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6 results on '"Armance Marchal"'

1. Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction

Author

Matthias Titeux, David Michonneau, Nicolas Pallet, Armance Marchal, Soëli Charbonnier, Juliette Leon, Julien Zuber, Katrin Vogt, Marianne Delville, Hélène Vinçon, Ivan Nemazanyy, Isabelle André, Jean-Luc Taupin, Christophe Legendre, Birgit Sawitzki, Tifanie Blein, Marina Cavazzana, Dany Anglicheau, Sylvain Latour, Baptiste Lamarthée, Lucas Rabaux, Emmanuelle Six, Emmanuel Martin, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Harvard Medical School [Boston] (HMS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and LATOUR, Sylvain

Subjects
Male, Adoptive cell transfer, [SDV]Life Sciences [q-bio], Cell, Graft vs Host Disease, Translational immunology, General Physics and Astronomy, Mice, SCID, Signal transduction, Immunotherapy, Adoptive, T-Lymphocytes, Regulatory, Immune tolerance, Jurkat Cells, 0302 clinical medicine, Mice, Inbred NOD, Mice, Knockout, 0303 health sciences, Receptors, Chimeric Antigen, Multidisciplinary, Chemistry, TOR Serine-Threonine Kinases, CD28, food and beverages, hemic and immune systems, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Immunosuppressive Agents, Science, Transplantation, Heterologous, chemical and pharmacologic phenomena, Article, General Biochemistry, Genetics and Molecular Biology, Tumor Necrosis Factor Receptor Superfamily, Member 9, 03 medical and health sciences, CD28 Antigens, In vivo, HLA-A2 Antigen, medicine, Animals, Humans, Tonic (music), PI3K/AKT/mTOR pathway, 030304 developmental biology, Sirolimus, Allotransplantation, General Chemistry, Chimeric antigen receptor, human activities, 030215 immunology
Abstract

The use of chimeric antigen receptor (CAR)-engineered regulatory T cells (Tregs) has emerged as a promising strategy to promote immune tolerance. However, in conventional T cells (Tconvs), CAR expression is often associated with tonic signaling, which can induce CAR-T cell dysfunction. The extent and effects of CAR tonic signaling vary greatly according to the expression intensity and intrinsic properties of the CAR. Here, we show that the 4-1BB CSD-associated tonic signal yields a more dramatic effect in CAR-Tregs than in CAR-Tconvs with respect to activation and proliferation. Compared to CD28 CAR-Tregs, 4-1BB CAR-Tregs exhibit decreased lineage stability and reduced in vivo suppressive capacities. Transient exposure of 4-1BB CAR-Tregs to a Treg stabilizing cocktail, including an mTOR inhibitor and vitamin C, during ex vivo expansion sharply improves their in vivo function and expansion after adoptive transfer. This study demonstrates that the negative effects of 4-1BB tonic signaling in Tregs can be mitigated by transient mTOR inhibition., Chimeric antigen receptor engineering in T cells has been shown to be of great potential therapeutic benefit in a range of immune pathologies, although the functionality of such cell therapies can be limited due to tonic signalling and the induction of dysfunction. Here the authors show transient inhibition of mTOR can rescue their 41-BB-CAR-Tregs from tonic signalling-induced dysfunction.

Published
2021
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2. Severe COVID-19 is associated with hyperactivation of the alternative complement pathway

Author

David M. Smadja, Jeremy Boussier, Benjamin Terrier, Carine El Sissy, Anne Bergeron, Pierre-Louis Tharaux, Solen Kernéis, Frédéric Pène, Véronique Frémeaux-Bacchi, Luc Mouthon, Jérôme Hadjadj, Frédéric Rieux-Laucat, Nader Yatim, Darragh Duffy, Bruno Charbit, Armance Marchal, Nicolas Carlier, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Supported by the Fonds IMMUNOV, for Innovation in Immunopathology, the Institut national de la santé et de la recherche médicale (Inserm), a government grant managed by the Agence national de la recherche as part of the Investment for the Future program (ANR-10-IAHU-01), and by grants from the Agence national de la recherche (ANR-flash COVID-19 'AIROCovid' and 'CoVarImm'). We also acknowledge funding from the Institut Pasteur for COVID-19 Research and an Institut Imagine MD-PhD Fellowship Program award supported by the Fondation Bettencourt Schueller (to J.H.)., ANR-20-COVI-0022,AIROCovid19,Analyse Omics de la réponse immune aigue au cours de l'infection à Covid19: rationnel moléculaire pour un traitement ciblé(2020), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-20-COVI-0053,CoVarImm,Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence(2020), Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Vougny, Marie-Christine, Analyse Omics de la réponse immune aigue au cours de l'infection à Covid19: rationnel moléculaire pour un traitement ciblé - - AIROCovid192020 - ANR-20-COVI-0022 - COVID-19 - VALID, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, and Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence - - CoVarImm2020 - ANR-20-COVI-0053 - COVID-19 - VALID

Subjects
Male, Low protein, Complement Pathway, Alternative, Comorbidity, Severity of Illness Index, immunology, 0302 clinical medicine, SARS-CoV-2, Severe acute respiratory syndrome coronavirus-2, Lectins, Neoplasms, Immunology and Allergy, Medicine, Complement Activation, 0303 health sciences, COVID-19, Coronavirus disease 2019, biology, Brief Report, Middle Aged, 3. Good health, Cardiovascular Diseases, Hypertension, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, Complement system, [SDV.IMM] Life Sciences [q-bio]/Immunology, alternative pathway, Inflammation, 03 medical and health sciences, Classical complement pathway, Diabetes Mellitus, Humans, 030304 developmental biology, Properdin, business.industry, SARS-CoV-2, C-reactive protein, COVID-19, Complement System Proteins, Disseminated Intravascular Coagulation, Respiration, Artificial, Gene Expression Regulation, Case-Control Studies, Immunology, Alternative complement pathway, biology.protein, hemostasis, business, Complement membrane attack complex, 030215 immunology
Abstract

International audience; Background: Severe coronavirus disease 2019 (COVID-19) is characterized by impaired type I interferon activity and a state of hyperinflammation leading to acute respiratory distress syndrome. The complement system has recently emerged as a key player in triggering and maintaining the inflammatory state, but the role of this molecular cascade in severe COVID-19 is still poorly characterized.Objective: We aimed at assessing the contribution of complement pathways at both the protein and transcriptomic levels.Methods: To this end, we systematically assessed the RNA levels of 28 complement genes in the circulating whole blood of patients with COVID-19 and healthy controls, including genes of the alternative pathway, for which data remain scarce.Results: We found differential expression of genes involved in the complement system, yet with various expression patterns: whereas patients displaying moderate disease had elevated expression of classical pathway genes, severe disease was associated with increased lectin and alternative pathway activation, which correlated with inflammation and coagulopathy markers. Additionally, properdin, a pivotal positive regulator of the alternative pathway, showed high RNA expression but was found at low protein concentrations in patients with a severe and critical disease, suggesting its deposition at the sites of complement activation. Notably, low properdin levels were significantly associated with the use of mechanical ventilation (area under the curve = 0.82; P = .002).Conclusion: This study sheds light on the role of the alternative pathway in severe COVID-19 and provides additional rationale for the testing of drugs inhibiting the alternative pathway of the complement system.

Published
2022
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3. Case Report: Adult Post-COVID-19 Multisystem Inflammatory Syndrome and Thrombotic Microangiopathy

Author

Idris Boudhabhay, Marion Rabant, Lubka T. Roumenina, Louis-Marie Coupry, Victoria Poillerat, Armance Marchal, Véronique Frémeaux-Bacchi, Khalil El Karoui, Mehran Monchi, Franck Pourcine, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Service d'anatomie pathologique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d'immunologie [HEGP, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Henri Mondor, Intensive Care Unit, Groupe Hospitalier Sud Ile de France, 270 avenue Marc Jacquet, 77000, Melun, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Gestionnaire, HAL Sorbonne Université 5

Subjects
0301 basic medicine, Thrombotic microangiopathy, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Renal function, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, otorhinolaryngologic diseases, Immunology and Allergy, Medicine, case report, complement system, Kidney, multisystem inflammatory syndrome, business.industry, Kidney metabolism, COVID-19, RC581-607, Eculizumab, medicine.disease, Pathophysiology, 3. Good health, Complement system, thrombotic microangiopathy, Systemic inflammatory response syndrome, 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, eculizumab, Immunologic diseases. Allergy, business, medicine.drug
Abstract

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has affected millions of people worldwide. A clinical series of Kawasaki-like multisystem inflammatory syndrome (MIS), occurring after SARS-CoV-2 infection, have been described in children (MIS-C) and adults (MIS-A), but the pathophysiology remains unknown.Case PresentationWe describe a case of post-COVID-19 MIS-A in a 46-year-old man with biopsy-proven renal thrombotic microangiopathy (TMA). Specific complement inhibition with eculizumab was initiated promptly and led to a dramatic improvement of renal function.ConclusionOur case suggests that that TMA could play a central role in the pathophysiology of post-COVID-19 MIS-A, making complement blockers an interesting therapeutic option.

Published
2021
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4. A combination of cyclophosphamide and interleukin-2 allows CD4+ T cells converted to Tregs to control scurfy syndrome

Author

Soëli Charbonnier, Sabrina Lizot, Isabelle André, Emmanuelle Six, Christophe Benoist, Roman Klifa, Steicy Sobrino, Juliette Leon, Juliette Olivré, Armance Marchal, David A. Gross, Hélène Vinçon, Baptiste Lamarthée, Julien Zuber, Alexandrine Garrigue, Marina Cavazzana, Marianne Delville, Mario Amendola, Romane Thouenon, Chantal Lagresle-Peyrou, Florence Bellier, Axel Schambach, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Harvard Medical School [Boston] (HMS), Généthon, Hannover Medical School [Hannover] (MHH), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Amendola, Mario, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), and Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon

Subjects
0301 basic medicine, Interleukin 2, CD4-Positive T-Lymphocytes, Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Adoptive cell transfer, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Immunology, Antineoplastic Agents, chemical and pharmacologic phenomena, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, medicine.disease_cause, Biochemistry, T-Lymphocytes, Regulatory, Autoimmunity, Viral vector, Autoimmune Diseases, 03 medical and health sciences, Mice, 0302 clinical medicine, In vivo, medicine, Animals, Cyclophosphamide, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Autoimmune disease, FOXP3, Forkhead Transcription Factors, Genetic Diseases, X-Linked, hemic and immune systems, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, Gene Therapy, medicine.disease, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Mice, Inbred C57BL, Haematopoiesis, Disease Models, Animal, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer research, Interleukin-2, Drug Therapy, Combination, Female, Immunosuppressive Agents, medicine.drug
Abstract

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by mutations in forkhead box P3 (FOXP3), which lead to the loss of function of regulatory T cells (Tregs) and the development of autoimmune manifestations early in life. The selective induction of a Treg program in autologous CD4+ T cells by FOXP3 gene transfer is a promising approach for curing IPEX. We have established a novel in vivo assay of Treg functionality, based on adoptive transfer of these cells into scurfy mice (an animal model of IPEX) and a combination of cyclophosphamide (Cy) conditioning and interleukin-2 (IL-2) treatment. This model highlighted the possibility of rescuing scurfy disease after the latter’s onset. By using this in vivo model and an optimized lentiviral vector expressing human Foxp3 and, as a reporter, a truncated form of the low-affinity nerve growth factor receptor (ΔLNGFR), we demonstrated that the adoptive transfer of FOXP3-transduced scurfy CD4+ T cells enabled the long-term rescue of scurfy autoimmune disease. The efficiency was similar to that seen with wild-type Tregs. After in vivo expansion, the converted CD4FOXP3 cells recapitulated the transcriptomic core signature for Tregs. These findings demonstrate that FOXP3 expression converts CD4+ T cells into functional Tregs capable of controlling severe autoimmune disease.

Published
2021
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5. Donor-targeted serotherapy as a rescue therapy for steroid-resistant acute GVHD after HLA-mismatched kidney transplantation

Author

Juliette Leon, Nathalie Aladjidi, Romain Berthaud, Armance Marchal, Jean Luc Taupin, Rémi Salomon, Baptiste Lamarthée, Rachid Djoudi, Romain Lévy, Marina Charbit, Sylvie Gross, Julien Zuber, Bénédicte Neven, Pierre Tiberghien, Astrid Godron-Dubrasquet, Michael Dussiot, Sarah Winter, Stéphane Blanche, Isabelle Jollet, Jonathan Visentin, Marina Cavazzana, Virginie Renac, Marion Rabant, Saoussen Krid, Nathalie Gouge‐Biebuyck, Brigitte Llanas, Olivia Boyer, Lise Allard, Isabelle André, Florence Lacaille, Melissa Ould Rabah, and Pauline Krug

Subjects
Adoptive cell transfer, Transplantation Conditioning, medicine.medical_treatment, T cell, Graft vs Host Disease, Human leukocyte antigen, 030230 surgery, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Immunology and Allergy, Humans, Pharmacology (medical), Child, Kidney transplantation, Transplantation, biology, business.industry, Immunization, Passive, Immunosuppression, medicine.disease, Kidney Transplantation, Histocompatibility, surgical procedures, operative, medicine.anatomical_structure, Immunology, biology.protein, Steroids, Antibody, business
Abstract

Acute graft-versus-host disease (GVHD) is a rare but frequently lethal complication after solid organ transplantation. GVHD occurs in unduly immunocompromised hosts but requires the escalation of immunosuppression, which does not discriminate between host and donor cells. In contrast, donor-targeted therapy would ideally mitigate graft-versus-host reactivity while sparing recipient immune functions. We report two children with end-stage renal disease and severe primary immune deficiency (Schimke syndrome) who developed severe steroid-resistant acute GVHD along with full and sustained donor T cell chimerism after isolated kidney transplantation. Facing a therapeutic dead end, we used a novel strategy based on the adoptive transfer of anti-HLA donor-specific antibodies (DSAs) through the transfusion of highly selected plasma. After approval by the appropriate regulatory authority, an urgent nationwide search was launched among more than 3800 registered blood donors with known anti-HLA sensitization. Adoptively transferred DSAs bound to and selectively depleted circulating donor T cells. The administration of DSA-rich plasma was well tolerated and notably did not induce antibody-mediated rejection of the renal allografts. Acute GVHD symptoms promptly resolved in one child. This report provides a proof of concept for a highly targeted novel therapeutic approach for solid organ transplantation-associated GVHD.

Published
2019

6. Eculizumab as an emergency treatment for adult patients with severe COVID-19 in the intensive care unit: A proof-of-concept study

Author

Djillali Annane, Lamiae Grimaldi-Bensouda, Armance Marchal, Pierre Moine, Hugues Michelon, Anne Laure Roux, N Heming, Martin Rottman, Marie Vigan, Véronique Frémeaux-Bacchi, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service médical des soins intensifs [CHU Raymond Poincaré], Hôpital Raymond Poincaré [AP-HP], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre National de Référence des Méningocoques et Haemophilus influenzae - National Reference Center Meningococci and Haemophilus influenzae (CNR), Institut Pasteur [Paris] (IP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Gestionnaire, Hal Sorbonne Université, École Pratique des Hautes Études (EPHE), ANR-18-RHUS-0004,RECORDS,Rapid rEcognition of CS sensitive or resistant Sepsis(2018), Institut Pasteur [Paris], and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP)

Subjects
medicine.medical_specialty, [SDV]Life Sciences [q-bio], Complement pathway, 01 natural sciences, law.invention, Sepsis, 03 medical and health sciences, 0302 clinical medicine, law, Internal medicine, Fraction of inspired oxygen, medicine, 030212 general & internal medicine, 0101 mathematics, Adverse effect, Blood urea nitrogen, Prothrombin time, Complement component 5, lcsh:R5-920, Acute respiratory distress syndrome, medicine.diagnostic_test, business.industry, 010102 general mathematics, Pneumonia, General Medicine, Eculizumab, medicine.disease, Intensive care unit, 3. Good health, Coronavirus, [SDV] Life Sciences [q-bio], C5 inhibitor, Cytokines, lcsh:Medicine (General), business, Research Paper, medicine.drug
Abstract

Background Complement pathway inhibition may provide benefit for severe acute respiratory illnesses caused by viral infections such as COVID-19. We present results from a nonrandomized proof-of-concept study of complement C5 inhibitor eculizumab for treatment of severe COVID-19. Methods All patients (N = 80) with confirmed SARS-CoV-2 infection and severe COVID-19 admitted to our intensive care unit between March 10 and May 5, 2020 were included. Forty-five patients were treated with standard care and 35 with standard care plus eculizumab through expanded-access emergency treatment. The prespecified primary outcome was day-15 survival. Clinical laboratory values and biomarkers, complement levels, and treatment-emergent serious adverse events (TESAEs) were also assessed. Findings At day 15, estimated survival was 82.9% (95% CI: 70.4%‒95.3%) with eculizumab and 62.2% (48.1%‒76.4%) without eculizumab (log-rank test, P = 0.04). Patients treated with eculizumab experienced a significantly more rapid decrease in lactate, blood urea nitrogen, total and conjugated bilirubin levels and a significantly more rapid increase in platelet count, prothrombin time, and in the ratio of arterial oxygen tension over fraction of inspired oxygen versus patients treated without eculizumab. Eculizumab-associated changes in complement levels, laboratory values, and biomarkers were consistent with terminal complement inhibition, reduced hypoxia, and decreased inflammation. TESAEs of special interest occurring in >5% of patients treated with/without eculizumab were ventilator-associated pneumonia (51%/24%), bacteremia (11%/2%), gastroduodenal hemorrhage (14%/16%), and hemolysis (3%/18%). Interpretation Findings from this proof-of-concept study suggest eculizumab may improve survival and reduce hypoxia in patients with severe COVID-19. Randomized studies evaluating the efficacy and safety of this treatment approach are needed. Funding Programme d'Investissements d'Avenir: ANR-18-RHUS60004.

Published
2020
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