K Tezuka

Kyoto Prefectural University of Medicine, Kioto, Kyōto, Japan

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Publications (8)29.8 Total impact

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    ABSTRACT: 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.
    No preview · Article · Aug 2003 · Immunology Letters
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    ABSTRACT: We investigated the relationship between ICOS, CD28, CTLA-4, and IL-2 to gain a better understanding of this family of costimulatory receptors in the immune response. Using magnetic beads coated with anti-CD3 and varying amounts of anti-ICOS and anti-CTLA-4 Abs, we show that CTLA-4 ligation blocks ICOS costimulation. In addition to inhibiting cellular proliferation, CTLA-4 engagement prevented ICOS-costimulated T cells from producing IL-4, IL-10, and IL-13. Both an indirect and direct mechanism of CTLA-4's actions were examined. First, CTLA-4 engagement on resting cells was found to indirectly block ICOS costimulation by interferring with the signals needed to induce ICOS cell surface expression. Second, on preactivated cells that had high levels of ICOS expression, CTLA-4 ligation blocked the ICOS-mediated induction of IL-4, IL-10, and IL-13, suggesting an interference with downstream signaling pathways. The addition of IL-2 not only overcame both mechanisms, but also greatly augmented the level of cellular activation suggesting synergy between ICOS and IL-2 signaling. This cooperation between ICOS and IL-2 signaling was explored further by showing that the minimum level of IL-2 produced by ICOS costimulation was required for T cell proliferation. Finally, exogenous IL-2 was required for sustained growth of ICOS-costimulated T cells. These results indicate that stringent control of ICOS costimulation is maintained initially by CTLA-4 engagement and later by a requirement for exogenous IL-2.
    Full-text · Article · May 2001 · The Journal of Immunology
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    ABSTRACT: Activation-inducible lymphocyte immuno-mediatory molecule (AILIM/ICOS) is the third member of the co-stimulatory molecule CD28/CTLA-4 (CD152) family, and an inducible cell surface glycoprotein expressed on lymphocytes following activation. To determine the expression profile of the molecule, we generated monoclonal antibodies (MAbs) against human, rat, and mouse AILIM/ICOS. None of the MAbs bound to AILIM/ICOS of other species. The numbers of AILIM/ICOS-positive cells among human peripheral blood mononuclear cells (PBMC), and rat and mouse splenocytes were very low (0.5, 0.4, and 1.2%, respectively), and the cells included many CD4-positive T cells except in the case of rat. Rat AILIM/ICOS-positive cells among splenocytes included many CD45RA-positive B cells, although the expression on lymph node cells was similar to that on human PBMC and mouse splenocytes. Among rat thymocytes, the AILIM/ICOS expression was mainly localized on CD4- and CD8-double positive T cells. The binding of AILIM/ICOS to B7h-Ig, which is the ligand-Fc chimeric protein, was inhibited by all AILIM/ICOS-specific MAbs except for SG430. The potency of the co-stimulatory activity of CD3 and AILIM/ICOS as to T-cell proliferation was found to be substantial in human. Interestingly, the levels of stimulation with the two types of MAbs were equal to that with CD3 and CD28 despite the different functions of the two MAbs in the AILIM/ICOS-B7h interaction. On the other hand, the potencies in rat and mouse, although two independent MAbs were tested, were relatively lower than that of CD28-mediated co-stimulation.
    No preview · Article · Feb 2001 · Hybridoma and Hybridomics
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    T Tamatani · K Tezuka · N Hanzawa-Higuchi
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    ABSTRACT: The adhesive interaction between T cells and antigen-presenting cells is required for the formation of the immunological synapse. Inducible co-stimulator (ICOS) is a third member of the CD28 family of co-stimulatory molecules. Here we describe a novel lymphocyte adhesion molecule, of relative molecular mass 47,000, designated AILIM, that is a rat homolog of ICOS. Rat AILIM was constitutively expressed on thymocytes and was induced on naive T cells after activation. Human thymoma cells bound to purified AILIM. Furthermore, cells transfected with the AILIM gene aggregated in an AILIM-dependent manner. These results suggest a novel function for AILIM/ICOS as an adhesion molecule, which plays an important role in T cell activation.
    Preview · Article · Jan 2000 · International Immunology
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    ABSTRACT: Recently, we cloned a messenger RNA (mRNA) predominantly expressed in chondrocytes from a human chondrosarcoma-derived chondrocytic cell line, HCS-2/8, by differential display PCR and found that its gene, named hcs24, was identical with that of connective tissue growth factor (CTGF). Here we investigated CTGF/Hcs24 function in the chondrocytic cell line HCS-2/8 and rabbit growth cartilage (RGC) cells. HCS-2/8 cells transfected with recombinant adenoviruses that generate CTGF/Hcs24 sense RNA (mRNA) proliferated more rapidly than HCS-2/8 cells transfected with control adenoviruses. HCS-2/8 cells transfected with recombinant adenoviruses that generate CTGF/Hcs24 sense RNA expressed more mRNA of aggrecan and type X collagen than the control cells. To elucidate the direct action of CTGF/Hcs24 on the cells, we transfected HeLa cells with CTGF/Hcs24 expression vectors, obtained stable transfectants, and purified recombinant CTGF/Hcs24 protein from conditioned medium of the transfectants. The recombinant CTGF/Hcs24 effectively promoted the proliferation of HCS-2/8 cells and RGC cells in a dose-dependent manner and also dose dependently increased proteoglycan synthesis in these cells. In addition, these stimulatory effects of CTGF/Hcs24 were neutralized by the addition of anti-CTGF antibodies. Furthermore, the recombinant CTGF/Hcs24 effectively increased alkaline phosphatase activity in RGC cells in culture. Moreover, RT-PCR analysis revealed that the recombinant CTGF/Hcs24 stimulated gene expression of aggrecan and collagen types II and X in RGC cells in culture. These results indicate that CTGF/Hcs24 directly promotes the proliferation and differentiation of chondrocytes.
    No preview · Article · Jan 2000 · Endocrinology
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    ABSTRACT: Connective tissue growth factor (CTGF) is a novel cysteine-rich, secreted protein. Recently, we found that inhibition of the endogenous expression of CTGF by its antisense oligonu-cleotide and antisense RNA suppresses the proliferation and migration of vascular endo-thelial cells. In the present study, the following observations demonstrated the angiogenic function of CTGF in vitro and in vivo: (i) purified recombinant CTGF (rCTGF) promoted the adhesion, proliferation and migration of vascular endothelial cells in a dose-dependent manner under serum-free conditions, and these effects were inhibited by anti-CTGF antibodies; (ii) rCTGF markedly induced the tube formation of vascular endothelial cells, and this effect was stronger than that of basic fibroblast growth factor or vascular endothelial growth factor; (iii) application of rCTGF to the chicken chorioallantoic membrane resulted in a gross angiogenic response, and this effect was also inhibited by anti-CTGF antibodies. (iv) rCTGF injected with collagen gel into the backs of mice induced strong angiogenesis in vivo. These findings indicate that CTGF is a novel, potent angiogenesis factor which functions in multi-stages in this process.
    No preview · Article · Aug 1999 · Journal of Biochemistry
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    ABSTRACT: Connective tissue growth factor (CTGF) is a mitogenic, chemotactic, and cell matrix-inducing factor for fibroblasts. We generated murine monoclonal antibodies against CTGF and established a sandwich enzyme-linked immunosorbent assay (ELISA) for detection of CTGF. By using the ELISA, we confirmed that CTGF was specifically induced in human fibroblasts by TGF-beta but not by PDGF, FGF, IGF-I, or EGF. We also found that the serum levels of CTGF were significantly correlated with the progression of hepatic fibrosis in biliary atresia. These results indicated that CTGF is potentially a useful parameter for monitoring certain types of fibrotic disorders.
    Preview · Article · Nov 1998 · Biochemical and Biophysical Research Communications
  • T Tsuji · I Waga · K Tezuka · M Kamada · K Yatsunami · H Kodama
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    ABSTRACT: Cellular interactions between hematopoietic cells and stromal cells play important roles in the proliferation and differentiation of hematopoietic cells. The proliferation of a human erythroleukemia cell line, HEL cells, which can differentiate into macrophage- and megakaryocyte-like cells, and erythroid precursors was dramatically induced on coculture with a hematopoietic-supportive stromal cell line, HESS-5 cells, which can support long-term hematopoiesis in vitro without fetal bovine serum. HEL cells proliferated when they were cocultured with but not without direct cell contact. Because the coculture supernatants with direct cell contact and cytokines such as interleukins and growth factors did not exhibit growth-stimulating activity toward HEL cells, it was suggested that some molecule that has growth-stimulating activity exists on the surface of the cells. Extracellular matrix components such as fibronectin, laminin, vitronectin, and collagen did not affect the proliferation of HEL cells. An anti-CD18 monoclonal antibody, which recognizes the common beta chain of the beta2 integrin subfamily, induced dramatic proliferation of HEL cells. Moreover, the proliferation of HEL cells was inhibited by an antisense oligonucleotide of CD18 mRNA. As judged from these observations, the proliferation of HEL cells was mediated by CD18 molecules expressed on HEL cells. On the contrary, the common counter-receptor of the beta2 integrin subfamily, intercellular adhesion molecule-1, which is expressed on CHO-K1 cells, did not stimulate the growth of HEL cells. It is known that other counter molecules of the beta2 integrin subfamily, such as complement C3bi and fibrinogen, are not produced by stromal cells. These findings suggest that the proliferation of HEL cells may be induced through an interaction between a novel molecule of the beta2 integrin subfamily on HEL cells and the counter-receptor on HESS-5 cells. The beta2 integrin subfamily may regulate the growth of hematopoietic cells in hematopoiesis in vivo and/or cause the abnormal growth of leukemia cells.
    No preview · Article · Mar 1998 · Blood