28 results on '"Ryffel, Bernhard"'
Search Results
2. Infection-Mediated Priming of Phagocytes Protects against Lethal Secondary Aspergillus fumigatus Challenge
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Savers, Amélie, primary, Rasid, Orhan, additional, Parlato, Marianna, additional, Brock, Matthias, additional, Jouvion, Gregory, additional, Ryffel, Bernhard, additional, Cavaillon, Jean-Marc, additional, Eberl, Gerard, additional, and Ibrahim-Granet, Oumaïma, additional
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- 2016
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3. In Situ Characterization of Splenic Brucella melitensis Reservoir Cells during the Chronic Phase of Infection in Susceptible Mice
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Hanot Mambres, Delphine, primary, Machelart, Arnaud, additional, Vanderwinden, Jean-Marie, additional, De Trez, Carl, additional, Ryffel, Bernhard, additional, Letesson, Jean-Jacques, additional, and Muraille, Eric, additional
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- 2015
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4. Limited Contribution of IL-36 versus IL-1 and TNF Pathways in Host Response to Mycobacterial Infection
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Segueni, Noria, primary, Vigne, Solenne, additional, Palmer, Gaby, additional, Bourigault, Marie-Laure, additional, Olleros, Maria L., additional, Vesin, Dominique, additional, Garcia, Irene, additional, Ryffel, Bernhard, additional, Quesniaux, Valérie F. J., additional, and Gabay, Cem, additional
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- 2015
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5. Role of IL-1β in Experimental Cystic Fibrosis upon P. aeruginosa Infection
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Palomo, Jennifer, primary, Marchiol, Tiffany, additional, Piotet, Julie, additional, Fauconnier, Louis, additional, Robinet, Marieke, additional, Reverchon, Flora, additional, Le Bert, Marc, additional, Togbe, Dieudonnée, additional, Buijs-Offerman, Ruvalic, additional, Stolarczyk, Marta, additional, Quesniaux, Valérie F. J., additional, Scholte, Bob J., additional, and Ryffel, Bernhard, additional
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- 2014
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6. The Anti-Pseudomonas aeruginosa Antibody Panobacumab Is Efficacious on Acute Pneumonia in Neutropenic Mice and Has Additive Effects with Meropenem
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Secher, Thomas, primary, Fas, Stefanie, additional, Fauconnier, Louis, additional, Mathieu, Marieke, additional, Rutschi, Oliver, additional, Ryffel, Bernhard, additional, and Rudolf, Michael, additional
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- 2013
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7. Complement C5 Activation during Influenza A Infection in Mice Contributes to Neutrophil Recruitment and Lung Injury
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Garcia, Cristiana C., primary, Weston-Davies, Wynne, additional, Russo, Remo C., additional, Tavares, Luciana P., additional, Rachid, Milene A., additional, Alves-Filho, José C., additional, Machado, Alexandre V., additional, Ryffel, Bernhard, additional, Nunn, Miles A., additional, and Teixeira, Mauro M., additional
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- 2013
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8. GM-CSF Priming Drives Bone Marrow-Derived Macrophages to a Pro-Inflammatory Pattern and Downmodulates PGE2 in Response to TLR2 Ligands
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Sorgi, Carlos Arterio, primary, Rose, Stephanie, additional, Court, Nathalie, additional, Carlos, Daniela, additional, Paula-Silva, Francisco Wanderley Garcia, additional, Assis, Patricia Aparecida, additional, Frantz, Fabiani Gai, additional, Ryffel, Bernhard, additional, Quesniaux, Valerie, additional, and Faccioli, Lúcia Helena, additional
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- 2012
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9. Adoptive Transfer of Induced-Treg Cells Effectively Attenuates Murine Airway Allergic Inflammation
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Xu, Wei, primary, Lan, Qin, additional, Chen, Maogen, additional, Chen, Hui, additional, Zhu, Ning, additional, Zhou, Xiaohui, additional, Wang, Julie, additional, Fan, Huimin, additional, Yan, Chun-Song, additional, Kuang, Jiu-Long, additional, Warburton, David, additional, Togbe, Dieudonnée, additional, Ryffel, Bernhard, additional, Zheng, Song-Guo, additional, and Shi, Wei, additional
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- 2012
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10. Priming with a Recombinant Pantothenate Auxotroph of Mycobacterium bovis BCG and Boosting with MVA Elicits HIV-1 Gag Specific CD8+ T Cells
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Chapman, Rosamund, primary, Shephard, Enid, additional, Stutz, Helen, additional, Douglass, Nicola, additional, Sambandamurthy, Vasan, additional, Garcia, Irene, additional, Ryffel, Bernhard, additional, Jacobs, William, additional, and Williamson, Anna-Lise, additional
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- 2012
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11. All-Trans Retinoic Acid Promotes TGF-β-Induced Tregs via Histone Modification but Not DNA Demethylation on Foxp3 Gene Locus
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Lu, Ling, primary, Ma, Jilin, additional, Li, Zhiyuan, additional, Lan, Qin, additional, Chen, Maogen, additional, Liu, Ya, additional, Xia, Zanxian, additional, Wang, Julie, additional, Han, Yuanping, additional, Shi, Wei, additional, Quesniaux, Valerie, additional, Ryffel, Bernhard, additional, Brand, David, additional, Li, Bin, additional, Liu, Zhongmin, additional, and Zheng, Song Guo, additional
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- 2011
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12. IL-1 and IL-23 Mediate Early IL-17A Production in Pulmonary Inflammation Leading to Late Fibrosis
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Gasse, Paméla, primary, Riteau, Nicolas, additional, Vacher, Rachel, additional, Michel, Marie-Laure, additional, Fautrel, Alain, additional, di Padova, Franco, additional, Fick, Lizette, additional, Charron, Sabine, additional, Lagente, Vincent, additional, Eberl, Gérard, additional, Le Bert, Marc, additional, Quesniaux, Valérie F. J., additional, Huaux, François, additional, Leite-de-Moraes, Maria, additional, Ryffel, Bernhard, additional, and Couillin, Isabelle, additional
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- 2011
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13. Role of the Chemokine Receptors CCR1, CCR2 and CCR4 in the Pathogenesis of Experimental Dengue Infection in Mice
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Guabiraba, Rodrigo, primary, Marques, Rafael Elias, additional, Besnard, Anne-Gaëlle, additional, Fagundes, Caio T., additional, Souza, Danielle G., additional, Ryffel, Bernhard, additional, and Teixeira, Mauro M., additional
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- 2010
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14. Both Functional LTβ Receptor and TNF Receptor 2 Are Required for the Development of Experimental Cerebral Malaria
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Togbe, Dieudonnée, primary, Loureiro de Sousa, Paulo, additional, Fauconnier, Mathilde, additional, Boissay, Victorine, additional, Fick, Lizette, additional, Scheu, Stefanie, additional, Pfeffer, Klaus, additional, Menard, Robert, additional, Grau, Georges E., additional, Doan, Bich-Thuy, additional, Beloeil, Jean Claude, additional, Renia, Laurent, additional, Hansen, Anna M., additional, Ball, Helen J., additional, Hunt, Nicholas H., additional, Ryffel, Bernhard, additional, and Quesniaux, Valerie F. J., additional
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- 2008
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15. SIRT1 Activators Suppress Inflammatory Responses through Promotion of p65 Deacetylation and Inhibition of NF-κB Activity.
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Hongying Yang, Wei Zhang, Pan, Heng, Feldser, Heidi G., Lainez, Elden, Miller, Christine, Leung, Stewart, Zhong Zhong, Huizhen Zhao, Sweitzer, Sharon, Considine, Thomas, Riera, Thomas, Suri, Vipin, White, Brian, Ellis, James L., Vlasuk, George P., Loh, Christine, and Ryffel, Bernhard
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INFLAMMATION ,DISEASE research ,AGING ,PROTEIN research ,DEACETYLASES ,ANTI-inflammatory agents - Abstract
Chronic inflammation is a major contributing factor in the pathogenesis of many age-associated diseases. One central protein that regulates inflammation is NF-κB, the activity of which is modulated by post-translational modifications as well as by association with co-activator and co-repressor proteins. SIRT1, an NAD
+ -dependent protein deacetylase, has been shown to suppress NF-κB signaling through deacetylation of the p65 subunit of NF-κB resulting in the reduction of the inflammatory responses mediated by this transcription factor. The role of SIRT1 in the regulation of NF-κB provides the necessary validation for the development of pharmacological strategies for activating SIRT1 as an approach for the development of a new class of anti-inflammatory therapeutics. We report herein the development of a quantitative assay to assess compound effects on acetylated p65 protein in the cell. We demonstrate that small molecule activators of SIRT1 (STACs) enhance deacetylation of cellular p65 protein, which results in the suppression of TNFα-induced NF-κB transcriptional activation and reduction of LPS-stimulated TNFα secretion in a SIRT1-dependent manner. In an acute mouse model of LPS-induced inflammation, the STAC SRTCX1003 decreased the production of the proinflammatory cytokines TNFα and IL-12. Our studies indicate that increasing SIRT1-mediated NF-κB deacetylation using small molecule activating compounds is a novel approach to the development of a new class of therapeutic anti-inflammatory agents. [ABSTRACT FROM AUTHOR]- Published
- 2012
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16. Interaction between Lysophosphatidic Acid, Prostaglandins and the Endocannabinoid System during the Window of Implantation in the Rat Uterus.
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Sordelli, Micaela S., Beltrame, Jimena S., Cella, Maximiliano, Gervasi, María Gracia, Martinez, Silvina Perez, Burdet, Juliana, Zotta, Elsa, Franchi, Ana M., Ribeiro, María Laura, and Ryffel, Bernhard
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LIPIDS ,PROSTAGLANDINS ,CARBOXYLIC acids ,UTERUS ,FATTY acids ,ANTIARTHRITIC agents - Abstract
Bioactive lipid molecules as lysophosphatidic acid (LPA), prostaglandins (PG) and endocannabinoids are important mediators of embryo implantation. Based on previous published data we became interested in studying the interaction between these three groups of lipid derivatives in the rat uterus during the window of implantation. Thus, we adopted a pharmacological approach in vitro using LPA, DGPP (a selective antagonist of LPA3, an LPA receptor), endocannabinoids' receptor selective antagonists (AM251 and AM630) and non selective (indomethacin) and selective (NS-398) inhibitors of cyclooxygenase-1 and 2 enzymes. Cyclooxygenase isoforms participate in prostaglandins' synthesis. The incubation of the uterus from rats pregnant on day 5 of gestation (implantation window) with LPA augmented the activity and the expression of fatty acid amide hydrolase, the main enzyme involved in the degradation of endocannabinoids in the rodent uteri, suggesting that LPA decreased endocannabinoids' levels during embryo implantation. It has been reported that high endocannabinoids are deleterious for implantation. Also, LPA increased PGE2 production and cyclooxygenase-2 expression. The incubation of LPA with indomethacin or NS-398 reversed the increment in PGE2 production, suggesting that cyclooxygenase-2 was the isoform involved in LPA effect. PGs are important mediators of decidualization and vascularization at the implantation sites. All these effects were mediated by LPA3, as the incubation with DGPP completely reversed LPA stimulatory actions. Besides, we also observed that endocannabinoids mediated the stimulatory effect of LPA on cyclooxygenase-2 derived PGE2 production, as the incubation of LPA with AM251 or AM630 completely reversed LPA effect. Also, LPA augmented via LPA3 decidualization and vascularization markers. Overall, the results presented here demonstrate the participation of LPA3 in the process of implantation through the interaction with other groups of lipid molecules, prostaglandins and endocannabinoids, which prepare the uterine milieu for embryo invasion during the window of implantation. [ABSTRACT FROM AUTHOR]
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- 2012
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17. IL-36α Exerts Pro-Inflammatory Effects in the Lungs of Mice.
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Ramadas, Ravisankar A., Ewart, Susan L., Iwakura, Yoichiro, Medoff, Benjamin D., LeVine, Ann Marie, and Ryffel, Bernhard
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INTERLEUKINS ,PHYSIOLOGICAL effects of cytokines ,PNEUMONIA ,NEUTROPHILS ,LABORATORY mice ,MESSENGER RNA ,CHEMOKINES ,T cells - Abstract
Interleukin (IL-) 36 cytokines (previously designated as novel IL-1 family member cytokines; IL-1F5-- IL-1F10) constitute a novel cluster of cytokines structurally and functionally similar to members of the IL-1 cytokine cluster. The effects of IL-36 cytokines in inflammatory lung disorders remains poorly understood. The current study sought to investigate the effects of IL-36α (IL-1F6) and test the hypothesis that IL-36α acts as a pro-inflammatory cytokine in the lung in vivo. Intratracheal instillation of recombinant mouse IL-36a induced neutrophil influx in the lungs of wild-type C57BL/6 mice and IL-1αβ
-/- mice in vivo. IL-36α induced neutrophil influx was also associated with increased mRNA expression of neutrophil-specific chemokines CXCL1 and CXCL2 in the lungs of C57BL/6 and IL-1αβ-/- mice in vivo. In addition, intratracheal instillation of IL- 36α enhanced mRNA expression of its receptor IL-36R in the lungs of C57BL/6 as well as IL-1αβ mice in vivo. Furthermore, in vitro incubation of CD11c cells with IL-36a resulted in the generation of neutrophil-specific chemokines CXCL1, CXCL2 as well as TNFaα IL-36α increased the expression of the co-stimulatory molecule CD40 and enhanced the ability of CD11c+ cells to induce CD4 T cell proliferation in vitro. Furthermore, stimulation with IL-36α activated NF-κB in a mouse macrophage cell line. These results demonstrate that IL-36α acts as a pro-inflammatory cytokine in the lung without the contribution of IL-1α and IL-1β. The current study describes the pro-inflammatory effects of IL-36α in the lung, demonstrates the functional redundancy of IL-36α with other agonist cytokines in the IL-1 and IL-36 cytokine cluster, and suggests that therapeutic targeting of IL-36 cytokines could be beneficial in inflammatory lung diseases. [ABSTRACT FROM AUTHOR]- Published
- 2012
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18. Deletion of IL-33R (ST2) Abrogates Resistance to EAE in BALB/C Mice by Enhancing Polarization of APC to Inflammatory Phenotype.
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Milovanovic, Marija, Volarevic, Vladislav, Ljujic, Biljana, Radosavljevic, Gordana, Jovanovic, Ivan, Arsenijevic, Nebojsa, Lukic, Miodrag L., and Ryffel, Bernhard
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INTERLEUKIN-33 ,INTERLEUKINS ,CELLULAR immunity ,AUTOIMMUNITY ,T cells ,DENDRITIC cells - Abstract
The administration of interleukin 33 and deletion of IL-33 receptor, ST2 molecule, affects the induction of autoimmunity in different experimental models of human autoimmune diseases. The aim of this study was to analyze the effect of ST2 deletion on the induction of experimental autoimmune encephalomyelitis (EAE) in resistant BALB/c mice. Mice were immunized with MOG
35-55 peptide or disease was induced by passive transfer of encephalitogenic singenic cells and EAE was clinically and histologically evaluated. Expression of intracellular inflammatory cytokines, markers of activation and chemokine receptors on lymphoid tissue and CNS infiltrating mononuclear cells was analyzed by flow cytometry. We report here that deletion of ST2-/- molecule abrogates resistance of BALB/c mice to EAE induction based on clinical and histopathological findings. Brain and spinal cord infiltrates of ST2-/- mice had significantly higher number of CD4+ T lymphocytes containing inflammatory cytokines compared to BALB/c WT mice. Adoptive transfer of ST2-/- primed lymphocytes induced clinical signs of the disease in ST2-/- as well as in WT mice. MOG35-55 restimulated ST2-/- CD4+ cells as well as ex vivo analyzed lymph node cells had higher expression of T-bet and IL-17, IFN-γ, TNF-α and GM-CSF in comparison with WT CD4+ cells. ST2-/- mice had higher percentages of CD4+ cells expressing chemokine receptors important for migration to CNS in comparison with WT CD4+ cells. Draining lymph nodes of ST2-/- mice contained higher percentage of CD11c+ CD11b+ CD8- cells containing inflammatory cytokines IL-6 and IL-12 with higher expression of activation markers. Transfer of ST2-/- but not WT dendritic cells induced EAE in MOG35-55 immunized WT mice. Our results indicate that ST2 deficiency attenuates inherent resistance of BALB/c mice to EAE induction by enhancing differentiation of proinflammatory antigen presenting cells and consecutive differentiation of encephalitogenic T cells in the draining lymph node rather than affecting their action in the target tissue. [ABSTRACT FROM AUTHOR]- Published
- 2012
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19. Host Platelets and, in Part, Neutrophils Mediate Lung Accumulation of Transfused UVB-Irradiated Human Platelets in a Mouse Model of Acute Lung Injury.
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Xuan Chi, Li Zhi, Gelderman, Monique P., Vostal, Jaroslav G., and Ryffel, Bernhard
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ULTRAVIOLET radiation ,BLOOD platelets ,LUNG diseases ,LABORATORY mice ,NEUTROPHILS ,PROTEIN research - Abstract
We previously reported that ultraviolet light B (UVB)-treated human platelets (hPLTs) can cause acute lung injury (ALI) in a two-event SCID mouse model in which the predisposing event was Lipopolysaccharide (LPS) injection and the second event was infusion of UVB-treated hPLTs. To delineate contributions of host mouse platelets (mPLTs) and neutrophils in the pathogenesis of ALI in this mouse model, we depleted mPLTs or neutrophils and measured hPLT accumulation in the lung. We also assessed lung injury by protein content in bronchoalveolar lavage fluid (BALF). LPS injection followed by infusion of UVB-treated hPLTs resulted in sequestration of both mPLTs and hPLTs in the lungs of SCID mice, although the numbers of neutrophils in the lung were not significantly different from the control group. Depletion of mouse neutrophils caused only a mild reduction in UVB-hPLTs accumulation in the lungs and a mild reduction in protein content in BALF. In comparison, depletion of mPLTs almost completely abolished hPLTs accumulation in the lung and significantly reduced protein content in BALF. UVB-treated hPLTs bound to host mPLTs, but did not bind to neutrophils in the lung. Aspirin treatment of hPLTs in vitro abolished hPLT accumulation in the lung and protected mice from lung injury. Our data indicate that host mPLTs accumulated in the lungs in response to an inflammatory challenge and subsequently mediated the attachment of transfused UVB-hPLTs. Neutrophils also recruited a small percentage of platelets to the lung. These findings may help develop therapeutic strategies for ALI which could potentially result from transfusion of UV illuminated platelets. [ABSTRACT FROM AUTHOR]
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- 2012
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20. A Novel Highly Potent Therapeutic Antibody Neutralizes Multiple Human Chemokines and Mimics Viral Immune Modulation.
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Scalley-Kim, Michelle L., Hess, Bruce W., Kelly, Ryan L., Krostag, Anne-Rachel F., Lustig, Kurt H., Marken, John S., Ovendale, Pamela J., Posey, Aaron R., Smolak, Pamela J., Taylor, Janelle D. L., Wood, C. L., Bienvenue, David L., Probst, Peter, Salmon, Ruth A., Allison, Daniel S., Foy, Teresa M., Raport, Carol J., and Ryffel, Bernhard
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CHEMOKINES ,LEUCOCYTES ,AUTOIMMUNE diseases ,CHEMOKINE receptors ,IMMUNOGLOBULINS ,CHEMOTAXIS - Abstract
Chemokines play a key role in leukocyte recruitment during inflammation and are implicated in the pathogenesis of a number of autoimmune diseases. As such, inhibiting chemokine signaling has been of keen interest for the development of therapeutic agents. This endeavor, however, has been hampered due to complexities in the chemokine system. Many chemokines have been shown to signal through multiple receptors and, conversely, most chemokine receptors bind to more than one chemokine. One approach to overcoming this complexity is to develop a single therapeutic agent that binds and inactivates multiple chemokines, similar to an immune evasion strategy utilized by a number of viruses. Here, we describe the development and characterization of a novel therapeutic antibody that targets a subset of human CC chemokines, specifically CCL3, CCL4, and CCL5, involved in chronic inflammatory diseases. Using a sequential immunization approach, followed by humanization and phage display affinity maturation, a therapeutic antibody was developed that displays high binding affinity towards the three targeted chemokines. In vitro, this antibody potently inhibits chemotaxis and chemokine-mediated signaling through CCR1 and CCR5, primary chemokine receptors for the targeted chemokines. Furthermore, we have demonstrated in vivo efficacy of the antibody in a SCID-hu mouse model of skin leukocyte migration, thus confirming its potential as a novel therapeutic chemokine antagonist. We anticipate that this antibody will have broad therapeutic utility in the treatment of a number of autoimmune diseases due to its ability to simultaneously neutralize multiple chemokines implicated in disease pathogenesis. [ABSTRACT FROM AUTHOR]
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- 2012
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21. Mucosal Healing and Fibrosis after Acute or Chronic Inflammation in Wild Type FVB-N Mice and C57BL6 Procollagen α1(I)-Promoter-GFP Reporter Mice.
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Shengli Ding, Walton, Kristen L. W., Blue, Randall Eric, MacNaughton, Kirk, Magness, Scott T., Lund, Pauline Kay, and Ryffel, Bernhard
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FIBROSIS ,CROHN'S disease ,LABORATORY mice ,INFLAMMATION ,FLUORESCENCE microscopy ,GREEN fluorescent protein - Abstract
Background: Injury and intestinal inflammation trigger wound healing responses that can restore mucosal architecture but if chronic, can promote intestinal fibrosis. Intestinal fibrosis is a major complication of Crohn's disease. The cellular and molecular basis of mucosal healing and intestinal fibrosis are not well defined and better understanding requires well characterized mouse models. Methods: FVB-N wild type mice and C57BL6 procollagen α1(I)-GFP reporter mice were given one (DSS1) or two (DSS2) cycles of 3% DSS (5 days/cycle) followed by 7 days recovery. Histological scoring of inflammation and fibrosis were performed at DSS1, DSS1+3, DSS1+7, DSS2, DSS2+3, and DSS2+7. Procollagen α1(I)-GFP activation was assessed in DSS and also TNBS models by whole colon GFP imaging and fluorescence microscopy. Colocalization of GFP with α-smooth muscle actin (α-SMA) or vimentin was examined. GFP mRNA levels were tested for correlation with endogenous collagen α1(I) mRNA. Results: Males were more susceptible to DSS-induced disease and mortality than females. In FVB-N mice one DSS cycle induced transient mucosal inflammation and fibrosis that resolved by 7 days of recovery. Two DSS cycles induced transmural inflammation and fibrosis in a subset of FVB-N mice but overall, did not yield more consistent, severe or sustained fibrosis. In C57BL6 mice, procollagen α1(I)-GFP reporter was activated at the end of DSS1 and through DSS+7 with more dramatic and transmural activation at DSS2 through DSS2+7, and in TNBS treated mice. In DSS and TNBS models GFP reporter expression localized to vimentin+ cells and much fewer α-SMA
+ cells. GFP mRNA strongly correlated with collagen α1(I) mRNA. Conclusions:One DSS cycle in FVB-N mice provides a model to study mucosal injury and subsequent mucosal healing. The procollagen α1(I)-GFP transgenic provides a useful model to study activation of a gene encoding a major extracellular matrix protein during acute or chronic experimental intestinal inflammation and fibrosis. [ABSTRACT FROM AUTHOR]- Published
- 2012
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22. Dengue Virus Serotype 2 Blocks Extracellular Signal- Regulated Kinase and Nuclear Factor-κB Activation to Downregulate Cytokine Production.
- Author
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Tsung-Hsien Chang, Siang-Ru Chen, Chia-Yi Yu, You-Sheng Lin, Yao-Shen Chen, Toru Kubota, Mayumi Matsuoka, Yi-Ling Lin, and Ryffel, Bernhard
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DENGUE viruses ,VIRUS diseases ,INTERFERONS ,CYTOKINES ,IMMUNE system ,TOLL-like receptors - Abstract
Background: Dengue virus (DENV) infection is the most common mosquito- borne viral disease threatening human health around the world. Type I interferon (IFN) and cytokine production are crucial in the innate immune system. We previously reported that DENV serotype 2 (DENV-2) induced low levels of interferon regulatory factor 3 and NF-κB activation, thus leading to reduced production of IFN-β in the early phase of infection. Here, we determined whether DENV infection not only hampers type I IFN activation but also cytokine production triggered by Toll-like receptor (TLR) signaling. Methodology/Principal Findings: We used quantitative RT-PCR and found that only low levels of IFN-β and inflammatory cytokines such as interleukin 10 (IL- 10), IL-12 and tumor necrosis factor α (TNFα) mRNA were detected in DENV-2-infected bone-marrow-derived dendritic cells. Furthermore, DENV-2 infection repressed cytokine production triggered by TLR signaling. To elucidate the molecular mechanisms underlying this suppression event, we measured NF- κB activation by p65 nuclear translocation and luciferase reporter assay and found that NF-κB activation triggered by TLR ligands was blocked by DENV-2 infection. As well, extracellular signal-regulated kinase (ERK) activity was suppressed by DENV-2 infection. Conclusions/Significance:To downregulate the host innate immunity, DENV-2 by itself is a weak inducer of type I IFN and cytokines, furthermore DENV-2 can also block the TLR-triggered ERK-NF-κB activation and cytokine production. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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23. GM-CSF Priming Drives Bone Marrow-Derived Macrophages to a Pro-Inflammatory Pattern and Downmodulates PGE2 in Response to TLR2 Ligands.
- Author
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Sorgi, Carlos Arterio, Rose, Stephanie, Court, Nathalie, Carlos, Daniela, Garcia Paula-Silva, Francisco Wanderley, Assis, Patricia Aparecida, Frantz, Fabiani Gai, Ryffel, Bernhard, Quesniaux, Valerie, and Faccioli, Lúcia Helena
- Subjects
GRANULOCYTE-macrophage colony-stimulating factor ,BONE marrow ,IMMUNE system ,KILLER cells ,CYTOKINES ,IMMUNOREGULATION ,IMMUNE response - Abstract
In response to pathogen recognition by Toll-like receptors (TLRs) on their cell surface, macrophages release lipid mediators and cytokines that are widely distributed throughout the body and play essential roles in host responses. Granulocyte macrophage colony-stimulating factor (GM-CSF) is important for the immune response during infections to improve the clearance of microorganisms. In this study, we examined the release of mediators in response to TLR2 ligands by bone marrow-derived macrophages (BMDMs) primed with GM-CSF. We demonstrated that when stimulated with TLR2 ligands, non-primed BMDMs preferentially produced PGE
2 in greater amounts than LTB4 . However, GM-CSF priming shifted the release of lipid mediators by BMDMs, resulting in a significant decrease of PGE2 production in response to the same stimuli. The decrease of PGE2 production from primed BMDMs was accompanied by a decrease in PGE-synthase mRNA expression and an increase in TNF-α and nitric oxide (NO) production. Moreover, some GM-CSF effects were potentiated by the addition of IFN-γ. Using a variety of TLR2 ligands, we established that PGE2 release by GM-CSF-primed BMDMs was dependent on TLR2 co-receptors (TLR1, TLR6), CD14, MyD88 and the nuclear translocation of NFkB but was not dependent on peroxisome proliferator-activated receptor-γ (PPAR-γ) activation. Indeed, GM-CSF priming enhanced TLR2, TLR4 and MyD88 mRNA expression and phospho-IkBa formation. These findings demonstrate that GM-CSF drives BMDMs to present a profile relevant to the host during infections. [ABSTRACT FROM AUTHOR]- Published
- 2012
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24. Adoptive Transfer of Induced-Treg Cells Effectively Attenuates Murine Airway Allergic Inflammation.
- Author
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Wei Xu, Qin Lan, Maogen Chen, Hui Chen, Ning Zhu, Xiaohui Zhou, Julie Wang, Huimin Fan, Chun-Song Yan, Jiu-Long Kuang, Warburton, David, Togbe, Dieudonnée, Ryffel, Bernhard, Song-Guo Zhen, and Wei Shi
- Subjects
LYMPHOCYTES ,LEUCOCYTES ,OBSTRUCTIVE lung diseases ,INFLAMMATION ,PATHOLOGY - Abstract
Both nature and induced regulatory T (Treg) lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic inflammation, exogenously induced Treg cells were infused into ovalbumin-sensitized mice prior to or during intranasal ovalbumin challenge. The results showed that adoptive transfer of induced Treg cells prior to allergen challenge markedly reduced airway hyperresponsiveness, eosinophil recruitment, mucus hyper-production, airway remodeling, and IgE levels. This effect was associated with increase of Treg cells (CD4
+ FoxP3+ ) and decrease of dendritic cells in the draining lymph nodes, and with reduction of Th1, Th2, and Th17 cell response as compared to the controls. Moreover, adoptive transfer of induced Treg cells during allergen challenge also effectively attenuate airway inflammation and improve airway function, which are comparable to those by natural Treg cell infusion. Therefore, adoptive transfer of in vitro induced Treg cells may be a promising therapeutic approach to prevent and treat severe asthma. [ABSTRACT FROM AUTHOR]- Published
- 2012
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25. Priming with a Recombinant Pantothenate Auxotroph of Mycobacterium bovis BCG and Boosting with MVA Elicits HIV-1 Gag Specific CD8+ T Cells.
- Author
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Chapman, Rosamund, Shephard, Enid, Stutz, Helen, Douglass, Nicola, Sambandamurthy, Vasan, Garcia, Irene, Ryffel, Bernhard, Jacobs, William, and Williamson, Anna-Lise
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AUXOTROPHY ,MYCOBACTERIUM ,T cells ,AIDS vaccines ,GENETIC code ,DELETION mutation - Abstract
A safe and effective HIV vaccine is required to significantly reduce the number of people becoming infected with HIV each year. In this study wild type Mycobacterium bovis BCG Pasteur and an attenuated pantothenate auxotroph strain (BCGΔpanCD) that is safe in SCID mice, have been compared as vaccine vectors for HIV-1 subtype C Gag. Genetically stable vaccines BCG[pHS400] (BCG-Gag) and BCGΔpanCD[pHS400] (BCGpan-Gag) were generated using the Pasteur strain of BCG, and a panothenate auxotroph of Pasteur respectively. Stability was achieved by the use of a codon optimised gag gene and deletion of the hsp60-lysA promoter-gene cassette from the episomal vector pCB119. In this vector expression of gag is driven by the mtrA promoter and the Gag protein is fused to the Mycobacterium tuberculosis 19 kDa signal sequence. Both BCG-Gag and BCGpan-Gag primed the immune system of BALB/c mice for a boost with a recombinant modified vaccinia virus Ankara expressing Gag (MVA-Gag). After the boost high frequencies of predominantly Gag-specific CD8
+ T cells were detected when BCGpan-Gag was the prime in contrast to induction of predominantly Gag-specific CD4+ T cells when priming with BCG-Gag. The differing Gag-specific T-cell phenotype elicited by the prime-boost regimens may be related to the reduced inflammation observed with the pantothenate auxotroph strain compared to the parent strain. These features make BCGpan-Gag a more desirable HIV vaccine candidate than BCG-Gag. Although no Gag-specific cells could be detected after vaccination of BALB/c mice with either recombinant BCG vaccine alone, BCGpan-Gag protected mice against a surrogate vaccinia virus challenge. [ABSTRACT FROM AUTHOR]- Published
- 2012
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- View/download PDF
26. All-Trans Retinoic Acid Promotes TGF-b-Induced Tregs via Histone Modification but Not DNA Demethylation on Foxp3 Gene Locus.
- Author
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Ling Lu, Jilin Ma, Zhiyuan Li, Qin Lan, Maogen Chen, Ya Liu, Zanxian Xia, Julie Wang, Yuanping Han, Wei Shi, Quesniaux, Valerie, Ryffel, Bernhard, Brand, David, Bin Li, Zhongmin Liu, and Song Guo Zheng
- Subjects
TRETINOIN ,DEMETHYLATION ,LOCUS (Genetics) ,IMMUNOREGULATION ,CELLULAR mechanics ,T cell differentiation ,GENE expression ,CELLULAR signal transduction - Abstract
Background: It has been documented all-trans retinoic acid (atRA) promotes the development of TGF-β-induced CD4
+ Foxp3+ regulatory T cells (iTreg) that play a vital role in the prevention of autoimmune responses, however, molecular mechanisms involved remain elusive. Our objective, therefore, was to determine how atRA promotes the differentiation of iTregs. Methodology/Principal Findings: Addition of atRA to naïve CD4+ CD252 cells stimulated with anti-CD3/CD28 antibodies in the presence of TGF-β not only increased Foxp3+ iTreg differentiation, but maintained Foxp3 expression through apoptosis inhibition. atRA/TGF-b-treated CD4+ cells developed complete anergy and displayed increased suppressive activity. Infusion of atRA/TGF-b-treated CD4+ cells resulted in the greater effects on suppressing symptoms and protecting the survival of chronic GVHD mice with typical lupus-like syndromes than did CD4+ cells treated with TGF-β alone. atRA did not significantly affect the phosphorylation levels of Smad2/3 and still promoted iTreg differentiation in CD4+ cells isolated from Smad3 KO and Smad2 conditional KO mice. Conversely, atRA markedly increased ERK1/2 activation, and blockade of ERK1/2 signaling completely abolished the enhanced effects of atRA on Foxp3 expression. Moreover, atRA significantly increased histone methylation and acetylation within the promoter and conserved non-coding DNA sequence (CNS) elements at the Foxp3 gene locus and the recruitment of phosphor-RNA polymerase II, while DNA methylation in the CNS3 was not significantly altered. Conclusions/Significance: We have identified the cellular and molecular mechanism(s) by which atRA promotes the development and maintenance of iTregs. These results will help to enhance the quantity and quality of development of iTregs and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
27. The Anti-Pseudomonas aeruginosa Antibody Panobacumab Is Efficacious on Acute Pneumonia in Neutropenic Mice and Has Additive Effects with Meropenem.
- Author
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Secher, Thomas, Fas, Stefanie, Fauconnier, Louis, Mathieu, Marieke, Rutschi, Oliver, Ryffel, Bernhard, and Rudolf, Michael
- Subjects
PSEUDOMONAS aeruginosa ,ANTI-antibodies ,MONOCLONAL antibodies ,DRUG efficacy ,PNEUMONIA ,LABORATORY mice ,IMMUNOCOMPROMISED patients ,DRUG resistance - Abstract
Pseudomonas aeruginosa (P. aeruginosa) infections are associated with considerable morbidity and mortality in immunocompromised patients due to antibiotic resistance. Therefore, we investigated the efficacy of the anti-P. aeruginosa serotype O11 lipopolysaccharide monoclonal antibody Panobacumab in a clinically relevant murine model of neutropenia induced by cyclophosphamide and in combination with meropenem in susceptible and meropenem resistant P. aeruginosa induced pneumonia. We observed that P. aeruginosa induced pneumonia was dramatically increased in neutropenic mice compared to immunocompetent mice. First, Panobacumab significantly reduced lung inflammation and enhanced bacterial clearance from the lung of neutropenic host. Secondly, combination of Panobacumab and meropenem had an additive effect. Third, Panobacumab retained activity on a meropenem resistant P. aeruginosa strain. In conclusion, the present data established that Panobacumab contributes to the clearance of P. aeruginosa in neutropenic hosts as well as in combination with antibiotics in immunocompetent hosts. This suggests beneficial effects of co-treatment even in immunocompromised individuals, suffering most of the morbidity and mortality of P. aeruginosa infections. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
28. Determinants of Divergent Adaptive Immune Responses after Airway Sensitization with Ligands of Toll-Like Receptor 5 or Toll-Like Receptor 9
- Author
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Linda M. Lee, Sankar Ghosh, Anthony L. DeFranco, Ming Ji, Clifford A. Lowell, Xin Ren, Matthew B. Dong, Richard M. Locksley, Yanli Wang, Meenal Sinha, and Ryffel, Bernhard
- Subjects
0301 basic medicine ,Male ,Physiology ,Oligonucleotides ,lcsh:Medicine ,Adaptive Immunity ,Inbred C57BL ,Pathology and Laboratory Medicine ,Biochemistry ,White Blood Cells ,Immunologic Adjuvants ,Mice ,0302 clinical medicine ,Cell Signaling ,Animal Cells ,Microbial Physiology ,Immune Physiology ,Medicine and Health Sciences ,2.1 Biological and endogenous factors ,Public and Occupational Health ,Membrane Receptor Signaling ,Bacterial Physiology ,Aetiology ,lcsh:Science ,Lung ,Immune Response ,Toll-like receptor ,Innate Immune System ,Multidisciplinary ,T Cells ,Acquired immune system ,Immune Receptor Signaling ,Vaccination and Immunization ,3. Good health ,Cell biology ,Mutant Strains ,medicine.anatomical_structure ,Respiratory ,Cytokines ,Female ,Cellular Types ,Research Article ,Signal Transduction ,Thymic stromal lymphopoietin ,General Science & Technology ,T cell ,Immune Cells ,Immunology ,Biology ,Microbiology ,03 medical and health sciences ,Immune system ,Signs and Symptoms ,Thymic Stromal Lymphopoietin ,Diagnostic Medicine ,medicine ,Animals ,T Helper Cells ,Inflammation ,Blood Cells ,Inflammatory and immune system ,lcsh:R ,TLR9 ,Biology and Life Sciences ,Proteins ,Bacteriology ,Cell Biology ,Molecular Development ,Interleukin-33 ,Mice, Mutant Strains ,Interleukin 33 ,Mice, Inbred C57BL ,Toll-Like Receptor 5 ,030104 developmental biology ,TLR5 ,Immune System ,Toll-Like Receptor 9 ,Myeloid Differentiation Factor 88 ,lcsh:Q ,Preventive Medicine ,030215 immunology ,Flagellin ,Developmental Biology ,Interleukin-1 - Abstract
Excessive type 2 helper T cell responses to environmental antigens can cause immunopathology such as asthma and allergy, but how such immune responses are induced remains unclear. We studied this process in the airways by immunizing mice intranasally with the antigen ovalbumin together with either of two Toll-like receptor (TLR) ligands. We found the TLR5 ligand flagellin promoted a type 2 helper T cell response, whereas, a TLR9 ligand CpG oligodeoxyribonucleotide (ODN) promoted a type 1 helper T cell response. CpG ODN induced mRNA encoding interleukin (IL)-12 p40, whereas, flagellin caused IL-33 secretion and induced mRNAs encoding IL-1 and thymic stromal lymphopoietin (TSLP). By using mice deficient in the TLR and IL-1R signaling molecule, myeloid differentiation primary response 88 (MyD88), in conventional dendritic cells (cDCs) and alveolar macrophages (AMs), and by cell sorting different lung populations after 2 hours of in vivo stimulation, we characterized the cell types that rapidly produced inflammatory cytokines in response to TLR stimulation. CpG ODN was likely recognized by TLR9 on cDCs and AMs, which made mRNA encoding IL-12. IL-12 was necessary for the subsequent innate and adaptive interferon-γ production. In contrast, flagellin stimulated multiple cells of hematopoietic and non-hematopoietic origin, including AMs, DCs, monocytes, and lung epithelial cells. AMs were largely responsible for IL-1α, whereas lung epithelial cells made TSLP. Multiple hematopoietic cells, including AMs, DCs, and monocytes contributed to other cytokines, including IL-1β and TNFα. MyD88-dependent signals, likely through IL-1R and IL-33R, and MyD88-independent signals, likely from TSLP, were necessary in cDCs for promotion of the early IL-4 response by CD4 T cells in the draining lymph node. Thus, the cell types that responded to TLR ligands were a critical determinant of the innate cytokines produced and the character of the resulting adaptive immune response in the airways.
- Published
- 2016
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