25 results on '"Gillis, Caitlin M."'
Search Results
2. An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.
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Lee, Chang-Han, Kang, Tae Hyun, Godon, Ophélie, Watanabe, Makiko, Delidakis, George, Gillis, Caitlin M, Sterlin, Delphine, Hardy, David, Cogné, Michel, Macdonald, Lynn E, Murphy, Andrew J, Tu, Naxin, Lee, Jiwon, McDaniel, Jonathan R, Makowski, Emily, Tessier, Peter M, Meyer, Aaron S, Bruhns, Pierre, and Georgiou, George
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Animals ,Mice ,Inbred BALB C ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Humans ,Mice ,Immunoglobulin G ,Receptors ,Fc ,Recombinant Proteins ,Histocompatibility Antigens Class I ,Genetic Engineering ,Protein Engineering ,Pharmacokinetics ,Hydrogen-Ion Concentration ,Half-Life ,Protein Domains ,Inbred BALB C ,Inbred C57BL ,Transgenic ,Receptors ,Fc - 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.
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- 2019
3. Rocuronium-specific antibodies drive perioperative anaphylaxis but can also function as reversal agents in preclinical models.
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Dejoux, Alice, Zhu, Qianqian, Ganneau, Christelle, Goff, Odile Richard-Le, Godon, Ophélie, Lemaitre, Julien, Relouzat, Francis, Huetz, François, Sokal, Aurélien, Vandenberghe, Alexis, Pecalvel, Cyprien, Hunault, Lise, Derenne, Thomas, Gillis, Caitlin M., Iannascoli, Bruno, Wang, Yidan, Rose, Thierry, Mertens, Christel, Nicaise-Roland, Pascale, and England, Patrick
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IMMUNOGLOBULIN E ,IMMUNOLOGIC memory ,NEUROMUSCULAR blocking agents ,NEUROMUSCULAR blockade ,MAST cells - 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. Editor's summary: Neuromuscular blocking agents (NMBAs) such as rocuronium are used during anesthesia to assist with surgeries and intubations. Although these agents are effective, they are not without risk. Patients can develop postoperative residual neuromuscular blockade, which can be treated with an NMBA reversal agent, and life-threatening anaphylaxis can occur in rare cases. Here, Dejoux et al. isolated and characterized memory B cells from three individuals who developed reactions to NMBA treatment and had serum antibodies to rocuronium. The authors found that IgE antibodies generated from these memory B cells were sufficient to induce anaphylaxis in mice treated with rocuronium, although they were too low affinity to be used as reversal agents. This led the authors to immunize mice with rocuronium to generate antibodies of higher affinity, which were able to reverse neuromuscular blockade in rocuronium-treated nonhuman primates. Together, these data explain why these three patients had a reaction and offer a therapeutic approach to reversing neuromuscular blockade. —Courtney Malo [ABSTRACT FROM AUTHOR]
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- 2024
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4. Anaphylaxis (Immediate Hypersensitivity): From Old to New Mechanisms
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Gillis, Caitlin M., Gouel-Chéron, Aurélie, Bruhns, Pierre, and Parnham, Michael J., editor
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- 2016
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5. IgG subclasses determine pathways of anaphylaxis in mice
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Beutier, Héloïse, Gillis, Caitlin M., Iannascoli, Bruno, Godon, Ophélie, England, Patrick, Sibilano, Riccardo, Reber, Laurent L., Galli, Stephen J., Cragg, Mark S., Van Rooijen, Nico, Mancardi, David A., Bruhns, Pierre, and Jönsson, Friederike
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- 2017
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6. Conditional neutrophil depletion challenges their contribution to mouse models of anaphylaxis
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Stackowicz, Julien, primary, Gillis, Caitlin M., additional, Godon, Ophélie, additional, Iannascoli, Bruno, additional, Conde, Eva, additional, Leveque, Edouard, additional, Worrall, William P. M., additional, Galli, Stephen J., additional, Bruhns, Pierre, additional, Reber, Laurent L., additional, and Jönsson, Friederike, additional
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- 2023
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7. IgG Subclass-Dependent Pulmonary Antigen Retention during Acute IgG-Dependent Systemic Anaphylaxis in Mice
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Todorova, Biliana, primary, Godon, Ophélie, additional, Conde, Eva, additional, Gillis, Caitlin M., additional, Iannascoli, Bruno, additional, Richard-Le Goff, Odile, additional, Fiole, Daniel, additional, Roumenina, Lubka T., additional, Leusen, Jeanette H. W., additional, Murphy, Andrew J., additional, Macdonald, Lynn E., additional, Reber, Laurent L., additional, Jönsson, Friederike, additional, and Bruhns, Pierre, additional
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- 2022
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8. Low end-tidal CO2 as a real-time severity marker of intra-anaesthetic acute hypersensitivity reactions
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Gouel-Chéron, A, de Chaisemartin, L, Jönsson, F, Nicaise-Roland, P, Granger, V, Sabahov, A, Guinnepain, M-T, Chollet-Martin, S, Bruhns, P, Neukirch, C, Longrois, D, Montravers, Philippe, Gillis, Caitlin M, Mancardi, David A, Aubier, Michel, Sauvan, Caroline, Fischler, Marc, Bresson, Julie, Paugam-Burtz, Catherine, Necib, Skander, Mebazaa, Alexandre, Le Dorze, Matthieu, Jacob, Laurent, Chahine, Carole, Keita-Meyer, Hawa, Faitot, Valentina, Langeron, Olivier, Roche, Sabrine, Cholley, Bernard, and Mantz, Jean
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- 2017
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9. IgG Subclass-Dependent Pulmonary Antigen Retention during Acute IgG-Dependent Systemic Anaphylaxis in Mice
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CTI Leusen, UMC Utrecht Holding, Cancer, Infection & Immunity, Todorova, Biliana, Godon, Ophélie, Conde, Eva, Gillis, Caitlin M., Iannascoli, Bruno, Richard-Le Goff, Odile, Fiole, Daniel, Roumenina, Lubka T., Leusen, Jeanette H.W., Murphy, Andrew J., Macdonald, Lynn E., Reber, Laurent L., Jönsson, Friederike, Bruhns, Pierre, CTI Leusen, UMC Utrecht Holding, Cancer, Infection & Immunity, Todorova, Biliana, Godon, Ophélie, Conde, Eva, Gillis, Caitlin M., Iannascoli, Bruno, Richard-Le Goff, Odile, Fiole, Daniel, Roumenina, Lubka T., Leusen, Jeanette H.W., Murphy, Andrew J., Macdonald, Lynn E., Reber, Laurent L., Jönsson, Friederike, and Bruhns, Pierre
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- 2022
10. Anaphylaxis (Immediate Hypersensitivity): From Old to New Mechanisms
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Gillis, Caitlin M., primary, Gouel-Chéron, Aurélie, additional, and Bruhns, Pierre, additional
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- 2015
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11. Necroptosis Signaling Promotes Inflammation, Airway Remodeling, and Emphysema in Chronic Obstructive Pulmonary Disease
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Lu, Zhe, primary, Van Eeckhoutte, Hannelore P., additional, Liu, Gang, additional, Nair, Prema M., additional, Jones, Bernadette, additional, Gillis, Caitlin M., additional, Nalkurthi, B. Christina, additional, Verhamme, Fien, additional, Buyle-Huybrecht, Tamariche, additional, Vandenabeele, Peter, additional, Vanden Berghe, Tom, additional, Brusselle, Guy G., additional, Horvat, Jay C., additional, Murphy, James M., additional, Wark, Peter A., additional, Bracke, Ken R., additional, Fricker, Michael, additional, and Hansbro, Philip M., additional
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- 2021
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12. Necroptosis Signalling Promotes Inflammation, Airway Remodelling and Emphysema in COPD.
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Zhe Lu, Van Eeckhoutte, Hannelore P., Gang Liu, Nair, Prema M., Jones, Bernadette, Gillis, Caitlin M., Nalkurthi, B. Christina, Verhamme, Fien, Buyle-Huybrecht, Tamariche, Vandenabeele, Peter, Berghe, Tom Vanden, Brusselle, Guy G., Horvat, Jay C., Murphy, James M., Wark, Peter A., Bracke, Ken R., Fricker, Michael, Hansbro, Philip M., Lu, Zhe, and Liu, Gang
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CHRONIC obstructive pulmonary disease ,APOPTOSIS ,INFLAMMATION ,MESSENGER RNA ,TISSUES - Abstract
Rationale: Necroptosis, mediated by RIPK3 and MLKL, is a form of regulated necrosis that can drive tissue inflammation and destruction, however its contribution to COPD pathogenesis is poorly understood.Objectives: To determine the role of necroptosis in COPD.Methods: Levels of RIPK3, MLKL and activated phospho-MLKL were measured in lung tissues of COPD patients and non-COPD controls. Necroptosis-related mRNA and proteins and cell death were examined in the lungs and pulmonary macrophages of mice with cigarette smoke (CS)-induced experimental COPD. The responses of Ripk3- and Mlkl-deficient (-/-) mice to CS exposure were compared to wild-type mice. Combined inhibition of apoptosis (pan-caspase inhibitor qVD-OPh) and necroptosis (Mlkl-/- mice) was assessed.Measurements and Main Results: Protein levels of MLKL and pMLKL but not RIPK3 were increased in lung tissues of COPD patients compared to never smokers or smoker non-COPD controls. Necroptosis-related mRNA and protein levels were increased in lung tissue and macrophages in CS-exposed mice/experimental COPD. Ripk3 or Mlkl deletion prevented airway inflammation in response to acute CS-exposure. Ripk3 deficiency reduced airway inflammation and remodelling and development of emphysematous pathology following chronic CS-exposure. Mlkl deletion and qVD-OPh treatment reduced chronic CS-induced airway inflammation, but only Mlkl deletion prevented airway remodelling and emphysema. Ripk3 or Mlkl deletion and qVD-OPh treatment reduced CS-induced lung cell death.Conclusions: Necroptosis is induced by CS exposure and increased in COPD patient lungs and experimental COPD. Inhibiting necroptosis attenuates CS-induced airway inflammation, airway remodelling and emphysema. Targeted inhibition of necroptosis is a potential therapeutic strategy in COPD. [ABSTRACT FROM AUTHOR]- Published
- 2021
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13. CD32A-expressing platelets determine the severity of experimental anaphylaxis
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Beutier, Héloïse, Hechler, Béatrice, Godon, Ophélie, Wang, Yu, Gillis, Caitlin M., de Chaisemartin, Luc, Gouel-Chéron, Aurélie, Magnenat, Stéphanie, Macdonald, Lynn, Murphy, Andrew, Chollet-Martin, Sylvie, Longrois, Dan, Gachet, Christian, Bruhns, Pierre, Jönsson, Friederike, Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Biologie et Pharmacologie des Plaquettes sanguines : hémostase, thrombose, transfusion (BPP), Université de Strasbourg (UNISTRA)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Laboratoire d'Immunologie 'Autoimmunité et Hypersensibilités' [AP-HP Hôpital Bichat, Paris], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Cytokines, chimiokines et immunopathologie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Anesthésie Réanimation [CHU Bichat-Claude-Bernard], Regeneron Pharmaceuticals [Tarrytown], Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), We are thankful to our colleagues F. Abdallah, B. Iannascoli, and O. Richard-Le Goff at Institut Pasteur (Paris) for technical help. We are thankful to our colleagues for their gifts: M. P. Reilly and S. McKenzie (Jefferson Medical College, Philadelphia, PA) for FCGR2A transgenic mice and LFB Biomédicaments (Les Ulis, France) for human albumin and fibrinogen. Funding: This work was supported by the European Research Council (ERC)–Seventh Framework Program (ERC-2013-CoG 616050), by a Jeunes Chercheuses/Jeunes Chercheurs grant from the Agence National de la Recherche (ANR-16-CE15-0012-01), the Institut Pasteur, INSERM, the Société Française d’Allergologie (Soutien de la Recherche en Allergologie), and the Etablissement Français du Sang. H.B. was supported by a fellowship from the Université Pierre et Marie Curie. C.M.G. was supported partly by a stipend from the Pasteur-Paris University (PPU) International PhD program, by the Institut Carnot Pasteur Maladies Infectieuses, and partly by the Balsan company. Y.W. is part of the PPU International PhD Program that received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 665807 and from the Labex Milieu Intérieur, Institut Pasteur. A.G.-C. benefited from a stipend provided by Assistance Publique–Hôpitaux de Paris (Paris, France) and by the Institut Pasteur (Paris, France) (Postes d’accueil pour Praticiens Hospitaliers) and from a grant provided by INSERM, SFAR (Société Francaise d’Anesthésie et de Reanimation), and SRLF (Société de Réanimation de Langue Francaise) through the 'Bourse de Recherche du Comité d’interface INSERM-SFAR-SRLF 2012'. F.J. is an employee of CNRS., NASA study group : Vanessa Granger (UF Auto-immunité et Hypersensibilités, Hôpital Bichat, APHP, Paris, France, UMR996 - Inflammation, Chemokines et Immunopathology -, INSERM, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France), Philippe Montravers (Département d’anesthésie-réanimation, Hôpital Bichat, AP-HP, Paris, France), Michel Aubier & Caroline Sauvan (Service de pneumologie et d’allergologie, Hôpital Bichat, AP-HP, Paris, France), Marc Fischler & Julie Bresson (Département d’anesthésie-réanimation, Hôpital Foch, Suresnes, France), Catherine Paugam-Burtz & Skander Necib (Département d’anesthésie-réanimation, Hôpital Beaujon, AP-HP, Clichy, France), Alexandre Mebazaa & Matthieu Le Dorze (Département d’anesthésie-réanimation, Hôpital Lariboisière, AP-HP, Paris, France), Laurent Jacob & Carole Chahine (Département d’anesthésie-réanimation, Hôpital Saint Louis, AP-HP, Paris, France), Hawa Keita-Meyer & Valentina Faitot (Département d’anesthésie-réanimation, Hôpital Louis Mourier, AP-HP, Colombes, France), Olivier Langeron & Sabrine Roche (Département d’anesthésie-réanimation, Hôpital Pitié Salpêtrière, AP-HP, Paris, France), Bernard Cholley & Jean Manz (Département d’anesthésie-réanimation, Hôpital Européen Georges Pompidou, AP-HP, Paris, France)., ANR-16-CE15-0012,PlanA,Rôle des plaquettes et leurs interactions dans les réactions anaphylactiques(2016), European Project: 616050,EC:FP7:ERC,ERC-2013-CoG,MYELOSHOCK(2014), European Project: 665807,H2020,H2020-MSCA-COFUND-2014,PASTEURDOC(2015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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[SDV.IMM]Life Sciences [q-bio]/Immunology ,[SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology - Abstract
International audience; 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.
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- 2018
14. An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis
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Jönsson, Friederike, primary, de Chaisemartin, Luc, additional, Granger, Vanessa, additional, Gouel-Chéron, Aurélie, additional, Gillis, Caitlin M., additional, Zhu, Qianqian, additional, Dib, Fadia, additional, Nicaise-Roland, Pascale, additional, Ganneau, Christelle, additional, Hurtado-Nedelec, Maria, additional, Paugam-Burtz, Catherine, additional, Necib, Skander, additional, Keita-Meyer, Hawa, additional, Le Dorze, Matthieu, additional, Cholley, Bernard, additional, Langeron, Olivier, additional, Jacob, Laurent, additional, Plaud, Benoit, additional, Fischler, Marc, additional, Sauvan, Caroline, additional, Guinnepain, Marie-Thérèse, additional, Montravers, Philippe, additional, Aubier, Michel, additional, Bay, Sylvie, additional, Neukirch, Catherine, additional, Tubach, Florence, additional, Longrois, Dan, additional, Chollet-Martin, Sylvie, additional, and Bruhns, Pierre, additional
- Published
- 2019
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15. Un nouveau modèle de souris pour comprendre le rôle des neutrophiles
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Gillis, Caitlin M., primary and Reber, Laurent L., additional
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- 2018
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16. In vivo effector functions of high-affinity mouse IgG receptor FcγRI in disease and therapy models
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Gillis, Caitlin M., primary, Zenatti, Priscila P., additional, Mancardi, David A., additional, Beutier, Héloïse, additional, Fiette, Laurence, additional, Macdonald, Lynn E., additional, Murphy, Andrew J., additional, Celli, Susanna, additional, Bousso, Philippe, additional, Jönsson, Friederike, additional, and Bruhns, Pierre, additional
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- 2017
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17. Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide
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Reber, Laurent L., primary, Gillis, Caitlin M., additional, Starkl, Philipp, additional, Jönsson, Friederike, additional, Sibilano, Riccardo, additional, Marichal, Thomas, additional, Gaudenzio, Nicolas, additional, Bérard, Marion, additional, Rogalla, Stephan, additional, Contag, Christopher H., additional, Bruhns, Pierre, additional, and Galli, Stephen J., additional
- Published
- 2017
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18. Mechanisms of anaphylaxis in human low-affinity IgG receptor locus knock-in mice
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Gillis, Caitlin M., primary, Jönsson, Friederike, additional, Mancardi, David A., additional, Tu, Naxin, additional, Beutier, Héloïse, additional, Van Rooijen, Nico, additional, Macdonald, Lynn E., additional, Murphy, Andrew J., additional, and Bruhns, Pierre, additional
- Published
- 2017
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19. Platelets expressing IgG receptor FcγRIIA/CD32A determine the severity of experimental anaphylaxis.
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Beutier, Héloïse, Hechler, Béatrice, Godon, Ophélie, Wang, Yu, Gillis, Caitlin M., de Chaisemartin, Luc, Gouel-Chéron, Aurélie, Magnenat, Stéphanie, Macdonald, Lynn E., Murphy, Andrew J., Chollet-Martin, Sylvie, Longrois, Dan, Gachet, Christian, Bruhns, Pierre, and Jönsson, Friederike
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ANAPHYLAXIS ,BLOOD platelets ,IMMUNOGLOBULIN G ,IMMUNOGLOBULIN receptors ,PLATELET count ,BLOOD platelet disorders - Abstract
Potent platelets: Anaphylaxis results from inappropriate immune responses to allergens. Human platelets express the IgG receptor FcγRIIA/CD32A and release inflammatory mediators in response to their engagement, but their contribution to anaphylaxis is not well understood. Beutier et al. developed mouse models that express either human FcγRIIA/CD32A alone or the full human IgG receptor complexity to understand the role of platelets in anaphylaxis. Anaphylaxis induced a marked decrease in platelet levels, but preventive platelet depletion reduced anaphylaxis severity. A clinical study of patients with drug-induced anaphylaxis revealed that a severe reaction was likewise associated with fewer circulating platelets. Activated platelets released serotonin, which contributed to anaphylaxis severity. These results reveal a critical role for platelets in IgG-mediated anaphylaxis. 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. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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20. Epitope‐specific CD4+, but not CD8+, T‐cell responses induced by recombinant influenza A viruses protect against Mycobacterium tuberculosis infection
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Flórido, Manuela, primary, Pillay, Roman, additional, Gillis, Caitlin M., additional, Xia, Yingju, additional, Turner, Stephen J., additional, Triccas, James A., additional, Stambas, John, additional, and Britton, Warwick J., additional
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- 2014
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21. Influenza A Virus Infection Impairs Mycobacteria-Specific T Cell Responses and Mycobacterial Clearance in the Lung during Pulmonary Coinfection
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Flórido, Manuela, primary, Grima, Michael A., additional, Gillis, Caitlin M., additional, Xia, Yingju, additional, Turner, Stephen J., additional, Triccas, James A., additional, Stambas, John, additional, and Britton, Warwick J., additional
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- 2013
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22. Epitope-specific CD4+, but not CD8+, T-cell responses induced by recombinant influenza A viruses protect against Mycobacterium tuberculosis infection.
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Flórido, Manuela, Pillay, Roman, Gillis, Caitlin M., Xia, Yingju, Turner, Stephen J., Triccas, James A., Stambas, John, and Britton, Warwick J.
- Abstract
Tuberculosis remains a global health problem, in part due to failure of the currently available vaccine, BCG, to protect adults against pulmonary forms of the disease. We explored the impact of pulmonary delivery of recombinant influenza A viruses (rIAVs) on the induction of Mycobacterium tuberculosis ( M. tuberculosis)-specific CD4
+ and CD8+ T-cell responses and the resultant protection against M. tuberculosis infection in C57BL/6 mice. Intranasal infection with rIAVs expressing a CD4+ T-cell epitope from the Ag85B protein (PR8.p25) or CD8+ T-cell epitope from the TB10.4 protein (PR8.TB10.4) generated strong T-cell responses to the M. tuberculosis-specific epitopes in the lung that persisted long after the rIAVs were cleared. Infection with PR8.p25 conferred protection against subsequent M. tuberculosis challenge in the lung, and this was associated with increased levels of poly-functional CD4+ T cells at the time of challenge. By contrast, infection with PR8.TB10.4 did not induce protection despite the presence of IFN-γ-producing M. tuberculosis-specific CD8+ T cells in the lung at the time of challenge and during infection. Therefore, the induction of pulmonary M. tuberculosis epitope-specific CD4+ , but not CD8+ T cells, is essential for protection against acute M. tuberculosis infection in the lung. [ABSTRACT FROM AUTHOR]- Published
- 2015
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23. 4-Octyl Itaconate Alleviates Airway Eosinophilic Inflammation by Suppressing Chemokines and Eosinophil Development.
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Yin M, Wadhwa R, Marshall JE, Gillis CM, Kim RY, Dua K, Palsson-McDermott EM, Fallon PG, Hansbro PM, and O'Neill LAJ
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- Mice, Animals, Chemokines, Inflammation drug therapy, Eosinophils, Pulmonary Eosinophilia drug therapy
- Abstract
4-Octyl itaconate (4-OI) is a derivative of the Krebs cycle-derived metabolite itaconate and displays an array of antimicrobial and anti-inflammatory properties through modifying cysteine residues within protein targets. We have found that 4-OI significantly reduces the production of eosinophil-targeted chemokines in a variety of cell types, including M1 and M2 macrophages, Th2 cells, and A549 respiratory epithelial cells. Notably, the suppression of these chemokines in M1 macrophages was found to be NRF2-dependent. In addition, 4-OI can interfere with IL-5 signaling and directly affect eosinophil differentiation. In a model of eosinophilic airway inflammation in BALB/c mice, 4-OI alleviated airway resistance and reduced eosinophil recruitment to the lungs. Our findings suggest that itaconate derivatives could be promising therapeutic agents for the treatment of eosinophilic asthma., (Copyright © 2023 by The American Association of Immunologists, Inc.)
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- 2024
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24. [PMN DTR mice: a new model to study neutrophils in vivo].
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Gillis CM and Reber LL
- Subjects
- Animals, Diphtheria Toxin, Drug Resistance genetics, Heparin-binding EGF-like Growth Factor metabolism, Humans, Inflammation genetics, Inflammation immunology, Mice, Neutropenia chemically induced, Neutropenia genetics, Neutropenia pathology, Shock, Septic genetics, Shock, Septic immunology, Disease Models, Animal, Heparin-binding EGF-like Growth Factor genetics, Mice, Transgenic, Neutrophils metabolism, Neutrophils physiology
- Abstract
Neutrophils play a key role in host defense against pathogens. They can contribute to pathological inflammation, and are thought to exacerbate tissue injury upon exposure to bacterial products, such as endotoxin (LPS). Recent findings suggest that neutrophils can also participate in adaptive immune responses and contribute to inflammation resolution. Many discoveries regarding the in vivo role of neutrophils were made possible by the use of genetically modified neutrophil-deficient mice, or by the use of neutrophil-depleting antibodies. Here we describe a new mouse model, PMN
DTR mice, in which neutrophils can be selectively depleted upon injection of diphtheria toxin. Using this model, we have recently demonstrated that neutrophils play a protective role during lethal endotoxin-induced systemic shock. This new mouse model presents several major advantages over more classical models of neutropenia, which are discussed herein., (© 2018 médecine/sciences – Inserm.)- Published
- 2018
- Full Text
- View/download PDF
25. Epitope-specific CD4+, but not CD8+, T-cell responses induced by recombinant influenza A viruses protect against Mycobacterium tuberculosis infection.
- Author
-
Flórido M, Pillay R, Gillis CM, Xia Y, Turner SJ, Triccas JA, Stambas J, and Britton WJ
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, Epitopes genetics, Female, Mice, Mycobacterium tuberculosis genetics, Tuberculosis Vaccines genetics, Tuberculosis, Pulmonary immunology, CD4-Positive T-Lymphocytes immunology, Epitopes immunology, Influenza A virus, Mycobacterium tuberculosis immunology, Tuberculosis Vaccines immunology, Tuberculosis, Pulmonary prevention & control
- Abstract
Tuberculosis remains a global health problem, in part due to failure of the currently available vaccine, BCG, to protect adults against pulmonary forms of the disease. We explored the impact of pulmonary delivery of recombinant influenza A viruses (rIAVs) on the induction of Mycobacterium tuberculosis (M. tuberculosis)-specific CD4(+) and CD8(+) T-cell responses and the resultant protection against M. tuberculosis infection in C57BL/6 mice. Intranasal infection with rIAVs expressing a CD4(+) T-cell epitope from the Ag85B protein (PR8.p25) or CD8(+) T-cell epitope from the TB10.4 protein (PR8.TB10.4) generated strong T-cell responses to the M. tuberculosis-specific epitopes in the lung that persisted long after the rIAVs were cleared. Infection with PR8.p25 conferred protection against subsequent M. tuberculosis challenge in the lung, and this was associated with increased levels of poly-functional CD4(+) T cells at the time of challenge. By contrast, infection with PR8.TB10.4 did not induce protection despite the presence of IFN-γ-producing M. tuberculosis-specific CD8(+) T cells in the lung at the time of challenge and during infection. Therefore, the induction of pulmonary M. tuberculosis epitope-specific CD4(+), but not CD8(+) T cells, is essential for protection against acute M. tuberculosis infection in the lung., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2015
- Full Text
- View/download PDF
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