Author: "Antoine Toubert" / Topic: humans - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Antoine Toubert"' showing total 147 results

Start Over Author "Antoine Toubert" Topic humans

147 results on '"Antoine Toubert"'

1. Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation

Author: Celine Posseme, Alba Llibre, Bruno Charbit, Vincent Bondet, Vincent Rouilly, Violaine Saint-André, Jeremy Boussier, Jacob Bergstedt, Nikaïa Smith, Liam Townsend, Jamie A. Sugrue, Clíona Ní Cheallaigh, Niall Conlon, Maxime Rotival, Michael S. Kobor, Estelle Mottez, Stanislas Pol, Etienne Patin, Matthew L. Albert, Lluis Quintana-Murci, Darragh Duffy, Laurent Abel, Andres Alcover, Hugues Aschard, Philippe Bousso, Nollaig Bourke, Petter Brodin, Pierre Bruhns, Nadine Cerf-Bensussan, Ana Cumano, Caroline Demangel, null Christophe d’Enfert, Ludovic Deriano, Marie-Agnès Dillies, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Ivo Gomperts-Boneca, Milena Hasan, Magnus Fontes, Gunilla Karlsson Hedestam, Serge Hercberg, Molly A. Ingersoll, Rose Anne Kenny, Olivier Lantz, Mickael Ménager, Frédérique Michel, Hugo Mouquet, Cliona O'Farrelly, Sandra Pellegrini, Antonio Rausell, Frédéric Rieux-Laucat, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Christophe Zimmer, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Ecole Doctorale Frontiere de l’Innovation en Recherche et Education (ED 474 FIRE), Université Paris Cité (UPCité)-Université Paris sciences et lettres (PSL), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Datactix, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), St James’s Hospital [Dublin, Ireland], Trinity College Dublin, University of British Columbia [Vancouver], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), HIBIO [South San Francisco], Collège de France - Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), This study was funded with support from the French Governments Investissement dAvenir Program, Laboratoire Excellence Milieu Interieur Grant ANR-10-LABX-69-01 and by an Agence National de Recherche foundation grant (CE17001002)., The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker), Andres Alcover, Hugues Aschard, Philippe Bousso, Nollaig Bourke (Trinity College Dublin), Petter Brodin (Karolinska Institutet), Pierre Bruhns, Nadine Cerf-Bensussan (INSERM UMR 1163 – Institut Imagine), Ana Cumano, Caroline Demangel, Christophe d’Enfert, Ludovic Deriano, Marie-Agnès Dillies, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay (EPFL, Lausanne), Ivo Gomperts-Boneca, Milena Hasan, Magnus Fontes (Institut Roche), Gunilla Karlsson Hedestam (Karolinska Institutet), Serge Hercberg (Université Paris 13), Molly Ingersoll, Rose Anne Kenny (Trinity College Dublin), Olivier Lantz (Institut Curie), Frédérique Michel, Hugo Mouquet, Cliona O'Farrelly (Trinity College Dublin), Etienne Patin, Sandra Pellegrini, Stanislas Pol (Hôpital Côchin), Antonio Rausell (INSERM UMR 1163 – Institut Imagine), Frédéric Rieux-Laucat (INSERM UMR 1163 – Institut Imagine), Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert (Hôpital Saint-Louis), Mathilde Touvier (Université Paris 13), Marie-Noëlle Ungeheuer, Christophe Zimmer, Matthew L. Albert (In Sitro), Darragh Duffy, Lluis Quintana-Murci, ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-20-CE17-0010,ELECTRO,Inhibition de l'Exchange Protein directly activated by cAMP -1 pour traiter la Fibrillation Atrial(2020), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute-University of British Columbia (UBC), University of Cape Town, Département d'hépatologie [CHU Cochin], 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), Insitro [San Francisco], St James's University Hospital, Leeds Teaching Hospitals NHS Trust, University of British Columbia (UBC), This study was funded with support from the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Milieu Intérieur' grant ANR-10-LABX-69-01, and by an Agence National de Recherche Foundation grant (CE17001002). We thank the UTechS CB of the Center for Translational Research, Institut Pasteur for supporting data generation, Pierre-Henri Commere for help with flow cytometry sorting, Aurelie Bisiaux for flow cytometry advice, and Dr. Molly Ingersoll for scientific advice and critical reading of the manuscript. D.D. thanks Immunoqure for provision of the mAbs under an MTA for the Simoa IFNα assay. We thank the STTAR-Bioresource of TCD-SJH-TUH COVID-19 bioresource, which supported collection of COVID-19 patient samples, and the 'URGENCE COVID-19' fundraising campaign of the Institut Pasteur (CoVarImm and Steroid Response) for supporting data generation of COVID-19 samples. N.S. is a recipient of the Pasteur-Roux-Cantarini Fellowship. N.C. and C.N.C. are part funded by a Science Foundation Ireland (SFI) grant, grant code 20/SPP/3685. L.T. is supported by the Irish Clinical Academic Training (ICAT) Program, supported by the Wellcome Trust and the Health Research Board (grant number 203930/B/16/Z), the Health Service Executive, National Doctors Training and Planning, and the Health and Social Care, Research and Development Division, Northern Ireland., Milieu Intérieur Consortium: Laurent Abel, Andres Alcover, Hugues Aschard, Philippe Bousso, Nollaig Bourke, Petter Brodin, Pierre Bruhns, Nadine Cerf-Bensussan, Ana Cumano, Caroline Demangel, Christophe d'Enfert, Ludovic Deriano, Marie-Agnès Dillies, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Ivo Gomperts-Boneca, Milena Hasan, Magnus Fontes, Gunilla Karlsson Hedestam, Serge Hercberg, Molly A Ingersoll, Rose Anne Kenny, Olivier Lantz, Mickael Ménager, Frédérique Michel, Hugo Mouquet, Cliona O'Farrelly, Etienne Patin, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Frédéric Rieux-Laucat, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Christophe Zimmer, Matthew L Albert, Darragh Duffy, Lluis Quintana-Murci, and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
Subjects: Lipopolysaccharides, Proteomics, History, Polymers and Plastics, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Disease, systems immunology, Biology, General Biochemistry, Genetics and Molecular Biology, Industrial and Manufacturing Engineering, Immune system, medicine, Humans, Secretion, Epigenetics, Business and International Management, Epigenomics, TLR4 immune responses, Systems immunology, SARS-CoV-2, COVID-19, CP: Immunology, Interferon-beta, Interleukin-12, Toll-Like Receptor 4, Cytokine, IL-12p70, type I interferons, Immunology, TLR4, Cytokine variability, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines
Abstract: International audience; The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon β (IFNβ) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNβ as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNβ-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNβ in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.
Published: 2021

2. Autologous organoid co-culture model reveals T cell-driven epithelial cell death in Crohn's Disease

Author: Nassim Hammoudi, Sarah Hamoudi, Julie Bonnereau, Hugo Bottois, Kevin Pérez, Madeleine Bezault, Déborah Hassid, Victor Chardiny, Céline Grand, Brice Gergaud, Joëlle Bonnet, Leila Chedouba, My-Linh Tran Minh, Jean-Marc Gornet, Clotilde Baudry, Hélène Corte, Léon Maggiori, Antoine Toubert, Jacqueline McBride, Camille Brochier, Margaret Neighbors, Lionel Le Bourhis, and Matthieu Allez
Subjects: EXPRESSION, Science & Technology, STRESS, crohn's disease, INDUCTION, KILLER-CELLS, Immunology, Epithelial Cells, EXPANSION, IMMUNITY, Inflammatory Bowel Diseases, inflammatory bowel diseases, Coculture Techniques, NKG2D, lymphoepithelial interactions, Organoids, IL-15, Crohn Disease, COLON, CD103, Immunology and Allergy, Humans, Life Sciences & Biomedicine, organoids, INFLAMMATORY-BOWEL-DISEASE
Abstract: Lympho-epithelial interactions between intestinal T resident memory cells (Trm) and the epithelium have been associated with inflammatory bowel disease (IBD) activity. We developed ex vivo autologous organoid-mucosal T cell cocultures to functionally assess lymphoepithelial interactions in Crohn's Disease (CD) patients compared to controls. We demonstrate the direct epithelial cell death induced by autologous mucosal T cells in CD patients but not in controls. These findings were positively correlated with T cell infiltration of the organoids. This potential was inhibited by limiting lympho-epithelial interactions through CD103 and NKG2D blocking antibodies. These data directly demonstrate for the first time the direct deleterious effect of mucosal T cells on the epithelium of CD patients. Such ex-vivo models are promising techniques to unravel the pathophysiology of these diseases and the potential mode of action of current and future therapies. ispartof: FRONTIERS IN IMMUNOLOGY vol:13 ispartof: location:Switzerland status: published
Published: 2022

3. Innate lymphoid cells: NK and cytotoxic ILC3 subsets infiltrate metastatic breast cancer lymph nodes

Author: Louise Rethacker, Maxime Boy, Valeria Bisio, France Roussin, Jordan Denizeau, Anne Vincent-Salomon, Edith Borcoman, Christine Sedlik, Eliane Piaggio, Antoine Toubert, Nicolas Dulphy, and Anne Caignard
Subjects: Killer Cells, Natural, Oncology, Immunology, Tumor Microenvironment, Immunology and Allergy, Humans, Antineoplastic Agents, Breast Neoplasms, Female, Lymph Nodes, Immunity, Innate
Abstract: Innate lymphoid cells (ILCs) - which include cytotoxic Natural Killer (NK) cells and helper-type ILC - are important regulators of tissue immune homeostasis, with possible roles in tumor surveillance. We analyzed ILC and their functionality in human lymph nodes (LN). In LN, NK cells and ILC3 were the prominent subpopulations. Among the ILC3s, we identified a CD56
Published: 2022

4. Immune Profiling Enables Stratification of Patients With Active Tuberculosis Disease or Mycobacteriu m tuberculosis Infection

Author: Françoise Dromer, Antonio Rausell, Elizabeth Filander, Bruno Charbit, Odile Gelpi, Kalla Astrom, Stanislas Pol, Elisa Nemes, Vincent Rouilly, Mark Hatherill, Hadn Africa, Humphrey Mulenga, Ana Cumano, Hugo Mouquet, Etienne Patin, Lluis Quintana-Murci, Lungisa Jaxa, Laurent Abel, Milena Hasan, James P. Di Santo, Claude Leclerc, Spencer L. Shorte, Vassili Soumelis, Stéphanie Thomas, Caroline Demangel, Mathilde Touvier, Andrés Alcover, Thomas J. Scriba, Matthew L. Albert, Anavaj Sakuntabhai, Hugues Aschard, Nikaïa Smith, Serge Hercberg, Darragh Duffy, Jost Enninga, Olivier Schwartz, Ivo Gomperts-Boneca, Marie-Noëlle Ungeheuer, Simbarashe Mabwe, Ludovic Deriano, Frédéric Tangy, Gérard Eberl, Sandra Pellegrini, Antoine Toubert, Lars Rogge, Stephanus T. Malherbe, Gerhard Walzl, Michele Tameris, Munyaradzi Musvosvi, Alba Llibre, Benno Schwikowski, Olivier Lantz, Nicole Bilek, Philippe Bousso, Pierre Bruhns, Jacques Fellay, and Eric Tartour
Subjects: 0301 basic medicine, Microbiology (medical), Tuberculosis, Enzyme-Linked Immunosorbent Assay, Disease, Asymptomatic, QuantiFERON, Mycobacterium tuberculosis, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Antigen, Latent Tuberculosis, medicine, Humans, 030212 general & internal medicine, Online only Articles, Whole blood, biology, business.industry, immune profiling, biomarkers, patient stratification, bacterial infections and mycoses, medicine.disease, biology.organism_classification, cytokines, 3. Good health, AcademicSubjects/MED00290, 030104 developmental biology, Infectious Diseases, Cohort, Immunology, medicine.symptom, business, Interferon-gamma Release Tests
Abstract: Background Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is a major public health problem. Clinical challenges include the lack of a blood-based test for active disease. Current blood-based tests, such as QuantiFERON (QFT) do not distinguish active TB disease from asymptomatic Mtb infection. Methods We hypothesized that TruCulture, an immunomonitoring method for whole-blood stimulation, could discriminate active disease from latent Mtb infection (LTBI). We stimulated whole blood from patients with active TB and compared with LTBI donors. Mtb-specific antigens and live bacillus Calmette-Guérin (BCG) were used as stimuli, with direct comparison to QFT. Protein analyses were performed using conventional and digital enzyme-linked immunosorbent assay (ELISA), as well as Luminex. Results TruCulture showed discrimination of active TB cases from LTBI (P < .0001, AUC = .81) compared with QFT (P = .45, AUC = .56), based on an interferon γ (IFNγ) readout after Mtb antigen (Ag) stimulation. This result was replicated in an independent cohort (AUC = .89). In exploratory analyses, TB stratification could be further improved by the Mtb antigen to BCG IFNγ ratio (P < .0001, AUC = .91). Finally, the combination of digital ELISA and transcriptional analysis showed that LTBI donors with high IFNγ clustered with patients with TB, suggesting the possibility to identify subclinical disease. Conclusions TruCulture offers a next-generation solution for whole-blood stimulation and immunomonitoring with the possibility to discriminate active and latent infection., We tested TruCulture, an immunomonitoring tool, to identify active disease from latent Mtb infection. TruCulture showed improved discrimination of tuberculosis cases from LTBI as compared with QuantiFERON. Tuberculosis stratification could be further improved by the Mtb Ag:BCG IFNγ ratio.
Published: 2020

5. Primary immune responses are negatively impacted by persistent herpesvirus infections in older people: results from an observational study on healthy subjects and a vaccination trial on subjects aged more than 70 years old

Author: Francesco Nicoli, Emmanuel Clave, Kerstin Wanke, Amrei von Braun, Vincent Bondet, Cécile Alanio, Corinne Douay, Margaux Baque, Claire Lependu, Peggy Marconi, Karin Stiasny, Franz X. Heinz, Margot Muetsch, Darragh Duffy, Jacques Boddaert, Delphine Sauce, Antoine Toubert, Urs Karrer, Victor Appay, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Ferrara = University of Ferrara (UniFE), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University hospital of Zurich [Zurich], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Virology (Vienna), Medizinische Universität Wien = Medical University of Vienna, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Funding: This work was supported by the ANR (Project ANR-14-CE14-0030-01) and by Universita ItaloFrancese/Univeriste FrancoItalienne (Galileo Project G10-718, PHC Galilee Project 39582TJ), by the Swiss National Science Foundation (grant PP0033-110737 to UK), by the Heuberg Foundation (Zurich, Switzerland), by the AETAS Foundation (Geneva, Switzerland) and by a Senior IdEx Chair of the University of Bordeaux (France). EC, VB, CA, MA, DD and AT were supported by the French Government's Investissement d'Avenir Program, Laboratoire d'Excellence 'Milieu Interieur' Grant ANR-10-LABX-69-01. EC and AT are supported by the Agence Nationale de la Recherche (Project RANKLthym ANR-19- CE18-0021-02)., ANR-19-CE18-0021,RANKLthym,Évaluer le potentiel de RANK ligand pour rétablir des fonctions thymiques efficaces après greffe de moelle osseuse et vieillissement(2019), Kumamoto University, This work was supported by the ANR (Project ANR-14-CE14-0030-01) and by Università ItaloFrancese/Univeristé FrancoItalienne (Galileo Project G10-718, PHC Galilee Project 39582TJ), by the Swiss National Science Foundation (grant PP0033-110737 to UK), by the Heuberg Foundation (Zurich, Switzerland), by the AETAS Foundation (Geneva, Switzerland) and by a Senior IdEx Chair of the University of Bordeaux (France). EC, VB, CA, MA, DD and AT were supported by the French Government's Investissement d'Avenir Program, Laboratoire d'Excellence 'Milieu Intérieur' Grant ANR-10-LABX-69-01. EC and AT are supported by the Agence Nationale de la Recherche (Project RANKLthym ANR-19- CE18-0021-02)., ANR-14-CE14-0030,PriCelAge,Induction de réponses cellulaires T avec l'âge avancé(2014), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), HAL-SU, Gestionnaire, Appel à projets générique - Induction de réponses cellulaires T avec l'âge avancé - - PriCelAge2014 - ANR-14-CE14-0030 - Appel à projets générique - VALID, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, and Évaluer le potentiel de RANK ligand pour rétablir des fonctions thymiques efficaces après greffe de moelle osseuse et vieillissement - - RANKLthym2019 - ANR-19-CE18-0021 - AAPG2019 - VALID
Subjects: Adult, Medicine (General), Vaccines, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV]Life Sciences [q-bio], Vaccination, Naive T lymphocytes, General Medicine, General Biochemistry, Genetics and Molecular Biology, Healthy Volunteers, NO, Thymus, Young Adult, R5-920, Elderly, Antibody Formation, Cytomegalovirus Infections, T-cell responses, Medicine, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, Herpesviridae, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Aged
Abstract: Advanced age is accompanied by a decline of immune functions, which may play a role in increased vulnerability to emerging pathogens and low efficacy of primary vaccinations in elderly people. The capacity to mount immune responses against new antigens is particularly affected in this population. However, its precise determinants are not fully understood. We aimed here at establishing the influence of persistent viral infections on the naive T-cell compartment and primary immune responsiveness in older adults.We assessed immunological parameters, related to CD8We demonstrate a prevalent effect of age and CMV infection on CD8These data provide insights on the changes in adaptive immunity over time and the associated decline in vaccine efficacy with ageing. This knowledge is important for the management of emerging infectious diseases in elderly populations.This work was supported by the ANR (Project ANR-14-CE14-0030-01) and by Universita ItaloFrancese/Univeriste FrancoItalienne (Galileo Project G10-718; PHC Galilee Project 39582TJ), by the Swiss National Science Foundation (grant PP0033-110737 to UK), by the Heuberg Foundation (Zurich, Switzerland), by the AETAS Foundation (Geneva, Switzerland) and by a Senior IdEx Chair of the University of Bordeaux (France). EC, VB, CA, MA, DD and AT were supported by the French Government's Investissement d'Avenir Program, Laboratoire d'Excellence "Milieu Interieur" Grant ANR-10-LABX-69-01. EC and AT are supported by the Agence Nationale de la Recherche (Project RANKLthym ANR-19- CE18-0021-02).
Published: 2022

6. Mogamulizumab induces long-term immune restoration and reshapes tumour heterogeneity in Sézary syndrome

Author: Marie Roelens, Adèle de Masson, Anais Andrillon, Caroline Ram‐Wolff, Lucie Biard, Marie Boisson, Samia Mourah, Maxime Battistella, Antoine Toubert, Martine Bagot, and Hélène Moins‐Teisserenc
Subjects: Immune Reconstitution, Skin Neoplasms, Tumor Microenvironment, Humans, Sezary Syndrome, Receptors, KIR3DL2, Dermatology, Antibodies, Monoclonal, Humanized, Lymphoma, T-Cell, Cutaneous
Abstract: Mogamulizumab, an anti-CCR4 monoclonal antibody, has been shown to increase progression-free survival in cutaneous T-cell lymphoma.We hypothesized that besides the targeted depletion of Sézary cells (SCs), mogamulizumab may reshape the immune tumour microenvironment.Both malignant and benign compartments from 26 patients with B2 stage Sézary syndrome before mogamulizumab initiation were prospectively analysed using KIR3DL2 and TCRVβ markers, serological markers and molecular assessments of clonality.Prior to mogamulizumab, the benign subset of CD4Mogamulizumab likely contributes to the restoration of efficient immunity and reshapes not only the malignant lymphocyte subset but also the benign subset. These results have potential implications for optimal therapeutic sequences and/or combinations. What is already known about this topic? Management of Sézary syndrome (SS) involves successive therapies that participate as cause and consequence in the emergence of resistant clones, on a background of immunodeficiency. We and others have reported the complex and dynamic heterogeneity of Sézary cells (SCs) during disease progression. Mogamulizumab therapy, by targeting the skin-homing receptor CCR4, mainly expressed by SCs, has been shown to increase progression-free survival in patients with SS. What does this study add? Using multicolour flow cytometry, we provide quantification of CCR4 and immune checkpoint molecules on malignant SCs and benign CD4
Published: 2021

7. High-dimensional mass cytometry analysis of NK cell alterations in AML identifies a subgroup with adverse clinical outcome

Author: Anne-Sophie Chretien, Raynier Devillier, Samuel Granjeaud, Charlotte Cordier, Clemence Demerle, Nassim Salem, Julia Wlosik, Florence Orlanducci, Laurent Gorvel, Stephane Fattori, Marie-Anne Hospital, Jihane Pakradouni, Emilie Gregori, Magali Paul, Philippe Rochigneux, Thomas Pagliardini, Mathieu Morey, Cyril Fauriat, Nicolas Dulphy, Antoine Toubert, Herve Luche, Marie Malissen, Didier Blaise, Jacques A. Nunès, Norbert Vey, Daniel Olive, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ImCheck Therapeutics [Marseille], Datactivist, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPC), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Immunologie de Marseille - Luminy (CIML), Université Paris Cité (UPCité), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, mass cytometry, Medical Sciences, CD96, [SDV]Life Sciences [q-bio], Cell, chemical and pharmacologic phenomena, CD56−CD16+ NK cells, Lymphocyte Activation, Immunophenotyping, 03 medical and health sciences, 0302 clinical medicine, Immune system, AML, Antigens, CD, medicine, Humans, Mass cytometry, Receptor, Multidisciplinary, Innate immune system, natural killer cells, business.industry, Remission Induction, Myeloid leukemia, hemic and immune systems, Biological Sciences, Flow Cytometry, NKG2D, Killer Cells, Natural, Leukemia, Myeloid, Acute, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, business
Abstract: Significance This work provides a report of accumulation of unconventional CD56−CD16+ NK cells in nonvirally induced malignancies. Increased frequency of CD56−CD16+ NK cells is associated with adverse clinical outcome in AML, as well as other maturation defects, and might contribute to a defective control of AML progression. Pseudotime analysis highlights a disruption in the maturation process of conventional NK cells in AML patients, leading to a bifurcation point absent in healthy subjects. This analysis, combined with the reduced frequency of conventional NK cells observed in AML patients, suggests that unconventional CD56−CD16+ NK cells derive from an aberrant maturation of conventional NK cells. Overall, accumulation of CD56−CD16+ NK cells could be an important feature of immune escape from innate immunity., Natural killer (NK) cells are major antileukemic immune effectors. Leukemic blasts have a negative impact on NK cell function and promote the emergence of phenotypically and functionally impaired NK cells. In the current work, we highlight an accumulation of CD56−CD16+ unconventional NK cells in acute myeloid leukemia (AML), an aberrant subset initially described as being elevated in patients chronically infected with HIV-1. Deep phenotyping of NK cells was performed using peripheral blood from patients with newly diagnosed AML (n = 48, HEMATOBIO cohort, NCT02320656) and healthy subjects (n = 18) by mass cytometry. We showed evidence of a moderate to drastic accumulation of CD56−CD16+ unconventional NK cells in 27% of patients. These NK cells displayed decreased expression of NKG2A as well as the triggering receptors NKp30 and NKp46, in line with previous observations in HIV-infected patients. High-dimensional characterization of these NK cells highlighted a decreased expression of three additional major triggering receptors required for NK cell activation, NKG2D, DNAM-1, and CD96. A high proportion of CD56−CD16+ NK cells at diagnosis was associated with an adverse clinical outcome and decreased overall survival (HR = 0.13; P = 0.0002) and event-free survival (HR = 0.33; P = 0.018) and retained statistical significance in multivariate analysis. Pseudotime analysis of the NK cell compartment highlighted a disruption of the maturation process, with a bifurcation from conventional NK cells toward CD56−CD16+ NK cells. Overall, our data suggest that the accumulation of CD56−CD16+ NK cells may be the consequence of immune escape from innate immunity during AML progression.
Published: 2021

8. Corrigendum: Unveiling Interindividual Variability of Human Fibroblast Innate Immune Response Using Robust Cell-Based Protocols

Author: Audrey Chansard, Nelly Dubrulle, Mathilde Poujol de Molliens, Pierre B. Falanga, Tharshana Stephen, Milena Hasan, Ger van Zandbergen, Nathalie Aulner, Spencer L. Shorte, Brigitte David-Watine, the Milieu Intérieur Consortium, Laurent Abel, Andres Alcover, Hugues Aschard, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Ivo Gomperts-Boneca, Serge Hercberg, Olivier Lantz, Hugo Mouquet, Etienne Patin, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert, Mathilde Trouvier, Marie-Noëlle Ungeheuer, Darragh Duffy, Matthew L. Albert, Lluis Quintana-Murci, BioImagerie Photonique – Photonic BioImaging (UTechS PBI), Institut Pasteur [Paris], Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Paul-Ehrlich-Institute - Federal Institute for Vaccines and Biomedicines (EPI), Institut Pasteur Korea - Institut Pasteur de Corée, Réseau International des Instituts Pasteur (RIIP), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Lipopolysaccharides, 0301 basic medicine, Cell, Gene Expression, Herpesvirus 1, Human, immortalization, NF-κB, 0302 clinical medicine, TLR (Toll like receptors), FACS, innate immunity, human primary cells, HSV-1, cytokines, Angeborene Immunität, Genes, Reporter, Immunology and Allergy, Polylysine, NF-kB, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Original Research, education.field_of_study, Middle Aged, Flow Cytometry, medicine.anatomical_structure, Host-Pathogen Interactions, [SDV.IMM]Life Sciences [q-bio]/Immunology, Biological Assay, Female, Cell activation, Population, Immunology, Context (language use), Computational biology, Biology, Cell Line, 03 medical and health sciences, Immune system, medicine, Humans, education, Fibroblast, Innate immune system, Correction, Fibroblasts, RC581-607, Immunity, Innate, Toll-Like Receptor 3, Toll-Like Receptor 4, Poly I-C, 030104 developmental biology, Biological Variation, Population, TLR3, Immunologic diseases. Allergy, 030217 neurology & neurosurgery, 030215 immunology
Abstract: The LabEx Milieu Interieur (MI) project is a clinical study centered on the detailed characterization of the baseline and induced immune responses in blood samples from 1,000 healthy donors. Analyses of these samples has lay ground for seminal studies on the genetic and environmental determinants of immunologic variance in a healthy cohort population. In the current study we developed in vitro methods enabling standardized quantification of MI-cohort-derived primary fibroblasts responses. Our results show that in vitro human donor cohort fibroblast responses to stimulation by different MAMPs analogs allows to characterize individual donor immune-phenotype variability. The results provide proof-of-concept foundation to a new experimental framework for such studies. A bio-bank of primary fibroblast lines was generated from 323 out of 1,000 healthy individuals selected from the MI-study cohort. To study inter-donor variability of innate immune response in primary human dermal fibroblasts we chose to measure the TLR3 and TLR4 response pathways, both receptors being expressed and previously studied in fibroblasts. We established high-throughput automation compatible methods for standardized primary fibroblast cell activation, using purified MAMPS analogs, poly I:C and LPS that stimulate TLR3 and TLR4 pathways respectively. These results were in turn compared with a stimulation method using infection by HSV-1 virus. Our “Add-only” protocol minimizes high-throughput automation system variability facilitating whole process automation from cell plating through stimulation to recovery of cell supernatants, and fluorescent labeling. Images were acquired automatically by high-throughput acquisition on an automated high-content imaging microscope. Under these methodological conditions standardized image acquisition provided for quantification of cellular responses allowing biological variability to be measured with low system noise and high biological signal fidelity. Optimal for automated analysis of immuno-phenotype of primary human cell responses our method and experimental framework as reported here is highly compatible to high-throughput screening protocols like those necessary for chemo-genomic screening. In context of primary fibroblasts derived from donors enrolled to the MI-clinical-study our results open the way to assert the utility of studying immune-phenotype characteristics relevant to a human clinical cohort.
Published: 2021
Full Text: View/download PDF

9. Accelerated thymopoiesis and improved T‐cell responses in HLA‐A2/‐DR2 transgenic BRGS‐based human immune system mice

Author: Sylvie Darche, Hergen Spits, James P. Di Santo, Helene Strick-Marchand, Silvia Lopez-Lastra, Yan Li, Guillemette Masse-Ranson, Olivier Schwartz, Maud Boussand, Mathilde Dusséaux, Yves Levy, Antoine Toubert, Timothée Bruel, Oriane Fiquet, Erwan Corcuff, Mireille Centlivre, Nicolas Legrand, Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'immunologie clinique et maladies infectieuses [Créteil], Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Supported by grants from the Institut Pasteur, INSERM, Gates Foundation (Grand Challenges in Global Health, J.P.D.), Agence Nationale de la Recherche (ANR) programme RPIB (Im_HIS, J.P.D.), the Laboratoire d'Excellence REVIVE (ANR‐10‐LABX‐73, J.P.D.), the Laboratoire d'Excellence Vaccine Research Institute (ANR‐10‐LABX‐77, Y.L.), the Laboratoire d'Excellence Milieu Intérieur (ANR‐10‐LABX‐69, H.M.), the Laboratoire d'Excellence IBEID (ANR‐10‐LABX‐62, O.S.), the Agence Nationale de Recherche sur le SIDA et les hepatites virales (ANRS 15465, O.S.), the European Commission Seventh Framework Programme n°305578 (PathCO, J.P.D.), and Gilead Sciences (00397, O.S. and J.P.D.)., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), European Project: 305578,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,PATHCO(2012), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaccine Research Institute (VRI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Experimental Immunology, AGEM - Digestive immunity, and AII - Inflammatory diseases
Subjects: MESH: Cell Differentiation, MESH: Mice, Transgenic, T-Lymphocytes, Transgene, T cell, Immunology, MESH: Mice, Inbred BALB C, Mice, Transgenic, Human leukocyte antigen, Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunity, Humanized mice, MESH: B-Lymphocytes, MESH: HLA-A2 Antigen, HLA-A2 Antigen, medicine, Animals, Humans, Immunology and Allergy, MESH: Animals, HLA-DR2 Antigen, MESH: Mice, 030304 developmental biology, B-Lymphocytes, Mice, Inbred BALB C, 0303 health sciences, MESH: Humans, Lymphopoiesis, Cell Differentiation, MESH: Lymphopoiesis, Animal models, 3. Good health, Cell biology, Disease Models, Animal, MESH: HLA-DR2 Antigen, Lymphocyte development, MESH: T-Lymphocytes, medicine.anatomical_structure, Lymphatic system, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, MESH: Disease Models, Animal, Stem cell, CD8, 030215 immunology
Abstract: International audience; Human immune system (HIS) mouse models provide a robust in vivo platform to study human immunity. Nevertheless, the signals that guide human lymphocyte differentiation in HIS mice remain poorly understood. Here, we have developed a novel Balb/c Rag2-/- Il2rg-/- SirpaNOD (BRGS) HIS mouse model expressing human HLA-A2 and -DR2 transgenes (BRGSA2DR2). When comparing BRGS and BRGSA2DR2 HIS mice engrafted with human CD34+ stem cells, a more rapid emergence of T cells in the circulation of hosts bearing human HLA was shown, which may reflect a more efficient human T-cell development in the mouse thymus. Development of CD4+ and CD8+ T cells was accelerated in BRGSA2DR2 HIS mice and generated more balanced B and T-cell compartments in peripheral lymphoid organs. Both B- and T-cell function appeared enhanced in the presence of human HLA transgenes with higher levels of class switched Ig, increased percentages of polyfunctional T cells and clear evidence for antigen-specific T-cell responses following immunization. Taken together, the presence of human HLA class I and II molecules can improve multiple aspects of human B- and T-cell homeostasis and function in the BRGS-based HIS mouse model.
Published: 2019

10. Successful in utero stem cell transplantation in X-linked severe combined immunodeficiency

Author: Aurélie Gabrion, Elisabeth A. Macintyre, Emmanuel Clave, Anne-Marie Darras, Alessandra Magnani, Stéphane Blanche, Brigitte Ternaux, Antoine Toubert, Capucine Picard, Marina Cavazzana, Cécile Roudaut, Laure Caccavelli, Jérémie Rosain, Elisa Magrin, Nizar Mahlaoui, Jennifer Nisoy, Fabien Touzot, Marion Alcantara, Isabelle Radford-Weiss, Jean-Marie Jouannic, Sven Kracker, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre pluridisciplinaire de diagnostic prénatal [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], CHU Necker - Enfants Malades [AP-HP], Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: Transplantation Conditioning, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Hematopoietic stem cell transplantation, X-Linked Combined Immunodeficiency Diseases, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, X-linked severe combined immunodeficiency, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Severe combined immunodeficiency, business.industry, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, Stimulus Report, 3. Good health, Transplantation, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, In utero, Child, Preschool, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Bone marrow, Stem cell, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Key Points IUT enables rapid immune reconstitution and avoids many clinical and economic problems; however, the indication is still limited. IUT may be a treatment option in select cases, eg, fetuses exposed to a significant infectious risk, where a matched sibling donor exists.
Published: 2019

11. Mother Donors Improve Outcomes after HLA Haploidentical Transplantation: A Study by the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation

Author: Loredana Ruggeri, Dirk-Jan Eikema, Attilio Bondanza, Maddalena Noviello, Anja van Biezen, Liesbeth C. de Wreede, Lara Crucitti, Luca Vago, Sara Ciardelli, Peter Bader, Yener Koc, Franco Locatelli, Joan H. Veelken, Bernd Gruhn, Pamela Evans, Christian Chabannon, Antoine Toubert, Andrea Velardi, Ruggeri, L., Eikema, D. -J., Bondanza, A., Noviello, M., van Biezen, A., de Wreede, L. C., Crucitti, L., Vago, L., Ciardelli, S., Bader, P., Koc, Y., Locatelli, F., Veelken, J. H., Gruhn, B., Evans, P., Chabannon, C., Toubert, A., and Velardi, A.
Subjects: Adult, Transplantation, Haploidentical hematopoietic stem cell transplantation, Mothers, Cell Biology, Hematology, stem cell transplantation, Leukemia, Myeloid, Acute, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Haploidentical hematopoietic, Bone Marrow, Pregnancy, Transplantation, Haploidentical, Humans, Molecular Medicine, Immunology and Allergy, Female, Child, Maternal donor, Retrospective Studies
Abstract: Transplacental trafficking of maternal and fetal cells during pregnancy establishes long-term reciprocal microchimerism in both mother and child. Consequently, the maternal immune system may become sensitized to paternal histocompatibility antigens. It has been hypothesized that mother's "exposure" to paternal HLA haplotype antigens during pregnancy may affect the outcome of hematopoietic stem cell transplantation (HSCT) when the mother serves as a donor for the child. In T cell-depleted HLA-haploidentical HSCT, maternal donors have been associated with improved transplantation outcomes. The present retrospective multicenter study, conducted on behalf of the Cellular Therapy and Immunobiology Working Party of the European Society of Blood and Marrow Transplantation, involved 409 patients (102 pediatric and 307 adult) with acute leukemia who underwent HLA-haploidentical HSCT. The goal of the study was to evaluate the role of maternal donors in a large cohort of haploidentical transplantation recipients. Transplantation from maternal donors was associated with a lower relapse incidence in T cell-depleted HSCTs (hazard ratio [HR], 2.13; 95% confidence interval [CI], 1.16 to 3.92; P = .018) as well as in a limited series of unmanipulated in vivo T cell-depleted HSCTs (HR, 4.15; 95% CI, 0.94 to 18.35; P= .06), along with better graft-versus-host disease/relapse-free survival (GRFS) in T cell-depleted HSCT (HR, 1.67; 95% CI, 1.02 to 2.73; P = .04). These results indicate that the mother is the preferred donor to provide better GRFS in T cell-depleted HLA-haploidentical HSCT for acute leukemia. (C) 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.
Published: 2022

12. Prevalence of UBA1 mutations in MDS/CMML patients with systemic inflammatory and auto-immune disease

Author: Rathana Kim, Valeria Bisio, Raphael Itzykson, Lionel Ades, Mohamed Bedis Dhouaieb, Arsène Mekinian, Pierre Lemaire, Stephanie Mathis, Alice Marceau-Renaut, Claude Preudhomme, Emmanuelle Clappier, Pierre Fenaux, Lin-Pierre Zhao, Antoine Toubert, Bérénice Schell, Olivier Fain, Clémentine Chauvel, Maxime Boy, Lise Larcher, Nicolas Dulphy, and Marie Sebert
Subjects: Male, Cancer Research, MEDLINE, Ubiquitin-Activating Enzymes, Autoimmune Diseases, medicine, Prevalence, Humans, Genetic testing, Aged, Retrospective Studies, Inflammation, medicine.diagnostic_test, business.industry, Case-control study, Retrospective cohort study, Leukemia, Myelomonocytic, Chronic, Hematology, UBA1, Middle Aged, medicine.disease, Prognosis, Leukemia, Oncology, Case-Control Studies, Myelodysplastic Syndromes, Mutation (genetic algorithm), Immunology, Mutation, Auto immune disease, business
Published: 2021

13. Altered Basal Lipid Metabolism Underlies the Functional Impairment of Naive CD8

Author: Francesco, Nicoli, Mariela P, Cabral-Piccin, Laura, Papagno, Eleonora, Gallerani, Mathieu, Fusaro, Victor, Folcher, Marion, Dubois, Emmanuel, Clave, Hélène, Vallet, Justin J, Frere, Emma, Gostick, Sian, Llewellyn-Lacey, David A, Price, Antoine, Toubert, Loïc, Dupré, Jacques, Boddaert, Antonella, Caputo, Riccardo, Gavioli, and Victor, Appay
Subjects: Adult, Male, Aging, Apoptosis, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Cancer Vaccines, Rosiglitazone, Young Adult, MART-1 Antigen, Fenofibrate, Neoplasms, HLA-A2 Antigen, Influenza, Human, Humans, Single-Blind Method, Aged, Hypolipidemic Agents, Aged, 80 and over, Vaccination, COVID-19, Viral Vaccines, Middle Aged, Lipid Metabolism, Peptide Fragments, Glucose, Female, Immunocompetence, Cell Division
Abstract: Aging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered Ags. The mechanisms that underlie this phenomenon have nonetheless remained unclear. We found that naive CD8
Published: 2021

14. The role of the thymus in allogeneic bone marrow transplantation and the recovery of the peripheral T-cell compartment

Author: Antoine Toubert, Franco Locatelli, Lucas C. M. Arruda, Emmanuel Clave, Enrico Velardi, and Francesca Benini
Subjects: 0301 basic medicine, medicine.medical_treatment, T cell, T-Lymphocytes, Immunology, Recent Thymic Emigrant, Graft vs Host Disease, Hematopoietic stem cell transplantation, Neogenesis, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunology and Allergy, Medicine, Humans, Transplantation, Homologous, Cytoreductive therapies, Receptor, Bone Marrow Transplantation, biology, business.industry, Regeneration (biology), T-cells, Hematopoietic Stem Cell Transplantation, Immune reconstitution, Allogeneic hematopoietic stem cell transplantation, thymus, biology.organism_classification, Acquired immune system, Thymus, 030104 developmental biology, medicine.anatomical_structure, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, business, 030215 immunology
Abstract: As the thymus represents the primary site of T-cell development, optimal thymic function is of paramount importance for the successful reconstitution of the adaptive immunity after allogeneic hematopoietic stem cell transplantation. Thymus involutes as part of the aging process and several factors, including previous chemotherapy treatments, conditioning regimen used in preparation to the allograft, occurrence of graft-versus-host disease, and steroid therapy that impair the integrity of the thymus, thus affecting its role in supporting T-cell neogenesis. Although the pathways governing its regeneration are still poorly understood, the thymus has a remarkable capacity to recover its function after damage. Measurement of both recent thymic emigrants and T-cell receptor excision circles is valuable tools to assess thymic output and gain insights on its function. In this review, we will extensively discuss available data on factors regulating thymic function after allogeneic hematopoietic stem cell transplantation, as well as the strategies and therapeutic approaches under investigation to promote thymic reconstitution and accelerate immune recovery in transplanted patients, including the use of cytokines, sex-steroid ablation, precursor T-cells, and thymus bioengineering. Although none of them is routinely used in the clinic, these approaches have the potential to enhance thymic function and immune recovery, not only in patients given an allograft but also in other conditions characterized by immune deficiencies related to a defective function of the thymus.
Published: 2021

15. Severe Altered Immune Status After Burn Injury Is Associated With Bacterial Infection and Septic Shock

Author: Hélène Moins-Teisserenc, Debora Jorge Cordeiro, Vincent Audigier, Quentin Ressaire, Mourad Benyamina, Jérome Lambert, Guitta Maki, Laurence Homyrda, Antoine Toubert, Matthieu Legrand, Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CEDRIC. Méthodes statistiques de data-mining et apprentissage (CEDRIC - MSDMA), Centre d'études et de recherche en informatique et communications (CEDRIC), Ecole Nationale Supérieure d'Informatique pour l'Industrie et l'Entreprise (ENSIIE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Ecole Nationale Supérieure d'Informatique pour l'Industrie et l'Entreprise (ENSIIE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Université de Paris (UP), University of California [Los Angeles] (UCLA), University of California, ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Audigier, Vincent, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ecole Nationale Supérieure d'Informatique pour l'Industrie et l'Entreprise (ENSIIE)-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)-Ecole Nationale Supérieure d'Informatique pour l'Industrie et l'Entreprise (ENSIIE)-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 Paris Cité (UPCité), and University of California (UC)
Subjects: Male, Burn injury, T-Lymphocytes, Comorbidity, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 2.1 Biological and endogenous factors, Immunology and Allergy, 030212 general & internal medicine, Aetiology, Original Research, intensive care, immunosuppression, Shock, Hematology, Bacterial Infections, Middle Aged, Acquired immune system, Shock, Septic, 3. Good health, Infectious Diseases, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Medical Microbiology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, outcome, Cytokines, Female, Disease Susceptibility, medicine.symptom, Infection, lcsh:Immunologic diseases. Allergy, Adult, Physical Injury - Accidents and Adverse Effects, Secondary infection, Immunology, Inflammation, Immunophenotyping, 03 medical and health sciences, Immunocompromised Host, burns, Immune system, Clinical Research, Sepsis, Intensive care, medicine, Humans, Mortality, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Innate immune system, Septic shock, business.industry, Septic, Inflammatory and immune system, 030208 emergency & critical care medicine, biochemical phenomena, metabolism, and nutrition, medicine.disease, Good Health and Well Being, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, inflammation, bacteria, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, lcsh:RC581-607, business, prognostic, Biomarkers
Abstract: Introduction: Burn injury is associated with a high risk of death. Whether a pattern of immune and inflammatory responses after burn is associated with outcome is unknown. The aim of this study was to explore the association between systemic immune and inflammatory responses and outcome in severely-ill burn patients.Materials and Methods: Innate immunity, adaptive immunity, activation and stress and inflammation biomarkers were collected at admission and days 2, 7, 14, and 28 in severely-ill adult burn patients. Primary endpoint was mortality at day 90, secondary endpoint was secondary infections. Healthy donors (HD) served as controls. Multiple Factorial Analysis (MFA) was used to identify patterns of immune response.Results: 50 patients were included. Age was 49.2 (44.2–54.2) years, total burn body surface area was 38.0% (32.7–43.3). Burn injury showed an upregulation of adaptive immunity and activation biomarkers and a down regulation of innate immunity and stress/inflammation biomarkers. High interleukin-10 (IL-10) at admission was associated with risk of death. However, no cluster of immune/inflammatory biomarkers at early timepoints was associated with mortality. HLA-DR molecules on monocytes at admission were associated with bacterial infections and septic shock. Later altered immune/inflammatory responses in patients who died may had been driven by the development of septic shock.Conclusion: Burn injury induced an early and profound upregulation of adaptive immunity and activation biomarkers and a down regulation of innate immunity and stress/inflammation biomarkers. Immune and inflammatory responses were associated with bacterial infection and septic shock. Absence of immune recovery patterns was associated with poor prognosis.
Published: 2021

16. Natural killer cell alloreactivity in HLA-haploidentical hematopoietic transplantation: a study on behalf of the CTIWP of the EBMT

Author: Linda Koster, Mara Merluzzi, Miguel Angel Diaz, Loredana Ruggeri, Arnon Nagler, Andrea Velardi, Steffie van der Werf, Franco Locatelli, Pavel Jindra, José Luis Díez-Martín, Diderik-Jan Eikema, Chiara Bonini, Anja van Biezen, Antoine Toubert, Luca Vago, Christian Chabannon, Liesbeth C. de Wreede, Fabio Ciceri, José A. Pérez-Simón, Giuseppe Milone, Ruggeri, L., Vago, L., Eikema, D. -J., de Wreede, L. C., Ciceri, F., Diaz, M. A., Locatelli, F., Jindra, P., Milone, G., Diez-Martin, J. L., Perez-Simon, J. A., Merluzzi, M., Koster, L., van der Werf, S., van Biezen, A., Toubert, A., Nagler, A., Chabannon, C., Bonini, C., and Velardi, A.
Subjects: Myeloid, NK, Graft vs Host Disease, Human leukocyte antigen, Natural killer cell, Cell therapy, Mice, Medicine, Animals, Humans, Prospective Studies, Prospective cohort study, Transplantation, business.industry, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Hematology, Killer Cells, Natural, Haematopoiesis, Leukemia, Myeloid, Acute, surgical procedures, operative, medicine.anatomical_structure, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Immunology, Transplantation, Haploidentical, business
Abstract: Human leukocyte antigen (HLA) class-I mismatches that trigger donor-versus-recipient natural killer (NK)-cell alloreactivity reduce the incidence of leukemia relapse and improve survival of acute myeloid leukemia patients after T-cell-depleted HLA-haplotype mismatched (“haploidentical”) hematopoietic transplantation. In murine graft-versus-host disease (GvHD) models, alloreactive NK-cells also prevent GvHD. Here we report the results of a non-interventional, prospective study performed on behalf of the Cellular Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation. The study was aimed at re-assessing the role of NK-cell alloreactivity in a cohort of haploidentical transplants performed in Europe between 2012 and 2015 and composed of unmanipulated, as well as T-cell-depleted transplants. One hundred thirty-eight patients with acute myeloid or lymphoid leukemias were analyzed. Eighty-six patients received ex-vivo T-cell-depleted transplants, 52 patients received unmanipulated transplants. Fifty patients were transplanted from NK alloreactive donors, 88 from non-NK alloreactive donors. NK cell alloreactivity did not impact on GvHD/relapse-free survival (GRFS) in unmanipulated transplants (HR: 1.66 (0.9–3.1), p = 0.1). In contrast, it did impact beneficially on GRFS in T-cell-depleted transplants (HR: 0.6, (0.3–1.2), p = 0.14, interaction p < 0.001). This effect was the consequence of reduced incidences of acute and chronic GvHD and non-relapse mortality.
Published: 2021

17. Immune system and intestinal microbiota determine efficacy of androgen deprivation therapy against prostate cancer

Author: Safae Terrisse, Anne-Gaelle Goubet, Kousuke Ueda, Andrew Maltez Thomas, Valentin Quiniou, Cassandra Thelemaque, Garett Dunsmore, Emmanuel Clave, Melissa Gamat-Huber, Satoru Yonekura, Gladys Ferrere, Conrad Rauber, Hang Phuong Pham, Jean-Eudes Fahrner, Eugenie Pizzato, Pierre Ly, Marine Fidelle, Marine Mazzenga, Carolina Alves Costa Silva, Federica Armanini, Federica Pinto, Francesco Asnicar, Romain Daillère, Lisa Derosa, Corentin Richard, Pierre Blanchard, Bertrand Routy, Stéphane Culine, Paule Opolon, Aymeric Silvin, Florent Ginhoux, Antoine Toubert, Nicola Segata, Douglas G McNeel, Karim Fizazi, Guido Kroemer, and Laurence Zitvogel
Subjects: Male, Pharmacology, Cancer Research, Immunology, Prostatic Neoplasms, Androgen Antagonists, adaptive immunity, immunomodulation, Castration-Resistant, Gastrointestinal Microbiome, Prostatic Neoplasms, Castration-Resistant, Mice, prostatic neoplasms, translational medical research, Androgens, Animals, Humans, Immune System, Oncology, Molecular Medicine, Immunology and Allergy
Abstract: BackgroundProstate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT.MethodsPreclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients (Oncobiotic trial) to analyze their feces and blood specimens.ResultsIn PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice or oral gavage with Akkermansia improved the efficacy of ADT. This appears to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy, feces from PC patients failed to do so.ConclusionsThese findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients.
Published: 2022

18. Genomic landscape of MDS/CMML associated with systemic inflammatory and autoimmune disease

Author: Lin-Pierre, Zhao, Maxime, Boy, Célia, Azoulay, Emmanuelle, Clappier, Marie, Sébert, Ludivine, Amable, Jihene, Klibi, Kamel, Benlagha, Marion, Espéli, Karl, Balabanian, Claude, Preudhomme, Alice, Marceau-Renaut, Lina, Benajiba, Raphaël, Itzykson, Arsène, Mekinian, Olivier, Fain, Antoine, Toubert, Pierre, Fenaux, Nicolas, Dulphy, and Lionel, Adès
Subjects: Inflammation, Myelodysplastic Syndromes, Mutation, Biomarkers, Tumor, Humans, Leukemia, Myelomonocytic, Chronic, Genomics, Prognosis, Autoimmune Diseases, Retrospective Studies
Published: 2020

19. Evaluating Thymic Function After Human Hematopoietic Stem Cell Transplantation in the Personalized Medicine Era

Author: Ahmed, Gaballa, Emmanuel, Clave, Michael, Uhlin, Antoine, Toubert, and Lucas C M, Arruda
Subjects: Lymphopoiesis, Mini Review, T-cells, Immunology, Thymus Gland, immune reconstitution, surgical procedures, operative, thymus, thymic function, hematopoietic stem cell transplantation, Humans, Immunology and Allergy, Precision Medicine, TREC
Abstract: Hematopoietic stem cell transplantation (HSCT) is an effective treatment option for several malignant and non-malignant hematological diseases. The clinical outcome of this procedure relies to a large extent on optimal recovery of adaptive immunity. In this regard, the thymus plays a central role as the primary site for de novo generation of functional, diverse, and immunocompetent T-lymphocytes. The thymus is exquisitely sensitive to several insults during HSCT, including conditioning drugs, corticosteroids, infections, and graft-vs.-host disease. Impaired thymic recovery has been clearly associated with increased risk of opportunistic infections and poor clinical outcomes in HSCT recipients. Therefore, better understanding of thymic function can provide valuable information for improving HSCT outcomes. Recent data have shown that, besides gender and age, a specific single-nucleotide polymorphism affects thymopoiesis and may also influence thymic output post-HSCT, suggesting that the time of precision medicine of thymic function has arrived. Here, we review the current knowledge about thymic role in HSCT and the recent work of genetic control of human thymopoiesis. We also discuss different transplant-related factors that have been associated with impaired thymic recovery and the use of T-cell receptor excision circles (TREC) to assess thymic output, including its clinical significance. Finally, we present therapeutic strategies that could boost thymic recovery post-HSCT.
Published: 2020
Full Text: View/download PDF

20. Editorial: Immune Profile After Autologous Hematopoietic Stem Cell Transplantation for Autoimmune Diseases: Where Do We Stand?

Author: Kelen Cristina Ribeiro Malmegrim, Antoine Toubert, Dominique Farge, and Maria Carolina Oliveira
Subjects: lcsh:Immunologic diseases. Allergy, immune monitoring, business.industry, medicine.medical_treatment, Immunology, immune reconstitution, Hematopoietic stem cell transplantation, Immune monitoring, Transplantation, Autologous, Cell therapy, Editorial, Immune system, hematopoietic stem cell transplantation, Humans, Immunology and Allergy, Medicine, autoimmune diseases, cell therapy, lcsh:RC581-607, business
Published: 2020

21. Compatibility at amino acid position 98 of MICB reduces the incidence of graft-versus host disease in conjunction with the CMV status

Author: Philippe Moreau, Machteld Oudshoorn, Catherine Paillard, Valérie Dubois, Raphael Carapito, Irina Kotova, Antoine Toubert, Ismail Aouadi, Perrine Spinnhirny, Eric Spierings, A. Parissiadis, Ibrahim Yakoub-Agha, Mauricette Michallet, Myriam Labalette, Seiamak Bahram, Régis Peffault de Latour, Jürgen Kuball, Mohamad Mohty, Christophe Picard, Bronno van der Holt, Didier Blaise, Ryad Tamouza, Myriam Maumy-Bertrand, Frédéric Bertrand, Pascale Loiseau, Véronique Rolli, Jan J. Cornelissen, Aurore Morlon, Anne Cesbron, Gérard Socié, Yasuo Morishima, Peter A. von dem Borne, Frans H.J. Claas, Cécile Macquin, Angélique Pichot, Bruno Lioure, Dominique Charron, Katia Gagne, Equipe Plate-forme GENOMAX (Inserm U1109), Fédération Hospitalo-Universitaire OMICARE-Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA)-Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), LabEx Transplantex [Strasbourg], Université de Strasbourg (UNISTRA), INSERM Franco-Japanese Nextgen HLA Laboratory [Strasbourg] (FJ-HLA), Laboratoire International Associé (LIA), INSERM Franco-Japanese Nextgen HLA Laboratory[Nagano], Pôle de Biologie - Laboratoire d’Immunologie [Nouvel Hôpital Civil, Strasbourg] (Plateau Technique de Biologie), Nouvel Hôpital Civil - NHC [Strasbourg], BIOMICA SA [Strasbourg], Etablissement Français du Sang [Nantes], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Europdonor operated by Matchis Foundation [Leiden], Leiden University Medical Center (LUMC), Erasmus MC Cancer Institute, Rotterdam, Laboratoire d'Immunologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Medical Center [Utrecht], Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Etablissement Français du Sang - Grand Est (EFS - alsace strasbourg), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut de Recherche Mathématique Avancée (IRMA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Hôtel-Dieu [Paris], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre & marie Curie, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [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), Aichi Cancer Center Research Institute, This work was supported by grants from the Agence Nationale de la Recherche (ANR) (ANR-11-LABX-0070_TRANSPLANTEX), and the INSERM (UMR_S 1109), the Institut Universitaire de France (IUF), all to SB, from the University of Strasbourg (IDEX UNISTRA) to CP and SB, from the European regional development fund (European Union) INTERREG V program (project n°3.2 TRIDIAG) to RC and SB, and from MSD-Avenir grant AUTOGEN to SB., We would like to thank Prof. Robert Zeiser (University of Freiburg/Germany) for critical reading of this manuscript. We thank Martin Verniquet for critical review of statistical analyses. We would also like to thank Nicole Raus (SFGM-TC, Lyon, France) for retrieving the clinical data from the ProMISe database., Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Hospitalo-Universitaire OMICARE-Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA)-Université de Strasbourg (UNISTRA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Universiteit Leiden, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hematology, Erasmus MC other, and Bernardo, Elizabeth
Subjects: medicine.medical_specialty, Congenital cytomegalovirus infection, Graft vs Host Disease, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Typing, Amino Acids, Retrospective Studies, Transplantation, business.industry, Incidence (epidemiology), Incidence, Hazard ratio, Hematopoietic Stem Cell Transplantation, Hematology, medicine.disease, 3. Good health, Graft-versus-host disease, 030220 oncology & carcinogenesis, Cytomegalovirus Infections, business, 030215 immunology
Abstract: International audience; Graft-versus-host disease (GVHD) and cytomegalovirus (CMV)-related complications are leading causes of mortality after unrelated-donor hematopoietic cell transplantation (UD-HCT). The non-conventional MHC class I gene MICB, alike MICA, encodes a stress-induced polymorphic NKG2D ligand. However, unlike MICA, MICB interacts with the CMV-encoded UL16, which sequestrates MICB intracellularly, leading to immune evasion. Here, we retrospectively analyzed the impact of mismatches in MICB amino acid position 98 (MICB98), a key polymorphic residue involved in UL16 binding, in 943 UD-HCT pairs who were allele-matched at HLA-A, -B, -C, -DRB1, -DQB1 and MICA loci. HLA-DP typing was further available. MICB98 mismatches were significantly associated with an increased incidence of acute (grade II-IV: HR, 1.20; 95% CI, 1.15 to 1.24; P < 0.001; grade III-IV: HR, 2.28; 95% CI, 1.56 to 3.34; P < 0.001) and chronic GVHD (HR, 1.21; 95% CI, 1.10 to 1.33; P < 0.001). MICB98 matching significantly reduced the effect of CMV status on overall mortality from a hazard ratio of 1.77 to 1.16. MICB98 mismatches showed a GVHD-independent association with a higher incidence of CMV infection/reactivation (HR, 1.84; 95% CI, 1.34 to 2.51; P < 0.001). Hence selecting a MICB98-matched donor significantly reduces the GVHD incidence and lowers the impact of CMV status on overall survival.
Published: 2020

22. Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients

Author: Emmanuel Clave, Kelen C. R. Malmegrim, Hélène Moins-Teisserenc, Corinne Douay, Dimas Tadeu Covas, Antonio José Alberdi, Belinda Pinto Simões, Pauline Lansiaux, Maria Carolina Oliveira, Isabelle Fournier, Antoine Toubert, Lucas C. M. Arruda, João R Lima-Júnior, Juliana Bernardes Elias Dias, and Daniela A. Moraes
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_treatment, Recent Thymic Emigrant, chemical and pharmacologic phenomena, Thymus Gland, Hematopoietic stem cell transplantation, Systemic scleroderma, T-Lymphocytes, Regulatory, Transplantation, Autologous, Neogenesis, Young Adult, 03 medical and health sciences, Immune system, Bone Marrow, medicine, Humans, Lymphocyte Count, Retrospective Studies, B-Lymphocytes, Transplantation, TIMO (GLÂNDULA ENDÓCRINA), Scleroderma, Systemic, biology, business.industry, T-cell receptor, Hematopoietic Stem Cell Transplantation, hemic and immune systems, Hematology, Middle Aged, Prognosis, medicine.disease, biology.organism_classification, Interleukin 10, Treatment Outcome, 030104 developmental biology, medicine.anatomical_structure, Immune System, Immunology, Female, Bone marrow, business
Abstract: To evaluate the immunological mechanisms associated with clinical outcomes after autologous hematopoietic stem cell transplantation (AHSCT), focusing on regulatory T- (Treg) and B- (Breg) cell immune reconstitution, 31 systemic sclerosis (SSc) patients underwent simultaneous clinical and immunological evaluations over 36-month posttransplantation follow-up. Patients were retrospectively grouped into responders (n = 25) and nonresponders (n = 6), according to clinical response after AHSCT. Thymic function and B-cell neogenesis were respectively assessed by quantification of DNA excision circles generated during T- and B-cell receptor rearrangements. At the 1-year post-AHSCT evaluation of the total set of transplanted SSc patients, thymic rebound led to renewal of the immune system, with higher T-cell receptor (TCR) diversity, positive correlation between recent thymic emigrant and Treg counts, and higher expression of CTLA-4 and GITR on Tregs, when compared with pretransplant levels. In parallel, increased bone marrow output of newly generated naive B-cells, starting at 6 months after AHSCT, renovated the B-cell populations in peripheral blood. At 6 and 12 months after AHSCT, Bregs increased and produced higher interleukin-10 levels than before transplant. When the nonresponder patients were evaluated separately, Treg and Breg counts did not increase after AHSCT, and high TCR repertoire overlap between pre- and posttransplant periods indicated maintenance of underlying disease mechanisms. These data suggest that clinical improvement of SSc patients is related to increased counts of newly generated Tregs and Bregs after AHSCT as a result of coordinated thymic and bone marrow rebound.
Published: 2018

23. Circulating and skin-derived Sézary cells: clonal but with phenotypic plasticity

Author: Caroline Ram-Wolff, Martine Bagot, Anne Marie-Cardine, Marc Delord, Hélène Moins-Teisserenc, Antonio José Alberdi, Laurence Homyrda, Guitta Maki, Armand Bensussan, Marie Roelens, and Antoine Toubert
Subjects: 0301 basic medicine, Skin Neoplasms, Receptors, Antigen, T-Cell, alpha-beta, T cell, Immunology, Cell Separation, Biology, Biochemistry, Immunophenotyping, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Antigens, CD, Antigens, Neoplasm, T-Lymphocyte Subsets, hemic and lymphatic diseases, Biomarkers, Tumor, medicine, Humans, Sezary Syndrome, Gene Rearrangement, beta-Chain T-Cell Antigen Receptor, Receptors, Cytokine, Receptor, Sezary Cell, Skin, medicine.diagnostic_test, T-cell receptor, Receptors, KIR3DL2, Cell Biology, Hematology, Gene rearrangement, Flow Cytometry, Neoplastic Cells, Circulating, Molecular biology, Clone Cells, 030104 developmental biology, medicine.anatomical_structure, Receptors, KIR2DL2, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Cytokines, Transcriptome, Immunologic Memory, CD8
Abstract: To the editor: Sezary syndrome (SS) is a rare, aggressive leukemic form of primary cutaneous T-cell lymphoma.[1][1] The diagnostic criteria associate a clonal T-cell receptor (TCR) rearrangement with peripheral Sezary cell (SC) counts of ≥1 G/L, an increased CD4/CD8 ratio of ≥10, CD4+CD7−
Published: 2017

24. Revisiting the initial diagnosis and blood staging of Mycosis Fungoides and Sézary Syndrome with the KIR 3 DL 2 marker

Author: Caroline Ram-Wolff, J‐M. Cayuela, Hélène Moins-Teisserenc, A. de Masson, Anne Marie-Cardine, Martine Bagot, Marie Roelens, Guitta Maki, Armand Bensussan, Antoine Toubert, Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Réseaux, Information, Multimédia (RIM-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Centre G2I, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), L'Oréal Recherche France (L'Oréal Recherche), L'OREAL, and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: Oncology, medicine.medical_specialty, Skin Neoplasms, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, Disease, Flow cytometry, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Mycosis Fungoides, Internal medicine, medicine, Humans, Sezary Syndrome, Prospective Studies, Prospective cohort study, Sezary Cell, ComputingMilieux_MISCELLANEOUS, Mycosis fungoides, medicine.diagnostic_test, business.industry, Reproducibility of Results, Receptors, KIR3DL2, medicine.disease, 3. Good health, Lymphoma, Clinical trial, KIR3DL2, business
Abstract: Background The early diagnosis of Sezary syndrome (SS) is challenging. Loss of CD7 and CD26 expression on CD4+ T cells is the currently used criterion in the initial diagnosis and staging of patients with SS. Objectives Our aim was to evaluate the respective value of CD26, CD7 and KIR3DL2 expression on CD4+ T cells and total lymphocytes at initial diagnosis of SS. Methods This prospective study included 254 patients with clinical features consistent with cutaneous T-cell lymphoma seen at our institution between March 2014 and February 2019. Peripheral blood analysis by flow cytometry was performed for each patient at the time of diagnosis and during follow-up. The diagnosis of SS was based on ISCL/EORTC criteria. Results The presence of KIR3DL2+ Sezary cells (SCs) ≥ 200 μL-1 correlated with the diagnosis of SS, with sensitivity of 88·6% and specificity of 96·3%. All 154 patients with either inflammatory skin disease or other haematological disease had KIR3DL2+ cells Conclusions KIR3DL2 expression on T cells is highly specific and helps the early diagnosis of SS, especially in those patients with lymphopenia. What's already known about this topic? In the ISCL/EORTC cutaneous T-cell lymphoma (CTCL) categorization of blood involvement (B0-B2), B2 is defined as a T-cell receptor clonal rearrangement in blood, associated with high blood-smear Sezary cell (SC) count. Flow cytometry was developed to circumvent interobserver variability of SC manual counts; however, it mostly relies on detection of cells lacking CD7 and/or CD26 expression. We previously reported the reliability of KIR3DL2 as the first positive SC marker. What does this study add? Based on our analysis of 254 patients, we propose that KIR3DL2 be added to the ISCL/EORTC criteria for initial diagnosis of Sezary syndrome (SS) and B2 staging. This marker improved sensitivity of SS B2-stage CTCL diagnosis with a specificity > 95%, especially for patients with lymphopenia. We found KIR3DL2 helped early diagnosis of SS and was more reliable than CD26 in assessing blood tumour burden during therapy. What is the translational message? SC quantification is the major means of staging at initial diagnosis and monitoring blood tumour burden in a clinical trials setting. We recommend using a threshold value of KIR3DL2+ SCs ≥ 200 μL-1 or KIR3DL2+ SCs/lymphocytes ≥ 10% in the diagnostic criteria of SS and propose a novel algorithm for CTCL B2 blood staging.
Published: 2019

25. NKG2D/NKG2-Ligand Pathway Offers New Opportunities in Cancer Treatment

Author: Alexandra Frazao, Louise Rethacker, Meriem Messaoudene, Marie-Françoise Avril, Antoine Toubert, Nicolas Dulphy, and Anne Caignard
Subjects: lcsh:Immunologic diseases. Allergy, 0301 basic medicine, medicine.medical_treatment, Mini Review, Immunology, chemical and pharmacologic phenomena, NKG2, NKG2D ligands, Ligands, NKG2D, 03 medical and health sciences, 0302 clinical medicine, NKG2D CARs, Cell surface receptor, Monitoring, Immunologic, Neoplasms, medicine, Immunology and Allergy, Animals, Humans, natural killer cells, Polymorphism, Genetic, Chemistry, Cell growth, Cancer, hemic and immune systems, Immunotherapy, medicine.disease, Chimeric antigen receptor, biological factors, tumor immunosurveillance, 030104 developmental biology, NK Cell Lectin-Like Receptor Subfamily K, Cancer research, lcsh:RC581-607, Function (biology), 030215 immunology, Signal Transduction
Abstract: The antitumor functions of NK cells are regulated by the integration of positive and negative signals triggered by numerous membrane receptors present on the NK cells themselves. Among the main activating receptors, NKG2D binds several stress-induced molecules on tumor targets. Engagement of NKG2D by its ligands (NKG2D-Ls) induces NK cell activation leading to production of cytokines and target cell lysis. These effects have therapeutic potential as NKG2D-Ls are widely expressed by solid tumors, whereas their expression in healthy cells is limited. Here, we describe the genetic and environmental factors regulating the NKG2D/NKG2D-L pathway in tumors. NKG2D-L expression is linked to cellular stress and cell proliferation, and has been associated with oncogenic mutations. Tumors have been found to alter their to NKG2D-L expression as they progress, which interferes with the antitumor function of the pathway. Nevertheless, this pathway could be advantageously exploited for cancer therapy. Various cancer treatments, including chemotherapy and targeted therapies, indirectly interfere with the cellular and soluble forms of NKG2D-Ls. In addition, NKG2D introduced into chimeric antigen receptors in T- and NK cells is a promising tumor immunotherapy approach.
Published: 2019

26. Recovery of central memory and naive peripheral T cells in Follicular Lymphoma patients receiving rituximab-chemotherapy based regimen

Author: Nathalie Josseaume, P. Brice, Sandy Amorim, Quentin Riller, Benoit Milcent, Sophie Sibéril, Florent Petitprez, Jean-Luc Teillaud, Catherine Thieblemont, Antoine Toubert, Pascale Loiseau, 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)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sorbonne Paris Cité (USPC), Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), NF-kappaB, Différenciation et Cancer (OncokappaB - EA 7324), Université Paris Descartes - Paris 5 (UPD5), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Dieu-Nosjean, Marie-Caroline, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service d'hématologie greffe [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Teillaud, Jean-Luc, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Follicular lymphoma, lcsh:Medicine, CD38, Lymphocyte Activation, 0302 clinical medicine, Immunophenotyping, immune system diseases, T-Lymphocyte Subsets, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, lcsh:Science, Lymphoma, Follicular, Immunity, Cellular, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Treatment Outcome, Vincristine, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, Female, Immunotherapy, medicine.drug, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Adaptive immunity, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, TIGIT, medicine, Humans, Lymphocyte Count, Cyclophosphamide, Aged, Neoplasm Staging, business.industry, lcsh:R, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, 030104 developmental biology, Doxorubicin, Cancer research, Prednisone, lcsh:Q, Neoplasm Grading, business, Immunologic Memory, CD8, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomarkers
Abstract: International audience; Preclinical models and clinical studies have shown that anti-CD20-based treatment has multifaceted consequences on t-cell immunity. We have performed a prospective study of peripheral t-cell compartment in FL patients, all exhibiting high tumor burden and receiving rituximab-chemotherapy-based regimen (R-CHOP). Before treatment, FL patients harbor low amounts of peripheral naive T cells, but high levels of CD4 + t eM , CD4 + t reg and CD8 + t eMRA subsets and significant amounts of CD38 + HLA-DR + activated T cells. A portion of these activated/differentiated T cells also expressed PD-1 and/or TIGIT immune checkpoints. Hierarchical clustering of phenotyping data revealed that 5/8 patients with only a partial response to R-cHop induction therapy or with disease progression segregate into a group exhibiting a highly activated/differentiated T cell profile and a markedly low proportion of naive T cells before treatment. Rituximab-based therapy induced a shift of CD4 + and CD8 + t cells toward a central memory phenotype and of CD8 + T cells to a naive phenotype. In parallel, a decrease in the number of peripheral T cells expressing both PD-1 and TIGIT was detected. These observations suggest that the standard rituximab-based therapy partially reverts the profound alterations observed in t-cell subsets in FL patients, and that blood T-cell phenotyping could provide a better understanding of the mechanisms of rituximab-based treatment. Follicular lymphoma (FL) is the second most common form of non-Hodgkin lymphoma (NHL). Its clinical course is highly variable and survival medians are 7-15 years depending on the studies. Follicular lymphoma management is characterized by a risk-adapted therapy based on the stage of the disease and the symptoms of the patients. For high tumor burden patients, treatment options could be either rituximab plus cyclophosphamide, vincristine and prednisone with (R-CHOP) or without (R-CVP) doxorubicin or other anthracyclines, or rituxi-mab plus fludarabine for patients not eligible for anthracyclines, or rituximab plus bendamustine. Experimental therapies as well as allogeneic stem cell transplantation are rather considered for relapsed and more refractory disease 1. The addition of the anti-CD20 monoclonal antibody (mAb) rituximab to chemotherapy has resulted in a higher rate of complete remission and improved survival 2. In addition, rituximab as maintenance therapy
Published: 2019

27. Standardized Whole-Blood Transcriptional Profiling Enables the Deconvolution of Complex Induced Immune Responses

Author: Alejandra Urrutia, Darragh Duffy, Vincent Rouilly, Céline Posseme, Raouf Djebali, Gabriel Illanes, Valentina Libri, Benoit Albaud, David Gentien, Barbara Piasecka, Milena Hasan, Magnus Fontes, Lluis Quintana-Murci, Matthew L. Albert, Laurent Abel, Andres Alcover, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Antonio Freitas, Odile Gelpi, Ivo Gomperts-Boneca, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, Marie-Noëlle Ungeheuer, Illanes Gabriel, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Matemática., Urrutia Alejandra, Rouilly Vincent, Posseme Céline, Djebali Raouf, Libri Valentina, Albaud Benoit, Gentien David, Piasecka Barbara, Hasan Milena, Fontes Magnus, Quintana-Murci Lluis, Albert Matthew L., Genentech, Inc. [San Francisco], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris], Centro de Matemática [Montevideo] (CMAT), Universidad de la República [Montevideo] (UCUR), International Group for Data Analysis (IGDA), Plateforme de génomique [Institut Curie], Institut Curie [Paris], Centre for Mathematical Sciences, Mathematical Statistics, Lund University [Lund], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work benefited from support of the French government’s Invest in theFuture program managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01), Milieu Intérérieur Consortium (34 collaborateurs) : Abel L, Alcover A, Astrom K, Bousso P, Bruhns P, Cumano A, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Fellay J, Freitas A, Gelpi O, Gomperts-Boneca I, Hercberg S, Lantz O, Leclerc C, Mouquet H, Pellegrini S, Pol S, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Ungeheuer MN, Quintana-Murci L, Albert ML., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Vougny, Marie-Christine, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Universidad de la República [Montevideo] (UDELAR), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Adult, Male, Cell type, [SDV.IMM] Life Sciences [q-bio]/Immunology, Transcription, Genetic, medicine.medical_treatment, Stimulation, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, Complex induced immune responses, Gene expression, medicine, Humans, Lymphocytes, Receptor, Gene, lcsh:QH301-705.5, Innate immune system, Bacteria, Gene Expression Profiling, Toll-Like Receptors, Immunity, 030104 developmental biology, Cytokine, Blood, Gene Expression Regulation, lcsh:Biology (General), Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Female, Whole-blood
Abstract: Figura como autor también el Milieu Intérieur Consortium Systems approaches for the study of immune signaling pathways have been traditionally based on purified cells or cultured lines. However, in vivo responses involve the coordinated action of multiple cell types, which interact to establish an inflammatory microenvironment. We employed standardized whole-blood stimulation systems to test the hypothesis that responses to Toll-like receptor ligands or whole microbes can be defined by the transcriptional signatures of key cytokines. We found 44 genes, identified using Support Vector Machine learning, that captured the diversity of complex innate immune responses with improved segregation between distinct stimuli. Furthermore, we used donor variability to identify shared inter-cellular pathways and trace cytokine loops involved in gene expression. This provides strategies for dimension reduction of large datasets and deconvolution of innate immune responses applicable for characterizing immunomodulatory molecules. Moreover, we provide an interactive R-Shiny application with healthy donor reference values for induced inflammatory genes.
Published: 2016
Full Text: View/download PDF

28. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

Author: Christophe Picard, Cécile Macquin, Sergi Querol, Catherine Paillard, Katharina Fleischhauer, Gaëlle Giacometti, Bronno van der Holt, Ibrahim Yakoub-Agha, Wassila Ilias, Anne Cesbron, Myriam Labopin, Masao Ota, Jorge Sierra, Fabio Ciceri, Dominique Charron, Ryad Tamouza, Régis Peffault de Latour, Xavier Lafarge, Katia Gagne, Seiamak Bahram, Myriam Maumy-Bertrand, Meiggie Untrau, Pascale Loiseau, Raphael Carapito, Jürgen Kuball, Bruno Lioure, Frans H.J. Claas, Noel Milpied, Antoine Toubert, Jan J. Cornelissen, Irina Kotova, Philippe Moreau, Eric Spierings, Mauricette Michallet, Arnon Nagler, Annette Schmitt-Graeff, Angélique Pichot, Petya Apostolova, Mohamad Mohty, Aurore Morlon, Myriam Labalette, Nicolas Jung, Didier Blaise, Yoshihiko Katsuyama, Hidetoshi Inoko, A. Parissiadis, Frédéric Bertrand, Marius Kwemou, Sandra Michel, Machteld Oudshoorn, Gérard Socié, Robert Zeiser, Peter A. von dem Borne, Valérie Dubois, Luca Vago, Carapito, Raphael, Jung, Nicola, Kwemou, Mariu, Untrau, Meiggie, Michel, Sandra, Pichot, Angélique, Giacometti, Gaëlle, Macquin, Cécile, Ilias, Wassila, Morlon, Aurore, Kotova, Irina, Apostolova, Petya, Schmitt Graeff, Annette, Cesbron, Anne, Gagne, Katia, Oudshoorn, Machteld, Van Der Holt, Bronno, Labalette, Myriam, Spierings, Eric, Picard, Christophe, Loiseau, Pascale, Tamouza, Ryad, Toubert, Antoine, Parissiadis, Anne, Dubois, Valérie, Lafarge, Xavier, Maumy Bertrand, Myriam, Bertrand, Frédéric, Vago, Luca, Ciceri, Fabio, Paillard, Catherine, Querol, Sergi, Sierra, Jorge, Fleischhauer, Katharina, Nagler, Arnon, Labopin, Myriam, Inoko, Hidetoshi, Von Dem Borne, Peter A., Kuball, Jürgen, Ota, Masao, Katsuyama, Yoshihiko, Michallet, Mauricette, Lioure, Bruno, De Latour, Régis Peffault, Blaise, Didier, Cornelissen, Jan J., Yakoub Agha, Ibrahim, Claas, Fran, Moreau, Philippe, Milpied, Noël, Charron, Dominique, Mohty, Mohamad, Zeiser, Robert, Socié, Gérard, Bahram, Seiamak, inconnu, Inconnu, Institut de Recherche Mathématique Avancée (IRMA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Mathématiques et Modélisation d'Evry (LaMME), Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), laboratoire d'Etudes et de recherches en Statistiques et Développement (LERSTAD), Université Gaston Bergé Sénégal, Laboratoire d'Acoustique Environnementale (IFSTTAR/AME/LAE), Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université de Lyon-PRES Université Nantes Angers Le Mans (UNAM), Physique des interactions ioniques et moléculaires (PIIM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), LabEx Transplantex [Strasbourg], Université de Strasbourg (UNISTRA), Etablissement Français du Sang [Nantes], Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Service de pneumologie [Rennes] = Pneumology [Rennes], CHU Pontchaillou [Rennes], Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Sociétés, Acteurs, Gouvernement en Europe (SAGE), Politique, Religion, Institutions et Sociétés : Mutations Européennes - Groupe de Sociologie Politique Européenne (PRISME-GSPE), Centre National de la Recherche Scientifique (CNRS), Centre de Transfusion Sanguine Aquitaine-Limousin (CTS AQUITAINE-LIMOUSIN), Centre de Transfusion Sanguine, Ospedale San Raffaele, Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Barcelona Cord Blood Bank, Agrosystèmes tropicaux (ASTRO), Institut National de la Recherche Agronomique (INRA), Chaim Sheba Medical Center [Ramat Gan, Israel], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Université Paris Diderot - Paris 7 (UPD7), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d'Investigations Biomédicales-Hématologie, Oncologie et Greffes (CIB-HOG), Hôpital St Louis, Assistance Publique des Hôpitaux de Paris (AP-HP), Centre d'Investigations Biomédicales-Hématologie, Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-ENSIIE-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), ALWP-EBMT & Département d'hématologie et de thérapie cellulaire [AP-HP Hôpital Saint-Antoine], AP-HP - Hôpital Saint-Antoine, Hematology, Institut de Recherche Mathématique Avancée ( IRMA ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Mathématiques et Modélisation d'Evry ( LaMME ), Institut National de la Recherche Agronomique ( INRA ) -Université d'Évry-Val-d'Essonne ( UEVE ) -ENSIIE-Centre National de la Recherche Scientifique ( CNRS ), laboratoire d'Etudes et de recherches en Statistiques et Développement ( LERSTAD ), Laboratoire d'Acoustique Environnementale ( IFSTTAR/AME/LAE ), Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ) -Université de Lyon-PRES Université Nantes Angers Le Mans ( UNAM ), Laboratoire d'Histoire des Sciences et de Philosophie - Archives Henri Poincaré ( LHSP ), Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Physique des interactions ioniques et moléculaires ( PIIM ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Functional Genomics and Cancer, Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes], Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Sociétés, Acteurs, Gouvernement en Europe ( SAGE ), Politique, Religion, Institutions et Sociétés : Mutations Européennes - Groupe de Sociologie Politique Européenne ( PRISME-GSPE ), Centre National de la Recherche Scientifique ( CNRS ), Centre de Transfusion Sanguine Aquitaine-Limousin ( CTS AQUITAINE-LIMOUSIN ), Géographie de l'environnement ( GEODE ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse - Jean Jaurès ( UT2J ), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie ( UPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Agrosystèmes tropicaux ( ASTRO ), Institut National de la Recherche Agronomique ( INRA ), Hospices Civils de Lyon ( HCL ), IFR Saint-Louis, institut d'hématologie ( ISLIH ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Erasmus MC University medical Centre / Daniel den Hoed Cancer centre, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Laboratoire de Mathématiques et Modélisation d'Evry, PRES Université Nantes Angers Le Mans (UNAM)-Université de Lyon-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS)-ENSIIE-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Medizin, Graft vs Host Disease, Hematopoietic stem cell transplantation, Biochemistry, Linkage Disequilibrium, immune system diseases, HLA Antigens, Cytotoxic T cell, Child, ComputingMilieux_MISCELLANEOUS, HLA-DQB1, biology, Histocompatibility Testing, Incidence, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, Allografts, 3. Good health, surgical procedures, operative, NK Cell Lectin-Like Receptor Subfamily K, Child, Preschool, Acute Disease, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Adult, Adolescent, Immunology, Human leukocyte antigen, 03 medical and health sciences, MHC class I, medicine, Journal Article, Humans, Aged, Retrospective Studies, Transplantation, [ SDV ] Life Sciences [q-bio], Histocompatibility Antigens Class I, Infant, Newborn, Infant, Cell Biology, medicine.disease, Histocompatibility, stomatognathic diseases, 030104 developmental biology, Graft-versus-host disease, Chronic Disease, biology.protein
Abstract: Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B. Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA. MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.
Published: 2016

29. Natural Killer Lymphocytes Are Dysfunctional in Kidney Transplant Recipients on Diagnosis of Cancer

Author: Antoine Durrbach, Nicolas Dulphy, Antoine Toubert, Caroline Suberbielle, Jeannig Berrou, Vincent Vieillard, Denis Glotz, Patrice Debré, Dominique Charron, Marion Venot, Marie-Noëlle Peraldi, Sylvie Chevret, and Victor Chardiny
Subjects: Graft Rejection, Male, Paris, Cell, Immunophenotyping, Interferon-gamma, Immune system, Risk Factors, Lymphopenia, Neoplasms, medicine, Humans, Interferon gamma, Receptor, Cells, Cultured, Kidney transplantation, Aged, Transplantation, Natural Cytotoxicity Triggering Receptor 1, business.industry, Incidence, Cancer, Middle Aged, medicine.disease, Kidney Transplantation, CD56 Antigen, Lymphocyte Subsets, Transplant Recipients, Killer Cells, Natural, Cytolysis, Cross-Sectional Studies, Phenotype, Treatment Outcome, medicine.anatomical_structure, Case-Control Studies, Cytomegalovirus Infections, Immunology, Female, business, Biomarkers, medicine.drug
Abstract: BACKGROUND The incidence of cancer is increased after solid organ transplantation. Natural killer (NK) cells are key effectors of the tumor immune response. METHODS We conducted a cross sectional multicentre matched case-control study including 42 kidney transplant recipients (KTRs) on diagnosis of cancer and 41 KTRs without cancer. Extensive phenotyping of NK cells populations and functional tests of NK cells were performed. RESULTS Kidney transplant recipients with cancer had a higher incidence of acute rejection (P = 0.02) and cytomegalovirus (CMV) infection (P = 0.03) than controls. They had more lymphopenia than control KTRs (1020/mm3 +/- 32 vs 1218/mm3 +/- 34; P = 0.001) including a CD4+ lymphopenia (P = 0.01). Total CD3-/CD56+ NK cell counts were similar in both groups. However, KTRs with cancer had a lower frequency of the cytokine-enriched CD56bright NK cell subset (P = 0.001). The percentage of NK cells expressing NKp46 was decreased in KTRs with cancer (45% vs 53 %, P = 0.001). Furthermore, the ability of NK cells to degranulate CD107a+ cytolytic vesicles was reduced (11% vs 22%; P = 0.02), and the percentage of NK cells secreting IFN[gamma] was decreased (7.5% vs 28.8%; P = 0.01) in KTRs with cancer. CONCLUSIONS These results reveal an imbalance between NK cell subpopulations and functional NK cell defects in KTRs at the diagnosis of malignancy, including a decreased expression of NKp46 and decreased numbers of NK cells producing INF[gamma]. This study highlights the role of NKp46, a major activating NK cell receptor, which could be considered as a potential marker during immunological follow-up of KTRs.
Published: 2015

30. Naïve CD8

Author: Francesco, Nicoli, Laura, Papagno, Justin J, Frere, Mariela Pires, Cabral-Piccin, Emmanuel, Clave, Emma, Gostick, Antoine, Toubert, David A, Price, Antonella, Caputo, and Victor, Appay
Subjects: Adult, Male, TOR Serine-Threonine Kinases, Immunology, immunometabolism, CD8+ T-lymphocytes, CD8-Positive T-Lymphocytes, Middle Aged, Lymphocyte Activation, naïve T-cells, Autophagy, mTOR, Humans, Female, priming, Glycolysis, Immunologic Memory, Aged, Original Research
Abstract: Background: Characterization of the intracellular biochemical processes that regulate the generation and maintenance of effector and memory CD8+ T-cells from naïve precursors is essential for our understanding of adaptive immune responses and the development of immunotherapies. However, the metabolic determinants of antigen-driven activation and differentiation remain poorly defined, especially in humans. Methods: We used a variety of different approaches, including gene expression profiling and measurements of nutrient flux, to characterize the basal and activation-induced energetic requirements of naïve and phenotypically-defined subsets of human memory CD8+ T-cells. Findings: Profound metabolic differences were apparent as a function of differentiation status, both at rest and in response to stimulation via the T cell receptor (TCR). Of particular note, resting naïve CD8+ T cells were largely quiescent, but rapidly upregulated diverse energetic pathways after ligation of surface-expressed TCRs. Moreover, autophagy and the mechanistic target of rapamycin (mTOR)-dependent glycolytic pathway were identified as critical mediators of antigen-driven priming in the naïve CD8+ T cell pool, the efficiency of which was dampened by the presence of neutral lipids and fatty acids. Interpretation: These observations provide a metabolic roadmap of the CD8+ T-cell compartment in humans and reveal potentially selective targets for novel immunotherapies.
Published: 2018

31. [NK cells: a major role in the antitumoral immunomodulation in CML]

Author: Antoine, Toubert, Ali, Turhan, Agnès, Guerci-Bresler, Nicolas, Dulphy, and Delphine, Réa
Subjects: Immunomodulation, Killer Cells, Natural, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Humans, Hematopoietic Stem Cells
Abstract: Convincing clinical and experimental evidence is converging on the essential role of NK (Natural Killer) cells in the recognition and eradication of tumors. Recent studies emphasized the role of NK cells in the immune control of chronic myeloid leukemia (CML), a malignancy arising from hematopoietic stem cells, and the treatment of which has been revolutionized by the use of tyrosine kinase inhibitors (TKI). Three major findings are emerging: 1) the impairment of the numbers and function of NK cells at diagnosis, 2) the restoration of the NK cell function and numbers during remissions induced with TKI therapies and 3) the potential role of the more mature NK CD56
Published: 2018

32. CD16

Author: Alexandra, Frazao, Meriem, Messaoudene, Nicolas, Nunez, Nicolas, Dulphy, France, Roussin, Christine, Sedlik, Laurence, Zitvogel, Eliane, Piaggio, Antoine, Toubert, and Anne, Caignard
Subjects: Adult, Aged, 80 and over, Receptors, IgG, Breast Neoplasms, Middle Aged, GPI-Linked Proteins, Lymphocyte Activation, Killer Cells, Natural, Lymphocytes, Tumor-Infiltrating, Phenotype, Cell Line, Tumor, Humans, Female, Lymph Nodes, NK Cell Lectin-Like Receptor Subfamily C, Aged, Neoplasm Staging
Abstract: Tumor-draining lymph nodes (TD-LNs) are the first site of metastasis of breast cancer. Natural killer (NK) cells that infiltrate TD-LNs [including noninvaded (NI) or metastatic (M)-LNs from breast cancer patients] and NK cells from healthy donor (HD)-LNs were characterized, and their phenotype analyzed by flow cytometry. Low percentages of tumor cells invaded M-LNs, and these cells expressed ULBP2 and HLA class I molecules. Although NK cells from paired NI and M-LNs were similar, they expressed different markers compared with HD-LN NK cells. Compared with HD-LNs, TD-LN NK cells expressed activating DNAM-1, NKG2C and inhibitory NKG2A receptors, and exhibited elevated CXCR3 expression. CD16, NKG2A, and NKp46 expression were shown to be increased in stage IIIA breast cancer patients. TD-LNs contained a large proportion of activated CD56
Published: 2018

33. Hematopoietic stem cell transplantation in its 60s: A platform for cellular therapies

Author: Jürgen Kuball, Katharina Fleischhauer, Attilio Bondanza, Paolo Pedrazzoli, Francesco Dazzi, Antoine Toubert, Chiara Bonini, Christian Chabannon, Annalisa Ruggeri, Chabannon, Christian, Kubal, Jurgen, Bondanza, Attilio, Dazzi, Francesco, Pedrazzoli, Paolo, Toubert, Antoine, Ruggeri, Annalisa, Fleischhauer, Katharina, and Bonini, Chiara
Subjects: 0301 basic medicine, medicine.medical_specialty, Hematopoietic cell, business.industry, medicine.medical_treatment, Medicine (all), Cell- and Tissue-Based Therapy, Hematopoietic Stem Cell Transplantation, Medizin, General Medicine, Hematopoietic stem cell transplantation, Regenerative Medicine, Transplantation, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Innovative Therapies, Underlying disease, 030220 oncology & carcinogenesis, medicine, Animals, Humans, Intensive care medicine, business
Abstract: Over the last 60 years, more than a million patients received hematopoietic cell transplantation. Having incorporated multiple changes in clinical practices, it remains a complex procedure facing a dual challenge: cure of the underlying disease and prevention of relapse while controlling potentially severe complications. Improved understanding of underlying biological processes resulted in the design of innovative therapies engineered from defined cell populations and testing of these therapies as addition or substitution at virtually every step of the procedure. This review provides an overview of these developments, many of them now applied outside the historical field of hematopoietic cell transplantation.
Published: 2018

34. Editorial: Tailoring NK Cell Receptor–Ligand Interactions: An Art in Evolution

Author: Ulrike Koehl, Antoine Toubert, and Gianfranco Pittari
Subjects: lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Bispecific antibody, medicine.medical_treatment, Immune checkpoint inhibitors, Immunology, Evolution, Molecular, Mice, 03 medical and health sciences, medicine, Animals, Humans, cancer, Immunology and Allergy, ddc:610, Receptor, immune evasion, natural killer cells, Chemistry, natural killer cells, NK receptors, cancer, immunotherapy, immune evasion, checkpoint inhibitors, chimeric antigen receptors, bispecific antibodies, Cancer, NK receptors, Immunotherapy, chimeric antigen receptors, Ligand (biochemistry), medicine.disease, Chimeric antigen receptor, Killer Cells, Natural, Transplantation, Editorial, 030104 developmental biology, Cancer research, Receptors, Natural Killer Cell, immunotherapy, bispecific antibodies, lcsh:RC581-607, checkpoint inhibitors
Published: 2018

35. Immune monitoring in allogeneic hematopoietic stem cell transplant recipients: a survey from the EBMT-CTIWP

Author: Fabio Ciceri, Jacopo Peccatori, Giacomo Oliveira, Jürgen Kuball, Maddalena Noviello, Ulrike Koehl, Antoine Toubert, Ebmt Cellular Therapy, Chiara Bonini, Katharina Fleischhauer, Christian Chabannon, Nicoletta Cieri, Francesco Dazzi, Attilio Bondanza, Dirk-Jan Eikema, Vanderson Rocha, Raffaella Greco, Steffie van der Werf, Annalisa Ruggeri, Luca Vago, Sofie Rosanne Terwel, Greco, Raffaella, Ciceri, Fabio, Noviello, Maddalena, Bondanza, Attilio, Vago, Luca, Oliveira, Giacomo, Peccatori, Jacopo, Cieri, Nicoletta, Ruggeri, Annalisa, Koehl, Ulrike, Fleischhauer, Katharina, Rocha, Vanderson, Dazzi, Francesco, van der Werf, Steffie Maria, Eikema, Dirk-Jan, Terwel, Sofie Rosanne, Kuball, Jürgen, Toubert, Antoine, Chabannon, Christian, and Bonini, Chiara
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Medizin, MEDLINE, Immune monitoring, 03 medical and health sciences, 0302 clinical medicine, Monitoring, Immunologic, Internal medicine, Surveys and Questionnaires, medicine, Humans, Transplantation, Homologous, Transplantation, Hematology, business.industry, Hematopoietic Stem Cell Transplantation, Transplant Recipients, 030104 developmental biology, Multicenter study, Transplantation, Haploidentical, Allogeneic hematopoietic stem cell transplant, business, Unrelated Donors, 030215 immunology
Published: 2018

36. A human immune system mouse model with robust lymph node development

Author: Hugo Mouquet, Grégory Jouvion, Helene Strick-Marchand, Ai Ing Lim, Nicolas Serafini, Zacarias Garcia, Philippe Bousso, Yan Li, Daniela Finke, Olivier Schwartz, Timothée Bruel, Ayrin Kök, Franck Bourgade, Guillemette Masse-Ranson, Thierry Hieu, Antoine Toubert, Mathilde Dusséaux, James P. Di Santo, Immunité Innée - Innate Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamiques des Réponses immunes - Dynamics of Immune Responses, Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Réponse humorale aux pathogènes, Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris]-Université de Paris (UP), Animalerie centrale (Plate-forme), Institut Pasteur [Paris], Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Developmental Immunology, University of Basel (Unibas), This work was supported by the Agence Nationale de la Recherche (ANR) programme RPIB (Im_HIS to J.P.D.), the Laboratoire d’Excellence REVIVE (grant ANR-10-LABX-73 to Y.L. and J.P.D.), the Laboratoire d’Excellence Vaccine Research Institute (grant ANR-10-LABX-77 to T.B. and O.S.), the Laboratoire d’Excellence Milieu Intérieur (grant ANR-10-LABX-69 to H.M.), the Laboratoire d’Excellence IBEID (grant ANR-10-LABX-62 to O.S.), the Agence Nationale de Recherche sur le SIDA et les hepatitis (grant 15465 to O.S.), the European Commission Seventh Framework Programme no. 305578 (PathCO, to J.P.D.), the European Research Council (grant ERC-2013-StG 337146 to A.K. and T.H., grant ERC-2017-AvG 771167 to P.B.), Gilead Sciences (grant 00397 to G.M.-R. and J.P.D.), the Institut Pasteur (Core grant to J.P.D., G5 Program to H.M.), and INSERM (Core grant to J.P.D.)., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 305578,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,PATHCO(2012), European Project: 337146,EC:FP7:ERC,ERC-2013-StG,HUMANTIVIRUSES(2014), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Vaccine Research Institute [Créteil, France] (VRI), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), and Institut Pasteur [Paris]-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Male, T-Lymphocytes, MESH: Lymph Nodes, HIV Infections, Biochemistry, MESH: Mice, Knockout, MESH: HIV-1, Mice, MESH: Animals, Lymph node, Mice, Knockout, MESH: Cytokines, B-Lymphocytes, Mice, Inbred BALB C, MESH: Virus Latency, MESH: HIV Infections, 3. Good health, Virus Latency, medicine.anatomical_structure, Lymphatic system, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, MESH: Immunoglobulin Class Switching, Cytokines, Female, Lymph, Biotechnology, Interleukin Receptor Common gamma Subunit, MESH: Mice, Transgenic, Transgene, MESH: Mice, Inbred BALB C, Mice, Transgenic, Biology, MESH: Models, Immunological, 03 medical and health sciences, Immune system, Thymic Stromal Lymphopoietin, Immunity, MESH: Mice, Inbred C57BL, MESH: B-Lymphocytes, medicine, Animals, Humans, Secondary lymphoid tissue, Molecular Biology, MESH: Mice, MESH: Humans, MESH: Interleukin Receptor Common gamma Subunit, Models, Immunological, Cell Biology, Immunoglobulin Class Switching, MESH: Male, Mice, Inbred C57BL, 030104 developmental biology, MESH: T-Lymphocytes, Immunoglobulin class switching, Immunology, HIV-1, Lymph Nodes, MESH: Female
Abstract: International audience; Lymph nodes (LNs) facilitate the cellular interactions that orchestrate immune responses. Human immune system (HIS) mice are powerful tools for interrogation of human immunity but lack secondary lymphoid tissue (SLT) as a result of a deficiency in Il2rg-dependent lymphoid tissue inducer cells. To restore LN development, we induced expression of thymic-stromal-cell-derived lymphopoietin (TSLP) in a Balb/c Rag2-/-Il2rg-/-SirpaNOD (BRGS) HIS mouse model. The resulting BRGST HIS mice developed a full array of LNs with compartmentalized human B and T cells. Compared with BRGS HIS mice, BRGST HIS mice have a larger thymus, more mature B cells, and abundant IL-21-producing follicular helper T (TFH) cells, and show enhanced antigen-specific responses. Using BRGST HIS mice, we demonstrated that LN TFH cells are targets of acute HIV infection and represent a reservoir for latent HIV. In summary, BRGST HIS mice reflect the effects of SLT development on human immune responses and provide a model for visualization and interrogation of regulators of immunity.
Published: 2017

37. Natural killer cell deficiency in patients with non-Hodgkin lymphoma after lung transplantation

Author: Florence Baychelier, Caroline Besson, Antoine Toubert, Martine Raphael, Alain Chapelier, Vincent Vieillard, Abla Achour, Michel Marty, Damien Roos-Weil, Didier Samuel, Patrice Debré, Armelle Arnoux, and Stéphanie Nguyen
Subjects: Male, Pulmonary and Respiratory Medicine, Natural killer cell, Interleukin 21, Postoperative Complications, immune system diseases, hemic and lymphatic diseases, medicine, Humans, Transplantation, biology, business.industry, Lymphoma, Non-Hodgkin, Degranulation, Middle Aged, medicine.disease, NKG2D, Acquired immune system, Lymphoma, Killer Cells, Natural, medicine.anatomical_structure, Perforin, Immunology, biology.protein, Female, Surgery, Cardiology and Cardiovascular Medicine, business, Lung Transplantation
Abstract: Background Post-transplant non-Hodgkin lymphoma (NHL) is a well-recognized complication of solid-organ transplantation, and pharmacologic suppression of adaptive immunity plays a major role in its development. However, the role of natural killer (NK) cells in post-lung transplant de novo NHL is unknown. Methods Extensive phenotypic analyses of NK cells from patients diagnosed with NHL after liver or lung transplantation were conducted with multicolor flow cytometry. Polyfunctionality assays simultaneously assessed NK cell degranulation (CD107a) and intracellular cytokine production (interferon-γ and tumor necrosis factor-α) in the presence of NHL target cells. Results The development of de novo NHL is linked to NK-cell maturation defects, including overexpression of NKG2A and CD62L and down-modulation of inhibitory killer immunoglobulin-like receptors and CD57 receptors. More importantly, in patients who developed NHL after lung transplantation, we observed a specific down-modulation of the activating receptors (NKp30, NKp46, and NKG2D) and a sharp decrease in perforin expression and degranulation against NHL target cells. Conclusions Our results suggest that accumulation of abnormal NK cells could play a role in the outgrowth of NHL after lung transplantation, independently of the immunosuppressive regimen.
Published: 2015

38. Homeostatic proliferation leads to telomere attrition and increased PD-1 expression after autologous hematopoietic SCT for systemic sclerosis

Author: Lucas C M, Arruda, João R, Lima-Júnior, Emmanuel, Clave, Daniela A, Moraes, Corinne, Douay, Isabelle, Fournier, Hélène, Moins-Teisserenc, Dimas T, Covas, Belinda P, Simões, Dominique, Farge, Antoine, Toubert, Kelen C R, Malmegrim, and Maria Carolina, Oliveira
Subjects: Adult, Male, Scleroderma, Systemic, Programmed Cell Death 1 Receptor, Hematopoietic Stem Cell Transplantation, Telomere Homeostasis, CD8-Positive T-Lymphocytes, Middle Aged, Telomere, Transplantation, Autologous, Cytokines, Humans, Female, Prospective Studies, Cell Proliferation, Follow-Up Studies
Abstract: In the months that follow autologous hematopoietic stem cell transplantation (AHSCT), lymphopenia drives homeostatic proliferation, leading to oligoclonal expansion of residual cells. Here we evaluated how replicative senescent and exhausted cells associated with clinical outcomes of 25 systemic sclerosis (SSc) patients who underwent AHSCT. Patients were clinically monitored for skin (modified Rodnan's skin score, mRSS) and internal organ involvement and had blood samples collected before and semiannually, until 3 years post-AHSCT, for quantification of telomere length, CD8
Published: 2017

39. Human thymopoiesis is influenced by a common genetic variant within the

Author: Emmanuel, Clave, Itauá Leston, Araujo, Cécile, Alanio, Etienne, Patin, Jacob, Bergstedt, Alejandra, Urrutia, Silvia, Lopez-Lastra, Yan, Li, Bruno, Charbit, Cameron Ross, MacPherson, Milena, Hasan, Breno Luiz, Melo-Lima, Corinne, Douay, Noémie, Saut, Marine, Germain, David-Alexandre, Trégouët, Pierre-Emmanuel, Morange, Magnus, Fontes, Darragh, Duffy, James P, Di Santo, Lluis, Quintana-Murci, Matthew L, Albert, and Antoine, Toubert
Subjects: Adult, Male, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, Genetic Variation, Receptors, Antigen, T-Cell, gamma-delta, Mice, SCID, Thymus Gland, Middle Aged, Cohort Studies, Young Adult, Phenotype, Genetic Loci, Animals, Humans, Female, Biomarkers, Aged, Genome-Wide Association Study
Abstract: The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor
Published: 2017

40. Standardized whole blood stimulation improves immunomonitoring of induced immune responses in multi-center study

Author: Alain Savenay, Matthew L. Albert, Delphine Louis, Manfred Schmolz, Nina Salabert-Le Guen, Olivier Lantz, Régis Josien, Darragh Duffy, Françoise Mascart, Antoine Toubert, Marie Noelle Ungeheuer, Vincent Rouilly, Raouf Djebali, Lydia Redjah, José J.G. Ruiz de Morales, Catherine Ottone, Véronique Corbière, Eva Martínez-Cáceres, Cécile Braudeau, Samuel S.T. LaBrie, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle (CRT), Institut Pasteur [Paris], Laboratoire d’Immunologie, Centre d’Immunomonitorage Nantes Atlantique (CIMNA), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), laboratoire de vaccinologie et immunité mucosale, Université Libre de Bruxelles [Bruxelles] (ULB), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Myriad RBM, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospital Universitari Germans Trias I Pujol, Immunobiology Clinic, Hôpital Erasme, Complejo Asistencial Universitario de León, Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), HOT Screen GmbH, Genentech, Inc. [San Francisco], TruCulture tubes, stimuli, and protein Luminex XMAP analysis were provided by Myriad RBM, Inc (Austin, USA) and TruCulture tubes were manufactured at HOT Screen (Reutlingen, Germany). Donor recruitment costs were covered by each participating FOCIS center of excellence. Author contributions: DD, VR, VC, SL, OL, EMC, RP, MS, AT & MLA designed the study. CB, RD, MNU, DL, FM, JGRM, CO, LR, AS performed experiments. DD, VR, & MLA performed analysis and wrote the paper. All authors reviewed the manuscript., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Université libre de Bruxelles (ULB), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Translationnelle ( CRT ), Centre Hospitalier Universitaire de Nantes, Centre de Recherche en Transplantation et Immunologie ( U1064 Inserm - CRTI - CHU Nantes ), Université de Nantes ( UN ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université Libre de Bruxelles [Bruxelles] ( ULB ), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources ( ICAReB ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Curie, Alloimmunité-Autoimmunité-Transplantation ( A2T ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )
Subjects: 0301 basic medicine, Lipopolysaccharides, Whole blood stimulation, CD3 Complex, medicine.medical_treatment, CD8 Antigens, Point-of-Care Systems, Immunology, Stimulation, Blood Donors, Immunologic Tests, Peripheral blood mononuclear cell, Antibodies, Functional immune responses, 03 medical and health sciences, Immune system, medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Humans, Whole blood, biology, business.industry, Immunotherapy, Multi-center clinical studies, 3. Good health, Vaccination, Immunomonitoring, 030104 developmental biology, Gene Expression Regulation, PBMCs, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Antibody, business, Biomarkers
Abstract: Functional immune responses are increasingly important for clinical studies, providing in depth biomarker information to assess immunotherapy or vaccination. Incorporating functional immune assays into routine clinical practice has remained limited due to challenges in standardizing sample preparation. We recently described the use of a whole blood syringe-based system, TruCulture (R), which permits point-of-care standardized immune stimulation. Here, we report on a multi-center clinical study in seven FOCIS Centers of Excellence to directly compare TruCulture to conventional PBMC methods. Whole blood and PBMC5 from healthy donors were exposed to LPS, anti-CD3 anti-CD28 antibodies, or media alone. 55 protein analytes were analyzed centrally by Luminex multi-analyte profiling in a CLIA-certified laboratory. TruCulture responses showed greater reproducibility and improved the statistical power for monitoring differential immune response activation. The use of TruCulture addresses a major unmet need through a robust and flexible method for immunomonitoring that can be reproducibly applied in multi-center clinical studies. One sentence summary: A multi-center study revealed greater reproducibility from whole blood stimulation systems as compared to PBMC stimulation for studying induced immune responses. (C) 2017 Published by Elsevier Inc.
Published: 2017

41. Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study

Author: Antoine Toubert, Agnès Guerci-Bresler, Hélène Moins-Teisserenc, Gabriel Etienne, Delphine Rea, Françoise Huguet, Laurence Legros, François Guilhot, Frédéric Maloisel, Zena Khaznadar, Joelle Guilhot, Martine Gardembas, Philippe Rousselot, Francois-Xavier Mahon, Bruno Villemagne, Jean-Christophe Ianotto, Franck E. Nicolini, Nicolas Dulphy, Viviane Dubruille, Aude Charbonnier, Guylaine Henry, Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Institut Bergonié [Bordeaux], UNICANCER, INSERM CIC 0802 (INSERM - CHU de Poitiers), Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital l'Archet - CHU de Nice, Service des maladies du sang [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'Hématologie Clinique [Hôpital Hôtel Dieu, Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Hôtel Dieu, Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'hématologie clinique, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de cancérologie et d'hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hématologie clinique [CH La Roche-sur-Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alloimmunité-Autoimmunité-Transplantation (A2T), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, medicine.drug_class, Receptor expression, Chronic Myeloid Leukemia, Cell Count, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Tyrosine-kinase inhibitor, Article, Disease-Free Survival, Natural killer cell, 03 medical and health sciences, Interferon-gamma, 0302 clinical medicine, Recurrence, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, medicine, Cytotoxic T cell, Humans, Protein Kinase Inhibitors, business.industry, Degranulation, Myeloid leukemia, Imatinib, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, 3. Good health, Killer Cells, Natural, Leukemia, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Imatinib Mesylate, Receptors, Natural Killer Cell, business, medicine.drug
Abstract: Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56dim subset than had relapsing patients, while CD56bright natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56dim natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors, BCR-ABL1+ leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies. (ClinicalTrial.gov Identifier NCT00478985).
Published: 2017

42. Favorable impact of natural killer cell reconstitution on chronic graft-versus-host disease and cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation

Author: Hélène Moins-Teisserenc, Philippe Haas, Patricia Ribaud, Dominique Charron, Catherine Scieux, Marc Busson, Nicolas Dulphy, Gérard Socié, Aliénor Xhaard, Pascale Loiseau, Vissal David Kheav, Marie-Christine Mazeron, Emeline Masson, Antoine Toubert, Marie Robin, Guitta Maki, Maryvonnick Carmagnat, and Régis Peffault de Latour
Subjects: Adult, Male, Transplantation Conditioning, Adolescent, medicine.medical_treatment, Congenital cytomegalovirus infection, Cytomegalovirus, Graft vs Host Disease, Hematopoietic stem cell transplantation, Natural killer cell, Young Adult, medicine, Humans, Transplantation, Homologous, Prospective Studies, Neoplasm Staging, Natural Killer Cell Count, business.industry, Hematopoietic Stem Cell Transplantation, Articles, Hematology, Flow Cytometry, Prognosis, medicine.disease, Lymphocyte Subsets, Killer Cells, Natural, Survival Rate, Transplantation, medicine.anatomical_structure, Graft-versus-host disease, Hematologic Neoplasms, Chronic Disease, Cytomegalovirus Infections, Immunology, Female, Virus Activation, Stem cell, business, Follow-Up Studies
Abstract: Natural killer cells are the first lymphocyte subset to reconstitute, and play a major role in early immunity after allogeneic hematopoietic stem cell transplantation. Cells expressing the activating receptor NKG2C seem crucial in the resolution of cytomegalovirus episodes, even in the absence of T cells. We prospectively investigated natural killer-cell reconstitution in a cohort of 439 adult recipients who underwent non-T-cell-depleted allogeneic hematopoietic stem cell transplantation between 2005 and 2012. Freshly collected blood samples were analyzed 3, 6, 12 and 24 months after transplantation. Data were studied with respect to conditioning regimen, source of stem cells, underlying disease, occurrence of graft-versus-host disease, and profiles of cytomegalovirus reactivation. In multivariate analysis we found that the absolute numbers of CD56(bright) natural killer cells at month 3 were significantly higher after myeloablative conditioning than after reduced intensity conditioning. Acute graft-versus-host disease impaired reconstitution of total and CD56(dim) natural killer cells at month 3. In contrast, high natural killer cell count at month 3 was associated with a lower incidence of chronic graft-versus-host disease, independently of a previous episode of acute graft-versus-host disease and stem cell source. NKG2C(+)CD56(dim) and total natural killer cell counts at month 3 were lower in patients with reactivation of cytomegalovirus between month 0 and month 3, but expanded greatly afterwards. These cells were also less numerous in patients who experienced later cytomegalovirus reactivation between month 3 and month 6. Our results advocate a direct role of NKG2C-expressing natural killer cells in the early control of cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation.
Published: 2014

43. Reconstitution of regulatory T-cell subsets after allogeneic hematopoietic SCT

Author: Patricia Ribaud, Marie Robin, R. Peffault de Latour, Antoine Toubert, Aliénor Xhaard, Guitta Maki, Marc Busson, V-D Kheav, Sarah Abbes, Hélène Moins-Teisserenc, Nathalie Dhedin, Gérard Socié, and Maryvonnick Carmagnat
Subjects: Adult, Male, Time Factors, Adolescent, Regulatory T cell, medicine.medical_treatment, Graft vs Host Disease, chemical and pharmacologic phenomena, Hematopoietic stem cell transplantation, T-Lymphocytes, Regulatory, Flow cytometry, medicine, Humans, Prospective Studies, Child, Prospective cohort study, Aged, Transplantation, medicine.diagnostic_test, business.industry, Hematopoietic Stem Cell Transplantation, hemic and immune systems, Recovery of Function, Hematology, Middle Aged, Allografts, medicine.disease, Haematopoiesis, surgical procedures, operative, Graft-versus-host disease, medicine.anatomical_structure, Hematologic Neoplasms, Immunology, Stem cell, business, Immunologic Memory
Abstract: Previous studies on regulatory T-cell (Treg) reconstitution after allogeneic hematopoietic SCT (HSCT) have suggested that, within the GVHD process, imbalance between effector T cells and Tregs may be more important than the absolute numbers of circulating Tregs. No study has analyzed naive vs memory Treg reconstitution in a longitudinal cohort with large numbers of patients. The reconstitution of total and subsets of Treg was prospectively analyzed by flow cytometry in 185 consecutive recipients at 3, 6, 12 and 24 months after allogeneic HSCT. The levels of total, naive and memory Tregs increased, mainly within the memory subset, but remained lower than healthy controls up to 2 years after transplantation. Reduced-intensity conditioning and peripheral blood (PBSC) as the source of stem cells were associated with better 3-month reconstitution. In multivariate analysis, PBSC, recipient age ⩽25 and no anti-thymoglobulin in the conditioning regimen were associated with a better Treg reconstitution. Naive Treg long-term reconstitution was mainly influenced by recipient age. Whereas prior acute GVHD impaired Treg reconstitution, Treg subsets (absolute numbers and frequencies relative to CD4(+) T-cell subsets) at 3, 6 and 12 months after HSCT were not associated with the occurrence of a later episode of chronic GVHD.
Published: 2014

44. Tc1 Clonal T Cell Expansion during Chronic Graft-versus-Host Disease–Associated Hypereosinophilia

Author: Lionel Ades, Marie Robin, Régis Peffault de Latour, Corrine Douay, Emmanuel Clave, Jean Michel Cayuela, Aliénor Xhaard, Antoine Toubert, and Gérard Socié
Subjects: Adult, Male, T cell, T-Lymphocytes, Graft vs Host Disease, Hypereosinophilia, Antineoplastic Agents, Disease, Graft-versus-host disease, Epitope, Immunophenotyping, Eosinophilia, Medicine, Humans, Cell Proliferation, Peripheral Blood Stem Cell Transplantation, Transplantation, business.industry, Hematology, medicine.disease, Virology, Phenotype, 3. Good health, Clone Cells, Eosinophils, medicine.anatomical_structure, Hematologic Neoplasms, Immunology, Chronic Disease, Female, medicine.symptom, business, CD8
Abstract: Although hypereosinophilia (HE) associated with chronic graft-versus-host disease (GVHD) has long been recognized, biological data on this phenomenon are scarce. Here we compare patients with chronic GVHD with HE together with a clonal T cell expansion and control patients with acute or chronic GVHD but without HE. These clonal expansions share a CD8+ TC1 phenotype rather than a CD4+ Th2 profile. In contrast to the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, these allogeneic CD8+ clones do not recognize the epitopes of herpesviruses. Furthermore, these TC1 clones do not produce IL-17 as described in the DRESS syndrome.
Published: 2014
Full Text: View/download PDF

45. Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on

Author: Alexandra, Frazao, Marina, Colombo, Emmanuelle, Fourmentraux-Neves, Meriem, Messaoudene, Sylvie, Rusakiewicz, Laurence, Zitvogel, Eric, Vivier, Frédéric, Vély, Florence, Faure, Brigitte, Dréno, Houssem, Benlalam, Fanny, Bouquet, Ariel, Savina, Eric, Pasmant, Antoine, Toubert, Marie-Françoise, Avril, and Anne, Caignard
Subjects: Proto-Oncogene Proteins B-raf, Sulfonamides, B7 Antigens, Indoles, Natural Cytotoxicity Triggering Receptor 3, Histocompatibility Antigens Class I, GPI-Linked Proteins, Gene Expression Regulation, Neoplastic, Vemurafenib, NK Cell Lectin-Like Receptor Subfamily K, Mutation, Humans, Intercellular Signaling Peptides and Proteins, Natural Killer T-Cells, Cell Lineage, Melanoma, Cell Proliferation
Abstract: Over 60% of human melanoma tumors bear a mutation in the
Published: 2016

46. Lenalidomide consolidation and maintenance therapy after autologous stem cell transplant for multiple myeloma induces persistent changes in T-cell homeostasis

Author: Emmanuel Clave, Tereza Coman, Norbert Claude Gorin, Marc Busson, Maryvonnick Carmagnat, Laurent Garderet, Antoine Toubert, Hélène Moins-Teisserenc, Caroline Bompoint, Salomé Glauzy, and Corinne Douay
Subjects: Adult, Melphalan, Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Antineoplastic Agents, Thymus Gland, Hematopoietic stem cell transplantation, T-Lymphocytes, Regulatory, Transplantation, Autologous, Immunophenotyping, Maintenance Chemotherapy, Maintenance therapy, T-Lymphocyte Subsets, Internal medicine, Homeostasis, Humans, Medicine, Lenalidomide, Multiple myeloma, Neoplasm Staging, business.industry, Hematopoietic Stem Cell Transplantation, Consolidation Chemotherapy, Hematology, Middle Aged, medicine.disease, Thalidomide, Treatment Outcome, Case-Control Studies, Antigens, Surface, Immunology, Stem cell, Multiple Myeloma, business, medicine.drug
Abstract: Whether the efficacy of lenalidomide in the treatment of multiple myeloma (MM) is due to direct tumor toxicity only or to additional immunomodulatory effects is unclear. We studied the effect of lenalidomide treatment on T-cell immune reconstitution in patients with MM who had undergone autologous peripheral blood stem cell transplant (ASCT). Twenty-nine newly diagnosed patients with MM received induction therapy followed by high-dose melphalan and ASCT. After ASCT, 11 patients received lenalidomide consolidation therapy for 2 months followed by maintenance therapy until disease progression. The remaining 18 patients received no treatment. Serial analysis of thymic output, as given by numbers of T-cell receptor excision circles (sjTRECs), and T-cell phenotyping was performed until 18 months post-ASCT. Lenalidomide impaired long-term thymic T-cell reconstitution, decreased CD4 + and CD8 + CD45RA + CCR7 - effector-terminal T-cell absolute counts and increased CD4 + CD25 + CD127 - /low regulatory T-cells. Lenalidomide consolidation and long-term maintenance therapy, administered post-ASCT, may have a potentially negative impact on immune surveillance.
Published: 2013

47. HLA-A*31:01 and different types of carbamazepine-induced severe cutaneous adverse reactions: an international study and meta-analysis

Author: Dominique Charron, Fortier C, Teresa Bellón, Ryad Tamouza, Shuen-Iu Hung, Maja Mockenhaupt, Wolkenstein P, Jean-Claude Roujeau, Emmanuelle Génin, Chang Py, Wen-Hung Chung, Alain Hovnanian, Antoine Toubert, Martin Schumacher, Chen Dp, Tsai Sh, Wu Tl, and Peggy Sekula
Subjects: Pharmacology, HLA-A Antigens, business.industry, education, Genomics, macromolecular substances, Carbamazepine, Bioinformatics, Proteomics, HLA-A, Cohort Studies, Drug development, Meta-analysis, Genetics, Humans, Molecular Medicine, Medicine, business, Functional genomics, health care economics and organizations, Skin, medicine.drug
Abstract: HLA-A*31:01 was reported to be associated with carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCAR), including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We conducted an international study using consensus diagnosis criteria to enroll a total of 93 patients with CBZ-SCAR from Europe or Asia. We found that HLA-A*31:01 showed a significant association with CBZ-DRESS in Europeans (P0.001; odds ratio (OR) (95% confidence interval (CI))=57.6 (11.0-340)), and the strong association was also found in Chinese (P0.001; OR (95% CI)=23.0 (4.2-125)). However, HLA-A*31:01 had no association with CBZ-SJS/TEN in neither Chinese nor Europeans. By comparison, HLA-B*15:02 showed a strong association with CBZ-SJS/TEN in Chinese (P0.001, OR (95% CI)=58.1 (17.6-192)). A meta-analysis of this and other published studies confirmed that in all populations, HLA-A*31:01 had an extremely strong association with CBZ-DRESS (P0.001, a pooled OR (95% CI)=13.2 (8.4-20.8)), but a much weaker association with CBZ-SJS/TEN (P=0.01, OR (95% CI)=3.94 (1.4-11.5)). Our data revealed that HLA-A*31:01 is a specific predictor for CBZ-DRESS but not for CBZ-SJS/TEN. More studies are needed to investigate the genetic determinant of CBZ-SJS/TEN in Europeans. Considering the potential clinical utility, the cost-effectiveness of the combined HLA-A*31:01 and HLA-B*15:02 genetic test to prevent CBZ-SCAR in Chinese needs further investigation.
Published: 2013

48. Soluble MICA-NKG2D interaction upregulates IFN-γ production by activated CD3−CD56+ NK cells: Potential impact on chronic graft versus host disease

Author: Gérard Socié, Régis Peffault de Latour, Reem Al-Daccak, Antoine Toubert, Nicolas Dulphy, Catherine Fortier, Meriem Bennabi, Wahid Boukouaci, Kahina Amokrane, Rajagopal Krishnamoorthy, Ryad Tamouza, François Marzais, Laura Lauden, and Dominique Charron
Subjects: CD3 Complex, CD3, Immunology, Graft vs Host Disease, Lymphocyte Activation, Interferon-gamma, Immune system, MHC class I, medicine, Humans, Immunology and Allergy, Cytotoxic T cell, Interferon gamma, Receptor, biology, Histocompatibility Antigens Class I, General Medicine, NKG2D, CD56 Antigen, Killer Cells, Natural, stomatognathic diseases, Gene Expression Regulation, NK Cell Lectin-Like Receptor Subfamily K, Chronic Disease, biology.protein, Cancer research, Antibody, Protein Binding, medicine.drug
Abstract: A soluble isoform of MHC class I chain-related molecule A (soluble MICA), generated by proteolytic shedding from the membrane-bound MICA of various tumor cells, has been shown to downregulate both the expression of natural killer group 2-member D receptor and the cytotoxic function of effectors cells and was postulated as a mechanism for tumor immune evasion. Its effect on the expression of cytokines by the effector cells remained unexplored. Here we demonstrate that the sMICA molecules upregulate interferon gamma expression by interleukin-12/interleukin-18-activated CD3(-)CD56(+) natural killer cells, witnessing the pro-inflammatory effect of soluble MICA. Overall, these data are in line with our previous observations that the raised serum levels of soluble MICA, following allogeneic hematopoietic stem cell transplantation, confer susceptibility to and the presence of pre-transplantation anti-MICA antibodies in the patient's serum confer protection against chronic graft versus host disease.
Published: 2013

49. Natural Killer Cell Dysfunction in Uremia: The Role of Oxidative Stress and the Effects of Dialysis

Author: Fabien Metivier, Jeannig Berrou, Antoine Toubert, and Marie-Noëlle Peraldi
Subjects: medicine.medical_specialty, NK Cell Lectin-Like Receptor Subfamily K, medicine.medical_treatment, T cell, CD8-Positive T-Lymphocytes, Biology, Natural killer cell, Peritoneal dialysis, Renal Dialysis, Internal medicine, medicine, Humans, Lymphocyte Count, Dialysis, Uremia, Histocompatibility Antigens Class I, Membranes, Artificial, Hematology, General Medicine, NKG2D, Killer Cells, Natural, Oxidative Stress, medicine.anatomical_structure, Endocrinology, Gene Expression Regulation, Nephrology, Immunology, Kidney Failure, Chronic, Hemodialysis, CD8
Abstract: Immune deficiency is one of the numerous consequences of chronic renal failure. We can hypothesize that an abnormal natural killer (NK) cell response is present in patients with end-stage renal disease (ESRD). To characterize the immune defect in ESRD patients, we performed a NK cell subset analysis in 66 patients with ESRD treated by hemodialysis or peritoneal dialysis. Compared with healthy blood donors, patients undergoing chronic dialysis showed a profound decrease in NKG2D(+) cells within both CD8(+) T cell (58 vs. 67%, p = 0.03) and NK cell (39 vs. 56%, p = 0.002) populations. We further studied NK cell subsets in 55 hemodialysis patients and 17 patients treated by peritoneal dialysis. As compared to healthy donors, all these patients had significantly decreased NKG2D-positive NK cells. Patients using PMMA membranes (BK-F) or Helixone-FX membranes had a smaller decrease in NKG2D-positive NK cells when compared to patients treated with Nephral membranes. The expression of MICA on the cell surface of monocytes, which is a marker of inflammation induced by cellular stress, was also lower in patients using BK-F membranes. In conclusion, these data suggest that a subpopulation of NK cells is decreased in patients with ESRD. This decrease is associated with high circulating levels of the HLA-related molecule MICA. The dialysis membrane can influence the modulation of both the phenotype of NK cells and MICA overexpression.
Published: 2013

50. Relevance of serum biomarkers associated with melanoma during follow-up of anti-CTLA-4 immunotherapy

Author: Raphaël Porcher, Martine Bagot, Anne Caignard, Eve Maubec, Marie-Hélène Schlageter, Cécile Pagès, Wahid Boukouaci, Ryad Tamouza, Antoine Toubert, Barouyr Baroudjian, Bruno Cassinat, Hélène Moins-Teisserenc, Joana Felix, Céleste Lebbé, and Laurence Homyrda
Subjects: 0301 basic medicine, Oncology, Male, Skin Neoplasms, medicine.medical_treatment, Cohort Studies, 0302 clinical medicine, Serum biomarkers, Immunology and Allergy, CTLA-4 Antigen, Melanoma, biology, Antibodies, Monoclonal, Middle Aged, 030220 oncology & carcinogenesis, Cohort, Female, Immunotherapy, Antibody, medicine.drug, Adult, medicine.medical_specialty, Immunology, Ipilimumab, Antineoplastic Agents, S100 Calcium Binding Protein beta Subunit, Antibodies, 03 medical and health sciences, Internal medicine, medicine, Biomarkers, Tumor, Humans, Aged, Monitoring, Physiologic, Neoplasm Staging, Pharmacology, L-Lactate Dehydrogenase, business.industry, Histocompatibility Antigens Class I, Cancer, medicine.disease, Survival Analysis, 030104 developmental biology, CTLA-4, biology.protein, business, Follow-Up Studies
Abstract: Metastatic melanoma is a rapidly spreading cancer whose prognosis remains poor although important therapy advances in recent years. Ipilimumab, an anti-CTLA-4 immunotherapy used in advanced melanoma, is an effective immunotherapy alone or combined with other agents but with few predictive biomarkers of response. Here, we sought to analyze the potential of S100B, MIA, soluble MICA, anti-MICA antibodies and LDH as serum biomarkers of response and survival in a cohort of 77 advanced melanoma patients subjected to ipilimumab. Lower levels of S100B, and LDH at baseline and at weeks 3 and 6 correlated to a better response and survival. After multivariate analysis LDH maintained its independence at baseline and week 6, whereas S100B might be a useful tool for anti-CTLA-4 treatment monitoring after the first two doses of ipilimumab (W6). In addition, higher sMICA serum levels at baseline were associated with less frequency of irAEs.
Published: 2016

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Journal

Database

Publisher

147 results on '"Antoine Toubert"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources