The Experts below are selected from a list of 9621 Experts worldwide ranked by ideXlab platform
Misako Matsumoto - One of the best experts on this subject based on the ideXlab platform.
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Isolation of RNA aptamers against human Toll-Like Receptor 3 ectodomain.
Nucleic acids symposium series (2004), 2020Co-Authors: Tomoya Watanabe, Misako Matsumoto, Tsukasa Seya, Satoshi Nishikawa, Tsunemi Hasegawa, Kotaro FukudaAbstract:Toll-Like Receptor 3 (TLR3) detects double-stranded RNA (dsRNA) known as a universal viral molecular pattern and activates the antiviral immune response. While TLR3 preferentially recognizes polyriboinosine-polyribocytidylic acid (poly (I:C)), a sequence-specific dsRNA has not yet been shown to activate TLR3. To determine whether TLR3 preferentially recognizes some specific sequence that acts on the signaling pathway of TLR3, in vitro selection against human TLR3 ectodomain (TLR3 ECD) was performed. After seventh selection cycle, two major classes, Family-I and -II, were emerged from 64 clones with binding constants of about 3 nM. Although these aptamers bound to TLR3 ECD with high affinity in vitro, they did not have agonist and antagonist effects on TLR3 signaling in TLR3-transfected HEK293 cells. Further analyses of the structure/function relationship of these aptamers will be carried out by mutagenesis, RNase mapping and competition assay using poly (I:C).
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Toll-Like Receptor 3: a link between Toll-Like Receptor, interferon and viruses.
Microbiology and Immunology, 2020Co-Authors: Misako Matsumoto, Hiroyuki Oshiumi, Kenji Funami, Tsukasa SeyaAbstract:Production of type I interferon (IFN-α/β) by virus-infected cells is the central event in their antiviral immune responses. In mammalian cells, IFN-α/β gene transcription is induced through distinct signaling pathways by viral infection or by treatment with double-stranded (ds) RNA, which is an intermediate of virus replication. Toll-Like Receptor 3 (TLR3) was found to recognize dsRNA and transmit signals to activate NF-κB and the IFN-β promoter. Recent identification of the TLR3-adaptor protein and its downstream signaling molecules, which are involved in IFN-α/β production, revealed a novel IFN-inducing pathway for an anti-viral immune response. Here, we summarize the current knowledge of TLR3-mediated immune responses.
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A Toll-Like Receptor 3 (TLR3) agonist ARNAX for therapeutic immunotherapy.
Advanced Drug Delivery Reviews, 2019Co-Authors: Tsukasa Seya, Yohei Takeda, Misako MatsumotoAbstract:Summary Vaccine immunotherapy consisting of tumor antigens combined with an immune-enhancing adjuvant fosters cytotoxic T cell (CTL) proliferation. Clinically, polyI:C has been used as an adjuvant to enhance cancer vaccine protocols. However, according to its long history, polyI:C promotes inflammation that causes cytokine toxicity. Although checkpoint inhibitor immunotherapy has improved the prognoses of patients with progressive cancer, over 75% of patients continue to experience resistance to antibody (Ab) against anti-programmed cell death-protein 1 (PD-1) or its ligand, PD-L1 therapy. In most cases, patients suffer from adverse events resulting from inflammation during anti-PD-1/L1 Ab therapy, which is a serious obstacle to patients' quality of life. We have studied the functional properties of double-stranded (ds)RNA and polyI:C, and developed a nucleic acid adjuvant that barely induces a significant increase in the level of serum inflammatory cytokines in mouse models. This adjuvant, termed ARNAX, consists of DNA-capped dsRNA that specifies the endosomal target for Toll-Like Receptor 3 (TLR3) in dendritic cells (DCs). We expect that this adjuvant is safe for administration in elderly patients with cancer receiving immunotherapy. Here, we summarize the properties of ARNAX for immunotherapy in mice. We suggest that DC-priming is essential to induce anti-tumor immunity; neither exogenous inflammation nor the administration of tumor antigens is always a prerequisite for DC-mediated CTL proliferation. If our mouse data can be extrapolated to humans, ARNAX and the liberated endogenous tumor antigens may facilitate effect of current therapies on patients with therapy-resistant tumors.
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Toll-Like Receptor 3 Signal in Dendritic Cells Benefits Cancer Immunotherapy.
Frontiers in Immunology, 2017Co-Authors: Misako Matsumoto, Megumi Tatematsu, Yohei Takeda, Tsukasa SeyaAbstract:Pattern recognition Receptors (PRRs) play a crucial role in the innate immune system and contribute to host defense against microbial infection. PRR-mediated anti-microbial signals provide robust type I IFN/cytokine production and trigger inflammation, thereby affecting tumor progression and autoimmune diseases. Accumulating evidence demonstrates that among the PRRs, only the signaling pathway of endosomal Toll-Like Receptor 3 (TLR3) induces no systemic inflammation and mediates cross-priming of antigen-specific CD8+ T cells by dendritic cells. Treatment with a newly-developed TLR3-specific ligand, ARNAX, along with tumor-associated antigens (TAAs), induces tumor-specific cytotoxic T lymphocytes, modulates the tumor microenvironment to establish Th1-type anti-tumor immunity, and leads to tumor regression without inflammation in mouse tumor models. Combination therapy using ARNAX/TAA and PD-1/PD-L1 blockade potently enhances anti-tumor response and overcomes anti-PD-1/PD-L1 resistance. In this review, we will discuss the TLR3-mediated signaling in anti-tumor immunity and its application to cancer immunotherapy.
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Beyond dsRNA: Toll-Like Receptor 3 signalling in RNA-induced immune responses
Biochemical Journal, 2014Co-Authors: Megumi Tatematsu, Tsukasa Seya, Misako MatsumotoAbstract:The innate immune system recognizes pathogen- and damage-associated molecular patterns using pattern-recognition Receptors that activate a wide range of signalling cascades to maintain host homoeostasis against infection and inflammation. Endosomal TLR3 (Toll-Like Receptor 3), a type I transmembrane protein, senses RNAs derived from cells with viral infection or sterile tissue damage, leading to the induction of type I interferon and cytokine production, as well as dendritic cell maturation. It has been accepted that TLR3 recognizes perfect dsRNA, but little has been addressed experimentally with regard to the structural features of virus- or host-derived RNAs that activate TLR3. Recently, a TLR3 agonist was identified, which was a virus-derived ‘structured’ RNA with incomplete stem structures. Both dsRNA and structured RNA are similarly internalized through clathrin- and raftlin-dependent endocytosis and delivered to endosomal TLR3. The dsRNA uptake machinery, in addition to TLR3, is critical for extracellular viral RNA-induced immune responses. A wide spectrum of TLR3 ligand structures beyond dsRNA and their delivery systems provide new insights into the physiological role of TLR3 in virus- or host-derived RNA-induced immune responses. In the present paper, we focus on the system for extracellular recognition of RNA and its delivery to TLR3.
Tsukasa Seya - One of the best experts on this subject based on the ideXlab platform.
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Isolation of RNA aptamers against human Toll-Like Receptor 3 ectodomain.
Nucleic acids symposium series (2004), 2020Co-Authors: Tomoya Watanabe, Misako Matsumoto, Tsukasa Seya, Satoshi Nishikawa, Tsunemi Hasegawa, Kotaro FukudaAbstract:Toll-Like Receptor 3 (TLR3) detects double-stranded RNA (dsRNA) known as a universal viral molecular pattern and activates the antiviral immune response. While TLR3 preferentially recognizes polyriboinosine-polyribocytidylic acid (poly (I:C)), a sequence-specific dsRNA has not yet been shown to activate TLR3. To determine whether TLR3 preferentially recognizes some specific sequence that acts on the signaling pathway of TLR3, in vitro selection against human TLR3 ectodomain (TLR3 ECD) was performed. After seventh selection cycle, two major classes, Family-I and -II, were emerged from 64 clones with binding constants of about 3 nM. Although these aptamers bound to TLR3 ECD with high affinity in vitro, they did not have agonist and antagonist effects on TLR3 signaling in TLR3-transfected HEK293 cells. Further analyses of the structure/function relationship of these aptamers will be carried out by mutagenesis, RNase mapping and competition assay using poly (I:C).
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Toll-Like Receptor 3: a link between Toll-Like Receptor, interferon and viruses.
Microbiology and Immunology, 2020Co-Authors: Misako Matsumoto, Hiroyuki Oshiumi, Kenji Funami, Tsukasa SeyaAbstract:Production of type I interferon (IFN-α/β) by virus-infected cells is the central event in their antiviral immune responses. In mammalian cells, IFN-α/β gene transcription is induced through distinct signaling pathways by viral infection or by treatment with double-stranded (ds) RNA, which is an intermediate of virus replication. Toll-Like Receptor 3 (TLR3) was found to recognize dsRNA and transmit signals to activate NF-κB and the IFN-β promoter. Recent identification of the TLR3-adaptor protein and its downstream signaling molecules, which are involved in IFN-α/β production, revealed a novel IFN-inducing pathway for an anti-viral immune response. Here, we summarize the current knowledge of TLR3-mediated immune responses.
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A Toll-Like Receptor 3 (TLR3) agonist ARNAX for therapeutic immunotherapy.
Advanced Drug Delivery Reviews, 2019Co-Authors: Tsukasa Seya, Yohei Takeda, Misako MatsumotoAbstract:Summary Vaccine immunotherapy consisting of tumor antigens combined with an immune-enhancing adjuvant fosters cytotoxic T cell (CTL) proliferation. Clinically, polyI:C has been used as an adjuvant to enhance cancer vaccine protocols. However, according to its long history, polyI:C promotes inflammation that causes cytokine toxicity. Although checkpoint inhibitor immunotherapy has improved the prognoses of patients with progressive cancer, over 75% of patients continue to experience resistance to antibody (Ab) against anti-programmed cell death-protein 1 (PD-1) or its ligand, PD-L1 therapy. In most cases, patients suffer from adverse events resulting from inflammation during anti-PD-1/L1 Ab therapy, which is a serious obstacle to patients' quality of life. We have studied the functional properties of double-stranded (ds)RNA and polyI:C, and developed a nucleic acid adjuvant that barely induces a significant increase in the level of serum inflammatory cytokines in mouse models. This adjuvant, termed ARNAX, consists of DNA-capped dsRNA that specifies the endosomal target for Toll-Like Receptor 3 (TLR3) in dendritic cells (DCs). We expect that this adjuvant is safe for administration in elderly patients with cancer receiving immunotherapy. Here, we summarize the properties of ARNAX for immunotherapy in mice. We suggest that DC-priming is essential to induce anti-tumor immunity; neither exogenous inflammation nor the administration of tumor antigens is always a prerequisite for DC-mediated CTL proliferation. If our mouse data can be extrapolated to humans, ARNAX and the liberated endogenous tumor antigens may facilitate effect of current therapies on patients with therapy-resistant tumors.
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Toll-Like Receptor 3 Signal in Dendritic Cells Benefits Cancer Immunotherapy.
Frontiers in Immunology, 2017Co-Authors: Misako Matsumoto, Megumi Tatematsu, Yohei Takeda, Tsukasa SeyaAbstract:Pattern recognition Receptors (PRRs) play a crucial role in the innate immune system and contribute to host defense against microbial infection. PRR-mediated anti-microbial signals provide robust type I IFN/cytokine production and trigger inflammation, thereby affecting tumor progression and autoimmune diseases. Accumulating evidence demonstrates that among the PRRs, only the signaling pathway of endosomal Toll-Like Receptor 3 (TLR3) induces no systemic inflammation and mediates cross-priming of antigen-specific CD8+ T cells by dendritic cells. Treatment with a newly-developed TLR3-specific ligand, ARNAX, along with tumor-associated antigens (TAAs), induces tumor-specific cytotoxic T lymphocytes, modulates the tumor microenvironment to establish Th1-type anti-tumor immunity, and leads to tumor regression without inflammation in mouse tumor models. Combination therapy using ARNAX/TAA and PD-1/PD-L1 blockade potently enhances anti-tumor response and overcomes anti-PD-1/PD-L1 resistance. In this review, we will discuss the TLR3-mediated signaling in anti-tumor immunity and its application to cancer immunotherapy.
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Beyond dsRNA: Toll-Like Receptor 3 signalling in RNA-induced immune responses
Biochemical Journal, 2014Co-Authors: Megumi Tatematsu, Tsukasa Seya, Misako MatsumotoAbstract:The innate immune system recognizes pathogen- and damage-associated molecular patterns using pattern-recognition Receptors that activate a wide range of signalling cascades to maintain host homoeostasis against infection and inflammation. Endosomal TLR3 (Toll-Like Receptor 3), a type I transmembrane protein, senses RNAs derived from cells with viral infection or sterile tissue damage, leading to the induction of type I interferon and cytokine production, as well as dendritic cell maturation. It has been accepted that TLR3 recognizes perfect dsRNA, but little has been addressed experimentally with regard to the structural features of virus- or host-derived RNAs that activate TLR3. Recently, a TLR3 agonist was identified, which was a virus-derived ‘structured’ RNA with incomplete stem structures. Both dsRNA and structured RNA are similarly internalized through clathrin- and raftlin-dependent endocytosis and delivered to endosomal TLR3. The dsRNA uptake machinery, in addition to TLR3, is critical for extracellular viral RNA-induced immune responses. A wide spectrum of TLR3 ligand structures beyond dsRNA and their delivery systems provide new insights into the physiological role of TLR3 in virus- or host-derived RNA-induced immune responses. In the present paper, we focus on the system for extracellular recognition of RNA and its delivery to TLR3.
Megumi Tatematsu - One of the best experts on this subject based on the ideXlab platform.
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Toll-Like Receptor 3 Signal in Dendritic Cells Benefits Cancer Immunotherapy.
Frontiers in Immunology, 2017Co-Authors: Misako Matsumoto, Megumi Tatematsu, Yohei Takeda, Tsukasa SeyaAbstract:Pattern recognition Receptors (PRRs) play a crucial role in the innate immune system and contribute to host defense against microbial infection. PRR-mediated anti-microbial signals provide robust type I IFN/cytokine production and trigger inflammation, thereby affecting tumor progression and autoimmune diseases. Accumulating evidence demonstrates that among the PRRs, only the signaling pathway of endosomal Toll-Like Receptor 3 (TLR3) induces no systemic inflammation and mediates cross-priming of antigen-specific CD8+ T cells by dendritic cells. Treatment with a newly-developed TLR3-specific ligand, ARNAX, along with tumor-associated antigens (TAAs), induces tumor-specific cytotoxic T lymphocytes, modulates the tumor microenvironment to establish Th1-type anti-tumor immunity, and leads to tumor regression without inflammation in mouse tumor models. Combination therapy using ARNAX/TAA and PD-1/PD-L1 blockade potently enhances anti-tumor response and overcomes anti-PD-1/PD-L1 resistance. In this review, we will discuss the TLR3-mediated signaling in anti-tumor immunity and its application to cancer immunotherapy.
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Beyond dsRNA: Toll-Like Receptor 3 signalling in RNA-induced immune responses
Biochemical Journal, 2014Co-Authors: Megumi Tatematsu, Tsukasa Seya, Misako MatsumotoAbstract:The innate immune system recognizes pathogen- and damage-associated molecular patterns using pattern-recognition Receptors that activate a wide range of signalling cascades to maintain host homoeostasis against infection and inflammation. Endosomal TLR3 (Toll-Like Receptor 3), a type I transmembrane protein, senses RNAs derived from cells with viral infection or sterile tissue damage, leading to the induction of type I interferon and cytokine production, as well as dendritic cell maturation. It has been accepted that TLR3 recognizes perfect dsRNA, but little has been addressed experimentally with regard to the structural features of virus- or host-derived RNAs that activate TLR3. Recently, a TLR3 agonist was identified, which was a virus-derived ‘structured’ RNA with incomplete stem structures. Both dsRNA and structured RNA are similarly internalized through clathrin- and raftlin-dependent endocytosis and delivered to endosomal TLR3. The dsRNA uptake machinery, in addition to TLR3, is critical for extracellular viral RNA-induced immune responses. A wide spectrum of TLR3 ligand structures beyond dsRNA and their delivery systems provide new insights into the physiological role of TLR3 in virus- or host-derived RNA-induced immune responses. In the present paper, we focus on the system for extracellular recognition of RNA and its delivery to TLR3.
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toll like Receptor 3 recognizes incomplete stem structures in single stranded viral rna
Nature Communications, 2013Co-Authors: Megumi Tatematsu, Tsukasa Seya, Fumiko Nishikawa, Misako MatsumotoAbstract:Toll-Like Receptor 3 is a sensor of viral infection and sterile tissue necrosis, and is known to be activated by double-stranded RNA. Tatematsu et al. demonstrate that TLR3 also recognizes incomplete stem structures that form in single-stranded poliovirus RNA.
T Lee - One of the best experts on this subject based on the ideXlab platform.
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Activation of Toll-Like Receptor 3 (TLR3) amplifies mesenchymal stem cell trophic factors and enhances therapeutic potency
AJP: Cell Physiology, 2012Co-Authors: M. Mastri, Gaku Suzuki, T. Mclaughlin, C. J. Greene, L. Baum, Zahir Shah, T LeeAbstract:Clinical trials of bone marrow mesenchymal stem cell (MSC) therapy have thus far demonstrated moderate and inconsistent benefits, indicating an urgent need to improve therapeutic efficacy. Although administration of sufficient cells is necessary to achieve maximal therapeutic benefits, documented MSC clinical trials have largely relied on injections of ∼1 × 10(6) cells/kg, which appears too low to elicit a robust therapeutic response according to published preclinical studies. However, repeated cell passaging necessary for large-scale expansion of MSC causes cellular senescence and reduces stem cell potency. Using the RNA mimetic polyinosinic-polycytidylic acid [poly(I:C)] to engage MSC Toll-Like Receptor 3 (TLR3), we found that poly(I:C), signaling through multiple mitogen-activated protein kinase pathways, induced therapeutically relevant trophic factors such as interleukin-6-type cytokines, stromal-derived factor 1, hepatocyte growth factor, and vascular endothelial growth factor while slightly inhibiting the proliferation and migration potentials of MSC. At the suboptimal injection dose of 1 × 10(6) cells/kg, poly(I:C)-treated MSC, but not untreated MSC, effectively stimulated regeneration of the failing hamster heart 1 mo after cell administration. The regenerating heart exhibited increased CD34(+)/Ki67(+) and CD34(+)/GATA4(+) progenitor cells in the presence of decreased inflammatory cells and cytokines. Cardiac functional improvement was associated with a ∼50% reduction in fibrosis, a ∼40% reduction in apoptosis, and a ∼55% increase in angiogenesis, culminating in prominent cardiomyogenesis evidenced by abundant distribution of small myocytes and a ∼90% increase in wall thickening. These functional, histological, and molecular characterizations thus establish the utility of TLR3 engagement for enabling the low-dose MSC therapy that may be translated to more efficacious clinical applications.
Decio L Eizirik - One of the best experts on this subject based on the ideXlab platform.
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toll like Receptor 3 and stat 1 contribute to double stranded rna interferon gamma induced apoptosis in primary pancreatic beta cells
Journal of Biological Chemistry, 2005Co-Authors: Joanne Rasschaert, Shizuo Akira, Laurence Ladriere, Maryse Urbain, Zeynep Dogusan, Bitshilualua Katabua, Shintaro Sato, Conny Gysemans, Chantal Mathieu, Decio L EizirikAbstract:Abstract Viral infections and local production of cytokines probably contribute to the pathogenesis of Type 1 diabetes. The viral replicative intermediate double-stranded RNA (dsRNA, tested in the form of polyinosinic-polycytidylic acid, PIC), in combination with the cytokine interferon-γ (IFN-γ), triggers β-cell apoptosis. We have previously observed by microarray analysis that PIC induces expression of several mRNAs encoding for genes downstream of Toll-Like Receptor 3 (TLR3) signaling pathway. In this report, we show that exposure of β-cells to dsRNA in combination with IFN-α, -β, or -γ significantly increases apoptosis. Moreover, dsRNA induces TLR3 mRNA expression and activates NF-κB and the IFN-β promoter in a TRIF-dependent manner. dsRNA also induces an early (1 h) and sustained increase in IFN-β mRNA expression, and blocking IFN-β with a specific antibody partially prevents PIC plus IFN-γ-induced β-cell death. On the other hand, dsRNA plus IFN-γ does not induce apoptosis in INS-1E cells, and expression of TLR3 and type I IFNs mRNAs is not detected in these cells. Of note, disruption of the STAT-1 signaling pathway protects β-cells against dsRNA plus IFN-γ-induced β-cell apoptosis. This study suggests that dsRNA plus IFN-γ triggers β-cell apoptosis by two complementary pathways, namely TLR3-TRIF-NF-κB and STAT-1.
