The Experts below are selected from a list of 189 Experts worldwide ranked by ideXlab platform
Stella Elkabes - One of the best experts on this subject based on the ideXlab platform.
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Toll like receptor 9 antagonism modulates spinal cord neuronal function and survival: Direct versus astrocyte-mediated mechanisms.
Brain behavior and immunity, 2016Co-Authors: Cigdem Acioglu, Robert F. Heary, Ayomi Ratnayake, Ersilia Mirabelli, Ahmet Tarik Baykal, Stella ElkabesAbstract:Toll like receptors (TLRs) are expressed by cells of the immune system and mediate the host innate immune responses to pathogens. However, increasing evidence indicates that they are important contributors to central nervous system (CNS) function in health and in pathological conditions involving sterile inflammation. In agreement with this idea, we have previously shown that intrathecal administration of a TLR9 antagonist, Cytidine-Phosphate-guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), ameliorates the outcomes of spinal cord injury (SCI). Although these earlier studies showed a marked effect of CpG ODN 2088 on inflammatory cells, the expression of TLR9 in spinal cord (SC) neurons and astrocytes suggested that the antagonist exerts additional effects through direct actions on these cells. The current study was undertaken to assess the direct effects of CpG ODN 2088 on SC neurons, astrocytes and astrocyte-neuron interactions, in vitro. We report, for the first time, that inhibition of TLR9 in cultured SC neurons alters their function and confers protection against kainic acid (KA)-induced excitotoxic death. Moreover, the TLR9 antagonist attenuated the KA-elicited endoplasmic reticulum (ER) stress response in neurons, in vitro. CpG ODN 2088 also reduced the transcript levels and release of chemokine (C-X-C) motif ligand 1 (CXCL1) and monocyte chemotactic protein 1 (MCP-1) by astrocytes and it diminished interleukin-6 (IL-6) release without affecting transcript levels in vitro. Conditioned medium (CM) of CpG ODN 2088-treated astroglial cultures decreased the viability of SC neurons compared to CM of vehicle-treated astrocytes. However, this toxicity was not observed when astrocytes were co-cultured with neurons. Although CpG ODN 2088 limited the survival-promoting effects of astroglia, it did not reduce neuronal viability compared to controls grown in the absence of astrocytes. We conclude that the TLR9 antagonist acts directly on both SC neurons and astrocytes. Neuronal TLR9 antagonism confers protection against excitotoxic death. It is likely that this neuroprotection is partly due to the attenuation of the ER stress response provoked by excitotoxicity. Although CpG ODN 2088 limits the supportive effects of astrocytes on neurons, it could potentially exert beneficial effects by decreasing the release of pro-inflammatory cytokines and chemokines by astroglia. These findings highlight the multiple roles of TLR9 in the SC and have implications for pathological conditions including SCI where excitotoxicity and neuroinflammation play a prominent role in neuronal degeneration.
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A toll-like receptor 9 antagonist improves bladder function and white matter sparing in spinal cord injury.
Journal of neurotrauma, 2014Co-Authors: Brian T. David, Sujitha Sampath, Wei Dong, Adee Heiman, Courtney E. Rella, Stella Elkabes, Robert F. HearyAbstract:Abstract Spinal cord injury (SCI) affects motor, sensory, and autonomic functions. As current therapies do not adequately alleviate functional deficits, the development of new and more effective approaches is of critical importance. Our earlier investigations indicated that intrathecal administration of a toll-like receptor 9 (TLR9) antagonist, Cytidine-Phosphate-guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe, mid-thoracic contusion injury diminished neuropathic pain but did not alter locomotor deficits. These changes were paralleled by a decrease in the pro-inflammatory response at the injury epicenter. Using the same SCI paradigm and treatment regimen, the current studies investigated the effects of the TLR9 antagonist on bladder function. We report that the TLR9 antagonist decreases SCI-elicited urinary retention and ameliorates bladder morphopathology without affecting kidney function. A significant improvement in white matter sparing was also observed, most likely due...
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A toll-like receptor 9 antagonist reduces pain hypersensitivity and the inflammatory response in spinal cord injury
Neurobiology of disease, 2013Co-Authors: Brian T. David, Sujitha Sampath, Wei Dong, Robert F. Heary, Ayomi Ratnayake, Matthew A. Amarante, Naresh Parvath Reddy, Stella ElkabesAbstract:Abstract Toll-like receptors (TLRs) are mediators of the innate immune response to exogenous pathogens. They have also been implicated in sterile inflammation associated with systemic injury and non-infectious diseases via binding of endogenous ligands, possibly released by damaged cells. Emerging evidence indicates that some TLRs play a role in nervous system injury and especially in injury-elicited pain and sterile inflammation. However, no information is available about the contribution of TLR9, a member of the TLR family, to traumatic spinal cord injury (SCI). Moreover, the therapeutic potential of TLR9 ligands in the functional outcomes of SCI, including pain, has not been explored. We report, for the first time, that the intrathecal administration of a TLR9 antagonist, Cytidine–Phosphate–guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe contusion SCI, diminishes injury-induced heat hypersensitivity. Investigations on the potential mechanisms underlying the reduction in pain sensitivity indicated an attenuation of the inflammatory reaction manifested by a decrease in the number of CD11b-, CD45- and CD3-immunoreactive cells and a reduction in tumor necrosis factor-α (TNF-α) expression at the epicenter. Conversely, intrathecal delivery of a TLR9 agonist, CpG ODN 1826, increased inflammatory cell numbers and TNF-α expression in the epicenter. The CpG ODN 2088 treatment did not appear to induce systemic adverse effects as shown by spleen histology and serum cytokine levels. We propose that CpG ODN 2088 dampens injury-induced heat hypersensitivity by suppressing the inflammatory response and TNF-α expression. This investigation defines a previously unreported therapeutic role for CpG ODN 2088 in SCI-induced pain.
Robert F. Heary - One of the best experts on this subject based on the ideXlab platform.
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Toll like receptor 9 antagonism modulates spinal cord neuronal function and survival: Direct versus astrocyte-mediated mechanisms.
Brain behavior and immunity, 2016Co-Authors: Cigdem Acioglu, Robert F. Heary, Ayomi Ratnayake, Ersilia Mirabelli, Ahmet Tarik Baykal, Stella ElkabesAbstract:Toll like receptors (TLRs) are expressed by cells of the immune system and mediate the host innate immune responses to pathogens. However, increasing evidence indicates that they are important contributors to central nervous system (CNS) function in health and in pathological conditions involving sterile inflammation. In agreement with this idea, we have previously shown that intrathecal administration of a TLR9 antagonist, Cytidine-Phosphate-guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), ameliorates the outcomes of spinal cord injury (SCI). Although these earlier studies showed a marked effect of CpG ODN 2088 on inflammatory cells, the expression of TLR9 in spinal cord (SC) neurons and astrocytes suggested that the antagonist exerts additional effects through direct actions on these cells. The current study was undertaken to assess the direct effects of CpG ODN 2088 on SC neurons, astrocytes and astrocyte-neuron interactions, in vitro. We report, for the first time, that inhibition of TLR9 in cultured SC neurons alters their function and confers protection against kainic acid (KA)-induced excitotoxic death. Moreover, the TLR9 antagonist attenuated the KA-elicited endoplasmic reticulum (ER) stress response in neurons, in vitro. CpG ODN 2088 also reduced the transcript levels and release of chemokine (C-X-C) motif ligand 1 (CXCL1) and monocyte chemotactic protein 1 (MCP-1) by astrocytes and it diminished interleukin-6 (IL-6) release without affecting transcript levels in vitro. Conditioned medium (CM) of CpG ODN 2088-treated astroglial cultures decreased the viability of SC neurons compared to CM of vehicle-treated astrocytes. However, this toxicity was not observed when astrocytes were co-cultured with neurons. Although CpG ODN 2088 limited the survival-promoting effects of astroglia, it did not reduce neuronal viability compared to controls grown in the absence of astrocytes. We conclude that the TLR9 antagonist acts directly on both SC neurons and astrocytes. Neuronal TLR9 antagonism confers protection against excitotoxic death. It is likely that this neuroprotection is partly due to the attenuation of the ER stress response provoked by excitotoxicity. Although CpG ODN 2088 limits the supportive effects of astrocytes on neurons, it could potentially exert beneficial effects by decreasing the release of pro-inflammatory cytokines and chemokines by astroglia. These findings highlight the multiple roles of TLR9 in the SC and have implications for pathological conditions including SCI where excitotoxicity and neuroinflammation play a prominent role in neuronal degeneration.
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A toll-like receptor 9 antagonist improves bladder function and white matter sparing in spinal cord injury.
Journal of neurotrauma, 2014Co-Authors: Brian T. David, Sujitha Sampath, Wei Dong, Adee Heiman, Courtney E. Rella, Stella Elkabes, Robert F. HearyAbstract:Abstract Spinal cord injury (SCI) affects motor, sensory, and autonomic functions. As current therapies do not adequately alleviate functional deficits, the development of new and more effective approaches is of critical importance. Our earlier investigations indicated that intrathecal administration of a toll-like receptor 9 (TLR9) antagonist, Cytidine-Phosphate-guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe, mid-thoracic contusion injury diminished neuropathic pain but did not alter locomotor deficits. These changes were paralleled by a decrease in the pro-inflammatory response at the injury epicenter. Using the same SCI paradigm and treatment regimen, the current studies investigated the effects of the TLR9 antagonist on bladder function. We report that the TLR9 antagonist decreases SCI-elicited urinary retention and ameliorates bladder morphopathology without affecting kidney function. A significant improvement in white matter sparing was also observed, most likely due...
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A toll-like receptor 9 antagonist reduces pain hypersensitivity and the inflammatory response in spinal cord injury
Neurobiology of disease, 2013Co-Authors: Brian T. David, Sujitha Sampath, Wei Dong, Robert F. Heary, Ayomi Ratnayake, Matthew A. Amarante, Naresh Parvath Reddy, Stella ElkabesAbstract:Abstract Toll-like receptors (TLRs) are mediators of the innate immune response to exogenous pathogens. They have also been implicated in sterile inflammation associated with systemic injury and non-infectious diseases via binding of endogenous ligands, possibly released by damaged cells. Emerging evidence indicates that some TLRs play a role in nervous system injury and especially in injury-elicited pain and sterile inflammation. However, no information is available about the contribution of TLR9, a member of the TLR family, to traumatic spinal cord injury (SCI). Moreover, the therapeutic potential of TLR9 ligands in the functional outcomes of SCI, including pain, has not been explored. We report, for the first time, that the intrathecal administration of a TLR9 antagonist, Cytidine–Phosphate–guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe contusion SCI, diminishes injury-induced heat hypersensitivity. Investigations on the potential mechanisms underlying the reduction in pain sensitivity indicated an attenuation of the inflammatory reaction manifested by a decrease in the number of CD11b-, CD45- and CD3-immunoreactive cells and a reduction in tumor necrosis factor-α (TNF-α) expression at the epicenter. Conversely, intrathecal delivery of a TLR9 agonist, CpG ODN 1826, increased inflammatory cell numbers and TNF-α expression in the epicenter. The CpG ODN 2088 treatment did not appear to induce systemic adverse effects as shown by spleen histology and serum cytokine levels. We propose that CpG ODN 2088 dampens injury-induced heat hypersensitivity by suppressing the inflammatory response and TNF-α expression. This investigation defines a previously unreported therapeutic role for CpG ODN 2088 in SCI-induced pain.
Arthur M Krieg - One of the best experts on this subject based on the ideXlab platform.
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Safety, pharmacokinetics and immune effects in normal volunteers of CPG 10101 (ACTILON), an investigational synthetic toll-like receptor 9 agonist.
Antiviral therapy, 2007Co-Authors: Alain Vicari, Arthur M Krieg, Tess Schmalbach, Julie A. Lekstrom‐himes, Mary Louise Morris, Mohammed J Al-adhami, Chantal Laframboise, Philip Leese, Susan M. Efler, Heather L. DavisAbstract:UNLABELLED CPG 10101 (ACTILON) is a novel potent and selective unmethylated Cytidine-Phosphate-guanosine (CpG)-containing oligodeoxynucleotide agonist of Toll-like receptor 9 (TLR9) being developed for the treatment of chronic infections such as HCV. OBJECTIVES AND METHODS In this randomized, double-blind, placebo-controlled Phase I study in 48 normal volunteers, we investigated the safety, pharmacokinetic parameters and immune effects of subcutaneous administration of CPG 10101. Five sequential escalating doses from 0.25 to 20 mg were administered twice, 14 days apart. In addition, a 4 mg dose was administered twice weekly for four weeks. RESULTS A maximum tolerated dose was not reached and the adverse event profile was consistent with the known immunostimulatory effects of TLR9 agonists, mostly consisting of injection site reactions or flu-like symptoms that were generally mild in intensity. CPG 10101 induced interferons, cytokines and chemokines in a pattern consistent with the biology of TLR9. The most sensitive marker was IP-10/CXCL10, whose induction was detected in some subjects even at the 0.25 mg dose. Some cytokines showed transient circulating levels, while the levels of others such as the antiviral cytokine 2',5'-oligoadenylate synthetase were sustained for several days. CONCLUSION This study warrants further investigation of CPG 10101 for the treatment of chronic infections such as HCV.
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Biodegradable microspheres containing group B Streptococcus vaccine: immune response in mice.
American journal of obstetrics and gynecology, 2001Co-Authors: Stephen K. Hunter, Mark E. Andracki, Arthur M KriegAbstract:Abstract Objective: This study seeks to show the feasibility of producing a group B Streptococcus (GBS) vaccine, which is capable of producing both a local IgA immune response at the mucosal surface where GBS is colonized and a humoral IgG response, which is capable of transplacental passive immunization. Study Design: Inactivated GBS antigen was microencapsulated in poly (D, L-lactic-co-glycolic acid) (PLG) with a water-in-oil-in-water double emulsion technique. Immunostimulatory synthetic oligodeoxynucleotides containing Cytidine-Phosphate-guanosine (CpG) motifs were coencapsulated as a potent adjuvant. The ICR strain of mouse was used in these studies. Female mice with normal immune systems were immunized with the PLG microparticles containing GBS type III polysaccharide (GBS PS) vaccine and CpG adjuvant (PLG/GBS/CpG) via the oral, vaginal, or nasal routes or by the intramuscular or intraperitoneal routes. Booster doses were administered 4 weeks after the initial immunization. Vaginal washings and blood samples were obtained 3 weeks after the booster dose and examined for both IgG and secretory IgA (sIgA) GBS antibodies with the use of an enzyme-linked immunoabsorbent assay method. Results: PLG/GBS/CpG microparticles elicited a significantly higher GBS antibody response when compared with nonencapsulated GBS antigen or PLG-encapsulated GBS PS vaccine without the addition of the CpG adjuvant. IgG and secretory IgA (sIgA) antibodies to GBS antigen were documented in both the vaginal washings and blood samples. Conclusion: Preliminary findings indicate that this novel PLG/GBS/CpG vaccine elicited both IgA and IgG antibody responses to the GBS PS antigen studied. This antibody response may provide both protection against maternal GBS colonization and passive transplacental immunization for the fetus and neonate. (Am J Obstet Gynecol 2001;185:1174-9.)
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enhanced dendritic cell maturation by tnf alpha or Cytidine Phosphate guanosine dna drives t cell activation in vitro and therapeutic anti tumor immune responses in vivo
Journal of Immunology, 2000Co-Authors: Christoph Brunner, Julia Seiderer, Angelika Schlamp, Martin Bidlingmaier, A Eigler, Wolfgang Haimerl, Hansanton Lehr, Arthur M Krieg, Gunther HartmannAbstract:Dendritic cells (DC) manipulated ex vivo can induce tumor immunity in experimental murine tumor models. To improve DC-based tumor vaccination, we studied whether DC maturation affects the T cell-activating potential in vitro and the induction of tumor immunity in vivo. Maturation of murine bone marrow-derived DC was induced by GM-CSF plus IL-4 alone or by further addition of TNF-α or a Cytidine-Phosphate-guanosine (CpG)-containing oligonucleotide (ODN-1826), which mimics the immunostimulatory effect of bacterial DNA. Flow cytometric analysis of costimulatory molecules and MHC class II showed that DC maturation was stimulated most by ODN-1826, whereas TNF-α had an intermediate effect. The extent of maturation correlated with the secretion of IL-12 and the induction of alloreactive T cell proliferation. In BALB/c mice, s.c. injection of colon carcinoma cells resulted in rapidly growing tumors. In this model, CpG-ODN-stimulated DC cocultured with irradiated tumor cells also induced prophylactic protection most effectively and were therapeutically effective when administered 3 days after tumor challenge. Thus, CpG-ODN-enhanced DC maturation may represent an efficient means to improve clinical tumor vaccination.
Brian T. David - One of the best experts on this subject based on the ideXlab platform.
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A toll-like receptor 9 antagonist improves bladder function and white matter sparing in spinal cord injury.
Journal of neurotrauma, 2014Co-Authors: Brian T. David, Sujitha Sampath, Wei Dong, Adee Heiman, Courtney E. Rella, Stella Elkabes, Robert F. HearyAbstract:Abstract Spinal cord injury (SCI) affects motor, sensory, and autonomic functions. As current therapies do not adequately alleviate functional deficits, the development of new and more effective approaches is of critical importance. Our earlier investigations indicated that intrathecal administration of a toll-like receptor 9 (TLR9) antagonist, Cytidine-Phosphate-guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe, mid-thoracic contusion injury diminished neuropathic pain but did not alter locomotor deficits. These changes were paralleled by a decrease in the pro-inflammatory response at the injury epicenter. Using the same SCI paradigm and treatment regimen, the current studies investigated the effects of the TLR9 antagonist on bladder function. We report that the TLR9 antagonist decreases SCI-elicited urinary retention and ameliorates bladder morphopathology without affecting kidney function. A significant improvement in white matter sparing was also observed, most likely due...
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A toll-like receptor 9 antagonist reduces pain hypersensitivity and the inflammatory response in spinal cord injury
Neurobiology of disease, 2013Co-Authors: Brian T. David, Sujitha Sampath, Wei Dong, Robert F. Heary, Ayomi Ratnayake, Matthew A. Amarante, Naresh Parvath Reddy, Stella ElkabesAbstract:Abstract Toll-like receptors (TLRs) are mediators of the innate immune response to exogenous pathogens. They have also been implicated in sterile inflammation associated with systemic injury and non-infectious diseases via binding of endogenous ligands, possibly released by damaged cells. Emerging evidence indicates that some TLRs play a role in nervous system injury and especially in injury-elicited pain and sterile inflammation. However, no information is available about the contribution of TLR9, a member of the TLR family, to traumatic spinal cord injury (SCI). Moreover, the therapeutic potential of TLR9 ligands in the functional outcomes of SCI, including pain, has not been explored. We report, for the first time, that the intrathecal administration of a TLR9 antagonist, Cytidine–Phosphate–guanosine oligodeoxynucleotide 2088 (CpG ODN 2088), to mice sustaining a severe contusion SCI, diminishes injury-induced heat hypersensitivity. Investigations on the potential mechanisms underlying the reduction in pain sensitivity indicated an attenuation of the inflammatory reaction manifested by a decrease in the number of CD11b-, CD45- and CD3-immunoreactive cells and a reduction in tumor necrosis factor-α (TNF-α) expression at the epicenter. Conversely, intrathecal delivery of a TLR9 agonist, CpG ODN 1826, increased inflammatory cell numbers and TNF-α expression in the epicenter. The CpG ODN 2088 treatment did not appear to induce systemic adverse effects as shown by spleen histology and serum cytokine levels. We propose that CpG ODN 2088 dampens injury-induced heat hypersensitivity by suppressing the inflammatory response and TNF-α expression. This investigation defines a previously unreported therapeutic role for CpG ODN 2088 in SCI-induced pain.
Jingyiing Wu - One of the best experts on this subject based on the ideXlab platform.
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adp ribosylation factor 3 mediates Cytidine Phosphate guanosine oligodeoxynucleotide induced responses by regulating toll like receptor 9 trafficking
Journal of Innate Immunity, 2015Co-Authors: Jingyiing WuAbstract:Toll-like receptor 9 (TLR9) trafficking from the endoplasmic reticulum (ER) into endolysosomes is critical for eliciting Cytidine-Phosphate-guanosine (CpG) DNA-mediated immune responses. ADP-ribosylation factor 3 (ARF3) is a member of the Ras superfamily, which is crucial for a wide variety of cellular events including protein trafficking. In this study, we found that the inhibition of ARF3 by dominant mutants and siRNA impaired CpG oligodeoxynucleotide (ODN)-mediated responses whereas cells expressing the constitutively active ARF3 mutant enhanced CpG ODN-induced NF-κB activation and cytokine production. Further experiments with MyD88-overexpressing fibroblast cells transfected with a dominant-negative mutant and a constitutively active mutant of ARF3 demonstrated that ARF3 regulated CpG ODN-mediated signaling upstream of MyD88. Additional studies have shown that ARF3 inhibition impairs TLR9 trafficking from the ER into endolysosomes, thereby inhibiting the functional cleavage of TLR9, although it has no significant effect on CpG ODN uptake. Furthermore, activated ARF3 is associated with Unc93B1 and TLR9, suggesting that ARF3 conducts TLR9 trafficking by forming the TLR9-Unc93B1-ARF3 complex. Overall, our findings demonstrate that a novel ARF3 axis pathway mediates CpG ODN-induced responses by regulating TLR9 trafficking.
