Publications (8)26.27 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.
    Immunology Letters 08/2003; 88(1):63-70. DOI:10.1016/S0165-2478(03)00054-3 · 2.37 Impact Factor
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    ABSTRACT: The functional role of inducible costimulator (ICOS)-mediated costimulation was examined in an in vivo model of alloantigen-driven Th1 or Th2 cytokine responses, the parent-into-F(1) model of acute or chronic graft-vs-host disease (GVHD), respectively. When the Ab specific for mouse ICOS was injected into chronic GVHD-induced mice, activation of B cells, production of autoantibody, and development of glomerulonephritis were strongly suppressed. In contrast, the same treatment enhanced donor T cell chimerism and host B cell depletion in acute GVHD induced host mice. Blocking of B7-CD28 interaction by injection of anti-B7-1 and anti-B7-2 Abs inhibited both acute and chronic GVHD. These observations clearly indicate that the costimulatory signal mediated by CD28 caused the initial allorecognition resulting in the clonal expansion of alloreactive T cells, whereas the costimulatory signal mediated by ICOS played a critical role in the functional differentiation and manifestation of alloreactive T cells. Furthermore, treatment with anti-ICOS Ab selectively suppresses Th2-dominant autoimmune disease.
    The Journal of Immunology 12/2001; 167(10):5741-8. DOI:10.4049/jimmunol.167.10.5741 · 5.36 Impact Factor
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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.
    The Journal of Immunology 05/2001; 166(8):4943-8. DOI:10.4049/jimmunol.166.8.4943 · 5.36 Impact Factor
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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.
    Hybridoma and Hybridomics 02/2001; 20(5-6):293-303. DOI:10.1089/15368590152740699
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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.
    International Immunology 01/2000; 12(1):51-5. · 3.18 Impact Factor
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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.
    Endocrinology 01/2000; 141(1):264-73. DOI:10.1210/endo.141.1.7267 · 4.64 Impact Factor
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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 oligonucleotide and antisense RNA suppresses the proliferation and migration of vascular endothelial 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.
    Journal of Biochemistry 08/1999; 126(1):137-45. DOI:10.1093/oxfordjournals.jbchem.a022414 · 3.07 Impact Factor
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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.
    Biochemical and Biophysical Research Communications 11/1998; 251(3):748-52. DOI:10.1006/bbrc.1998.9543 · 2.28 Impact Factor