33 results on '"Godon O"'
Search Results
2. Conditional neutrophil depletion challenges their contribution to mouse models of anaphylaxis.
- Author
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Stackowicz, J, Gillis, CM, Godon, O, Iannascoli, B, Conde, E, Leveque, E, Worrall, WPM, Galli, SJ, Bruhns, P, Reber, LL, Jönsson, F, Stackowicz, J, Gillis, CM, Godon, O, Iannascoli, B, Conde, E, Leveque, E, Worrall, WPM, Galli, SJ, Bruhns, P, Reber, LL, and Jönsson, F
- Published
- 2023
3. IgG Subclass-Dependent Pulmonary Antigen Retention during Acute IgG-Dependent Systemic Anaphylaxis in Mice.
- Author
-
Todorova, B, Godon, O, Conde, E, Gillis, CM, Iannascoli, B, Richard-Le Goff, O, Fiole, D, Roumenina, LT, Leusen, JHW, Murphy, AJ, Macdonald, LE, Reber, LL, Jönsson, F, Bruhns, P, Todorova, B, Godon, O, Conde, E, Gillis, CM, Iannascoli, B, Richard-Le Goff, O, Fiole, D, Roumenina, LT, Leusen, JHW, Murphy, AJ, Macdonald, LE, Reber, LL, Jönsson, F, and Bruhns, P
- Abstract
Mouse models of active systemic anaphylaxis rely predominantly on IgG Abs forming IgG-allergen immune complexes that induce IgG receptor-expressing neutrophils and monocytes/macrophages to release potent mediators, leading to systemic effects. Whether anaphylaxis initiates locally or systemically remains unknown. In this study, we aimed at identifying the anatomical location of IgG-allergen immune complexes during anaphylaxis. Active systemic anaphylaxis was induced following immunization with BSA and i.v. challenge with fluorescently labeled BSA. Ag retention across different organs was examined using whole-body fluorescence imaging, comparing immunized and naive animals. Various mouse models and in vivo deletion strategies were employed to determine the contribution of IgG receptors, complement component C1q, myeloid cell types, and anaphylaxis mediators. We found that following challenge, Ag diffused systemically, but specifically accumulated in the lungs of mice sensitized to that Ag, where it formed large Ab-dependent aggregates in the vasculature. Ag retention in the lungs did not rely on IgG receptors, C1q, neutrophils, or macrophages. IgG2a-mediated, but neither IgG1- nor IgG2b-mediated, passive systemic anaphylaxis led to Ag retention in the lung. Neutrophils and monocytes significantly accumulated in the lungs after challenge and captured high amounts of Ag, which led to downmodulation of surface IgG receptors and triggered their activation. Thus, within minutes of systemic injection in sensitized mice, Ag formed aggregates in the lung and liver vasculature, but accumulated specifically and dose-dependently in the lung. Neutrophils and monocytes recruited to the lung captured Ag and became activated. However, Ag aggregation in the lung vasculature was not necessary for anaphylaxis induction.
- Published
- 2022
4. Anti-HBV DNA vaccination does not prevent relapse after discontinuation of analogues in the treatment of chronic hepatitis B: a randomised trial—ANRS HB02 VAC-ADN
- Author
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Fontaine, H, Kahi, S, Chazallon, C, Bourgine, M, Varaut, A, Buffet, C, Godon, O, Meritet, J F, Saïdi, Y, Michel, M L, Scott-Algara, D, Aboulker, J P, and Pol, S
- Published
- 2015
- Full Text
- View/download PDF
5. T-cell responses to hepatitis B splice-generated protein of hepatitis B virus and inflammatory cytokines/chemokines in chronic hepatitis B patients. ANRS study: HB EP 02 HBSP-FIBRO
- Author
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Bayard, F., Godon, O., Nalpas, B., Costentin, C., Zhu, R., Soussan, P., Vallet-Pichard, A., Fontaine, H., Mallet, V., Pol, S., and Michel, M.-L.
- Published
- 2012
- Full Text
- View/download PDF
6. Platelets expressing IgG receptor FcγRIIA/CD32A determine the severity of experimental anaphylaxis
- Author
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Beutier, H, Hechler, B, Godon, O, Wang, Y, Gillis, CM, de Chaisemartin, L, Gouel-Chéron, A, Magnenat, S, Macdonald, LE, Murphy, AJ, NASA study group, Chollet-Martin, S, Longrois, D, Gachet, C, Bruhns, P, and Jönsson, F
- Subjects
Blood Platelets ,Mice, Knockout ,Thrombocytosis ,Serotonin ,Mice, 129 Strain ,Platelet Count ,Receptors, IgG ,Mice, Transgenic ,Platelet Activation ,Severity of Illness Index ,Mice, Inbred C57BL ,Disease Models, Animal ,Immunoglobulin G ,Animals ,Humans ,Anaphylaxis - Abstract
Platelets are key regulators of vascular integrity; however, their role in anaphylaxis, a life-threatening systemic allergic reaction characterized by the loss of vascular integrity and vascular leakage, remains unknown. Anaphylaxis is a consequence of inappropriate cellular responses triggered by antibodies to generally harmless antigens, resulting in a massive mediator release and rapidly occurring organ dysfunction. Human platelets express receptors for immunoglobulin G (IgG) antibodies and can release potent mediators, yet their contribution to anaphylaxis has not been previously addressed in mouse models, probably because mice do not express IgG receptors on platelets. We investigated the contribution of platelets to IgG-dependent anaphylaxis in human IgG receptor-expressing mouse models and a cohort of patients suffering from drug-induced anaphylaxis. Platelet counts dropped immediately and markedly upon anaphylaxis induction only when they expressed the human IgG receptor FcγRIIA/CD32A. Platelet depletion attenuated anaphylaxis, whereas thrombocythemia substantially worsened its severity. FcγRIIA-expressing platelets were directly activated by IgG immune complexes in vivo and were sufficient to restore susceptibility to anaphylaxis in resistant mice. Serotonin released by activated platelets contributed to anaphylaxis severity. Data from a cohort of patients suffering from drug-induced anaphylaxis indicated that platelet activation was associated with anaphylaxis severity and was accompanied by a reduction in circulating platelet numbers. Our findings identify platelets as critical players in IgG-dependent anaphylaxis and provide a rationale for the design of platelet-targeting strategies to attenuate the severity of anaphylactic reactions.
- Published
- 2018
7. TG1050, a novel immunotherapeutic for the treatment of chronic hepatitis B, can control HBsAg and provoke HBsAg seroconversion in HBV-persistent mouse models
- Author
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Lélu, K., primary, Evlachev, A., additional, Kratzer, R., additional, Godon, O., additional, Mancini-Bourgine, M., additional, Dion, S., additional, Schmitt, D., additional, Dubois, C., additional, Meritet, J.F., additional, Schlesinger, Y., additional, Marchand, J.B., additional, Geist, M., additional, Brandely, R., additional, Findeli, A., additional, Zhu, R., additional, Menguy, T., additional, Silvestre, N., additional, Michel, M.L., additional, Inchauspé, G., additional, and Martin, P., additional
- Published
- 2015
- Full Text
- View/download PDF
8. O031 : TG1050, a novel immunotherapeutic to treat chronic hepatitis B, can control HBsAg and provoke HBsAg seroconversion in HBV-persistent mouse models
- Author
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Lélu, K., primary, Evlachev, A., additional, Kratzer, R., additional, Dion, S., additional, Mancini-Bourgine, M., additional, Godon, O., additional, Schmitt, D., additional, Dubois, C., additional, Mériter, J.-F., additional, Schlesinger, Y., additional, Marchand, J.-B., additional, Geist, M., additional, Brandely, R., additional, Findeli, A., additional, Menguy, T., additional, Silvestre, N., additional, Michel, M.-L., additional, Inchauspe, G., additional, and Martin, P., additional
- Published
- 2015
- Full Text
- View/download PDF
9. Immunological and Antiviral Responses After Therapeutic DNA Immunization in Chronic Hepatitis B Patients Efficiently Treated by Analogues
- Author
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Godon, O, primary, Fontaine, H, additional, Kahi, S, additional, Meritet, JF, additional, Scott-Algara, D, additional, Pol, S, additional, Michel, ML, additional, and Bourgine, M, additional
- Published
- 2014
- Full Text
- View/download PDF
10. Anti-HBV DNA vaccination does not prevent relapse after discontinuation of analogues in the treatment of chronic hepatitis B: a randomised trial—ANRS HB02 VAC-ADN
- Author
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Fontaine, H, primary, Kahi, S, additional, Chazallon, C, additional, Bourgine, M, additional, Varaut, A, additional, Buffet, C, additional, Godon, O, additional, Meritet, J F, additional, Saïdi, Y, additional, Michel, M L, additional, Scott-Algara, D, additional, Aboulker, J P, additional, and Pol, S, additional
- Published
- 2014
- Full Text
- View/download PDF
11. Seroprevalence of peste des petits ruminants among domestic small and large ruminants in the semi-arid region of north-eastern Nigeria
- Author
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El-Yuguda, Abdul-Dahiru, primary, Baba, Saka Saheed, additional, Ambali, Abdul Ganiyu, additional, and Egwu, Godon O, additional
- Published
- 2013
- Full Text
- View/download PDF
12. 130 A MULTIVALENT ADENOVIRUS-BASED IMMUNOTHERAPEUTIC FOR TREATMENT OF CHRONIC HEPATITIS B INDUCES BROAD, ROBUST AND POLYFUNCTIONAL T CELLS IN NAIVE AND HBV TOLERANT MICE
- Author
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Martin, P., primary, Dubois, C., additional, Jacquier, E., additional, Evlachev, A., additional, Boukhebza, H., additional, Dion, S., additional, Mancini-Bourgine, M., additional, Godon, O., additional, Findeli, A., additional, Schlesinger, Y., additional, Brandely, R., additional, Marchand, J.-B., additional, Menguy, T., additional, Silvestre, N., additional, Schirmbeck, R., additional, Michel, M.-L., additional, and Inchauspé, G., additional
- Published
- 2013
- Full Text
- View/download PDF
13. 126 ESTABLISHMENT OF PERSISTENT HEPATITIS B VIRUS INFECTION IN MICE EXPRESSING HLA-A2 AND HLA-DR1 FOR EVALUATING IMMUNO-THERAPEUTICS FOR CHRONIC HEPATITIS B
- Author
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Dion, S., primary, Bourgine, M., additional, Godon, O., additional, Levillayer, F., additional, and Michel, M.-L., additional
- Published
- 2013
- Full Text
- View/download PDF
14. 1367 RELAPSE AFTER ANALOGUES TREATMENT DISCONTINUATION IS NOT PREVENTED BY DNA VACCINATION IN CHRONIC HEPATITIS B (ANRS HB 02 VAC-ADN)
- Author
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Fontaine, H., primary, Chazallon, C., additional, Mancini-Bourgine, M., additional, Lebray, P., additional, Buffet, C., additional, Kahi, S., additional, Godon, O., additional, Meritet, J.-F., additional, Saldi, Y., additional, Michel, M.-L., additional, Scott-Algara, D., additional, Aboulker, J.-P., additional, and Pol, S., additional
- Published
- 2011
- Full Text
- View/download PDF
15. Rocuronium-specific antibodies drive perioperative anaphylaxis but can also function as reversal agents in preclinical models.
- Author
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Dejoux A, Zhu Q, Ganneau C, Goff OR, Godon O, Lemaitre J, Relouzat F, Huetz F, Sokal A, Vandenberghe A, Pecalvel C, Hunault L, Derenne T, Gillis CM, Iannascoli B, Wang Y, Rose T, Mertens C, Nicaise-Roland P, England P, Mahévas M, de Chaisemartin L, Le Grand R, Letscher H, Saul F, Pissis C, Haouz A, Reber LL, Chappert P, Jönsson F, Ebo DG, Millot GA, Bay S, Chollet-Martin S, Gouel-Chéron A, and Bruhns P
- Subjects
- Animals, Humans, Antibodies, Mice, Perioperative Period, Androstanols adverse effects, Sugammadex adverse effects, Immunoglobulin E immunology, Antibody Specificity, Female, Disease Models, Animal, Male, Rocuronium adverse effects, Anaphylaxis immunology
- Abstract
Neuromuscular blocking agents (NMBAs) relax skeletal muscles to facilitate surgeries and ease intubation but can lead to adverse reactions, including complications because of postoperative residual neuromuscular blockade (rNMB) and, in rare cases, anaphylaxis. Both adverse reactions vary between types of NMBAs, with rocuronium, a widely used nondepolarizing NMBA, inducing one of the longest rNMB durations and highest anaphylaxis incidences. rNMB induced by rocuronium can be reversed by the synthetic γ-cyclodextrin sugammadex. However, in rare cases, sugammadex can provoke anaphylaxis. Thus, additional therapeutic options are needed. Rocuronium-induced anaphylaxis is proposed to rely on preexisting rocuronium-binding antibodies. To understand the pathogenesis of rocuronium-induced anaphylaxis and to identify potential therapeutics, we investigated the memory B cell antibody repertoire of patients with suspected hypersensitivity to rocuronium. We identified polyclonal antibody repertoires with a high diversity among V(D)J genes without evidence of clonal groups. When recombinantly expressed, these antibodies demonstrated specificity and low affinity for rocuronium without cross-reactivity for other NMBAs. Moreover, when these antibodies were expressed as human immunoglobulin E (IgE), they triggered human mast cell activation and passive systemic anaphylaxis in transgenic mice, although their affinities were insufficient to serve as reversal agents. Rocuronium-specific, high-affinity antibodies were thus isolated from rocuronium-immunized mice. The highest-affinity antibody was able to reverse rocuronium-induced neuromuscular blockade in nonhuman primates with kinetics comparable to that of sugammadex. Together, these data support the hypothesis that antibodies cause anaphylactic reactions to rocuronium and pave the way for improved diagnostics and neuromuscular blockade reversal agents.
- Published
- 2024
- Full Text
- View/download PDF
16. A monoclonal antibody collection for C. difficile typing ?
- Author
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Hunault L, England P, Barbut F, Iannascoli B, Godon O, Déjardin F, Thomas C, Dupuy B, Guo C, Macdonald L, Gorochov G, Sterlin D, and Bruhns P
- Abstract
Clostridioides difficile is the leading cause of antibiotic-associated diarrhea and pseudomembranous colitis in adults. Various C. difficile strains circulate currently, associated with different outcomes and antibiotic resistance profiles. However, most studies still focus on the reference strain 630 that does not circulate anymore, partly due to the lack of immunological tools to study current clinically important C. difficile PCR ribotypes. The goal of this study was to generate monoclonal antibodies recognizing various epidemic ribotypes of C. difficile. To do so, we immunized mice expressing human variable antibody genes with the Low Molecular Weight (LMW) subunit of the surface layer protein SlpA from various C. difficile strains. Monoclonal antibodies purified from hybridomas bound LMW with high-affinity and whole bacteria from current C. difficile ribotypes with different cross-specificities. This first collection of anti-C. difficile mAbs represent valuable tools for basic and clinical research., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
17. Isolation methods determine human neutrophil responses after stimulation.
- Author
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Krémer V, Godon O, Bruhns P, Jönsson F, and de Chaisemartin L
- Subjects
- Humans, Reactive Oxygen Species, Cell Death, Centrifugation, Density Gradient, Neutrophils physiology, Extracellular Traps
- Abstract
Studying neutrophils is challenging due to their limited lifespan, inability to proliferate, and resistance to genetic manipulation. Neutrophils can sense various cues, making them susceptible to activation by blood collection techniques, storage conditions, RBC lysis, and the isolation procedure itself. Here we assessed the impact of the five most used methods for neutrophil isolation on neutrophil yield, purity, activation status and responsiveness. We monitored surface markers, reactive oxygen species production, and DNA release as a surrogate for neutrophil extracellular trap (NET) formation. Our results show that neutrophils isolated by negative immunomagnetic selection and density gradient methods, without RBC lysis, resembled untouched neutrophils in whole blood. They were also less activated and more responsive to milder stimuli in functional assays compared to neutrophils obtained using density gradients requiring RBC lysis. Our study highlights the importance of selecting the appropriate method for studying neutrophils, and underscores the need for standardizing isolation protocols to facilitate neutrophil subset characterization and inter-study comparisons., Competing Interests: Unrelated to the submitted work, PB received consulting fees from Regeneron Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Krémer, Godon, Bruhns, Jönsson and de Chaisemartin.)
- Published
- 2023
- Full Text
- View/download PDF
18. Conditional neutrophil depletion challenges their contribution to mouse models of anaphylaxis.
- Author
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Stackowicz J, Gillis CM, Godon O, Iannascoli B, Conde E, Leveque E, Worrall WPM, Galli SJ, Bruhns P, Reber LL, and Jönsson F
- Subjects
- Mice, Animals, Neutrophils, Receptors, IgG, Immunoglobulin G, Disease Models, Animal, Anaphylaxis etiology
- Published
- 2023
- Full Text
- View/download PDF
19. A vaccine targeting human IL-4 and IL-13 protects against asthma in humanized mice.
- Author
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Lamanna E, Conde E, Mougel A, Bonnefoy J, Colaone F, Godon O, Hamdi S, Kamphuis JBJ, Drouet B, Serra V, Bruhns P, and Reber LL
- Subjects
- Humans, Mice, Animals, Interleukin-13, Interleukin-4, Mice, Inbred BALB C, Asthma prevention & control, Vaccines
- Published
- 2023
- Full Text
- View/download PDF
20. IgG Subclass-Dependent Pulmonary Antigen Retention during Acute IgG-Dependent Systemic Anaphylaxis in Mice.
- Author
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Todorova B, Godon O, Conde E, Gillis CM, Iannascoli B, Richard-Le Goff O, Fiole D, Roumenina LT, Leusen JHW, Murphy AJ, Macdonald LE, Reber LL, Jönsson F, and Bruhns P
- Subjects
- Allergens, Animals, Antigen-Antibody Complex, Complement C1q, Disease Models, Animal, Immunoglobulin G, Lung, Mice, Mice, Inbred C57BL, Receptors, Complement, Receptors, IgG, Anaphylaxis
- Abstract
Mouse models of active systemic anaphylaxis rely predominantly on IgG Abs forming IgG-allergen immune complexes that induce IgG receptor-expressing neutrophils and monocytes/macrophages to release potent mediators, leading to systemic effects. Whether anaphylaxis initiates locally or systemically remains unknown. In this study, we aimed at identifying the anatomical location of IgG-allergen immune complexes during anaphylaxis. Active systemic anaphylaxis was induced following immunization with BSA and i.v. challenge with fluorescently labeled BSA. Ag retention across different organs was examined using whole-body fluorescence imaging, comparing immunized and naive animals. Various mouse models and in vivo deletion strategies were employed to determine the contribution of IgG receptors, complement component C1q, myeloid cell types, and anaphylaxis mediators. We found that following challenge, Ag diffused systemically, but specifically accumulated in the lungs of mice sensitized to that Ag, where it formed large Ab-dependent aggregates in the vasculature. Ag retention in the lungs did not rely on IgG receptors, C1q, neutrophils, or macrophages. IgG2a-mediated, but neither IgG1- nor IgG2b-mediated, passive systemic anaphylaxis led to Ag retention in the lung. Neutrophils and monocytes significantly accumulated in the lungs after challenge and captured high amounts of Ag, which led to downmodulation of surface IgG receptors and triggered their activation. Thus, within minutes of systemic injection in sensitized mice, Ag formed aggregates in the lung and liver vasculature, but accumulated specifically and dose-dependently in the lung. Neutrophils and monocytes recruited to the lung captured Ag and became activated. However, Ag aggregation in the lung vasculature was not necessary for anaphylaxis induction., (Copyright © 2022 by The American Association of Immunologists, Inc.)
- Published
- 2022
- Full Text
- View/download PDF
21. Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome.
- Author
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Stackowicz J, Gaudenzio N, Serhan N, Conde E, Godon O, Marichal T, Starkl P, Balbino B, Roers A, Bruhns P, Jönsson F, Moguelet P, Georgin-Lavialle S, Broderick L, Hoffman HM, Galli SJ, and Reber LL
- Subjects
- Adolescent, Adult, Aged, 80 and over, Animals, Female, Gain of Function Mutation, Humans, Interleukin-1beta metabolism, Male, Mast Cells pathology, Mice, Transgenic, Middle Aged, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Cryopyrin-Associated Periodic Syndromes genetics, Cryopyrin-Associated Periodic Syndromes pathology, NLR Family, Pyrin Domain-Containing 3 Protein genetics, Neutrophils pathology, Neutrophils physiology
- Abstract
Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as "cryopyrin-associated periodic syndromes" (CAPS). Treatment of CAPS patients with IL-1-targeted therapies is effective, confirming a central pathogenic role for IL-1β. However, the specific myeloid cell population(s) exhibiting inflammasome activity and sustained IL-1β production in CAPS remains elusive. Previous reports suggested an important role for mast cells (MCs) in this process. Here, we report that, in mice, gain-of-function mutations in Nlrp3 restricted to neutrophils, and to a lesser extent macrophages/dendritic cells, but not MCs, are sufficient to trigger severe CAPS. Furthermore, in patients with clinically established CAPS, we show that skin-infiltrating neutrophils represent a substantial biological source of IL-1β. Together, our data indicate that neutrophils, rather than MCs, can represent the main cellular drivers of CAPS pathology., Competing Interests: Disclosures: L. Broderick reports "other" from Novartis, Inc. outside the submitted work. H.M. Hoffman reports "other" from Novartis, IFM, AB2Bio, Takeda, and Zomagen; and grants from Jecure outside the submitted work. No other disclosures were reported., (© 2021 Stackowicz et al.)
- Published
- 2021
- Full Text
- View/download PDF
22. The role of IgG subclasses and platelets in experimental anaphylaxis.
- Author
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Godon O, Hechler B, and Jönsson F
- Subjects
- Animals, Humans, Mice, Models, Animal, Nerve Tissue Proteins metabolism, Receptors, G-Protein-Coupled metabolism, Receptors, IgG metabolism, Receptors, Neuropeptide metabolism, Anaphylaxis immunology, Blood Platelets immunology, Immunoglobulin G metabolism, Immunoglobulin Isotypes metabolism
- Published
- 2021
- Full Text
- View/download PDF
23. The anti-IgE mAb omalizumab induces adverse reactions by engaging Fcγ receptors.
- Author
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Balbino B, Herviou P, Godon O, Stackowicz J, Goff OR, Iannascoli B, Sterlin D, Brûlé S, Millot GA, Harris FM, Voronina VA, Nadeau KC, Macdonald LE, Murphy AJ, Bruhns P, and Reber LL
- Subjects
- Anaphylaxis chemically induced, Anaphylaxis genetics, Anaphylaxis pathology, Animals, Asthma drug therapy, Asthma immunology, Asthma pathology, Drug Eruptions genetics, Drug Eruptions pathology, Mice, Mice, Knockout, Omalizumab genetics, Omalizumab pharmacology, Receptors, IgG genetics, Anaphylaxis immunology, Drug Eruptions immunology, Mutation, Omalizumab adverse effects, Receptors, IgG immunology
- Abstract
Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of omalizumab is associated with reported side effects ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune complexes formed between omalizumab and IgE can induce both skin inflammation and anaphylaxis through engagement of IgG receptors (FcγRs) in FcγR-humanized mice. We further developed an Fc-engineered mutant version of omalizumab, and demonstrated that this mAb is equally potent as omalizumab at blocking IgE-mediated allergic reactions, but does not induce FcγR-dependent adverse reactions. Overall, our data indicate that omalizumab can induce skin inflammation and anaphylaxis by engaging FcγRs, and demonstrate that Fc-engineered versions of the mAb could be used to reduce such adverse reactions.
- Published
- 2020
- Full Text
- View/download PDF
24. Publisher Correction: An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.
- Author
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Lee CH, Kang TH, Godon O, Watanabe M, Delidakis G, Gillis CM, Sterlin D, Hardy D, Cogné M, Macdonald LE, Murphy AJ, Tu N, Lee J, McDaniel JR, Makowski E, Tessier PM, Meyer AS, Bruhns P, and Georgiou G
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2019
- Full Text
- View/download PDF
25. An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.
- Author
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Lee CH, Kang TH, Godon O, Watanabe M, Delidakis G, Gillis CM, Sterlin D, Hardy D, Cogné M, Macdonald LE, Murphy AJ, Tu N, Lee J, McDaniel JR, Makowski E, Tessier PM, Meyer AS, Bruhns P, and Georgiou G
- Subjects
- Animals, Genetic Engineering, Half-Life, Histocompatibility Antigens Class I immunology, Humans, Hydrogen-Ion Concentration, Immunoglobulin G chemistry, Immunoglobulin G pharmacology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Pharmacokinetics, Protein Domains, Receptors, Fc immunology, Recombinant Proteins, Histocompatibility Antigens Class I chemistry, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I pharmacology, Protein Engineering, Receptors, Fc chemistry, Receptors, Fc genetics
- Abstract
The pharmacokinetic properties of antibodies are largely dictated by the pH-dependent binding of the IgG fragment crystallizable (Fc) domain to the human neonatal Fc receptor (hFcRn). Engineered Fc domains that confer a longer circulation half-life by virtue of more favorable pH-dependent binding to hFcRn are of great therapeutic interest. Here we developed a pH Toggle switch Fc variant containing the L309D/Q311H/N434S (DHS) substitutions, which exhibits markedly improved pharmacokinetics relative to both native IgG1 and widely used half-life extension variants, both in conventional hFcRn transgenic mice and in new knock-in mouse strains. engineered specifically to recapitulate all the key processes relevant to human antibody persistence in circulation, namely: (i) physiological expression of hFcRn, (ii) the impact of hFcγRs on antibody clearance and (iii) the role of competing endogenous IgG. DHS-IgG retains intact effector functions, which are important for the clearance of target pathogenic cells and also has favorable developability.
- Published
- 2019
- Full Text
- View/download PDF
26. Evidence that neutrophils do not promote Echis carinatus venom-induced tissue destruction.
- Author
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Stackowicz J, Balbino B, Todorova B, Godon O, Iannascoli B, Jönsson F, Bruhns P, and Reber LL
- Subjects
- Animals, Humans, Leukocyte Reduction Procedures, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutropenia pathology, Neutropenia physiopathology, Neutrophils pathology, Neutrophils physiology, Snake Bites etiology, Neutrophils drug effects, Snake Bites pathology, Snake Bites physiopathology, Viper Venoms toxicity, Viperidae
- Published
- 2018
- Full Text
- View/download PDF
27. Platelets expressing IgG receptor FcγRIIA/CD32A determine the severity of experimental anaphylaxis.
- Author
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Beutier H, Hechler B, Godon O, Wang Y, Gillis CM, de Chaisemartin L, Gouel-Chéron A, Magnenat S, Macdonald LE, Murphy AJ, Chollet-Martin S, Longrois D, Gachet C, Bruhns P, and Jönsson F
- Subjects
- Anaphylaxis blood, Anaphylaxis pathology, Animals, Blood Platelets metabolism, Humans, Immunoglobulin G immunology, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Platelet Activation, Platelet Count, Receptors, IgG genetics, Receptors, IgG metabolism, Serotonin blood, Serotonin immunology, Severity of Illness Index, Thrombocytosis blood, Thrombocytosis immunology, Anaphylaxis immunology, Blood Platelets immunology, Disease Models, Animal, Receptors, IgG immunology
- Abstract
Platelets are key regulators of vascular integrity; however, their role in anaphylaxis, a life-threatening systemic allergic reaction characterized by the loss of vascular integrity and vascular leakage, remains unknown. Anaphylaxis is a consequence of inappropriate cellular responses triggered by antibodies to generally harmless antigens, resulting in a massive mediator release and rapidly occurring organ dysfunction. Human platelets express receptors for immunoglobulin G (IgG) antibodies and can release potent mediators, yet their contribution to anaphylaxis has not been previously addressed in mouse models, probably because mice do not express IgG receptors on platelets. We investigated the contribution of platelets to IgG-dependent anaphylaxis in human IgG receptor-expressing mouse models and a cohort of patients suffering from drug-induced anaphylaxis. Platelet counts dropped immediately and markedly upon anaphylaxis induction only when they expressed the human IgG receptor FcγRIIA/CD32A. Platelet depletion attenuated anaphylaxis, whereas thrombocythemia substantially worsened its severity. FcγRIIA-expressing platelets were directly activated by IgG immune complexes in vivo and were sufficient to restore susceptibility to anaphylaxis in resistant mice. Serotonin released by activated platelets contributed to anaphylaxis severity. Data from a cohort of patients suffering from drug-induced anaphylaxis indicated that platelet activation was associated with anaphylaxis severity and was accompanied by a reduction in circulating platelet numbers. Our findings identify platelets as critical players in IgG-dependent anaphylaxis and provide a rationale for the design of platelet-targeting strategies to attenuate the severity of anaphylactic reactions., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
- Full Text
- View/download PDF
28. Innate Immune Basis for Rift Valley Fever Susceptibility in Mouse Models.
- Author
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Lathan R, Simon-Chazottes D, Jouvion G, Godon O, Malissen M, Flamand M, Bruhns P, and Panthier JJ
- Subjects
- Animals, Antigens, Viral immunology, Disease Models, Animal, Disease Susceptibility, Hepatitis, Viral, Animal genetics, Hepatitis, Viral, Animal immunology, Hepatitis, Viral, Animal virology, Leukocyte Count, Liver immunology, Male, Mice, Mice, Inbred BALB C, Neutrophils immunology, Neutrophils metabolism, Rift Valley Fever genetics, Rift Valley Fever pathology, Spleen immunology, Immunity, Innate, Rift Valley Fever immunology, Rift Valley Fever virology, Rift Valley fever virus immunology
- Abstract
Rift Valley fever virus (RVFV) leads to varied clinical manifestations in animals and in humans that range from moderate fever to fatal illness, suggesting that host immune responses are important determinants of the disease severity. We investigated the immune basis for the extreme susceptibility of MBT/Pas mice that die with mild to acute hepatitis by day 3 post-infection compared to more resistant BALB/cByJ mice that survive up to a week longer. Lower levels of neutrophils observed in the bone marrow and blood of infected MBT/Pas mice are unlikely to be causative of increased RVFV susceptibility as constitutive neutropenia in specific mutant mice did not change survival outcome. However, whereas MBT/Pas mice mounted an earlier inflammatory response accompanied by higher amounts of interferon (IFN)-α in the serum compared to BALB/cByJ mice, they failed to prevent high viral antigen load. Several immunological alterations were uncovered in infected MBT/Pas mice compared to BALB/cByJ mice, including low levels of leukocytes that expressed type I IFN receptor subunit 1 (IFNAR1) in the blood, spleen and liver, delayed leukocyte activation and decreased percentage of IFN-γ-producing leukocytes in the blood. These observations are consistent with the complex mode of inheritance of RVFV susceptibility in genetic studies.
- Published
- 2017
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29. IgG subclasses determine pathways of anaphylaxis in mice.
- Author
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Beutier H, Gillis CM, Iannascoli B, Godon O, England P, Sibilano R, Reber LL, Galli SJ, Cragg MS, Van Rooijen N, Mancardi DA, Bruhns P, and Jönsson F
- Subjects
- Animals, Antibodies, Monoclonal immunology, Female, Haptens immunology, Histamine immunology, Immunoglobulin E immunology, Mice, Inbred C57BL, Mice, Transgenic, Myeloid Cells immunology, Receptors, IgG genetics, Receptors, IgG immunology, Serum Albumin, Bovine immunology, Anaphylaxis immunology, Immunoglobulin G immunology, Protein Subunits immunology
- Abstract
Background: Animal models have demonstrated that allergen-specific IgG confers sensitivity to systemic anaphylaxis that relies on IgG Fc receptors (FcγRs). Mouse IgG
2a and IgG2b bind activating FcγRI, FcγRIII, and FcγRIV and inhibitory FcγRIIB; mouse IgG1 binds only FcγRIII and FcγRIIB. Although these interactions are of strikingly different affinities, these 3 IgG subclasses have been shown to enable induction of systemic anaphylaxis., Objective: We sought to determine which pathways control the induction of IgG1 -, IgG2a -, and IgG2b -dependent passive systemic anaphylaxis., Methods: Mice were sensitized with IgG1 , IgG2a , or IgG2b anti-trinitrophenyl mAbs and challenged with trinitrophenyl-BSA intravenously to induce systemic anaphylaxis that was monitored by using rectal temperature. Anaphylaxis was evaluated in mice deficient for FcγRs injected with mediator antagonists or in which basophils, monocytes/macrophages, or neutrophils had been depleted. FcγR expression was evaluated on these cells before and after anaphylaxis., Results: Activating FcγRIII is the receptor primarily responsible for all 3 models of anaphylaxis, and subsequent downregulation of this receptor was observed. These models differentially relied on histamine release and the contribution of mast cells, basophils, macrophages, and neutrophils. Strikingly, basophil contribution and histamine predominance in mice with IgG1 - and IgG2b -induced anaphylaxis correlated with the ability of inhibitory FcγRIIB to negatively regulate these models of anaphylaxis., Conclusion: We propose that the differential expression of inhibitory FcγRIIB on myeloid cells and its differential binding of IgG subclasses controls the contributions of mast cells, basophils, neutrophils, and macrophages to IgG subclass-dependent anaphylaxis. Collectively, our results unravel novel complexities in the involvement and regulation of cell populations in IgG-dependent reactions in vivo., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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30. TG1050, an immunotherapeutic to treat chronic hepatitis B, induces robust T cells and exerts an antiviral effect in HBV-persistent mice.
- Author
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Martin P, Dubois C, Jacquier E, Dion S, Mancini-Bourgine M, Godon O, Kratzer R, Lelu-Santolaria K, Evlachev A, Meritet JF, Schlesinger Y, Villeval D, Strub JM, Van Dorsselaer A, Marchand JB, Geist M, Brandely R, Findeli A, Boukhebza H, Menguy T, Silvestre N, Michel ML, and Inchauspé G
- Subjects
- Adenoviridae classification, Alanine Transaminase blood, Animals, DNA-Directed DNA Polymerase genetics, DNA-Directed DNA Polymerase immunology, Disease Models, Animal, Gene Products, env genetics, Gene Products, env immunology, Genetic Vectors, HLA-A2 Antigen genetics, Hepatitis B Core Antigens genetics, Hepatitis B Core Antigens immunology, Hepatitis B Surface Antigens blood, Hepatitis B, Chronic blood, Interferon-gamma blood, Lymphocyte Count, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Time Factors, Tumor Necrosis Factor-alpha blood, Viral Fusion Proteins genetics, Viral Load, Adenoviridae metabolism, CD8-Positive T-Lymphocytes metabolism, DNA, Viral blood, Hepatitis B virus immunology, Hepatitis B, Chronic therapy, Immunotherapy methods, Viral Fusion Proteins immunology
- Abstract
Objective: To assess a new adenovirus-based immunotherapy as a novel treatment approach to chronic hepatitis B (CHB)., Methods: TG1050 is a non-replicative adenovirus serotype 5 encoding a unique large fusion protein composed of a truncated HBV Core, a modified HBV Polymerase and two HBV Envelope domains. We used a recently described HBV-persistent mouse model based on a recombinant adenovirus-associated virus encoding an over length genome of HBV that induces the chronic production of HBsAg, HBeAg and infectious HBV particles to assess the ability of TG1050 to induce functional T cells in face of a chronic status., Results: In in vitro studies, TG1050 was shown to express the expected large polyprotein together with a dominant, smaller by-product. Following a single administration in mice, TG1050 induced robust, multispecific and long-lasting HBV-specific T cells detectable up to 1 year post-injection. These cells target all three encoded immunogens and display bifunctionality (i.e., capacity to produce both interferon γ and tumour necrosis factor α as well as cytolytic functions). In addition, control of circulating levels of HBV DNA and HBsAg was observed while alanine aminotransferase levels remain in the normal range., Conclusions: Injection of TG1050 induced both splenic and intrahepatic functional T cells producing cytokines and displaying cytolytic activity in HBV-naïve and HBV-persistent mouse models together with significant reduction of circulating viral parameters. These results warrant clinical evaluation of TG1050 in the treatment of CHB., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
- Published
- 2015
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31. Recognition of core-derived epitopes from a novel HBV-targeted immunotherapeutic by T-cells from patients infected by different viral genotypes.
- Author
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Godon O, Evlachev A, Bourgine M, Meritet JF, Martin P, Inchauspe G, and Michel ML
- Subjects
- Adenoviridae genetics, Cross Reactions, Drug Carriers, Epitopes genetics, Genotype, Hepatitis B Core Antigens genetics, Hepatitis B Vaccines genetics, Hepatitis B virus classification, Hepatitis B virus genetics, Humans, Recombinant Fusion Proteins genetics, Vaccines, Synthetic genetics, Vaccines, Synthetic immunology, Epitopes immunology, Hepatitis B Core Antigens immunology, Hepatitis B Vaccines immunology, Hepatitis B virus immunology, Hepatitis B, Chronic therapy, Recombinant Fusion Proteins immunology, T-Lymphocytes immunology
- Abstract
Hepatitis B virus (HBV) infects millions of people worldwide and is a leading cause of liver cirrhosis and hepatocellular carcinoma. Current therapies based on nucleos(t)ide analogs or pegylated-interferon-α lead to control of viral replication in most patients but rarely achieve cure. A potential strategy to control chronic hepatitis B is to restore or induce functional anti-HBV T-cell immune responses using HBV-specific immunotherapeutics. However, viral diversity is a challenge to the development of this class of products as HBV genotypes display a sequence diversity of up to 8%. We have developed a novel HBV-targeted immunotherapeutic, TG1050, based on a non-replicative Adenovirus vector encoding a unique and large fusion protein composed of multiple antigenic regions derived from a HBV genotype D sequence. Using peripheral blood mononuclear cells from 23 patients chronically infected by five distinct genotypes (gt A, B, C, D and E) and various sets of peptides encompassing conserved versus divergent regions of HBV core we have measured ability of TG1050 genotype D core-derived peptides to be recognized by T-cells from patients infected by various genotypes. Overall, PBMCs from 78% of genotype B or C- and 100% genotype A or E-infected patients lead to detection of HBV core-specific T-cells recognizing genotype D antigenic domains located both in conserved and variable regions. This proof-of-concept study supports the clinical development of TG1050 in large patient populations independently of infecting genotypes., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
32. Adeno-associated virus-mediated gene transfer leads to persistent hepatitis B virus replication in mice expressing HLA-A2 and HLA-DR1 molecules.
- Author
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Dion S, Bourgine M, Godon O, Levillayer F, and Michel ML
- Subjects
- Animals, DNA, Viral blood, Dependovirus genetics, Female, Gene Deletion, Genetic Vectors, H-2 Antigens genetics, HLA-A2 Antigen genetics, HLA-DR1 Antigen genetics, Hepatitis B Surface Antigens blood, Hepatitis B e Antigens blood, Hepatitis B virus physiology, Humans, Liver virology, Male, Mice, Mice, Knockout, Mice, Transgenic, Transgenes, Disease Models, Animal, HLA-A2 Antigen metabolism, HLA-DR1 Antigen metabolism, Hepatitis B virus pathogenicity, Virus Replication
- Abstract
Hepatitis B virus (HBV) persistence may be due to impaired HBV-specific immune responses being unable to eliminate efficiently or cure infected hepatocytes. The immune mechanisms that lead to HBV persistence have not been completely identified, and no appropriate animal model is available for such studies. Therefore, we established a chronic HBV infection model in a mouse strain with human leukocyte antigen A2/DR1 (HLA-A2/DR1) transgenes and an H-2 class I/class II knockout. The liver of these mice was transduced with adeno-associated virus serotype 2/8 (AAV2/8) carrying a replication-competent HBV DNA genome. In all AAV2/8-transduced mice, hepatitis B virus surface antigen, hepatitis B virus e antigen, and HBV DNA persisted in serum for at least 1 year. Viral replication intermediates and transcripts were detected in the livers of the AAV-injected mice. The hepatitis B core antigen was expressed in 60% of hepatocytes. No significant inflammation was observed in the liver. This was linked to a higher number of regulatory T cells in liver than in controls and a defect in HBV-specific functional T-cell responses. Despite the substantial tolerance resulting from expression of HBV antigens in hepatocytes, we succeeded in priming functional HBV-specific T-cell responses in peripheral tissues, which subsequently reached the liver. This AAV2/8-HBV-transduced HLA-A2/DR1 murine model recapitulates virological and immunological characteristics of chronic HBV infection, and it could be useful for the development of new treatments and immune-based therapies or therapeutic vaccines for chronic HBV infections.
- Published
- 2013
- Full Text
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33. Optimization of immune responses induced by therapeutic vaccination with cross-reactive antigens in a humanized hepatitis B surface antigen transgenic mouse model.
- Author
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Bourgine M, Dion S, Godon O, Guillen G, Michel ML, and Aguilar JC
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Disease Models, Animal, Female, Hepatitis B Core Antigens genetics, Hepatitis B Core Antigens immunology, Hepatitis B Surface Antigens genetics, Hepatitis B, Chronic immunology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Vaccines, DNA administration & dosage, Vaccines, DNA immunology, Vaccines, Subunit administration & dosage, Vaccines, Subunit immunology, Hepatitis B Surface Antigens immunology, Hepatitis B Vaccines administration & dosage, Hepatitis B Vaccines immunology, Hepatitis B, Chronic therapy, Vaccination methods
- Abstract
The absence of relevant animal models of chronic hepatitis B virus (HBV) infection has hampered the evaluation and development of therapeutic HBV vaccines. In this study, we generated a novel transgenic mouse lineage that expresses human class I and II HLA molecules and the hepatitis B surface antigen (HBsAg). HBsAg and hepatitis B core antigen (HBcAg) administered as plasmid DNAs and recombinant proteins, either alone or in combination, were evaluated as therapeutic vaccine candidates in this mouse model. Our results emphasize the importance of the route of administration in breaking HBsAg tolerance. Although immunizing the transgenic mice with DNA encoding homologous HBsAg was sufficient to induce CD8+ T-cell responses, HBsAg from a heterologous subtype was required to induce a CD4+ T-cell response. Importantly, only prime-boost immunization protocols that combined plasmid DNA injection followed by protein injection induced the production of antibodies against the HBsAg expressed by the transgenic mice., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
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