active mature protein of IL-18 was detected by Western blot analysis with anti-IL-18 antibody and its induction of interferon-γ (IFNγ) secretion from IL-18-responding human myelomonocytic KG-1 cells. The inhibitory activity on IL-18 binding to its receptor was determined by ¹²⁵I-IL-18 binding inhibition assay using the Chinese hamster ovary cell line transfected with a murine IL-18 receptor (CHO-K1/mIL-18R). Results. Concentrations of serum IL-18 were extremely elevated in patients with active ASD compared with those in patients with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis/dermatomyositis, Sjögren's syndrome, or healthy individuals. Levels of IL-18 were found to correlate with serum ferritin values and disease severity in ASD. Western blot analysis revealed that serum samples from patients with active ASD contained an 18-kd polypeptide of IL-18, corresponding in size to the mature form. Accordingly, the samples were able to induce IFNγ secretion from KG-1 cells, which was largely abolished by neutralizing anti-IL-18 antibody. However, the level of IL-18 bioactivity was more than 10-fold weaker than the concentration of IL-18 protein measured by ELISA. Serum samples from patients with active ASD showed an inhibitory effect on the binding of ¹²⁵I-IL-18 to CHO-K1/mIL-18R cells, and this activity was associated with elevation of IL-18. Conclusion. These data indicate that systemic overproduction of IL-18 may be closely related to the pathogenesis of ASD, despite the restriction on its inflammatory activity by IL-18 binding inhibitors such as IL-18BP. The disease activity appears to be determined on the basis of the relative levels of IL-18 and its specific inhibitors.

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Successful treatment of embryo implantation failure in patients with the Sjögren syndrome with low-dose prednisolone

Ishihara Osamu, Saitoh Masahiro, Hayashi Naoki, Kinoshita Katsuyuki, Takeuchi Tsutomu

Fertility and Sterility 75 （ 3 ） 640 - 641 2001年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0015-0282

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Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population

Ahmed S., Ihara K., Kanemitsu S., Nakashima H., Otsuka T., Tsuzaka K., Takeuchi T., Hara T.

Rheumatology 40 （ 6 ） 662 - 667 2001年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 1462-0324

Objective. Systemic lupus erythematosus (SLE) in a multisystem autoimmune disorder characterized by multiorgan pathology and autoantibodies against a variety of autoantigens. The CD28 and CTLA-4 genes might be candidate genes for SLE, because costimulation signals from CD80/CD86 to CD28/CTLA-4 have been suggested to play an important role in the activation or inactivation of T lymphocytes. Methods. We investigated three polymorphic regions within the CTLA-4 gene, a C/T base exchange in the promoter region - 318 (CTLA-4 - 318C/T), an A/G substitution in the exon 1 position 49 (CTLA-4 49A/G), an (AT)_n repeat polymorphism in the 3′ untranslated region of exon 4 [CTLA-4 3′ (AT)_n], and a CD28 gene polymorphism, a T/C substitution in the intron 3 position + 17 (CD28 IVS3 + 17T/C), in SLE patients and controls. Results. SLE patients had significantly higher frequencies of the CTLA-4 49G allele (P = 0.003) and of the CTLA-4 (AT)_n 106 bp allele (P = 0.0008) than controls. We also found a strong linkage disequilibrium between the A allele of CTLA-4 49A/G and the 86 bp allele of CTLA-4 3′ (AT)_n. On the contrary, no association was found between SLE and CTLA-4 -318C/T or CD28 IVS3 + 17T/C. Conclusion. We conclude that the CTLA-4 gene appears to play a significant role in the development of SLE in the Japanese population.

Complement component 9 deficiency is not a susceptibility factor for SLE

竹内勤

LUPUS 9 （ 6 ） 456 - 457 2000年

研究論文（学術雑誌）, ISSN 0961-2033

Mikulicz's disease and Sjogren's syndrome

Tsubota Kazuo, Fujita Hiromi, Tsuzaka Kensei, Takeuchi Tsutomu

Investigative Ophthalmology and Visual Science 41 （ 7 ） 1666 - 1673 2000年

研究論文（学術雑誌）, 共著, 査読有り, ISSN 0146-0404

PURPOSE. To characterize lacrimal gland function and lymphocyte infiltration in patients with Mikulicz's disease (MD) and Sjogren's syndrome (SS). METHODS. Four patients with MD and 5 with SS were recruited, on whom were performed Schirmer test I (Schirmer test without anesthesia), Schirmer test with nasal stimulation, and vital staining of the ocular surface. The lacrimal gland was then biopsied and the tissues stained with CD3, CD4, CD8, B220, APO2.7, Fas, and Fas ligand (Fas-L) antibodies. RESULTS. Although regular Schirmer test results in the MD group were less than 10 mm, those with nasal stimulation, 38.1 ± 3.4 mm, were significantly greater than the SS group. There were minimal ocular surface changes in MD. Morphologic staining with hematoxylin and eosin was identical in both groups, but the acinar cells were stained with APO2.7 only in the SS group. There was strong Fas and Fas-L staining in SS patients but not in those with MD. CONCLUSIONS. Lacrimal gland acinar cells in those with MD maintained their function and were not programmed for cell death. The sicca syndrome was not observed in MD patients. Although the pathology is similar for MD and SS, the difference in acinar cell apoptosis and function can explain clinical differences.

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