The Experts below are selected from a list of 2439 Experts worldwide ranked by ideXlab platform
Naoto Ishii - One of the best experts on this subject based on the ideXlab platform.
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OX40 Ligand newly expressed on bronchiolar progenitors mediates influenza infection and further exacerbates pneumonia
Embo Molecular Medicine, 2016Co-Authors: Taizou Hirano, Toshiaki Kikuchi, Naoki Tode, Arif Santoso, Mitsuhiro Yamada, Yoshiya Mitsuhashi, Riyo Komatsu, Takeshi Kawabe, Takeshi Tanimoto, Naoto IshiiAbstract:Abstract Influenza virus epidemics potentially cause pneumonia, which is responsible for much of the mortality due to the excessive immune responses. The role of costimulatory OX40–OX40 Ligand (OX40L) interactions has been explored in the non‐infectious pathology of influenza pneumonia. Here, we describe a critical contribution of OX40L to infectious pathology, with OX40L deficiency, but not OX40 deficiency, resulting in decreased susceptibility to influenza viral infection. Upon infection, bronchiolar progenitors increase in number for repairing the influenza‐damaged epithelia. The OX40L expression is induced on the progenitors for the antiviral immunity during the infectious process. However, these defense‐like host responses lead to more extensive infection owing to the induced OX40L with α‐2,6 sialic acid modification, which augments the interaction with the viral hemagglutinin. In fact, the specific antibody against the sialylated site of OX40L exhibited therapeutic potency in mitigating the OX40L‐mediated susceptibility to influenza. Our data illustrate that the influenza‐induced expression of OX40L on bronchiolar progenitors has pathogenic value to develop a novel therapeutic approach against influenza.
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OX40 Ligand regulates splenic cd8 dendritic cell induced th2 responses in vivo
Biochemical and Biophysical Research Communications, 2014Co-Authors: Fumitaka Kamachi, Naoto Ishii, Yoshihiko Usui, Ko Okumura, Norihiro Harada, Tamami Sakanishi, Sachiko Miyake, Hisaya AkibaAbstract:Abstract In mice, splenic conventional dendritic cells (cDCs) can be separated, based on their expression of CD8α into CD8− and CD8+ cDCs. Although previous experiments demonstrated that injection of antigen (Ag)-pulsed CD8− cDCs into mice induced CD4 T cell differentiation toward Th2 cells, the mechanism involved is unclear. In the current study, we investigated whether OX40 Ligand (OX40L) on CD8− cDCs contributes to the induction of Th2 responses by Ag-pulsed CD8− cDCs in vivo, because OX40–OX40L interactions may play a preferential role in Th2 cell development. When unseparated Ag-pulsed OX40L-deficient cDCs were injected into syngeneic BALB/c mice, Th2 cytokine (IL-4, IL-5, and IL-10) production in lymph node cells was significantly reduced. Splenic cDCs were separated to CD8− and CD8+ cDCs. OX40L expression was not observed on freshly isolated CD8− cDCs, but was induced by anti-CD40 mAb stimulation for 24 h. Administration of neutralizing anti-OX40L mAb significantly inhibited IL-4, IL-5, and IL-10 production induced by Ag-pulsed CD8− cDC injection. Moreover, administration of anti-OX40L mAb with Ag-pulsed CD8− cDCs during a secondary response also significantly inhibited Th2 cytokine production. Thus, OX40L on CD8− cDCs physiologically contributes to the development of Th2 cells and secondary Th2 responses induced by Ag-pulsed CD8− cDCs in vivo.
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indispensable roles of OX40l derived signal and epistatic genetic effect in immune mediated pathogenesis of spontaneous pulmonary hypertension
BMC Immunology, 2011Co-Authors: Moloud Rabieyousefi, Pejman Soroosh, Naoto Ishii, Kimio Satoh, Fumiko Date, Masahiro Yamashita, Masahiko Oka, Ivan F Mcmurtry, Hiroaki ShimokawaAbstract:Background: Pulmonary hypertension (PH) refers to a spectrum of diseases with elevated pulmonary artery pressure. Pulmonary arterial hypertension (PAH) is a disease category that clinically presents with severe PH and that is histopathologically characterized by the occlusion of pulmonary arterioles, medial muscular hypertrophy, and/or intimal fibrosis. PAH occurs with a secondary as well as a primary onset. Secondary PAH is known to be complicated with immunological disorders. The aim of the present study is to histopathologically and genetically characterize a new animal model of PAH and clarify the role of OX40 Ligand in the pathogenesis of PAH. Results: Spontaneous onset of PAH was stably identified in mice with immune abnormality because of
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OX40 Ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization
Cardiovascular Research, 2010Co-Authors: Makoto Nakano, Naoto Ishii, Kazuo Sugamura, Kimio Satoh, Yoshihiro Fukumoto, Yoshitaka Ito, Yutaka Kagaya, Hiroaki ShimokawaAbstract:Aims Atherosclerosis is characterized by infiltration of inflammatory cells and enhanced vasa vasorum formation, for which immunological mechanisms may be involved. OX40, a membrane-bound molecule of the tumour necrosis factor-receptor superfamily, is expressed by activated T-cells, while OX40 Ligand (OX40L) is expressed in activated macrophages and endothelial cells. In this study, we thus examined whether the OX40/OX40L system is involved in the pathogenesis of atherosclerosis. Methods and results We examined apolipoprotein E-deficient (ApoE−/−) mice and ApoE−/−/OX40L-double-deficient (ApoE−/−/OX40L−/−) mice fed on a high-fat diet for 8 weeks. The extent of aortic atheroma was significantly less in ApoE−/−/OX40L−/− mice compared with ApoE−/− mice. We also treated high-fat-fed ApoE−/− mice with or without MGP34 antibody (OX40L-specific neutralizing antibody) for 10 weeks. After the treatment, the extent of aortic atheroma was again significantly less in MGP34-treated mice compared with controls. Importantly, both vascular density in the aortic adventitia and vascular endothelial growth factor-induced angiogenesis in the Matrigel assay in vivo were significantly reduced in ApoE−/−/OX40L−/− mice compared with ApoE−/− mice. Finally, when high-fat-fed ApoE−/− mice were transplanted with bone marrow cells from either wild-type or OX40L−/− mice, the extent of aortic atheroma was comparable between the two groups. Conclusion These results indicate that the vascular OX40/OX40L system plays an important role in the formation of vasa vasorum and subsequent atherosclerosis, suggesting that the vascular OX40/OX40L system might be a new therapeutic target of atherosclerosis.
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OX40 OX40 Ligand interaction in t cell mediated immunity and immunopathology
Advances in Immunology, 2010Co-Authors: Naoto Ishii, Pejman Soroosh, Takeshi Takahashi, Kazuo SugamuraAbstract:T-cell activation is mediated not only by antigen stimulation through T-cell receptors but also by costimulatory signals through costimulatory molecules. Among several costimulatory molecules, the tumor necrosis factor (TNF) receptor family member OX40 plays a key role in the survival and homeostasis of effector and memory T cells. According to the conventional understanding of OX40 costimulation, an interaction between OX40 and OX40 Ligand (OX40L) occurs when activated T cells bind to professional antigen-presenting cells (APCs). The T-cell functions, including cytokine production, expansion, and survival, are then enhanced by the OX40 costimulatory signals. Over the last half-decade, evidence has accumulated that OX40 signals are critical for controlling the function and differentiation of Foxp3(+) regulatory T cells, indicating a new aspect of OX40-mediated autoimmunity. Furthermore, the expression of OX40L by mast cells was shown to be important for controlling inflammation through regulatory T-cell function. Besides the essential role played by OX40 signaling in generating memory CD4 T cells, recent reports show that it also has a unique role in generating memory CD8 T cells. In addition, recent genome-wide association studies have identified single-nucleotide polymorphisms of the OX40L and OX40 genes that are related to cardiovascular diseases and SLE, providing direct evidence for the involvement of the OX40-OX40L interaction in human diseases. Here, we review recent progress on how the OX40-OX40L interaction regulates T-cell tolerance, peripheral T-cell homeostasis, and T-cell-mediated inflammatory diseases.
Kazuo Sugamura - One of the best experts on this subject based on the ideXlab platform.
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OX40 Ligand plays an important role in the development of atherosclerosis through vasa vasorum neovascularization
Cardiovascular Research, 2010Co-Authors: Makoto Nakano, Naoto Ishii, Kazuo Sugamura, Kimio Satoh, Yoshihiro Fukumoto, Yoshitaka Ito, Yutaka Kagaya, Hiroaki ShimokawaAbstract:Aims Atherosclerosis is characterized by infiltration of inflammatory cells and enhanced vasa vasorum formation, for which immunological mechanisms may be involved. OX40, a membrane-bound molecule of the tumour necrosis factor-receptor superfamily, is expressed by activated T-cells, while OX40 Ligand (OX40L) is expressed in activated macrophages and endothelial cells. In this study, we thus examined whether the OX40/OX40L system is involved in the pathogenesis of atherosclerosis. Methods and results We examined apolipoprotein E-deficient (ApoE−/−) mice and ApoE−/−/OX40L-double-deficient (ApoE−/−/OX40L−/−) mice fed on a high-fat diet for 8 weeks. The extent of aortic atheroma was significantly less in ApoE−/−/OX40L−/− mice compared with ApoE−/− mice. We also treated high-fat-fed ApoE−/− mice with or without MGP34 antibody (OX40L-specific neutralizing antibody) for 10 weeks. After the treatment, the extent of aortic atheroma was again significantly less in MGP34-treated mice compared with controls. Importantly, both vascular density in the aortic adventitia and vascular endothelial growth factor-induced angiogenesis in the Matrigel assay in vivo were significantly reduced in ApoE−/−/OX40L−/− mice compared with ApoE−/− mice. Finally, when high-fat-fed ApoE−/− mice were transplanted with bone marrow cells from either wild-type or OX40L−/− mice, the extent of aortic atheroma was comparable between the two groups. Conclusion These results indicate that the vascular OX40/OX40L system plays an important role in the formation of vasa vasorum and subsequent atherosclerosis, suggesting that the vascular OX40/OX40L system might be a new therapeutic target of atherosclerosis.
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OX40 OX40 Ligand interaction in t cell mediated immunity and immunopathology
Advances in Immunology, 2010Co-Authors: Naoto Ishii, Pejman Soroosh, Takeshi Takahashi, Kazuo SugamuraAbstract:T-cell activation is mediated not only by antigen stimulation through T-cell receptors but also by costimulatory signals through costimulatory molecules. Among several costimulatory molecules, the tumor necrosis factor (TNF) receptor family member OX40 plays a key role in the survival and homeostasis of effector and memory T cells. According to the conventional understanding of OX40 costimulation, an interaction between OX40 and OX40 Ligand (OX40L) occurs when activated T cells bind to professional antigen-presenting cells (APCs). The T-cell functions, including cytokine production, expansion, and survival, are then enhanced by the OX40 costimulatory signals. Over the last half-decade, evidence has accumulated that OX40 signals are critical for controlling the function and differentiation of Foxp3(+) regulatory T cells, indicating a new aspect of OX40-mediated autoimmunity. Furthermore, the expression of OX40L by mast cells was shown to be important for controlling inflammation through regulatory T-cell function. Besides the essential role played by OX40 signaling in generating memory CD4 T cells, recent reports show that it also has a unique role in generating memory CD8 T cells. In addition, recent genome-wide association studies have identified single-nucleotide polymorphisms of the OX40L and OX40 genes that are related to cardiovascular diseases and SLE, providing direct evidence for the involvement of the OX40-OX40L interaction in human diseases. Here, we review recent progress on how the OX40-OX40L interaction regulates T-cell tolerance, peripheral T-cell homeostasis, and T-cell-mediated inflammatory diseases.
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OX40 Ligand expressed by dcs costimulates nkt and cd4 th cell antitumor immunity in mice
Journal of Clinical Investigation, 2007Co-Authors: Jamal Zaini, Naoto Ishii, Kazuo Sugamura, S Andarini, Minoru Tahara, Yasuo Saijo, Kazuyoshi Kawakami, Masaru Taniguchi, Toshihiro Nukiwa, Toshiaki KikuchiAbstract:The exceptional immunostimulatory capacity of DCs makes them potential targets for investigation of cancer immunotherapeutics. We show here in mice that TNF-alpha-stimulated DC maturation was accompanied by increased expression of OX40 Ligand (OX40L), the lack of which resulted in an inability of mature DCs to generate cellular antitumor immunity. Furthermore, intratumoral administration of DCs modified to express OX40L suppressed tumor growth through the generation of tumor-specific cytolytic T cell responses, which were mediated by CD4+ T cells and NKT cells. In the tumors treated with OX40L-expressing DCs, the NKT cell population significantly increased and exhibited a substantial level of IFN-gamma production essential for antitumor immunity. Additional studies evaluating NKT cell activation status, in terms of IFN-gamma production and CD69 expression, indicated that NKT cell activation by DCs presenting alpha-galactosylceramide in the context of CD1d was potentiated by OX40 expression on NKT cells. These results show a critical role for OX40L on DCs, via binding to OX40 on NKT cells and CD4+ T cells, in the induction of antitumor immunity in tumor-bearing mice.
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OX40-OX40 Ligand Interaction through T Cell-T Cell Contact Contributes to CD4 T Cell Longevity
Journal of Immunology, 2006Co-Authors: Pejman Soroosh, Kazuo Sugamura, Naoto IshiiAbstract:Signals through the OX40 costimulatory receptor on naive CD4 T cells are essential for full-fledged CD4 T cell activation and the generation of CD4 memory T cells. Because the Ligand for OX40 is mainly expressed by APCs, including activated B cells, dendritic cells, and Langerhans cells, the OX40-OX40 Ligand (OX40L) interaction has been thought to participate in T cell-APC interactions. Although several reports have revealed the expression of OX40L on T cells, the functional significance of its expression on them is still unclear. In this study, we demonstrate that Ag stimulation induced an increase in the surface expression and transcript levels of OX40L in CD4 T cells. Upon contact with OX40-expressing T cells, the cell surface expression of OX40L on CD4 T cells was markedly down-regulated, suggesting that OX40-OX40L binding occurs through a novel T cell-T cell interaction. To investigate the function of this phenomenon, we examined the proliferative response and survival of OX40L-deficient CD4 T cells when challenged with Ag. In vitro studies demonstrated markedly less CD3-induced proliferation of OX40L-deficient CD4 T cells compared with wild-type CD4 T cells. When using TCR transgenic CD4 T cells upon Ag stimulation, survival of OX40L-deficient T cells was impaired. Furthermore, we show that upon antigenic stimulation, fewer OX40L-deficient CD4 T cells than wild-type cells survived following transfer into wild-type and sublethally irradiated recipient mice. Taken together, our findings indicate that OX40L-expressing T cells have an autonomous machinery that provides OX40 signals through a T cell-T cell circuit, creating an additional mechanism for sustaining CD4 T cell longevity.
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distinct roles for the OX40 OX40 Ligand interaction in regulatory and nonregulatory t cells
Journal of Immunology, 2004Co-Authors: I Takeda, Kazuo Sugamura, Kazuko Murata, Lishomwa C. Ndhlovu, Shoji Ine, Nigel Killeen, Susumu Satomi, Naoto IshiiAbstract:The OX40 (CD134) molecule is induced primarily during T cell activation and, as we show in this study, is also expressed on CD25+CD4+ regulatory T (Treg) cells. A necessary role for OX40 in the development and homeostasis of Treg cells can be inferred from the reduced numbers of the cells present in the spleens of OX40-deficient mice, and their elevated numbers in the spleens of mice that overexpress the OX40 Ligand (OX40L). The homeostatic proliferation of Treg cells following transfer into lymphopenic mice was also found to be potentiated by the OX40-OX40L interaction. Suppression of T cell responses by Treg cells was significantly impaired in the absence of OX40, indicating that, in addition to its homeostatic functions, OX40 contributes to efficient Treg-mediated suppression. However, despite this, we found that CD25−CD4+ T cells became insensitive to Treg-mediated suppression when they were exposed to OX40L-expressing cells, or when they were treated with an agonistic OX40-specific mAb. OX40 signaling could also abrogate the disease-preventing activity of Treg cells in an experimental model of inflammatory bowel disease. Thus, although the data reveal important roles for OX40 signaling in Treg cell development, homeostasis, and suppressive activity, they also show that OX40 signals can oppose Treg-mediated suppression when they are delivered directly to Ag-engaged naive T cells.
Ko Okumura - One of the best experts on this subject based on the ideXlab platform.
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OX40 Ligand regulates splenic cd8 dendritic cell induced th2 responses in vivo
Biochemical and Biophysical Research Communications, 2014Co-Authors: Fumitaka Kamachi, Naoto Ishii, Yoshihiko Usui, Ko Okumura, Norihiro Harada, Tamami Sakanishi, Sachiko Miyake, Hisaya AkibaAbstract:Abstract In mice, splenic conventional dendritic cells (cDCs) can be separated, based on their expression of CD8α into CD8− and CD8+ cDCs. Although previous experiments demonstrated that injection of antigen (Ag)-pulsed CD8− cDCs into mice induced CD4 T cell differentiation toward Th2 cells, the mechanism involved is unclear. In the current study, we investigated whether OX40 Ligand (OX40L) on CD8− cDCs contributes to the induction of Th2 responses by Ag-pulsed CD8− cDCs in vivo, because OX40–OX40L interactions may play a preferential role in Th2 cell development. When unseparated Ag-pulsed OX40L-deficient cDCs were injected into syngeneic BALB/c mice, Th2 cytokine (IL-4, IL-5, and IL-10) production in lymph node cells was significantly reduced. Splenic cDCs were separated to CD8− and CD8+ cDCs. OX40L expression was not observed on freshly isolated CD8− cDCs, but was induced by anti-CD40 mAb stimulation for 24 h. Administration of neutralizing anti-OX40L mAb significantly inhibited IL-4, IL-5, and IL-10 production induced by Ag-pulsed CD8− cDC injection. Moreover, administration of anti-OX40L mAb with Ag-pulsed CD8− cDCs during a secondary response also significantly inhibited Th2 cytokine production. Thus, OX40L on CD8− cDCs physiologically contributes to the development of Th2 cells and secondary Th2 responses induced by Ag-pulsed CD8− cDCs in vivo.
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blockade of the OX40 Ligand prolongs corneal allograft survival
European Journal of Immunology, 2007Co-Authors: Takaaki Hattori, Yoshihiko Usui, Yoko Okunuki, Yasushi Sonoda, Masahiko Usui, Eiko Takada, Junichiro Mizuguchi, Hideo Yagita, Ko Okumura, Hisaya AkibaAbstract:Although corneal transplantation is one of the most common tissue transplantations and is known to have a high graft acceptance rate, occasional corneal graft rejection remains a cause of blindness. OX40, a member of the TNF receptor superfamily, is expressed on activated T cells, and transmits a costimulatory signal by binding to OX40 Ligand (OX40L) expressed on several cells with antigen-presenting functions. Using a blocking monoclonal antibody (mAb) against murine OX40L, we investigated the role of OX40 in a murine model of corneal transplantation. C3H/He mouse corneas were transplanted to BALB/c mice orthotopically. Administration of anti-OX40L mAb significantly reduced allograft rejection, and increased graft survival rate to 40% at 8 weeks after transplantation, while all corneas were rejected within 5 weeks in control IgG-treated mice. Similar reduced rejection was observed when wild-type donor corneas were transplanted to OX40L-deficient recipients. In vitro study revealed that the anti-OX40L mAb treatment reduced proliferative response and IFN-gamma production of draining lymph node cells in response to stimulation with donor alloantigen. These results demonstrate that OX40L blockade is effective for prolongation of corneal allograft survival by inhibiting recipient T cell activation.
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amelioration of experimental autoimmune encephalomyelitis with anti OX40 Ligand monoclonal antibody a critical role for OX40 Ligand in migration but not development of pathogenic t cells
Journal of Immunology, 2001Co-Authors: Chiyoko Nohara, Hideo Yagita, Hisaya Akiba, Atsuo Nakajima, Atsushi Inoue, Changsung Koh, Hideo Ohshima, Yoshikuni Mizuno, Ko OkumuraAbstract:OX40 (CD134) and its Ligand (OX40L) have been implicated in T cell activation and migration. In this study, we examined the contribution of these molecules to the pathogenesis of experimental autoimmune encephalomyelitis (EAE) by administering a neutralizing mAb against murine OX40L (RM134L) to proteolipid protein (139-151) peptide-induced EAE in SJL mice. Administration of RM134L effectively ameliorated the disease in both actively induced and adoptively transferred EAE models. Histological examination showed that the RM134L treatment greatly reduced mononuclear cell infiltration into the spinal cord. The RM134L treatment did not inhibit the development of pathogenic T cells, given that proliferative response and IFN-gamma production by draining lymph node cells were not reduced or rather enhanced upon restimulation with proteolipid protein (139-151) in vitro, and these cells effectively transferred EAE to naive SJL mice. Flow cytometric analyses showed that the RM134L treatment inhibited the accumulation of OX40-expressing CD4(+) T cells and the migration of adoptively transferred CD4(+) T cells in the spinal cord. Immunohistochemical staining showed that OX40L was most prominently expressed on endothelial cells in the inflamed spinal cord. These results suggest that the OX40/OX40L interaction plays a critical role for the migration of pathogenic T cells into the CNS in the pathogenesis of EAE.
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contribution of OX40 OX40 Ligand interaction to the pathogenesis of rheumatoid arthritis
European Journal of Immunology, 2000Co-Authors: Taro Yoshioka, Hideo Yagita, Hisaya Akiba, Atsuo Nakajima, Toshiyuki Ishiwata, Goro Asano, Shinichi Yoshino, Ko OkumuraAbstract:OX40 Ligand (OX40L) and OX40 (CD134) are a pair of cell surface molecules belonging to the TNF/TNF receptor family. Interaction of OX40L with its receptor OX40 is thought to be important in T cell activation through T cell/antigen-presenting cell interaction. However, involvement of these molecules in the pathogenesis of rheumatoid arthritis (RA) remains unclear. To explore the contribution of OX40/OX40L interaction to the pathogenesis of RA in vivo, we evaluated the effect of a neutralizing anti-OX40L monoclonal antibody (mAb) on the development of collagen-induced arthritis (CIA) in DBA/1 mice as an animal model for RA. Administration of anti-OX40L mAb into type II collagen (CII) -immunized DBA/1 mice dramatically ameliorated the disease severity. In vivo treatment with anti-OX40L mAb did not inhibit the expansion of CII-reactive T cells, but suppressed IFN-gamma and anti-CII IgG2a production. Therefore, OX40/OX40L interaction appears to play a critical role in the development of CIA by enhancing Th1-type autoimmune response. In addition, T lymphocytes in synovial fluid and synovial tissue from RA patients expressed OX40, while OX40L was expressed on sublining cells in synovial tissue. These results indicate that OX40/OX40L interaction may play a critical role in the development of RA.
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characterization of rat OX40 Ligand by monoclonal antibody
Biochemical and Biophysical Research Communications, 2000Co-Authors: Yoshiyuki Satake, Hideo Yagita, Hisaya Akiba, Kazuyoshi Takeda, Machiko Atsuta, Ko OkumuraAbstract:OX40 (CD134) is a member of the tumor necrosis factor (TNF) receptor superfamily first identified as a rat T cell activation marker. We previously identified the rat Ligand for OX40 (OX40L) by molecular cloning. In the present study, we newly generated an anti-rat OX40L mAb (ATM-2) that can inhibit the binding of OX40 to rat OX40L and thus efficiently inhibits the T cell costimulatory activity of rat OX40L. Flow cytometric analyses using ATM-2 and an anti-rat OX40 mAb (MRC OX40) indicated that OX40 was inducible on splenic CD4(+) T cells by stimulation with immobilized anti-CD3 mAb, while OX40L was not expressed on resting or activated T cells. OX40L was expressed on splenic B cells after stimulation with lipopolysaccharide (LPS), but not on peritoneal macrophages. Interestingly, splenic dendritic cells (DC) expressed OX40L constitutively, which was further upregulated by LPS stimulation. The potent costimulatory activities of splenic DC for anti-CD3-stimulated rat CD4(+) T cell proliferation and cytokine (IL-2, IFN-gamma, IL-10, and IL-13) production were substantially inhibited by ATM-2. These results indicated that OX40L is expressed on professional antigen-presenting cells (APC), and may be involved in humoral immune responses via T-B interaction and in cellular immune responses via T-DC interaction in the rat system.
Janette K Burgess - One of the best experts on this subject based on the ideXlab platform.
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cd40 and OX40 Ligand are differentially regulated on asthmatic airway smooth muscle
Allergy, 2009Co-Authors: David Krimmer, Judith L Black, Nicholas H Hunt, M Loseli, J M Hughes, Brian G Oliver, Lyn M Moir, Janette K BurgessAbstract:BACKGROUND: CD40 and OX40 Ligand (OX40L) are cell-surface molecules expressed on airway smooth muscle (ASM) that can enhance inflammatory cell activation and survival. The aim of this study was to examine the effect of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on ASM CD40 and OX40L expression. METHODS: CD40 and OX40L expression on human ASM cells from asthmatic and nonasthmatic donors following stimulation with TNF-alpha and/or IFN-gamma was measured using cell-surface enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Involvement of signalling pathway was investigated with pharmacological inhibitors. Soluble TNF receptor levels were quantified by ELISA. RESULTS: Interferon-gamma and TNF-alpha synergistically increased CD40 expression to a greater extent on asthmatic than on nonasthmatic ASM. In contrast, IFN-gamma reduced TNF-alpha-induced OX40L expression to a similar extent in both cell types. TNF-alpha and IFN-gamma induced CD40 via nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription-3 in both cell types and modulated OX40L via NF-kappaB and c-Jun N terminal kinase in nonasthmatic cells. Similar effects on the induction of OX40L in asthmatic cells were seen with NF-kappaB, but these were not statistically significant. The reduced OX40L expression with TNF-alpha and IFN-gamma involved extracellular regulated kinase 1/2 activation. CONCLUSION: Asthmatic ASM may modulate airway inflammation locally by increasing CD40 and OX40L expression in response to cytokines. IFN-gamma may regulate ASM pro-inflammatory actions by differentially modulating ASM CD40 and OX40L expression.
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cd40 and OX40 Ligand are increased on stimulated asthmatic airway smooth muscle
The Journal of Allergy and Clinical Immunology, 2005Co-Authors: Janette K Burgess, A E Blake, Sarah Boustany, Peter R A Johnson, Carol L Armour, Judith L Black, Nicholas H HuntAbstract:BACKGROUND: Severe, persistent asthma is characterized by airway smooth muscle hyperplasia, inflammatory cell infiltration into the smooth muscle, and increased expression of many cytokines, including IL-4, IL-13, IL-1beta, and TNF-alpha. These cytokines have the potential to alter the expression of surface receptors such as CD40 and OX40 Ligand on the airway smooth muscle cell. OBJECTIVE: To examine whether cytokines alter expression of CD40 and OX40 Ligand on airway smooth muscle cells and identify any differences in response between asthmatic and nonasthmatic airway smooth muscle cells. METHODS: We used flow cytometry and immunohistochemistry to detect CD40 and OX40 Ligand on airway smooth muscle cells cultured in the presence of TNF-alpha, IL-1beta, IL-4, or IL-13. Prostaglandin E 2 levels were assessed by ELISA. RESULTS: TNF-alpha increased expression of both CD40 and OX40 Ligand on both asthmatic and nonasthmatic airway smooth muscle cells. The level of expression was significantly greater on the asthmatic cells. IL-1beta alone had no effect, but it attenuated the TNF-induced expression of both CD40 and OX40 Ligand. The mechanism of inhibition was COX-dependent for CD40 and was COX-independent but cyclic AMP-dependent for OX40 Ligand. IL-4 and IL-13 had no effect. CONCLUSION: Our study has demonstrated that TNF-alpha and IL-1beta have the potential to modulate differentially the interactions between cells present in the inflamed airways of a patient with asthma and therefore to contribute to the regulation of airway inflammation and remodeling.
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detection and characterization of OX40 Ligand expression in human airway smooth muscle cells a possible role in asthma
The Journal of Allergy and Clinical Immunology, 2004Co-Authors: Janette K Burgess, Peter R A Johnson, Judith L Black, Stephen Carlin, Robert A Pack, Greg M Arndt, Nicholas H HuntAbstract:Abstract Background The airway smooth muscle (ASM) cell, originally thought of as a passive structural cell, is now well recognized as an active participant in the pathologic events that occur during persistent asthma. Cell-surface molecules play an important role in the development of an immune response. A number of cell-surface molecules are expressed on ASM cells, and these might contribute to the inflammatory reaction. Objective The purpose of this study was to determine whether OX40 Ligand (OX40L), a molecule known to be involved in T-cell activation, was present on the ASM cell surface. Methods We used real-time RT-PCR to detect mRNA expression and flow cytometry, ELISA, and immunoprecipitation to detect the presence of cell-surface protein on ASM cells isolated from asthmatic and nonasthmatic individuals. ELISAs and Western blotting were used to determine the functional outcomes of engagement of OX40L. Results OX40L was present on both asthmatic and nonasthmatic ASM cells. Engagement of OX40L with recombinant OX40:Fc resulted in a significantly greater increase in release of IL-6 from ASM cells of asthmatic patients than from ASM cells of nonasthmatic patients ( P 2 to the cell membrane. Conclusion Because the receptor for OX40L, OX40, is expressed on CD4 + T cells within 48 hours of stimulation through the T-cell receptor, elucidation of the cross-talk between OX40 and OX40L could be very important in understanding the interaction of cells present in the inflamed airways of an asthmatic patient.
Toshiyuki Hori - One of the best experts on this subject based on the ideXlab platform.
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involvement of OX40 Ligand mast cells in chronic gvhd after allogeneic hematopoietic stem cell transplantation
Bone Marrow Transplantation, 2007Co-Authors: Ai Kotani, Yuetsu Tanaka, Toshiyuki Hori, Takuya Fujita, Naotomo Kambe, Yumi Matsumura, T Ishikawa, Yoshiki Miyachi, K Nagai, T UchiyamaAbstract:Involvement of OX40 Ligand + mast cells in chronic GVHD after allogeneic hematopoietic stem cell transplantation
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type i interferons attenuate t cell activating functions of human mast cells by decreasing tnf alpha production and OX40 Ligand expression while increasing il 10 production
Journal of Clinical Immunology, 2006Co-Authors: Tomoko Fujita, Naotomo Kambe, Takashi Uchiyama, Toshiyuki HoriAbstract:Recent studies have demonstrated that mast cells not only mediate inflammatory reactions in type I allergy but also play an important role in adaptive immunity. In the present study, we investigated the effects of interferon-alpha, which shares the same receptor as IFN-beta, on human cord blood-derived mast cells. Mast cells produced TNF-alpha, and IL-10, and expressed OX40 Ligand upon activation by crosslinking of FcepsilonRI. When treated with interferon-alpha, TNF-alpha production was decreased while IL-10 and TGF-beta productions were increased. Furthermore, flow cytometric analysis revealed that interferon-alpha downregulated expression OX40 Ligand on mast cells which is crucial for mast cell-T cell interaction. We confirmed that the viability of mast cells was not affected by interferon-alpha treatment. Accordingly, interferon-alpha-treated mast cells induced lower levels of CD4+ T cell proliferation compared with those without interferon-alpha treatment. These results suggest that type I interferons suppress T cell immune responses through their regulatory effects on mast cells.
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tslp activated dendritic cells induce an inflammatory t helper type 2 cell response through OX40 Ligand
Journal of Experimental Medicine, 2005Co-Authors: Tomoki Ito, Yui-hsi Wang, Omar Duramad, Toshiyuki Hori, G Delespesse, Norihiko Watanabe, Xiao Feng F Qin, Zhengbin Yao, Wei CaoAbstract:We recently showed that dendritic cells (DCs) activated by thymic stromal lymphopoietin (TSLP) prime naive CD4 + T cells to differentiate into T helper type 2 (Th2) cells that produced high amounts of tumor necrosis factor- α (TNF- α ), but no interleukin (IL)-10. Here we report that TSLP induced human DCs to express OX40 Ligand (OX40L) but not IL-12. TSLP-induced OX40L on DCs was required for triggering naive CD4 + T cells to produce IL-4, -5, and -13. We further revealed the following three novel functional properties of OX40L: (a) OX40L selectively promoted TNF- α , but inhibited IL-10 production in developing Th2 cells; (b) OX40L lost the ability to polarize Th2 cells in the presence of IL-12; and (c) OX40L exacerbated IL-12–induced Th1 cell inflammation by promoting TNF- α , while inhibiting IL-10. We conclude that OX40L on TSLP-activated DCs triggers Th2 cell polarization in the absence of IL-12, and propose that OX40L can switch IL-10–producing regulatory Th cell responses into TNF- α –producing inflammatory Th cell responses.
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plasmacytoid dendritic cells regulate th cell responses through OX40 Ligand and type i ifns
Journal of Immunology, 2004Co-Authors: Tomoki Ito, Toshiyuki Hori, Muneo Inaba, Ryuichi Amakawa, Maiko Ota, Kengo Nakamura, Masashi Takebayashi, Michihiko Miyaji, Tomoo Yoshimura, Kayo InabaAbstract:Dendritic cells (DCs) show a functional plasticity in determining Th responses depending on their maturational stage or on maturational signals delivered to the DCs. Human plasmacytoid DCs (PDCs) can induce either Th1- or Th2-type immune responses upon exposure to viruses or IL-3, respectively. In this study we have investigated the Th-polarizing capacity of PDCs after short (24-h) or long (72-h) culture with stimuli and have assessed the expression and function of OX40 Ligand (OX40L) in PDC-mediated Th polarization in addition to type I IFN-dependent responses. IL-3-treated PDCs expressed OX40L, but produced almost no IFN-alpha in response to T cell stimulation (CD40 Ligand or T cell interaction), resulting in the preferential priming of Th2 cells through OX40L-dependent mechanisms. Meanwhile, PDCs were rapidly endowed by viral infection (Sendai virus) with a high potency to develop IFN-gamma-producing Th cells depending on their capacity to residually produce IFN-alpha. Although Sendai virus-stimulated PDCs simultaneously expressed OX40L in their maturational process, the Th1-inducing effect of endogenous type I IFNs may overcome and thus conceal the OX40L-dependent Th2 responses. However, during maturation in response to Sendai virus over the longer 72-h period, the expression level of OX40L was up-regulated, whereas the residual IFN-alpha-producing ability was down-regulated, and consequently, the PDCs with prolonged Sendai virus stimulation induced Th2 responses to some extent. Thus, PDCs have the distinct means to dictate an appropriate response to environmental stimuli.
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retroviral transduction of acute myeloid leukaemia derived dendritic cells with OX40 Ligand augments their antigen presenting activity
British Journal of Haematology, 2004Co-Authors: Soshi Yanagita, Toshiyuki Hori, Yasushi Matsubara, Takayuki Ishikawa, Takashi UchiyamaAbstract:Summary Recent studies have shown that human myeloid leukaemia cells can differentiate into dendritic cell (DC)-like cells (leukaemia-DCs) when cultured with a combination of cytokines. In the present study, we examined whether the transduction of leukaemia-DCs with OX40 Ligand (OX40L), a member of the tumour necrosis factor (TNF) family, resulted in augmentation of their antigen presenting activity. Bicistronic retroviral vectors expressing both human OX40L and enhanced green fluorescent protein (EGFP) or EGFP alone were generated and used for transduction. Fresh leukaemic cells from five patients with acute myeloid leukaemia (AML) were isolated and retrovirally transduced with OX40L during the culture with a combination of cytokines from stem cell factor, fms-like tyrosine kinase (Flt)-3 Ligand, granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-4 (IL-4) and TNF-α. After 7 d, the majority of cells showed DC-like morphology, and expressed higher levels of CD80, CD86 and HLA-DR than fresh leukaemic cells. The transduction efficiency was 8·5–27·2%. Leukaemia-DCs transduced with OX40L elicited higher proliferative response of allogeneic CD4+ T cells than fresh leukaemic cells, non-transduced, or mock-transduced leukaemia-DCs. Co-culture of allogeneic CD4+ T cells with OX40L-transduced leukaemia-DCs was superior in the generation of interferon (IFN)-γ producing CD4+ T cells and in production of IFN-γ. Furthermore, OX40L-transduced leukaemia-DCs could elicit significant proliferative response of human leucocyte antigen-matched T cells from the donor in allogeneic stem cell transplantation. These results indicate that retroviral transduction of leukaemia-DCs with OX40L augments their antigen presenting cell activity and thus renders them more suitable for tumour vaccines or ex vivo stimulation of leukaemia-specific T cells.
