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1. Efficacy of BAFF inhibition and B-cell depletion in non-obese diabetic mice as a spontaneous model for Sjögren’s disease

Author: Renaud Felten, Jacques-Eric Gottenberg, Lucienne Chatenoud, Jean Sibilia, Pascal Schneider, Hélène Dumortier, Fanny Monneaux, Anne-Perrine Foray, Cindy Marquet, Coralie Pecquet, and Fabrice Valette
Subjects: Medicine
Abstract: Introduction The therapeutic interest of targeting B-cell activating factor (BAFF) in Sjögren’s disease (SjD) can be suspected from the results of two phase II clinical trials but has not been evaluated in an animal model of the disease. We aimed to evaluate the therapeutic efficacy of this strategy on dryness and salivary gland (SG) infiltrates in the NOD mouse model of SjD.Material and methods Female NOD mice between ages 10 and 18 weeks were treated with a BAFF-blocking monoclonal antibody, Sandy-2 or an isotype control. Dryness was measured by the stimulated salivary flow. Salivary lymphocytic infiltrates were assessed by immunohistochemistry. Blood, SGs, spleen and lymph-node lymphocyte subpopulations were analysed by flow cytometry. SG mRNA expression was analysed by transcriptomic analysis.Results BAFF inhibition significantly decreased SG lymphocytic infiltrates, which was inversely correlated with salivary flow. The treatment markedly decreased B-cell number in SGs, blood, lymph nodes and spleen and increased Foxp3+ regulatory and CD3+CD4−CD8− double negative T-cell numbers in SGs.Conclusion A monoclonal antibody blocking BAFF and depleting B cells had therapeutic effectiveness in the NOD mouse model of SjD. The increase in regulatory T-lymphocyte populations might underlie the efficacy of this treatment.
Published: 2024
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2. Modulation of autoimmune diabetes by N-ethyl-N-nitrosourea- induced mutations in non-obese diabetic mice

Author: Lucienne Chatenoud, Cindy Marquet, Fabrice Valette, Lindsay Scott, Jiexia Quan, Chun Hui Bu, Sara Hildebrand, Eva Marie Y. Moresco, Jean-François Bach, and Bruce Beutler
Subjects: non-obese diabetic (nod) mice, autoimmune diabetes, type 1 diabetes, genetics, risk locus, protective locus, automated meiotic mapping, Medicine, Pathology, RB1-214
Abstract: Genetic association studies of type 1 diabetes (T1D) in humans, and in congenic non-obese diabetic (NOD) mice harboring DNA segments from T1D-resistant mice, face the challenge of assigning causation to specific gene variants among many within loci that affect disease risk. Here, we created random germline mutations in NOD/NckH mice and used automated meiotic mapping to identify mutations modifying T1D incidence and age of onset. In contrast with association studies in humans or congenic NOD mice, we analyzed a relatively small number of genetic changes in each pedigree, permitting implication of specific mutations as causative. Among 844 mice from 14 pedigrees bearing 594 coding/splicing changes, we identified seven mutations that accelerated T1D development, and five that delayed or suppressed T1D. Eleven mutations affected genes not previously known to influence T1D (Xpnpep1, Herc1, Srrm2, Rapgef1, Ppl, Zfp583, Aldh1l1, Col6a1, Ccdc13, Cd200r1, Atrnl1). A suppressor mutation in Coro1a validated the screen. Mutagenesis coupled with automated meiotic mapping can detect genes in which allelic variation influences T1D susceptibility in NOD mice. Variation of some of the orthologous/paralogous genes may influence T1D susceptibility in humans.
Published: 2022
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3. IL-4 and IL-17 Are Required for House Dust Mite-Driven Airway Hyperresponsiveness in Autoimmune Diabetes-Prone Non-Obese Diabetic Mice

Author: Anne-Perrine Foray, Céline Dietrich, Coralie Pecquet, François Machavoine, Lucienne Chatenoud, and Maria Leite-de-Moraes
Subjects: asthma, NOD mice, IL-17, iNKT cells, IL-4, house dust mite, Immunologic diseases. Allergy, RC581-607
Abstract: Allergic asthma is characterized by airway inflammation with a Th2-type cytokine profile, hyper-IgE production, mucus hypersecretion, and airway hyperreactivity (AHR). It is increasingly recognized that asthma is a heterogeneous disease implicating complex immune mechanisms resulting in distinct endotypes observed in patients. In this study, we showed that non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, undergo more severe allergic asthma airway inflammation and AHR than pro-Th2 BALB/c mice upon house dust mite (HDM) sensitization and challenge. The use of IL-4-deficient NOD mice and the in vivo neutralization of IL-17 demonstrated that both IL-4 and IL-17 are responsible by the exacerbated airway inflammation and AHR observed in NOD mice. Overall, our findings indicate that autoimmune diabetes-prone NOD mice might become useful as a new HDM-induced asthma model to elucidate allergic dysimmune mechanisms involving Th2 and Th17 responses that could better mimic some asthmatic endoytpes.
Published: 2021
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4. Understanding Pathogenesis and Care Challenges of Immune Reconstitution Inflammatory Syndrome in Fungal Infections

Author: Sarah Dellière, Romain Guery, Sophie Candon, Blandine Rammaert, Claire Aguilar, Fanny Lanternier, Lucienne Chatenoud, and Olivier Lortholary
Subjects: invasive fungal infections, mycoses, immune reconstitution inflammatory syndrome, fungal immunity, Biology (General), QH301-705.5
Abstract: Immune deficiency of diverse etiology, including human immunodeficiency virus (HIV), antineoplastic agents, immunosuppressive agents used in solid organ recipients, immunomodulatory therapy, and other biologics, all promote invasive fungal infections. Subsequent voluntary or unintended immune recovery may induce an exaggerated inflammatory response defining immune reconstitution inflammatory syndrome (IRIS), which causes significant mortality and morbidity. Fungal-associated IRIS raises several diagnostic and management issues. Mostly studied with Cryptococcus, it has also been described with other major fungi implicated in human invasive fungal infections, such as Pneumocystis, Aspergillus, Candida, and Histoplasma. Furthermore, the understanding of IRIS pathogenesis remains in its infancy. This review summarizes current knowledge regarding the clinical characteristics of IRIS depending on fungal species and existing strategies to predict, prevent, and treat IRIS in this patient population, and tries to propose a common immunological background to fungal IRIS.
Published: 2018
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5. Correction: Antibiotics in Early Life Alter the Gut Microbiome and Increase Disease Incidence in a Spontaneous Mouse Model of Autoimmune Insulin-Dependent Diabetes.

Author: Sophie Candon, Alicia Perez-Arroyo, Cindy Marquet, Fabrice Valette, Anne-Perrine Foray, Benjamin Pelletier, Christian Milani, Marco Ventura, Jean-François Bach, and Lucienne Chatenoud
Subjects: Medicine, Science
Published: 2016
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6. TGFβ-dependent expression of PD-1 and PD-L1 controls CD8+ T cell anergy in transplant tolerance

Author: Marije Baas, Alix Besançon, Tania Goncalves, Fabrice Valette, Hideo Yagita, Birgit Sawitzki, Hans-Dieter Volk, Emmanuelle Waeckel-Enée, Benedita Rocha, Lucienne Chatenoud, and Sylvaine You
Subjects: tolerance, CD8+ T cells, TGF-beta, PD-1/PD-L1, tranplantation, anergy, Medicine, Science, Biology (General), QH301-705.5
Abstract: CD8+ T cell anergy is a critical mechanism of peripheral tolerance, poorly investigated in response to immunotherapy. Here, using a pancreatic islet allograft model and CD3 antibody therapy, we showed, by single cell gene profiling, that intragraft CD8+ lymphocytes coexpressing granzyme B and perforin were selectively depleted through the Fas/FasL pathway. This step led to long-standing anergy of the remaining CD8+ T cells marked by the absence of cytotoxic/inflammatory gene expression also confirmed by transcriptome analysis. This sustained unresponsiveness required the presence of the alloantigens. Furthermore, tissue-resident CD8+ lymphocytes produced TGFβ and expressed the inhibitory receptors PD-1 and PD-L1. Blockade of TGFβ downregulated PD-1 and PD-L1 expression and precipitated graft rejection. Neutralizing PD-1, PD-L1 or TGFβRII signaling in T cells also abrogated CD3 antibody-induced tolerance. These studies unravel novel mechanisms underlying CD8+ T cell anergy and reveal a cell intrinsic regulatory link between the TGFβ and the PD-1/PD-L1 pathways.
Published: 2016
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7. Antibiotics in early life alter the gut microbiome and increase disease incidence in a spontaneous mouse model of autoimmune insulin-dependent diabetes.

Author: Sophie Candon, Alicia Perez-Arroyo, Cindy Marquet, Fabrice Valette, Anne-Perrine Foray, Benjamin Pelletier, Christian Milani, Marco Ventura, Jean-François Bach, and Lucienne Chatenoud
Subjects: Medicine, Science
Abstract: Insulin-dependent or type 1 diabetes is a prototypic autoimmune disease whose incidence steadily increased over the past decades in industrialized countries. Recent evidence suggests the importance of the gut microbiota to explain this trend. Here, non-obese diabetic (NOD) mice that spontaneously develop autoimmune type 1 diabetes were treated with different antibiotics to explore the influence of a targeted intestinal dysbiosis in the progression of the disease. A mixture of wide spectrum antibiotics (i.e. streptomycin, colistin and ampicillin) or vancomycin alone were administered orally from the moment of conception, treating breeding pairs, and during the postnatal and adult life until the end of follow-up at 40 weeks. Diabetes incidence significantly and similarly increased in male mice following treatment with these two antibiotic regimens. In NOD females a slight yet not significant trend towards an increase in disease incidence was observed. Changes in gut microbiota composition were assessed by sequencing the V3 region of bacterial 16S rRNA genes. Administration of the antibiotic mixture resulted in near complete ablation of the gut microbiota. Vancomycin treatment led to increased Escherichia, Lactobacillus and Sutterella genera and decreased members of the Clostridiales order and Lachnospiraceae, Prevotellaceae and Rikenellaceae families, as compared to control mice. Massive elimination of IL-17-producing cells, both CD4+TCRαβ+ and TCRγδ+ T cells was observed in the lamina propria of the ileum and the colon of vancomycin-treated mice. These results show that a directed even partial ablation of the gut microbiota, as induced by vancomycin, significantly increases type 1 diabetes incidence in male NOD mice thus prompting for caution in the use of antibiotics in pregnant women and newborns.
Published: 2015
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8. Therapeutic use of a selective S1P1 receptor modulator ponesimod in autoimmune diabetes.

Author: Sylvaine You, Luca Piali, Chantal Kuhn, Beat Steiner, Virginia Sauvaget, Fabrice Valette, Martine Clozel, Jean-François Bach, and Lucienne Chatenoud
Subjects: Medicine, Science
Abstract: In the present study, we investigated the therapeutic potential of a selective S1P1 receptor modulator, ponesimod, to protect and reverse autoimmune diabetes in non-obese diabetic (NOD) mice. Ponesimod was administered orally to NOD mice starting at 6, 10, 13 and 16 weeks of age up to 35 weeks of age or to NOD mice showing recent onset diabetes. Peripheral blood and spleen B and T cell counts were significantly reduced after ponesimod administration. In pancreatic lymph nodes, B lymphocytes were increased and expressed a transitional 1-like phenotype. Chronic oral ponesimod treatment efficiently prevented autoimmune diabetes in 6, 10 and 16 week-old pre-diabetic NOD mice. Treatment withdrawal led to synchronized disease relapse. Ponesimod did not inhibit the differentiation of autoreactive T cells as assessed by adoptive transfer of lymphocytes from treated disease-free NOD mice. In addition, it did not affect the migration, proliferation and activation of transgenic BDC2.5 cells into the target tissue. However, ponesimod inhibited spreading of the T cell responses to islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). Treatment of diabetic NOD mice with ponesimod induced disease remission. However, here again, upon treatment cessation, the disease rapidly recurred. This recurrence was effectively prevented by combination treatment with a CD3 antibody leading to the restoration of self-tolerance. In conclusion, treatment with a selective S1P1 modulator in combination with CD3 antibody represents a promising therapeutic approach for the treatment of autoimmune diabetes.
Published: 2013
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9. Key role of the GITR/GITRLigand pathway in the development of murine autoimmune diabetes: a potential therapeutic target.

Author: Sylvaine You, Lynn Poulton, Steve Cobbold, Chih-Pin Liu, Michael Rosenzweig, Douglas Ringler, Wen-Hui Lee, Berta Segovia, Jean-François Bach, Herman Waldmann, and Lucienne Chatenoud
Subjects: Medicine, Science
Abstract: The cross-talk between pathogenic T lymphocytes and regulatory T cells (Tregs) plays a major role in the progression of autoimmune diseases. Our objective is to identify molecules and/or pathways involved in this interaction and representing potential targets for innovative therapies. Glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand are key players in the T effector/Treg interaction. GITR is expressed at low levels on resting T cells and is significantly up-regulated upon activation. Constitutive high expression of GITR is detected only on Tregs. GITR interacts with its ligand mainly expressed on antigen presenting cells and endothelial cells. It has been suggested that GITR triggering activates effector T lymphocytes while inhibiting Tregs thus contributing to the amplification of immune responses. In this study, we examined the role of GITR/GITRLigand interaction in the progression of autoimmune diabetes.Treatment of 10-day-old non-obese diabetic (NOD) mice, which spontaneously develop diabetes, with an agonistic GITR-specific antibody induced a significant acceleration of disease onset (80% at 12 weeks of age). This activity was not due to a decline in the numbers or functional capacity of CD4(+)CD25(+)Foxp3(+) Tregs but rather to a major activation of 'diabetogenic' T cells. This conclusion was supported by results showing that anti-GITR antibody exacerbates diabetes also in CD28(-/-) NOD mice, which lack Tregs. In addition, treatment of NOD mice, infused with the diabetogenic CD4(+)BDC2.5 T cell clone, with GITR-specific antibody substantially increased their migration, proliferation and activation within the pancreatic islets and draining lymph nodes. As a mirror image, blockade of the GITR/GITRLigand pathway using a neutralizing GITRLigand-specific antibody significantly protected from diabetes even at late stages of disease progression. Experiments using the BDC2.5 T cell transfer model suggested that the GITRLigand antibody acted by limiting the homing and proliferation of pathogenic T cells in pancreatic lymph nodes.GITR triggering plays an important costimulatory role on diabetogenic T cells contributing to the development of autoimmune responses. Therefore, blockade of the GITR/GITRLigand pathway appears as a novel promising clinically oriented strategy as GITRLigand-specific antibody applied at an advanced stage of disease progression can prevent overt diabetes.
Published: 2009
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10. Aberrant Function and Long-Term Survival of Mouse β Cells Exposed In Vitro to High Glucose Concentrations

Author: Martine Pehuet-Figoni, Eric Ballot, Jean-François Bach, and Lucienne Chatenoud
Subjects: Medicine
Abstract: In vitro culture of murine Langerhans islets usually ends in islet death after 1-3 wk. Given contradictory published data, we studied the influence of glucose on the function and survival of islets from DBA/2 mice. Islets were cultured on plastic microwells, using 1, 2, or 11 g/l glucose concentrations. Using our routine technique, insulin secretion was evaluated after islet incubation for 15 min in basal medium [(bIS), 1 g/1 glucose], followed by 15 min in stimulating medium [(sIS), 3 g/l glucose, 20 mM/l arginine, 5 mM/l theophylline]. Insulin secretion of islets cultured in 1 g/l glucose remained stable and normal over a period of 2 mo [Day 7: bIS, 6.3 ± 3.1 pU/50 μl; sIS, 16.6 ± 6.8 μU/50 μl. Day 60: bIS, 6.0 ± 4.0 pU/50 μl; sIS, 21.3 ± 10.5 μU/50 μl]. Islet morphology also remained normal. Islets cultured in 2 g/l glucose showed elevated insulin response under basal and stimulating conditions during 2-3 wk, followed by a dramatic drop in insulin secretion [Day 7: bIS, 19.5 ± 5.7 μU/50 μl; sIS, 80.9 ± 10.7 μU/50 μl. Day 60: bIS, 5.4 ± 5.0 μU/50 μl; sIS, 2.7 ± 1.4 μU/50 μl]. Severe morphologic alterations appeared rapidly and islet destruction was nearly complete by 60 days. At 11 g/l glucose, functional and morphological islet alterations were accelerated [Day 7: bIS, 10.3 ± 2.7 μU/50 μl; sIS, 18.8 ± 4.9 μU/50 μl. Day 21: bIS and sIS almost undetectable]. On the basis of the results obtained in our experimental conditions, it may be concluded that the optimal glucose concentration for long-term murine islet cultures is 1 g/l. Based on the results of this study and testing an extracellular matrix, we thereafter cultured islets from DBA/2 mice at the 1 g/l glucose concentration. These islets remained functional for a period of time > 100 days. Abbreviations: bIS: insulin secretion in basal medium; sIS: insulin secretion in stimulating medium; MEM: minimal essential medium.
Published: 1994
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11. Adalimumab Therapy in Pediatric Crohn Disease: A 2-Year Follow-Up Comparing 'Top-Down' and 'Step-Up' Strategies

Author: Elise Payen, Antoine Neuraz, Letizia Zenzeri, Cécile Talbotec, Elie Abi Nader, Lucienne Chatenoud, Stephanie Chhun, Olivier Goulet, Frank M. Ruemmele, and Bénédicte Pigneur
Subjects: Pediatrics, Perinatology and Child Health, Gastroenterology
Published: 2022

12. Supplementary Methods, Figure Legends, Table Legend from Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia

Author: Vahid Asnafi, Jacques Ghysdael, Elizabeth Macintyre, Olivier Hermine, David-Alexandre Gross, Lucienne Chatenoud, Salvatore Spicuglia, Hervé Dombret, Norbert Ifrah, Françoise Pflumio, Els Verhoeyen, François-Loïc Cosset, Michael Dussiot, Melania Tesio, Ludovic Lhermitte, Cindy Da Costa de Jesus, Mohamed Belhocine, Benedetta Zaniboni, Francesca Rocchetti, Christine Tran Quang, Nuno R. dos Santos, and Amélie Trinquand
Abstract: Supplementary Methods, Figure Legends, Table Legend
Published: 2023

13. Supplementary Figures 1 - 3, Table 1 from Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia

Author: Vahid Asnafi, Jacques Ghysdael, Elizabeth Macintyre, Olivier Hermine, David-Alexandre Gross, Lucienne Chatenoud, Salvatore Spicuglia, Hervé Dombret, Norbert Ifrah, Françoise Pflumio, Els Verhoeyen, François-Loïc Cosset, Michael Dussiot, Melania Tesio, Ludovic Lhermitte, Cindy Da Costa de Jesus, Mohamed Belhocine, Benedetta Zaniboni, Francesca Rocchetti, Christine Tran Quang, Nuno R. dos Santos, and Amélie Trinquand
Abstract: Supplementary Figure 1. Anti-CD3 stimulation of primary human T-ALLs. Supplementary Figure 2. TCR stimulation by in vivo administration of agonistic monoclonal antibody in a preventive setting inhibits human TCR+ T-ALL development. Supplementary Figure 3. TCR signaling is essential to the anti-leukemic effect of OKT3. Supplementary Table 1. Immunophenotypic and oncogenic characteristics of T-ALL samples.
Published: 2023

14. Adalimumab therapy in pediatric Crohn's Disease: a two-year follow-up comparing 'top-down' and 'step-up' strategies

Author: Elise, Payen, Antoine, Neuraz, Letizia, Zenzeri, Cécile, Talbotec, Elie, Abi Nader, Lucienne, Chatenoud, Stephanie, Chhun, Olivier, Goulet, Frank M, Ruemmele, and Bénédicte, Pigneur
Abstract: European Crohn's Colitis Organization (ECCO) and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines recommend the early use of anti-TNF biologicals in pediatric Crohn disease (CD) patients with positive predictors for poor outcome.The objective of the present study was to compare early "Top-Down" use of Adalimumab (ADA) immunomodulator/biologics-naïve patients to conventional "Step-Up" management.One hundred and twenty consecutive patients with a confirmed diagnosis of CD and treated with Adalimumab (ADA) between 2008 and 2019 were included and allocated to the ADA-Top Down (n=59) or ADA-Step Up group (n=61). The primary endpoint was prolonged steroid-/enteral nutrition-free clinical remission at 24 months, defined by a wPCDAI12.5. Clinical and biological data were collected at 12 and 24 months.At start of ADA, disease activity was comparable between the ADA-Top Down group and the ADA-Step Up group (wPCDAI=31 ± 16 versus 31.3 ± 15.2 respectively, p=0.84). At 24 months, the remission rate was significantly higher in the ADA-Top Down group (73% versus 51%, p0.01). After propensity score, the Top-Down strategy is still more effective than the Step-Up strategy in maintaining remission at 24 months (HR=0.36, 95%CI[0.15-0.87], p=0.02). Patients in the ADA-Top Down group were mainly on monotherapy compared to patients in the ADA-Step Up group (53/55 versus 28/55 respectively, p0.001). Serum levels of Adalimumab were higher in the ADA-Top Down group than in the ADA-Step Up group (12.8µg/ml±4.3 versus 10.4µg/ml±3.9 respectively, p0.01).There were no serious adverse events.Early use of ADA appears to be more effective in maintaining relapse-free remission at 2 years, while using it as monotherapy. These findings further favor the recommendation of early anti-TNF use in high-risk CD patients.
Published: 2022

15. Trough Levels of Infliximab at Week 6 Are Predictive of Remission at Week 14 in Pediatric Crohn's Disease

Author: Sophie Candon, Lucienne Chatenoud, Jean-Pierre Hugot, Olivier Courbette, Camille Aupiais, Christine Martinez-Vinson, Jérôme Viala, Xavier Roblin, and Baptiste Louveau
Subjects: medicine.medical_specialty, Adolescent, Pediatric Crohn's disease, Early detection, Disease, Logistic regression, Crohn Disease, Gastrointestinal Agents, Internal medicine, medicine, Humans, Child, Retrospective Studies, business.industry, Crohn disease, Medical record, Remission Induction, Gastroenterology, Retrospective cohort study, Infliximab, Treatment Outcome, Child, Preschool, Pediatrics, Perinatology and Child Health, business, medicine.drug
Abstract: Infliximab (IFX) is a frequent therapeutic option for Crohn disease (CD) patients. Early detection of responders to IFX is critical for the management of CD in order to avoid long-term exposure to the drug without benefit. This retrospective study aimed at analysing which early parameters recorded during the induction period are able to predict response to IFX during the maintenance period in pediatric CD.Medical records of all CD patients ages from 2 to 18 years who received IFX at a tertiary IBD center were retrospectively analyzed. Children were classified in 3 groups according to their response at week 14 (W14) remission, clinical response or , no response. The factors recorded at W0, W2, and W6, which were associated with remission at W14 were analyzed using a logistic regression.Among the 111 patients included, 74.8% patients were responders to IFX at W14, including 38.7% in clinical remission and 36% with partial clinical response. Clinical remission at W14 was associated with normal growth (P 0.01), and normal albuminemia (P = 0.01) at baseline, It was also associated with trough levels to IFX8.3 μg/ml at week 6 (P 0.01).Trough levels to IFX8.3 μg/ml at week 6 are predictive of remission at W14 for luminal disease.
Published: 2020

16. Convalescent plasma therapy for B-cell–depleted patients with protracted COVID-19

Author: Stanislas Faguer, Pierre Tiberghien, Etienne Crickx, Fanny Pommeret, David Veyer, Claire Rouzaud, Fabrice Camou, Olivier Hermine, Elie Azoulay, Pierre Gallian, Cécile Pouderoux, Deborah Eshagh, Jonathan London, Fatiha Merabet, Philippe Petua, David Boutboul, Laure Anne Raillon, Valérie Zeller, Hélène Péré, Benjamin Planquette, Jérôme Pacanowski, Adrien Joseph, Marc Michel, Martin Martinot, Matthieu Mahévas, Lucienne Chatenoud, Karine Lacombe, Anne Lise Beaumont, David Ghez, Amani Ouedrani, Tali Anne Szwebel, Arsène Mekinian, Florence Ader, Thomas Hueso, Marc Garnier, and Sébastien Clerc
Subjects: 0301 basic medicine, Clinical Trials and Observations, Immunology, Pneumonia, Viral, Context (language use), 030204 cardiovascular system & hematology, Biochemistry, Immunoglobulin G, Serology, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, Agammaglobulinemia, medicine, Humans, Adverse effect, Pandemics, COVID-19 Serotherapy, Autoimmune disease, B-Lymphocytes, biology, business.industry, SARS-CoV-2, Brief Report, Bacterial pneumonia, Immunization, Passive, COVID-19, Cell Biology, Hematology, medicine.disease, 3. Good health, Pneumonia, 030104 developmental biology, biology.protein, Antibody, business, Coronavirus Infections
Abstract: There is a Blood Commentary on this article in this issue., Key Points As a proof of concept, COVID-19 convalescent plasma represents an interesting approach in B-cell–depleted patients with protracted COVID-19.COVID-19 convalescent plasma induces a decrease in temperature and inflammatory parameters within 1 week associated with oxygen weaning., Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti–SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2., Visual Abstract
Published: 2020

17. Anti-CD38 therapy impairs SARS-CoV-2 vaccine response against alpha and delta variants in patients with multiple myeloma

Author: Soledad Henriquez, Jérémie Zerbit, Timothée Bruel, Amani Ouedrani, Delphine Planas, Paul Deschamps, Isabelle Staropoli, Jérôme Hadjadj, Bruno Varet, Natalia Ermak, Didier Bouscary, Lise Willems, Guillemette Fouquet, Justine Decroocq, Patricia Franchi, Benedicte Deau-Fischer, Benjamin Terrier, Jérôme Tamburini, Lucienne Chatenoud, Olivier Schwartz, Marguerite Vignon, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), CHU Necker - Enfants Malades [AP-HP], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Université de Genève (UNIGE), Université Paris Descartes - Paris 5 (UPD5), This study was supported by Fonds IMMUNOV for Innovation in Immunopathology, by the Institut Pasteur (for work in the OS laboratory), the Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Fondation pour la Recherche Médicale, and ANRS, and by grants from the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2, and IDISCOVR. D.P. is supported by the Vaccine Research Institute., 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-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), 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 National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Université de Genève = University of Geneva (UNIGE)
Subjects: Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cell Biology, Hematology, Biochemistry, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2022

18. Immunogenicity of BNT162b2 vaccine against the Alpha and Delta variants in immunocompromised patients with systemic inflammatory diseases

Author: Jerome Hadjadj, Delphine Planas, Amani Ouedrani, Solene Buffier, Laure Delage, Yann Nguyen, Timothée Bruel, Marie-Claude Stolzenberg, Isabelle Staropoli, Natalia Ermak, Laure Macraigne, Caroline Morbieu, Soledad Henriquez, David Veyer, Hélène Péré, Marion Casadevall, Luc Mouthon, Frederic Rieux-Laucat, Lucienne Chatenoud, Olivier Schwartz, Benjamin Terrier, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vaccine Research Institute [Créteil, France] (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Sanofi [Vitry-sur-Seine], SANOFI Recherche, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Beaujon [AP-HP], Université Paris Cité (UPCité), Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), This study was supported by the Fonds IMMUNOV, for Innovation in Immunopathology. Work in OS lab is funded by Institut Pasteur, Urgence COVID-19 Fundraising Campaign of Institut Pasteur, Fondation pour la Recherche Médicale, ANRS, the Vaccine Research Institute (ANR-10-LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash COVID-19 PROTEO-SARS-CoV-2 and IDISCOVR. DP is supported by the Vaccine Research Institute, ANR-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
Subjects: COVID-19 Vaccines, SARS-CoV-2, Epidemiology, [SDV]Life Sciences [q-bio], Immunology, COVID-19, Antibodies, Viral, vaccination, General Biochemistry, Genetics and Molecular Biology, methotrexate, Immunocompromised Host, Immunogenicity, Vaccine, rituximab, Rheumatology, Immunology and Allergy, Humans, Prospective Studies, BNT162 Vaccine
Abstract: ObjectivesThe emergence of strains of SARS-CoV-2 exhibiting increase viral fitness and immune escape potential, such as the Delta variant (B.1.617.2), raises concerns in immunocompromised patients. We aimed to evaluate seroconversion, cross-neutralisation and T-cell responses induced by BNT162b2 in immunocompromised patients with systemic inflammatory diseases.MethodsProspective monocentric study including patients with systemic inflammatory diseases and healthcare immunocompetent workers as controls. Primary endpoints were anti-spike antibodies levels and cross-neutralisation of Alpha and Delta variants after BNT162b2 vaccine. Secondary endpoints were T-cell responses, breakthrough infections and safety.ResultsSixty-four cases and 21 controls not previously infected with SARS-CoV-2 were analysed. Kinetics of anti-spike IgG after BNT162b2 vaccine showed lower and delayed induction in cases, more pronounced with rituximab. Administration of two doses of BNT162b2 generated a neutralising response against Alpha and Delta in 100% of controls, while sera from only one of rituximab-treated patients neutralised Alpha (5%) and none Delta. Other therapeutic regimens induced a partial neutralising activity against Alpha, even lower against Delta. All controls and cases except those treated with methotrexate mounted a SARS-CoV-2 specific T-cell response. Methotrexate abrogated T-cell responses after one dose and dramatically impaired T-cell responses after two doses of BNT162b2. Third dose of vaccine improved immunogenicity in patients with low responses.ConclusionRituximab and methotrexate differentially impact the immunogenicity of BNT162b2, by impairing B-cell and T-cell responses, respectively. Delta fully escapes the humoral response of individuals treated with rituximab. These findings support efforts to improve BNT162b2 immunogenicity in immunocompromised individuals (ClinicalTrials.gov number, NCT04870411).
Published: 2022

19. De novo germline mutation in the dual specificity phosphatase 10 gene accelerates autoimmune diabetes

Author: Fabrice Valette, Pere Santamaria, Jean-François Bach, Claudio Scazzocchio, Sophie Candon, Sebastien Lemoine, Sara Hildebrand, Peipei Hu, Bruce Beutler, Sylvaine You, Francina Langa-Vives, Stephen Aplin Lyon, Anne-Perrine Foray, Eva Marie Y. Moresco, Chun Hui Bu, Lucienne Chatenoud, Coralie Pecquet, Darui Xu, Cindy Marquet, Michael Dumas, Lindsay Scott, Tao Wang, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Texas Southwestern Medical Center [Dallas], Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP), Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS)-Centre National de la Recherche Scientifique (CNRS), University of Calgary, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Imperial College London, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Funding was provided by NIH Grant R01 AI125581 (B.B.), NIH Grant U19 AI100627 (B.B.), European Research Council Advanced Grant, Hygiene No. 250290 (J.-F.B.), Institut National de la Santé et de la Recherche Scientifique (L.C.), Fondation Day Solvay (L.C.), and the Lyda Hill Foundation (B.B.)., European Project: 250290,EC:FP7:ERC,ERC-2009-AdG,HYGIENE(2010), LANGA VIVES, FRANCINA, and THE HYGIENE HYPOTHESIS : REVISITING THE CONCEPT BY INTEGRATING EPIDEMIOLOGY AND MECHANISTIC STUDIES - HYGIENE - - EC:FP7:ERC2010-08-01 - 2015-07-31 - 250290 - VALID
Subjects: Male, type 1 diabetes, Nod, Major histocompatibility complex, medicine.disease_cause, Autoimmune Diseases, Major Histocompatibility Complex, Islets of Langerhans, Mice, Germline mutation, Mice, Inbred NOD, medicine, Animals, Humans, Missense mutation, Genetic Predisposition to Disease, Germ-Line Mutation, NOD mice, Autoimmune disease, Genetics, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, biology, autoimmunity, Haplotype, Biological Sciences, medicine.disease, Mice, Inbred C57BL, Diabetes Mellitus, Type 1, Haplotypes, biology.protein, Dual-Specificity Phosphatases, Mitogen-Activated Protein Kinase Phosphatases, Female, genetic mapping, NOD mouse, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study
Abstract: International audience; Significance: The vast majority of autoimmune diseases are polygenic, and causal loci uncovered by genetic-mapping studies explain only a minority of the heritable contribution to trait variation. Multiple explanations for this missing heritability include rare meaningful variants, rare copy number variations or deletions, epistasis, epigenetics, disease heterogeneity, and rare or infrequent variants that segregate within individual families (even within monozygotic twins). Here we demonstrate that experimental models of spontaneous autoimmune diseases may be invaluable tools to map rare germline variants impacting disease susceptibility traits. We identified a variant of the dual-specificity phosphatase 10 encoding gene that accelerates disease in an autoimmune type 1 diabetes model, the nonobese diabetic mouse.Abstract: Insulin-dependent or type 1 diabetes (T1D) is a polygenic autoimmune disease. In humans, more than 60 loci carrying common variants that confer disease susceptibility have been identified by genome-wide association studies, with a low individual risk contribution for most variants excepting those of the major histocompatibility complex (MHC) region (40 to 50% of risk); hence the importance of missing heritability due in part to rare variants. Nonobese diabetic (NOD) mice recapitulate major features of the human disease including genetic aspects with a key role for the MHC haplotype and a series of Idd loci. Here we mapped in NOD mice rare variants arising from genetic drift and significantly impacting disease risk. To that aim we established by selective breeding two sublines of NOD mice from our inbred NOD/Nck colony exhibiting a significant difference in T1D incidence. Whole-genome sequencing of high (H)- and low (L)-incidence sublines (NOD/NckH and NOD/NckL) revealed a limited number of subline-specific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/NckH mice was unambiguously attributed to a recessive missense mutation of Dusp10, which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp10 with CRISPR-Cas9 in NOD/NckL mice, a manipulation that significantly increased disease incidence. The Dusp10 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against autoimmune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype.
Published: 2021

20. Absence of severe COVID-19 in patients with clonal mast cells activation disorders: effective anti-SARS-CoV-2 immune response

Author: Julien Rossignol, Amani Ouedrani, Cristina Bulai Livideanu, Stéphane Barete, Louis Terriou, David Launay, Richard Lemal, Celine Greco, Laurent Frenzel, Cecile Meni, Christine Bodemere-Skandalis, Laura Polivka, Anne-Florence Collange, Hassiba Hachichi, Sonia Bouzourine, Djazira Nait Messaoud, Mathilde Negretto, Laurence Vendrame, Marguerite Jambou, Marie Gousseff, Stéphane Durupt, Jean-Christophe Lega, Jean-Marc Durand, Caroline Gaudy, Gandhi Damaj, Marie-Pierre Gourin, Mohamed Hamidou, Laurence Bouillet, Edwige Le Mouel, Alexandre Maria, Patricia Zunic, Quentin Cabrera, Denis Vincent, Christian Lavigne, Etienne Riviere, Clement Gourguechon, Anne Brignier, Ludovic Lhermitte, Thierry Jo Molina, Julie Bruneau, Julie Agopian, Patrice Dubreuil, Dana Ranta, Alexandre Mania, Michel Arock, Isabelle Staropoli, Olivier Tournilhac, Olivier Lortholary, Olivier Schwartz, Lucienne Chatenoud, and Olivier Hermine
Subjects: education.field_of_study, Innate immune system, biology, business.industry, ELISPOT, Population, Tryptase, Acquired immune system, Immune system, Immunity, Immunology, biology.protein, Medicine, Antibody, education, business
Abstract: Mast cells are key actors of innate immunity and Th2 adaptive immune response which counterbalance Th1 response, critical for anti-viral immunity. Clonal Mast Cells Activation Disorders (cMCADs) such as mastocytosis and clonal mast cells activation syndrome are characterized by an abnormal mast cells accumulation and/or activation. No data have been published on the anti-viral immune response of patients with cMCADs. The aims of the study were to collected, in a comprehensive way, outcomes of cMCADs patients who experienced a biologically-proven COVID-19 and to characterize both anti-endemic coronaviruses and specific anti-SARS-CoV-2 immune responses in these patients. Clinical follow-up and outcome data were collected prospectively for one year within the French rare disease network CEREMAST encompassing patients from all over the country. Anti-SARS-CoV-2 and anti-endemic coronaviruses specific T-cells were assessed with an enzyme-linked immunospot assay (EliSpot) and anti-SARS-CoV-2 humoral response with dosage of circulating levels of specific IgG, IgA and neutralizing antibodies. Overall, 32 cMCADs patients were identified. None of them required non-invasive or mechanical ventilation; two patients were hospitalized to receive oxygen and steroid therapy. In 21 patients, a characterization of the SARS-CoV-2-specific immune response has been performed. A majority of patients showed a high proportion of circulating SARS-CoV-2-specific interferon (IFN)-γ producing T-cells and high levels of anti-Spike IgG antibodies with neutralizing activity. In addition, no defects in anti-endemic coronaviruses responses were found in patients with cMCADs compared to non-cMCADs controls. Patients with cMCADs frequently showed a spontaneous IFN-γ T-cell production in absence of any stimulation that correlated with circulating basal tryptase levels, a marker of mast cells burden. These findings underscore that patients with cMCADs might be not at risk of severe COVID-19 and the spontaneous IFN-γ production might explain this observation.Author SummaryMast cells are immune cells involved in many biological processes including the anti-microbial response. However, previous studies suggest that mast cells may have a detrimental role in the response against viruses such as SARS-CoV-2, responsible for COVID-19. When a mutation occurs in mast cells, it can lead to a group of diseases called clonal mast cells activation disorders (cMCADs), characterized by deregulated activation of these cells. Hence, patients with cMCADs might be more susceptible to severe COVID-19 than general population.We therefore conducted a 1-year study in France to collect data from all cMCADs patients included in the CEREMAST rare disease French network and who experienced COVID-19. Interestingly, we did not find any severe COVID-19 (i.e. requiring non-invasive or mechanical ventilation) in spite of well-known risk factors for severe COVID-19 in a part of cMCADs patients.We then have studied the immune response against SARS-CoV-2 and other endemic coronaviruses in these patients. We did not observe any abnormalities in the immune response either at the level of T and B lymphocytes. These findings underscore that these patients might not be at risk of severe COVID-19 as one might have feared.
Published: 2021

21. Immunogenicity of BNT162b2 vaccine Against the Alpha and Delta Variants in Immunocompromised Patients

Author: Soledad Henriquez, Isabelle Staropoli, Caroline Morbieu, Frédéric Rieux-Laucat, Benjamin Terrier, Delphine Planas, Marion Casadevall, Amani Ouedrani, Yann Nguyen, Luc Mouthon, Olivier Schwartz, Hélène Péré, Jérôme Hadjadj, Lucienne Chatenoud, Natalia Ermak, Marie-Claude Stolzenberg, Laure Delage, Solene Buffier, Laure Macraigne, Timothée Bruel, and David Veyer
Subjects: Delta, biology, business.industry, Immunogenicity, Alpha (ethology), Immunity, Immunology, biology.protein, Medicine, Methotrexate, Rituximab, Antibody, business, Prospective cohort study, medicine.drug
Abstract: BackgroundThe emergence of strains of SARS-CoV-2 exhibiting increase viral fitness and immune escape potential, such as the Delta variant (B.1.617.2), raises concerns in immunocompromised patients. To what extent Delta evades vaccine-induced immunity in immunocompromised individuals with systemic inflammatory diseases remains unclear.MethodsWe conducted a prospective study in patients with systemic inflammatory diseases (cases) and controls receiving two doses of BNT162b2. Primary end points were anti-spike antibodies levels and cross-neutralization of Alpha and Delta variants after BNT162b2 vaccine. Secondary end points were T-cell responses, breakthrough infections and safety.ResultsSixty-four cases and 21 controls not previously infected with SARS-CoV-2 were analyzed. Kinetics of anti-spike IgG and IgA after BNT162b2 vaccine showed lower and delayed induction in cases, more pronounced with rituximab. Administration of two doses of BNT162b2 generated a neutralizing response against Alpha and Delta in 100% of controls, while sera from only one of rituximab-treated patients neutralized Alpha (5%) and none Delta. Other therapeutic regimens induced a partial neutralizing activity against Alpha, even lower against Delta. All controls and cases except those treated with methotrexate mounted a SARS-CoV-2 specific T-cell response. Methotrexate abrogated T-cell responses after one dose and dramatically impaired T-cell responses after 2 doses of BNT162b2.ConclusionsRituximab and methotrexate differentially impact the immunogenicity of BNT162b2, by impairing B-cell and T-cell responses, respectively. Delta fully escapes the humoral response of individuals treated with rituximab. These findings support efforts to improve BNT162b2 immunogenicity in immunocompromised individuals (Funded by the Fonds IMMUNOV;ClinicalTrials.govnumber,NCT04870411).
Published: 2021

22. Anti-CD38 therapy impairs SARS-CoV-2 vaccine response in multiple myeloma patients

Author: Felipe Suarez, Olivier Schwartz, Jeremie Zerbit, Bruno Varet, Amani Ouedrani, Lise Willems, Soledad Henriquez, Patricia Franchi, Natalia Ermak, Bénédicte Deau-Fischer, Guillemette Fouquet, Jérôme Hadjadj, Delphine Planas, Justine Decroocq, Timothée Bruel, Marguerite Vignon, Benjamin Terrier, Paul Deschamps, Lucienne Chatenoud, Jerome Tamburini, Didier Bouscary, and Isabelle Staropoli
Subjects: biology, business.industry, medicine.medical_treatment, Immunogenicity, Immunotherapy, CD38, medicine.disease, Vaccination, Immune system, Immunology, biology.protein, Medicine, Antibody, business, Prospective cohort study, Multiple myeloma
Abstract: Multiple myeloma (MM) patients are at risk of fatal outcome after SARS-CoV-2 infection. Preliminary data suggest that MM patients have an impaired response to vaccination. This prospective study analyzed the humoral and cellular immune responses to two doses of BNT162b2 in 72 MM patients, including 48 receiving anti-CD38 immunotherapy. Results evidenced that MM patients display lower levels of SARS-CoV-2 specific IgG and IgA antibodies and decreased neutralization of alpha and delta variants when compared to healthy controls. They also showed decreased numbers of circulating IFNγ-producing Spike SARS-CoV-2 specific T lymphocytes. This defective immune response was particularly marked in patients receiving anti-CD38 immunotherapy. Furthermore, a retrospective investigation of MM patients among COVID-19-related death in the Paris area suggested a limited efficacy of BNT162b2 in patients treated with anti-CD38. Overall, these results show a decreased immunogenicity of BNT162b2 in MM patients and stress the need for novel strategies to improve SARS-CoV-2 prophylaxis in immunocompromised individuals.
Published: 2021

23. Infliximab Paradoxical Psoriasis in a Cohort of Children With Inflammatory Bowel Disease

Author: Jean-Pierre Hugot, Lucienne Chatenoud, Olivier Courbette, Christine Martinez-Vinson, Baptiste Louveau, Jérôme Viala, Camille Aupiais, and Emmanuelle Bourrat
Subjects: Male, medicine.medical_specialty, Adolescent, Side effect, Inflammatory bowel disease, Gastroenterology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, 030225 pediatrics, Internal medicine, Psoriasis, medicine, Humans, Child, Retrospective Studies, business.industry, Retrospective cohort study, Inflammatory Bowel Diseases, medicine.disease, Ulcerative colitis, Infliximab, Child, Preschool, Pediatrics, Perinatology and Child Health, Cohort, Female, 030211 gastroenterology & hepatology, Dermatologic Agents, France, business, medicine.drug
Abstract: Objectives In adult inflammatory bowel disease (IBD) treated by anti-TNF antibodies, paradoxical psoriasis has an estimated prevalence of 1.6 to 22%, especially in infliximab (IFX)-treated patients. Little is known in the pediatric IBD (PIBD) populations. Methods All patients ages from 2 to 18 years with Crohn disease (CD) or ulcerative colitis (UC) and treated for the first time by IFX between January 2002 and March 2014, were considered for inclusion in this retrospective study performed in a tertiary PIBD centre. Paradoxical psoriasis events together with clinical and biological data were collected in all patients. Comparisons between psoriasis and control groups were performed using univariate statistical analyses. Results One hundred and twenty-three CD patients and 24 UC patients were treated with IFX. Twenty patients (13.6%) experienced a paradoxical psoriasis. All of them were affected by CD. Perianal CD was more frequent in the psoriasis group (P = 0.033). Fourteen patients (70%) were in remission when skin lesions occurred. Paradoxical psoriasis was diagnosed 355 days (median, interquartile range [IQR] 239; 532) after the initiation of IFX corresponding to the eighth injection (median, IQR: 6; 15). Psoriasis lesions were controlled by local steroids in all cases and no patients discontinued IFX therapy. Conclusions 13.6% of our IBD patients treated with IFX developed psoriasis during a median follow-up of 23.9 months (IQR: 11.6; 36.5). Crohn disease patients with perianal disease were at a higher risk to develop this common side effect.
Published: 2019

24. Human peripheral blood DNAM-1neg NK cells are a terminally differentiated subset with limited effector functions

Author: Nigel J. Waterhouse, Mark J. Smyth, Ludovic Martinet, Frank Vari, Lucienne Chatenoud, Maher K. Gandhi, Sébastien Lemoine, Camille Guillerey, and Kimberley Stannard
Subjects: medicine.medical_treatment, Cell, dNaM, Hematology, Biology, medicine.disease, Lymphoma, Transcriptome, medicine.anatomical_structure, Cytokine, Antigen, medicine, Cancer research, Cytotoxic T cell, Neural cell adhesion molecule
Abstract: Natural killer (NK) cells are a heterogeneous population of innate lymphocytes whose potent anticancer properties make them ideal candidates for cellular therapeutic application. However, our lack of understanding of the role of NK cell diversity in antitumor responses has hindered advances in this area. In this study, we describe a new CD56dim NK cell subset characterized by the lack of expression of DNAX accessory molecule-1 (DNAM-1). Compared with CD56bright and CD56dimDNAM-1pos NK cell subsets, CD56dimDNAM-1neg NK cells displayed reduced motility, poor proliferation, lower production of interferon-γ, and limited killing capacities. Soluble factors secreted by CD56dimDNAM-1neg NK cells impaired CD56dimDNAM-1pos NK cell–mediated killing, indicating a potential inhibitory role for the CD56dimDNAM-1neg NK cell subset. Transcriptome analysis revealed that CD56dimDNAM-1neg NK cells constitute a new mature NK cell subset with a specific gene signature. Upon in vitro cytokine stimulation, CD56dimDNAM-1neg NK cells were found to differentiate from CD56dimDNAM-1pos NK cells. Finally, we report a dysregulation of NK cell subsets in the blood of patients diagnosed with Hodgkin lymphoma and diffuse large B-cell lymphoma, characterized by decreased CD56dimDNAM-1pos/CD56dimDNAM-1neg NK cell ratios and reduced cytotoxic activity of CD56dimDNAM-1pos NK cells. Altogether, our data offer a better understanding of human peripheral blood NK cell populations and have important clinical implications for the design of NK cell–targeting therapies.
Published: 2019

25. Remission of chronic acne fulminans and severe hidradenitis suppurativa with targeted antibiotherapy

Author: Lucienne Chatenoud, Olivier Lortholary, Alain Hovnanian, Sabine Duchatelet, Marie-Noëlle Ungeheuer, Olivier Join-Lambert, Thi Lam, Xavier Nassif, Aude Nassif, S. Miskinyte, Maïa Delage, Hélène Guet-Revillet, and Hélène Coignard-Biehler
Subjects: medicine.medical_specialty, host-microbiome disease, HS, hidradenitis suppurativa, Case Report, bacterial metagenomics, macromolecular substances, Dermatology, 030207 dermatology & venereal diseases, 03 medical and health sciences, remission, 0302 clinical medicine, medicine, AF, acne fulminans, antibiotherapy, genetics, Hidradenitis suppurativa, acne fulminans, TNF, tumor necrosis factor, Acne fulminans, treatment, Medical treatment, business.industry, hidradenitis suppurativa, Interleukin, medicine.disease, cytokines, IL, interleukin, 3. Good health, 030220 oncology & carcinogenesis, Tumor necrosis factor alpha, business
Abstract: Acne fulminans (AF) and hidradenitis suppurativa (HS) are 2 severe conditions with no consensus on medical treatment and no clear pathophysiology.1, 2 We report the remission of long-lasting and severe AF with HS that was unresponsive to many previous treatments.
Published: 2019

26. A future for CD3 antibodies in immunotherapy of type 1 diabetes

Author: Lucienne Chatenoud
Subjects: Type 1 diabetes, biology, Teplizumab, business.industry, Endocrinology, Diabetes and Metabolism, CD3, medicine.medical_treatment, Human physiology, Immunotherapy, medicine.disease, Autoimmune diabetes, Immunology, Internal Medicine, biology.protein, medicine, Antibody, business, medicine.drug
Published: 2019

27. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Author: Lara Gibellini, Sussan Nourshargh, Susanna Cardell, Wlodzimierz Maslinski, Mar Felipo-Benavent, Florian Mair, Hans-Martin Jäck, Lilly Lopez, Klaus Warnatz, John Trowsdale, Diana Ordonez, Marcus Eich, William Hwang, Anne Cooke, Dirk Mielenz, Alberto Orfao, Winfried F. Pickl, Vladimir Benes, Alice Yue, T. Vincent Shankey, Maria Tsoumakidou, Virginia Litwin, Gelo Victoriano Dela Cruz, Andrea Cavani, Sara De Biasi, Larissa Nogueira Almeida, Jonathan J M Landry, Claudia Haftmann, Charlotte Esser, Ana Cumano, Anneke Wilharm, Francesco Dieli, Rudi Beyaert, Alessio Mazzoni, Burkhard Ludewig, Carlo Pucillo, Dirk H. Busch, Joe Trotter, Stipan Jonjić, Marc Veldhoen, Josef Spidlen, Aja M. Rieger, Dieter Adam, Srijit Khan, Todd A. Fehniger, Giuseppe Matarese, Maximilien Evrard, Christian Maueröder, Steffen Schmitt, Kristin A. Hogquist, Barry Moran, Raghavendra Palankar, Markus Feuerer, S Schmid, Susann Rahmig, Amy E. Lovett-Racke, James V. Watson, Megan K. Levings, Susanne Melzer, Dinko Pavlinic, Christopher M. Harpur, Christina Stehle, A. Graham Pockley, Toshinori Nakayama, Attila Tárnok, Juhao Yang, Michael Lohoff, Paulo Vieira, Francisco Sala-de-Oyanguren, Christian Kurts, Anastasia Gangaev, Alfonso Blanco, Hans Scherer, Regine J. Dress, Bruno Silva-Santos, Kiyoshi Takeda, Bimba F. Hoyer, Ilenia Cammarata, Daryl Grummitt, Isabel Panse, Günnur Deniz, Bianka Baying, Friederike Ebner, Esther Schimisky, Leo Hansmann, Thomas Kamradt, Edwin van der Pol, Daniel Scott-Algara, Anna Iannone, Giorgia Alvisi, Sebastian R. Schulz, Francesco Liotta, Irmgard Förster, Beatriz Jávega, Hans-Peter Rahn, Caetano Reis e Sousa, Livius Penter, Xuetao Cao, David P. Sester, Keisuke Goda, Peter Wurst, Iain B. McInnes, Ricardo T. Gazzinelli, Federica Piancone, Gerald Willimsky, Yotam Raz, Pärt Peterson, Wolfgang Fritzsche, Yvonne Samstag, Martin Büscher, Thomas Schüler, Susanne Hartmann, Robert J. Wilkinson, Anna E. S. Brooks, Steven L. C. Ketelaars, Catherine Sautès-Fridman, Anna Rubartelli, Petra Bacher, Katja Kobow, Marco A. Cassatella, Andrea Hauser, Henrik E. Mei, Kilian Schober, Silvia Della Bella, Graham Anderson, Michael D. Ward, Garth Cameron, Sebastian Lunemann, Katharina Kriegsmann, Katarzyna M. Sitnik, Brice Gaudilliere, Chantip Dang-Heine, Marcello Pinti, Paul Klenerman, Frank A. Schildberg, Joana Barros-Martins, Laura G. Rico, Hanlin Zhang, Christian Münz, Thomas Dörner, Jakob Zimmermann, Andrea M. Cooper, Jonni S. Moore, Andreas Diefenbach, Yanling Liu, Wolfgang Bauer, Tobit Steinmetz, Katharina Pracht, Leonard Tan, Peter K. Jani, Alan M. Stall, Petra Hoffmann, Christine S. Falk, Jasmin Knopf, Simon Fillatreau, Hans-Dieter Volk, Luis E. Muñoz, David L. Haviland, William W. Agace, Jonathan Rebhahn, Ljiljana Cvetkovic, Mohamed Trebak, Jordi Petriz, Mario Clerici, Diether J. Recktenwald, Anders Ståhlberg, Tristan Holland, Helen M. McGuire, Sa A. Wang, Christian Kukat, Thomas Kroneis, Laura Cook, Wan Ting Kong, Xin M. Wang, Britta Engelhardt, Pierre Coulie, Genny Del Zotto, Sally A. Quataert, Kata Filkor, Gabriele Multhoff, Bartek Rajwa, Federica Calzetti, Hans Minderman, Cosima T. Baldari, Jens Geginat, Hervé Luche, Gert Van Isterdael, Linda Schadt, Sophia Urbanczyk, Giovanna Borsellino, Liping Yu, Dale I. Godfrey, Achille Anselmo, Rachael C. Walker, Andreas Grützkau, David W. Hedley, Birgit Sawitzki, Silvia Piconese, Maria Yazdanbakhsh, Burkhard Becher, Ramon Bellmas Sanz, Michael Delacher, Hyun-Dong Chang, Immanuel Andrä, Hans-Gustaf Ljunggren, José-Enrique O'Connor, Ahad Khalilnezhad, Sharon Sanderson, Federico Colombo, Götz R. A. Ehrhardt, Inga Sandrock, Enrico Lugli, Christian Bogdan, James B. Wing, Susann Müller, Tomohiro Kurosaki, Derek Davies, Ester B. M. Remmerswaal, Kylie M. Quinn, Christopher A. Hunter, Andreas Radbruch, Timothy P. Bushnell, Anna Erdei, Sabine Adam-Klages, Pascale Eede, Van Duc Dang, Rieke Winkelmann, Thomas Korn, Gemma A. Foulds, Dirk Baumjohann, Matthias Schiemann, Manfred Kopf, Jan Kisielow, Lisa Richter, Jochen Huehn, Gloria Martrus, Alexander Scheffold, Jessica G. Borger, Sidonia B G Eckle, John Bellamy Foster, Anna Katharina Simon, Alicia Wong, Mübeccel Akdis, Gisa Tiegs, Toralf Kaiser, James McCluskey, Anna Vittoria Mattioli, Aaron J. Marshall, Hui-Fern Koay, Eva Orlowski-Oliver, Anja E. Hauser, J. Paul Robinson, Jay K. Kolls, Luca Battistini, Mairi McGrath, Jane L. Grogan, Natalio Garbi, Timothy Tree, Kingston H. G. Mills, Stefan H. E. Kaufmann, Wolfgang Schuh, Ryan R. Brinkman, Tim R. Mosmann, Vincenzo Barnaba, Andreas Dolf, Lorenzo Cosmi, Bo Huang, Andreia C. Lino, Baerbel Keller, René A. W. van Lier, Alexandra J. Corbett, Paul S. Frenette, Pleun Hombrink, Helena Radbruch, Sofie Van Gassen, Olivier Lantz, Lorenzo Moretta, Désirée Kunkel, Kirsten A. Ward-Hartstonge, Armin Saalmüller, Leslie Y. T. Leung, Salvador Vento-Asturias, Paola Lanuti, Alicia Martínez-Romero, Sarah Warth, Zhiyong Poon, Diana Dudziak, Andrea Cossarizza, Kovit Pattanapanyasat, Konrad von Volkmann, Jessica P. Houston, Agnès Lehuen, Andrew Filby, Pratip K. Chattopadhyay, Stefano Casola, Annika Wiedemann, Hannes Stockinger, Jürgen Ruland, Arturo Zychlinsky, Claudia Waskow, Katrin Neumann, Ari Waisman, Lucienne Chatenoud, Sudipto Bari, Kamran Ghoreschi, David W. Galbraith, Yvan Saeys, Hamida Hammad, Andrea Gori, Miguel López-Botet, Gabriel Núñez, Sabine Ivison, Michael Hundemer, Dorothea Reimer, Mark C. Dessing, Günter J. Hämmerling, Rudolf A. Manz, Tomas Kalina, Jonas Hahn, Holden T. Maecker, Hendy Kristyanto, Martin S. Davey, Henning Ulrich, Michael L. Dustin, Takashi Saito, Yousuke Takahama, Milena Nasi, Johanna Huber, Jürgen Wienands, Paolo Dellabona, Andreas Schlitzer, Michael D. Leipold, Kerstin H. Mair, Christian Peth, Immo Prinz, Chiara Romagnani, José M. González-Navajas, Josephine Schlosser, Marina Saresella, Matthias Edinger, Dirk Brenner, Nicole Baumgarth, Rikard Holmdahl, Fang-Ping Huang, Guadalupe Herrera, Malte Paulsen, Gergely Toldi, Luka Cicin-Sain, Reiner Schulte, Christina E. Zielinski, Thomas Winkler, Christoph Goettlinger, Philip E. Boulais, Jennie H M Yang, Antonio Celada, Heike Kunze-Schumacher, Julia Tornack, Florian Ingelfinger, Jenny Mjösberg, Andy Riddell, Leonie Wegener, Thomas Höfer, Christoph Hess, James P. Di Santo, Anna E. Oja, J. Kühne, Willem van de Veen, Mary Bebawy, Alberto Mantovani, Bart Everts, Giovanna Lombardi, Laura Maggi, Anouk von Borstel, Pia Kvistborg, Elisabetta Traggiai, A Ochel, Nima Aghaeepour, Charles-Antoine Dutertre, Matthieu Allez, Thomas Höllt, Wenjun Ouyang, Regina Stark, Maries van den Broek, Shimon Sakaguchi, Paul K. Wallace, Silvano Sozzani, Francesca LaRosa, Annette Oxenius, Malgorzata J. Podolska, Ivana Marventano, Wilhelm Gerner, Oliver F. Wirz, Britta Frehse, Gevitha Ravichandran, Martin Herrmann, Carl S. Goodyear, Gary Warnes, Helen Ferry, Stefan Frischbutter, Tim R. Radstake, Salomé LeibundGut-Landmann, Yi Zhao, Axel Schulz, Angela Santoni, Pablo Engel, Daniela C. Hernández, Andreas Acs, Cristiano Scottà, Francesco Annunziato, Thomas Weisenburger, Wolfgang Beisker, Sue Chow, Fritz Melchers, Daniel E. Speiser, Immanuel Kwok, Florent Ginhoux, Dominic A. Boardman, Natalie Stanley, Carsten Watzl, Marie Follo, Erik Lubberts, Andreas Krueger, Susanne Ziegler, Göran K. Hansson, David Voehringer, Antonia Niedobitek, Eleni Christakou, Lai Guan Ng, Sabine Baumgart, Nicholas A Gherardin, Antonio Cosma, Orla Maguire, Jolene Bradford, Daniel Schraivogel, Linda Quatrini, Stephen D. Miller, Rheumatology, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Swiss Institute of Allergy and Asthma Research (SIAF), Universität Zürich [Zürich] = University of Zurich (UZH), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), 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), Department of Internal Medicine, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-DENOTHE Center, Institute of Clinical Molecular Biology, Kiel University, Department of Life Sciences [Siena, Italy], Università degli Studi di Siena = University of Siena (UNISI), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Dulbecco Telethon Institute/Department of Biology, Caprotec Bioanalytics GmbH, International Occultation Timing Association European Section (IOTA ES), International Occultation Timing Association European Section, European Molecular Biology Laboratory [Heidelberg] (EMBL), VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Fondazione Santa Lucia (IRCCS), Department of Immunology, Chinese Academy of Medical Sciences, FIRC Institute of Molecular Oncology Foundation, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Physiopatology and Transplantation, University of Milan (DEPT), University of Milan, Monash University [Clayton], Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institute of Cellular Pathology, Université Catholique de Louvain = Catholic University of Louvain (UCL), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Experimental Immunology Unit, Dept. of Oncology, DIBIT San Raffaele Scientific Institute, Immunité Innée - Innate Immunity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biopharmacy [Bruxelles, Belgium] (Institute for Medical Immunology IMI), Université libre de Bruxelles (ULB), Charité Hospital, Humboldt-Universität zu Berlin, Agency for science, technology and research [Singapore] (A*STAR), Laboratory of Molecular Immunology and the Howard Hughes Institute, Rockefeller University [New York], Kennedy Institute of Rheumatology [Oxford, UK], Imperial College London, Theodor Kocher Institute, University of Bern, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] ( IUF), Université Lumière - Lyon 2 (UL2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Edinburgh, Integrative Biology Program [Milano], Istituto Nazionale Genetica Molecolare [Milano] (INGM), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Universitat de Barcelona (UB), Rheumatologie, Cell Biology, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Department for Internal Medicine 3, Institute for Clinical Immunology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Delft University of Technology (TU Delft), Medical Inflammation Research, Karolinska Institutet [Stockholm], Department of Photonics Engineering [Lyngby], Technical University of Denmark [Lyngby] (DTU), Dpt of Experimental Immunology [Braunschweig], Helmholtz Centre for Infection Research (HZI), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], Department of Histology and Embryology, University of Rijeka, Freiburg University Medical Center, Nuffield Dept of Clinical Medicine, University of Oxford [Oxford]-NIHR Biomedical Research Centre, Institute of Integrative Biology, Molecular Biomedicine, Berlin Institute of Health (BIH), Laboratory for Lymphocyte Differentiation, RIKEN Research Center, Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Department of Surgery [Vancouver, BC, Canada] (Child and Family Research Institute), University of British Columbia (UBC)-Child and Family Research Institute [Vancouver, BC, Canada], College of Food Science and Technology [Shangai], Shanghai Ocean University, Institute for Medical Microbiology and Hygiene, University of Marburg, King‘s College London, Erasmus University Medical Center [Rotterdam] (Erasmus MC), 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), Brustzentrum Kantonsspital St. Gallen, Immunotechnology Section, Vaccine Research Center, National Institutes of Health [Bethesda] (NIH)-National Institute of Allergy and Infectious Diseases, Heinrich Pette Institute [Hamburg], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Immunology and Cell Biology, Mario Negri Institute, Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation, Institute of Translational Medicine, Klinik für Dermatologie, Venerologie und Allergologie, School of Biochemistry and Immunology, Department of Medicine Huddinge, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Lipid Laboratory, Università di Genova, Dipartimento di Medicina Sperimentale, Department of Environmental Microbiology, Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), Department of Radiation Oncology [Munich], Ludwig-Maximilians-Universität München (LMU), Centre de Recherche Publique- Santé, Université du Luxembourg (Uni.lu), William Harvey Research Institute, Barts and the London Medical School, University of Michigan [Ann Arbor], University of Michigan System, Centro de Investigacion del Cancer (CSIC), Universitario de Salamanca, Molecular Pathology [Tartu, Estonia], University of Tartu, Hannover Medical School [Hannover] (MHH), Centre d'Immunologie de Marseille - Luminy (CIML), Monash Biomedicine Discovery Institute, Cytometry Laboratories and School of Veterinary Medicine, Purdue University [West Lafayette], Data Mining and Modelling for Biomedicine [Ghent, Belgium], VIB Center for Inflammation Research [Ghent, Belgium], Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, RIKEN Research Center for Allergy and Immunology, Osaka University [Osaka], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institute of Medical Immunology [Berlin, Germany], FACS and Array Core Facility, Johannes Gutenberg - Universität Mainz (JGU), Otto-von-Guericke University [Magdeburg] (OVGU), SUPA School of Physics and Astronomy [University of St Andrews], University of St Andrews [Scotland]-Scottish Universities Physics Alliance (SUPA), Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), General Pathology and Immunology (GPI), University of Brescia, Université de Lausanne (UNIL), Terry Fox Laboratory, BC Cancer Agency (BCCRC)-British Columbia Cancer Agency Research Centre, Department of Molecular Immunology, Medizinische Universität Wien = Medical University of Vienna, Dept. Pediatric Cardiology, Universität Leipzig [Leipzig], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Cardiovascular Sciences, Albany Medical College, Dept Pathol, Div Immunol, University of Cambridge [UK] (CAM), Department of Information Technology [Gent], Universiteit Gent, Department of Plant Systems Biology, Department of Plant Biotechnology and Genetics, Universiteit Gent = Ghent University [Belgium] (UGENT), Division of Molecular Immunology, Institute for Immunology, Department of Geological Sciences, University of Oregon [Eugene], Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, University of Colorado [Colorado Springs] (UCCS), FACS laboratory, Cancer Research, London, Cancer Research UK, Regeneration in Hematopoiesis and Animal Models of Hematopoiesis, Faculty of Medicine, Dresden University of Technology, Barbara Davis Center for Childhood Diabetes (BDC), University of Colorado Anschutz [Aurora], School of Computer and Electronic Information [Guangxi University], Guangxi University [Nanning], School of Materials Science and Engineering, Nanyang Technological University [Singapour], Max Planck Institute for Infection Biology (MPIIB), Max-Planck-Gesellschaft, Work in the laboratory of Dieter Adam is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Projektnummer 125440785 – SFB 877, Project B2.Petra Hoffmann, Andrea Hauser, and Matthias Edinger thank BD Biosciences®, San José, CA, USA, and SKAN AG, Bale, Switzerland for fruitful cooperation during the development, construction, and installation of the GMP‐compliant cell sorting equipment and the Bavarian Immune Therapy Network (BayImmuNet) for financial support.Edwin van der Pol and Paola Lanuti acknowledge Aleksandra Gąsecka M.D. for excellent experimental support and Dr. Rienk Nieuwland for textual suggestions. This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO‐TTW), research program VENI 15924.Jessica G Borger, Kylie M Quinn, Mairi McGrath, and Regina Stark thank Francesco Siracusa and Patrick Maschmeyer for providing data.Larissa Nogueira Almeida was supported by DFG research grant MA 2273/14‐1. Rudolf A. Manz was supported by the Excellence Cluster 'Inflammation at Interfaces' (EXC 306/2).Susanne Hartmann and Friederike Ebner were supported by the German Research Foundation (GRK 2046).Hans Minderman was supported by NIH R50CA211108.This work was funded by the Deutsche Forschungsgemeinschaft through the grant TRR130 (project P11 and C03) to Thomas H. Winkler.Ramon Bellmàs Sanz, Jenny Kühne, and Christine S. Falk thank Jana Keil and Kerstin Daemen for excellent technical support. The work was funded by the Germany Research Foundation CRC738/B3 (CSF).The work by the Mei laboratory was supported by German Research Foundation Grant ME 3644/5‐1 and TRR130 TP24, the German Rheumatism Research Centre Berlin, European Union Innovative Medicines Initiative ‐ Joint Undertaking ‐ RTCure Grant Agreement 777357, the Else Kröner‐Fresenius‐Foundation, German Federal Ministry of Education and Research e:Med sysINFLAME Program Grant 01ZX1306B and KMU‐innovativ 'InnoCyt', and the Leibniz Science Campus for Chronic Inflammation (http://www.chronische-entzuendung.org).Axel Ronald Schulz, Antonio Cosma, Sabine Baumgart, Brice Gaudilliere, Helen M. McGuire, and Henrik E. Mei thank Michael D. Leipold for critically reading the manuscript.Christian Kukat acknowledges support from the ISAC SRL Emerging Leaders program.John Trowsdale received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant Agreement 695551)., European Project: 7728036(1978), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Firenze = University of Florence (UniFI)-DENOTHE Center, Università degli Studi di Milano = University of Milan (UNIMI), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humboldt University Of Berlin, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] (IUF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Universität Heidelberg [Heidelberg] = Heidelberg University, Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), University of Oxford-NIHR Biomedical Research Centre, Universität Bonn = University of Bonn, Università degli Studi di Firenze = University of Florence (UniFI), Università degli studi di Genova = University of Genoa (UniGe), Universidad de Salamanca, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Université de Lausanne = University of Lausanne (UNIL), Universität Leipzig, Universiteit Gent = Ghent University (UGENT), HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., Cossarizza, A., Chang, H. -D., Radbruch, A., Acs, A., Adam, D., Adam-Klages, S., Agace, W. W., Aghaeepour, N., Akdis, M., Allez, M., Almeida, L. N., Alvisi, G., Anderson, G., Andra, I., Annunziato, F., Anselmo, A., Bacher, P., Baldari, C. T., Bari, S., Barnaba, V., Barros-Martins, J., Battistini, L., Bauer, W., Baumgart, S., Baumgarth, N., Baumjohann, D., Baying, B., Bebawy, M., Becher, B., Beisker, W., Benes, V., Beyaert, R., Blanco, A., Boardman, D. A., Bogdan, C., Borger, J. G., Borsellino, G., Boulais, P. E., Bradford, J. A., Brenner, D., Brinkman, R. R., Brooks, A. E. S., Busch, D. H., Buscher, M., Bushnell, T. P., Calzetti, F., Cameron, G., Cammarata, I., Cao, X., Cardell, S. L., Casola, S., Cassatella, M. A., Cavani, A., Celada, A., Chatenoud, L., Chattopadhyay, P. K., Chow, S., Christakou, E., Cicin-Sain, L., Clerici, M., Colombo, F. S., Cook, L., Cooke, A., Cooper, A. M., Corbett, A. J., Cosma, A., Cosmi, L., Coulie, P. G., Cumano, A., Cvetkovic, L., Dang, V. D., Dang-Heine, C., Davey, M. S., Davies, D., De Biasi, S., Del Zotto, G., Dela Cruz, G. V., Delacher, M., Della Bella, S., Dellabona, P., Deniz, G., Dessing, M., Di Santo, J. P., Diefenbach, A., Dieli, F., Dolf, A., Dorner, T., Dress, R. J., Dudziak, D., Dustin, M., Dutertre, C. -A., Ebner, F., Eckle, S. B. G., Edinger, M., Eede, P., Ehrhardt, G. R. A., Eich, M., Engel, P., Engelhardt, B., Erdei, A., Esser, C., Everts, B., Evrard, M., Falk, C. S., Fehniger, T. A., Felipo-Benavent, M., Ferry, H., Feuerer, M., Filby, A., Filkor, K., Fillatreau, S., Follo, M., Forster, I., Foster, J., Foulds, G. A., Frehse, B., Frenette, P. S., Frischbutter, S., Fritzsche, W., Galbraith, D. W., Gangaev, A., Garbi, N., Gaudilliere, B., Gazzinelli, R. T., Geginat, J., Gerner, W., Gherardin, N. A., Ghoreschi, K., Gibellini, L., Ginhoux, F., Goda, K., Godfrey, D. I., Goettlinger, C., Gonzalez-Navajas, J. M., Goodyear, C. S., Gori, A., Grogan, J. L., Grummitt, D., Grutzkau, A., Haftmann, C., Hahn, J., Hammad, H., Hammerling, G., Hansmann, L., Hansson, G., Harpur, C. M., Hartmann, S., Hauser, A., Hauser, A. E., Haviland, D. L., Hedley, D., Hernandez, D. C., Herrera, G., Herrmann, M., Hess, C., Hofer, T., Hoffmann, P., Hogquist, K., Holland, T., Hollt, T., Holmdahl, R., Hombrink, P., Houston, J. P., Hoyer, B. F., Huang, B., Huang, F. -P., Huber, J. E., Huehn, J., Hundemer, M., Hunter, C. A., Hwang, W. Y. K., Iannone, A., Ingelfinger, F., Ivison, S. M., Jack, H. -M., Jani, P. K., Javega, B., Jonjic, S., Kaiser, T., Kalina, T., Kamradt, T., Kaufmann, S. H. E., Keller, B., Ketelaars, S. L. C., Khalilnezhad, A., Khan, S., Kisielow, J., Klenerman, P., Knopf, J., Koay, H. -F., Kobow, K., Kolls, J. K., Kong, W. T., Kopf, M., Korn, T., Kriegsmann, K., Kristyanto, H., Kroneis, T., Krueger, A., Kuhne, J., Kukat, C., Kunkel, D., Kunze-Schumacher, H., Kurosaki, T., Kurts, C., Kvistborg, P., Kwok, I., Landry, J., Lantz, O., Lanuti, P., Larosa, F., Lehuen, A., LeibundGut-Landmann, S., Leipold, M. D., Leung, L. Y. T., Levings, M. K., Lino, A. C., Liotta, F., Litwin, V., Liu, Y., Ljunggren, H. -G., Lohoff, M., Lombardi, G., Lopez, L., Lopez-Botet, M., Lovett-Racke, A. E., Lubberts, E., Luche, H., Ludewig, B., Lugli, E., Lunemann, S., Maecker, H. T., Maggi, L., Maguire, O., Mair, F., Mair, K. H., Mantovani, A., Manz, R. A., Marshall, A. J., Martinez-Romero, A., Martrus, G., Marventano, I., Maslinski, W., Matarese, G., Mattioli, A. V., Maueroder, C., Mazzoni, A., Mccluskey, J., Mcgrath, M., Mcguire, H. M., Mcinnes, I. B., Mei, H. E., Melchers, F., Melzer, S., Mielenz, D., Miller, S. D., Mills, K. H. G., Minderman, H., Mjosberg, J., Moore, J., Moran, B., Moretta, L., Mosmann, T. R., Muller, S., Multhoff, G., Munoz, L. E., Munz, C., Nakayama, T., Nasi, M., Neumann, K., Ng, L. G., Niedobitek, A., Nourshargh, S., Nunez, G., O'Connor, J. -E., Ochel, A., Oja, A., Ordonez, D., Orfao, A., Orlowski-Oliver, E., Ouyang, W., Oxenius, A., Palankar, R., Panse, I., Pattanapanyasat, K., Paulsen, M., Pavlinic, D., Penter, L., Peterson, P., Peth, C., Petriz, J., Piancone, F., Pickl, W. F., Piconese, S., Pinti, M., Pockley, A. G., Podolska, M. J., Poon, Z., Pracht, K., Prinz, I., Pucillo, C. E. M., Quataert, S. A., Quatrini, L., Quinn, K. M., Radbruch, H., Radstake, T. R. D. J., Rahmig, S., Rahn, H. -P., Rajwa, B., Ravichandran, G., Raz, Y., Rebhahn, J. A., Recktenwald, D., Reimer, D., Reis e Sousa, C., Remmerswaal, E. B. M., Richter, L., Rico, L. G., Riddell, A., Rieger, A. M., Robinson, J. P., Romagnani, C., Rubartelli, A., Ruland, J., Saalmuller, A., Saeys, Y., Saito, T., Sakaguchi, S., Sala-de-Oyanguren, F., Samstag, Y., Sanderson, S., Sandrock, I., Santoni, A., Sanz, R. B., Saresella, M., Sautes-Fridman, C., Sawitzki, B., Schadt, L., Scheffold, A., Scherer, H. U., Schiemann, M., Schildberg, F. A., Schimisky, E., Schlitzer, A., Schlosser, J., Schmid, S., Schmitt, S., Schober, K., Schraivogel, D., Schuh, W., Schuler, T., Schulte, R., Schulz, A. R., Schulz, S. R., Scotta, C., Scott-Algara, D., Sester, D. P., Shankey, T. V., Silva-Santos, B., Simon, A. K., Sitnik, K. M., Sozzani, S., Speiser, D. E., Spidlen, J., Stahlberg, A., Stall, A. M., Stanley, N., Stark, R., Stehle, C., Steinmetz, T., Stockinger, H., Takahama, Y., Takeda, K., Tan, L., Tarnok, A., Tiegs, G., Toldi, G., Tornack, J., Traggiai, E., Trebak, M., Tree, T. I. M., Trotter, J., Trowsdale, J., Tsoumakidou, M., Ulrich, H., Urbanczyk, S., van de Veen, W., van den Broek, M., van der Pol, E., Van Gassen, S., Van Isterdael, G., van Lier, R. A. W., Veldhoen, M., Vento-Asturias, S., Vieira, P., Voehringer, D., Volk, H. -D., von Borstel, A., von Volkmann, K., Waisman, A., Walker, R. V., Wallace, P. K., Wang, S. A., Wang, X. M., Ward, M. D., Ward-Hartstonge, K. A., Warnatz, K., Warnes, G., Warth, S., Waskow, C., Watson, J. V., Watzl, C., Wegener, L., Weisenburger, T., Wiedemann, A., Wienands, J., Wilharm, A., Wilkinson, R. J., Willimsky, G., Wing, J. B., Winkelmann, R., Winkler, T. H., Wirz, O. F., Wong, A., Wurst, P., Yang, J. H. M., Yang, J., Yazdanbakhsh, M., Yu, L., Yue, A., Zhang, H., Zhao, Y., Ziegler, S. M., Zielinski, C., Zimmermann, J., Zychlinsky, A., UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GECE - Génétique cellulaire, Netherlands Organization for Scientific Research, German Research Foundation, European Commission, European Research Council, Repositório da Universidade de Lisboa, CCA - Imaging and biomarkers, Experimental Immunology, AII - Infectious diseases, AII - Inflammatory diseases, Biomedical Engineering and Physics, ACS - Atherosclerosis & ischemic syndromes, and Landsteiner Laboratory
Subjects: 0301 basic medicine, Consensus, Immunology, Consensu, Cell Separation, Biology, Article, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Guidelines, Allergy and Immunology, medicine, Cell separation, Immunology and Allergy, Humans, guidelines, flow cytometry, immunology, medicine.diagnostic_test, BIOMEDICINE AND HEALTHCARE. Basic Medical Sciences, Cell sorting, Flow Cytometry, Cell selection, Data science, 3. Good health, 030104 developmental biology, Phenotype, [SDV.IMM]Life Sciences [q-bio]/Immunology, BIOMEDICINA I ZDRAVSTVO. Temeljne medicinske znanosti, 030215 immunology, Human
Abstract: All authors: Andrea Cossarizza Hyun‐Dong Chang Andreas Radbruch Andreas Acs Dieter Adam Sabine Adam‐Klages William W. Agace Nima Aghaeepour Mübeccel Akdis Matthieu Allez Larissa Nogueira Almeida Giorgia Alvisi Graham Anderson Immanuel Andrä Francesco Annunziato Achille Anselmo Petra Bacher Cosima T. Baldari Sudipto Bari Vincenzo Barnaba Joana Barros‐Martins Luca Battistini Wolfgang Bauer Sabine Baumgart Nicole Baumgarth Dirk Baumjohann Bianka Baying Mary Bebawy Burkhard Becher Wolfgang Beisker Vladimir Benes Rudi Beyaert Alfonso Blanco Dominic A. Boardman Christian Bogdan Jessica G. Borger Giovanna Borsellino Philip E. Boulais Jolene A. Bradford Dirk Brenner Ryan R. Brinkman Anna E. S. Brooks Dirk H. Busch Martin Büscher Timothy P. Bushnell Federica Calzetti Garth Cameron Ilenia Cammarata Xuetao Cao Susanna L. Cardell Stefano Casola Marco A. Cassatella Andrea Cavani Antonio Celada Lucienne Chatenoud Pratip K. Chattopadhyay Sue Chow Eleni Christakou Luka Čičin‐Šain Mario Clerici Federico S. Colombo Laura Cook Anne Cooke Andrea M. Cooper Alexandra J. Corbett Antonio Cosma Lorenzo Cosmi Pierre G. Coulie Ana Cumano Ljiljana Cvetkovic Van Duc Dang Chantip Dang‐Heine Martin S. Davey Derek Davies Sara De Biasi Genny Del Zotto Gelo Victoriano Dela Cruz Michael Delacher Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing James P. Di Santo Andreas Diefenbach Francesco Dieli Andreas Dolf Thomas Dörner Regine J. Dress Diana Dudziak Michael Dustin Charles‐Antoine Dutertre Friederike Ebner Sidonia B. G. Eckle Matthias Edinger Pascale Eede Götz R.A. Ehrhardt Marcus Eich Pablo Engel Britta Engelhardt Anna Erdei Charlotte Esser Bart Everts Maximilien Evrard Christine S. Falk Todd A. Fehniger Mar Felipo‐Benavent Helen Ferry Markus Feuerer Andrew Filby Kata Filkor Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A. Foulds Britta Frehse Paul S. Frenette Stefan Frischbutter Wolfgang Fritzsche David W. Galbraith Anastasia Gangaev Natalio Garbi Brice Gaudilliere Ricardo T. Gazzinelli Jens Geginat Wilhelm Gerner Nicholas A. Gherardin Kamran Ghoreschi Lara Gibellini Florent Ginhoux Keisuke Goda Dale I. Godfrey Christoph Goettlinger Jose M. González‐Navajas Carl S. Goodyear Andrea Gori Jane L. Grogan Daryl Grummitt Andreas Grützkau Claudia Haftmann Jonas Hahn Hamida Hammad Günter Hämmerling Leo Hansmann Goran Hansson Christopher M. Harpur Susanne Hartmann Andrea Hauser Anja E. Hauser David L. Haviland David Hedley Daniela C. Hernández Guadalupe Herrera Martin Herrmann Christoph Hess Thomas Höfer Petra Hoffmann Kristin Hogquist Tristan Holland Thomas Höllt Rikard Holmdahl Pleun Hombrink Jessica P. Houston Bimba F. Hoyer Bo Huang Fang‐Ping Huang Johanna E. Huber Jochen Huehn Michael Hundemer Christopher A. Hunter William Y. K. Hwang Anna Iannone Florian Ingelfinger Sabine M Ivison Hans‐Martin Jäck Peter K. Jani Beatriz Jávega Stipan Jonjic Toralf Kaiser Tomas Kalina Thomas Kamradt Stefan H. E. Kaufmann Baerbel Keller Steven L. C. Ketelaars Ahad Khalilnezhad Srijit Khan Jan Kisielow Paul Klenerman Jasmin Knopf Hui‐Fern Koay Katja Kobow Jay K. Kolls Wan Ting Kong Manfred Kopf Thomas Korn Katharina Kriegsmann Hendy Kristyanto Thomas Kroneis Andreas Krueger Jenny Kühne Christian Kukat Désirée Kunkel Heike Kunze‐Schumacher Tomohiro Kurosaki Christian Kurts Pia Kvistborg Immanuel Kwok Jonathan Landry Olivier Lantz Paola Lanuti Francesca LaRosa Agnès Lehuen Salomé LeibundGut‐Landmann Michael D. Leipold Leslie Y.T. Leung Megan K. Levings Andreia C. Lino Francesco Liotta Virginia Litwin Yanling Liu Hans‐Gustaf Ljunggren Michael Lohoff Giovanna Lombardi Lilly Lopez Miguel López‐Botet Amy E. Lovett‐Racke Erik Lubberts Herve Luche Burkhard Ludewig Enrico Lugli Sebastian Lunemann Holden T. Maecker Laura Maggi Orla Maguire Florian Mair Kerstin H. Mair Alberto Mantovani Rudolf A. Manz Aaron J. Marshall Alicia Martínez‐Romero Glòria Martrus Ivana Marventano Wlodzimierz Maslinski Giuseppe Matarese Anna Vittoria Mattioli Christian Maueröder Alessio Mazzoni James McCluskey Mairi McGrath Helen M. McGuire Iain B. McInnes Henrik E. Mei Fritz Melchers Susanne Melzer Dirk Mielenz Stephen D. Miller Kingston H.G. Mills Hans Minderman Jenny Mjösberg Jonni Moore Barry Moran Lorenzo Moretta Tim R. Mosmann Susann Müller Gabriele Multhoff Luis Enrique Muñoz Christian Münz Toshinori Nakayama Milena Nasi Katrin Neumann Lai Guan Ng Antonia Niedobitek Sussan Nourshargh Gabriel Núñez José‐Enrique O'Connor Aaron Ochel Anna Oja Diana Ordonez Alberto Orfao Eva Orlowski‐Oliver Wenjun Ouyang Annette Oxenius Raghavendra Palankar Isabel Panse Kovit Pattanapanyasat Malte Paulsen Dinko Pavlinic Livius Penter Pärt Peterson Christian Peth Jordi Petriz Federica Piancone Winfried F. Pickl Silvia Piconese Marcello Pinti A. Graham Pockley Malgorzata Justyna Podolska Zhiyong Poon Katharina Pracht Immo Prinz Carlo E. M. Pucillo Sally A. Quataert Linda Quatrini Kylie M. Quinn Helena Radbruch Tim R. D. J. Radstake Susann Rahmig Hans‐Peter Rahn Bartek Rajwa Gevitha Ravichandran Yotam Raz Jonathan A. Rebhahn Diether Recktenwald Dorothea Reimer Caetano Reis e Sousa Ester B.M. Remmerswaal Lisa Richter Laura G. Rico Andy Riddell Aja M. Rieger J. Paul Robinson Chiara Romagnani Anna Rubartelli Jürgen Ruland Armin Saalmüller Yvan Saeys Takashi Saito Shimon Sakaguchi Francisco Sala‐de‐Oyanguren Yvonne Samstag Sharon Sanderson Inga Sandrock Angela Santoni Ramon Bellmàs Sanz Marina Saresella Catherine Sautes‐Fridman Birgit Sawitzki Linda Schadt Alexander Scheffold Hans U. Scherer Matthias Schiemann Frank A. Schildberg Esther Schimisky Andreas Schlitzer Josephine Schlosser Stephan Schmid Steffen Schmitt Kilian Schober Daniel Schraivogel Wolfgang Schuh Thomas Schüler Reiner Schulte Axel Ronald Schulz Sebastian R. Schulz Cristiano Scottá Daniel Scott‐Algara David P. Sester T. Vincent Shankey Bruno Silva‐Santos Anna Katharina Simon Katarzyna M. Sitnik Silvano Sozzani Daniel E. Speiser Josef Spidlen Anders Stahlberg Alan M. Stall Natalie Stanley Regina Stark Christina Stehle Tobit Steinmetz Hannes Stockinger Yousuke Takahama Kiyoshi Takeda Leonard Tan Attila Tárnok Gisa Tiegs Gergely Toldi Julia Tornack Elisabetta Traggiai Mohamed Trebak Timothy I.M. Tree Joe Trotter John Trowsdale Maria Tsoumakidou Henning Ulrich Sophia Urbanczyk Willem van de Veen Maries van den Broek Edwin van der Pol Sofie Van Gassen Gert Van Isterdael René A.W. van Lier Marc Veldhoen Salvador Vento‐Asturias Paulo Vieira David Voehringer Hans‐Dieter Volk Anouk von Borstel Konrad von Volkmann Ari Waisman Rachael V. Walker Paul K. Wallace Sa A. Wang Xin M. Wang Michael D. Ward Kirsten A Ward‐Hartstonge Klaus Warnatz Gary Warnes Sarah Warth Claudia Waskow James V. Watson Carsten Watzl Leonie Wegener Thomas Weisenburger Annika Wiedemann Jürgen Wienands Anneke Wilharm Robert John Wilkinson Gerald Willimsky James B. Wing Rieke Winkelmann Thomas H. Winkler Oliver F. Wirz Alicia Wong Peter Wurst Jennie H. M. Yang Juhao Yang Maria Yazdanbakhsh Liping Yu Alice Yue Hanlin Zhang Yi Zhao Susanne Maria Ziegler Christina Zielinski Jakob Zimmermann Arturo Zychlinsky., These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion., This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO-TTW), research program VENI 15924. This work was funded by the Deutsche Forschungsgemeinschaft. European Union Innovative Medicines Initiative - Joint Undertaking - RTCure Grant Agreement 777357 and innovation program (Grant Agreement 695551).
Published: 2019

28. Poor Anti-SARS-CoV-2 Humoral and T-cell Responses After 2 Injections of mRNA Vaccine in Kidney Transplant Recipients Treated With Belatacept

Author: Chloé Couat, Julien Zuber, Estelle Vilain, Carole Burger, Marianne Leruez-Ville, Frank Martinez, Jacques Izopet, Rebecca Sberro-Soussan, Lucienne Chatenoud, Christophe Legendre, Dany Anglicheau, Nathalie Chavarot, Anne Scemla, Maroua Baaziz, Nassim Kamar, Fanny Lanternier, Arnaud Del Bello, Amani Ouedrani, Olivier Marion, and Florence Abravanel
Subjects: Transplantation, Messenger RNA, 2019-20 coronavirus outbreak, Vaccines, business.industry, SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), T cell, Abatacept, T-Lymphocytes, medicine.disease, Belatacept, Kidney transplant, Virology, Kidney Transplantation, Transplant Recipients, medicine.anatomical_structure, Medicine, RNA, Messenger, business, Letters to the Editor, Kidney transplantation, Immunosuppressive Agents, medicine.drug
Published: 2021

29. De novo germline mutation in the Dual Specificity Phosphatase 10 gene accelerates autoimmune diabetes in Non-Obese Diabetic (NOD) mice

Author: Chun Hui Bu, Bruce Beutler, Fabrice Valette, Sophie Candon, Sara Hildebrand, Sebastien Lemoine, Jean-François Bach, Anne-Perrine Foray, Stephen Aplin Lyon, Darui Xu, Eva Marie Y. Moresco, Francina Langa-Vives, Coralie Pecquet, Lucienne Chatenoud, Pere Santamaria, Tao Wang, Michael Dumas, Cindy Marquet, Claudio Scazzocchio, Peipei Hu, and Lindsay Scott
Subjects: Mutation, Type 1 diabetes, Nod, Biology, medicine.disease, medicine.disease_cause, Molecular biology, Germline mutation, Diabetes mellitus, Dual-specificity phosphatase, medicine, biology.protein, Gene, NOD mice
Abstract: Here we report the isolation by selective breeding of two sublines of Non-Obese Diabetic (NOD) mice exhibiting a significant difference in the incidence of autoimmune type 1 diabetes (T1D). Whole genome sequencing of the NOD/NckH (high T1D incidence) and NOD/NckL (low T1D incidence) revealed the presence of a limited number of variants specific to each subline. Treating the age of T1D onset as a quantitative trait and using automated meiotic mapping (AMM), enhanced susceptibility in the NOD/NckH subline was unambiguously attributed to a recessive allele of Dusp10 which encodes a dual specificity phosphatase. The causative effect of the mutation was verified with a high level of confidence by targeting Dusp10 with CRISPR/Cas9 in NOD/NckL mice: in these animals a higher incidence of diabetes was observed. Expression of wild-type Dusp10 correlated with higher levels of surface PD-L1 in the islets of NOD/NckL mice.
Published: 2021

30. Dissociation of humoral and cellular immune responses in kidney transplant recipients with EBV mucocutaneous ulcer

Author: Dominique Wendum, Thierry Jo Molina, Christophe Legendre, Julien Rossignol, Olivier Hermine, Rebecca Sberro-Soussan, Pierre Isnard, Julie Bruneau, and Lucienne Chatenoud
Subjects: Transplantation, biology, business.industry, Mucocutaneous zone, 030230 surgery, medicine.disease, medicine.disease_cause, Epstein–Barr virus, Post-transplant lymphoproliferative disorder, Pathophysiology, 03 medical and health sciences, 0302 clinical medicine, Infectious Diseases, Immune system, hemic and lymphatic diseases, Immunology, medicine, biology.protein, 030211 gastroenterology & hepatology, Stem cell, Antibody, business
Abstract: EBV-positive mucocutaneous ulcer (EBV-MCU) is a rare EBV-positive B-cell lymphoproliferative disorder occurring in immunocompromised patients such as patients with solid organ or hematopoietic stem cells transplantation. EBV-MCU often consists of an isolated and circumscribed cutaneous or mucosal ulcerative lesion with a self-limited growth potential and a high regression rate upon immunosuppressive treatment withdrawal or rituximab therapy. Nevertheless, the pathophysiology of this latent infection leading to clonal lymphoproliferation is not well established. We report here two cases of EBV-MCU in kidney transplant recipients with a dissociated immune response to EBV with the absence of EBV-related antibodies and a positive T-cell response to EBV suggesting a potential specific oncogenic mechanism in this lymphoproliferative disorder.
Published: 2021

31. COVID-19: individual and herd immunity

Author: Jean-François Bach, Patrick Berche, Lucienne Chatenoud, Alain-Jacques Valleron, Dominique Costagliola, Gestionnaire, Hal Sorbonne Université, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Immunity, Herd, 0106 biological sciences, 0301 basic medicine, animal diseases, [SDV]Life Sciences [q-bio], Population, T lymphocytes, chemical and pharmacologic phenomena, Biology, 01 natural sciences, Virus, Antibodies, Herd immunity, 03 medical and health sciences, Immune system, Immunity, Humans, education, education.field_of_study, Innate immune system, SARS-CoV-2, COVID-19, General Medicine, biochemical phenomena, metabolism, and nutrition, Antibodies, Neutralizing, 3. Good health, Individual immunity, [SDV] Life Sciences [q-bio], 030104 developmental biology, Humoral immunity, Immunology, biology.protein, bacteria, Antibody, 010606 plant biology & botany
Abstract: Immunity to the SARS-CoV-2 virus ensures protection against reinfection by this virus thanks to the combined action of neutralizing antibodies and T lymphocytes specific to viral proteins, in particular the Spike protein. It must be distinguished from the immune response that ensures healing of the infection following contamination that involves innate immunity, particularly type 1 interferons, and which is followed by adaptive cellular and humoral immunity. The importance of the effect of interferons is highlighted by the occurrence of severe forms of the disease in genetically deficient subjects or in patients with antibodies neutralizing type 1 interferon. Herd immunity is not an individual biological property. It is a mathematical property that qualifies the fact that when the proportion of subjects with individual immunity is high enough, there is little chance that an epidemic can occur. The level of that proportion-the herd immunity of the population can be computed under theoretical, often unrealistic, hypotheses, and is difficult to assess in natural conditions.L’immunité individuelle contre le virus SARS-CoV-2 assure la protection contre la réinfection par ce virus grâce à l’action conjuguée des anticorps neutralisants et des lymphocytes T spécifiques des protéines virales, notamment la protéine Spike (spicule). Il faut la distinguer de la réponse immunitaire qui assure la guérison de l’infection dans les jours suivant la contamination. Celle-ci fait intervenir l’immunité innée et tout particulièrement les interférons de type 1 puis l’immunité adaptative cellulaire et humorale. L’importance de l’effet des interférons est soulignée par la survenue de formes graves chez des sujets génétiquement déficients dans leur synthèse ou encore des patients présentant des anticorps neutralisant l’interféron de type 1. L’immunité collective caractérise la faible probabilité de développement d’une épidémie dans une population ayant un pourcentage élevé de sujets présentant une immunité individuelle. Le taux d’immunité collective nécessaire pour faire disparaître l’épidémie a été calculé dans des modèles mathématiques supposant la panmixie ; il est difficile à évaluer dans les populations réelles.
Published: 2021

32. Immunological and virological profile of children with chilblain‐like lesions and SARS‐CoV‐2

Author: Isabelle Sermet-Gaudelus, Smail Hadj-Rabia, A. Welfringer-Morin, Amani Ouedrani, Sarah Temmam, Christine Bodemer, Lucienne Chatenoud, L. Polivka, J Fourgeaud, Marc Eloit, L. Fertitta, S. Chhun, Service de Dermatologie [CHU-Necker], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de référence national des Maladies Génétiques à Expression Cutanée - National Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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), Laboratoire d'Immunologie [CHU Necker], Laboratoire de Virologie [CHU-Necker], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Découverte de pathogènes – Pathogen discovery, Institut Pasteur [Paris] (IP), Département de pneumologie [CHU-Necker], Reference Center Rare Diseases: cystic fibrosis, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), No funding sources, and TEMMAM, Sarah
Subjects: Male, viruses, Letter to Editor, SARS‐CoV‐2, 030207 dermatology & venereal diseases, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Pandemic, Medicine, MESH: COVID-19, Letters to Editor, Child, skin and connective tissue diseases, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Infant, Chilblains, Infectious Diseases, Child, Preschool, MESH: Chilblains, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, France, chilblain‐like lesions, 2019-20 coronavirus outbreak, MESH: Pandemics, Adolescent, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, Dermatology, 03 medical and health sciences, COVID‐19, 030225 pediatrics, Humans, MESH: SARS-CoV-2, Pandemics, MESH: Adolescent, MESH: Humans, SARS-CoV-2, business.industry, fungi, MESH: Child, Preschool, COVID-19, Infant, medicine.disease, Virology, MESH: Male, respiratory tract diseases, body regions, MESH: France, MESH: Pneumonia, Viral, business, MESH: Female
Abstract: International audience; The link between SARS‐CoV‐2 and the reported cutaneous manifestations has not been established. We assessed a possible correlation between the paediatric dermatological manifestations and the biological investigations, using for the first time 3 different SARS‐CoV‐2 tests.
Published: 2020
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33. Effective Anti–SARS-CoV-2 Immune Response in Patients With Clonal Mast Cell Disorders

Author: Julien Rossignol, Amani Ouedrani, Cristina Bulai Livideanu, Stéphane Barete, Louis Terriou, David Launay, Richard Lemal, Celine Greco, Laurent Frenzel, Cecile Meni, Christine Bodemere-Skandalis, Laura Polivka, Anne-Florence Collange, Hassiba Hachichi, Sonia Bouzourine, Djazira Nait Messaoud, Mathilde Negretto, Laurence Vendrame, Marguerite Jambou, Marie Gousseff, Stéphane Durupt, Jean-Christophe Lega, Jean-Marc Durand, Caroline Gaudy, Gandhi Damaj, Marie-Pierre Gourin, Mohamed Hamidou, Laurence Bouillet, Edwige Le Mouel, Alexandre Maria, Patricia Zunic, Quentin Cabrera, Denis Vincent, Christian Lavigne, Etienne Riviere, Clement Gourguechon, Marie Courbebaisse, David Lebeaux, Béatrice Parfait, Gérard Friedlander, Anne Brignier, Ludovic Lhermitte, Thierry Jo Molina, Julie Bruneau, Julie Agopian, Patrice Dubreuil, Dana Ranta, Alexandre Mania, Michel Arock, Isabelle Staropoli, Olivier Tournilhac, Olivier Lortholary, Olivier Schwartz, Lucienne Chatenoud, Olivier Hermine, Centre de référence des mastocytoses (CEREMAST), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence des Mastocytoses de Toulouse (CEREMAST), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), 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), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne (UCA), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), The authors would like to thank Fondation Université de Paris, AXA research fund, Fondation Hôpitaux de Paris-Hôpitaux de France, Mécénat du GH APHP. CUP, Fondation pour la Recherche en Physiologie and DMU BioPhyGen for the funding of the COVID-HOP study., ANR-20-COV1-0001,APCOD,Les cellules présentatrices d'antigènes dans la maladie de COVID-19 à résolution monocellulaire(2020), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), CHU Toulouse [Toulouse], Virus et Immunité - Virus and immunity, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: PBMC, peripheral blood mononuclear cell, BMI, body mass index, T cells, B-cells, CEREMAST, Centre de Référence des Mastocytoses, CM, cutaneous mastocytosis, MMAS, monoclonal mast cell activation syndrome, PHA, phytohemagglutinin, PMSI, Programme de médicalisation des systèmes d'information, Antibodies, Viral, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2, Antiviral Agents, WHO, World Health Organization, MIS, mastocytosis in the skin, HEK, human embryonic kidney, Humans, Immunology and Allergy, IFN, interferon, Mast Cells, APHP, Assistance Publique - Hôpitaux de Paris (Paris Public Hospital Group), B cells, SARS-CoV-2, T-cells, Immunity, COVID-19, ISM, indolent systemic mastocytosis, Clonal mast cell activation syndrome, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MCAS, mast cell activation syndrome, Original Article, Mast cell activation dis- orders, SSM, smoldering systemic mastocytosis, NK, natural killer, Mastocytosis, COVID-19, coronavirus disease 19, Mast cell activation disorders, cMCAD, clonal mast cell activation disorder
Abstract: International audience; BackgroundMast cells are key players in innate immunity and the TH2 adaptive immune response. The latter counterbalances the TH1 response, which is critical for antiviral immunity. Clonal mast cell activation disorders (cMCADs, such as mastocytosis and clonal mast cell activation syndrome) are characterized by abnormal mast cell accumulation and/or activation. No data on the antiviral immune response in patients with MCADs have been published.ObjectiveTo study a comprehensive range of outcomes in patients with cMCAD with PCR- or serologically confirmed coronavirus disease 2019 and to characterize the specific anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune response in this setting.MethodsClinical follow-up and outcome data were collected prospectively over a 12-month period by members of the French Centre de Référence des Mastocytoses rare disease network. Anti–SARS-CoV-2–specific T-cell activity was measured with an ELISA, and humoral responses were evaluated by assaying circulating levels of specific IgG, IgA, and neutralizing antibodies.ResultsOverall, 32 patients with cMCAD were evaluated. None required noninvasive or mechanical ventilation. Two patients were admitted to hospital for oxygen and steroid therapy. The SARS-CoV-2–specific immune response was characterized in 21 of the 32 patients. Most had high counts of circulating SARS-CoV-2–specific, IFN-γ–producing T cells and high titers of neutralizing antispike IgGs. The patients frequently showed spontaneous T-cell IFN-γ production in the absence of stimulation; this production was correlated with basal circulating tryptase levels (a marker of the mast cell burden).ConclusionsPatients with cMCADs might not be at risk of severe coronavirus disease 2019, perhaps due to their spontaneous production of IFN-γ.
Published: 2022

34. Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling

Author: Nicolas Manel, Siham Boulisfane-El Khalifi, Mary Brennan, Darragh Duffy, Nadia Nathan, Serge Amselem, Kathryn J. McKenzie, Maria José Martin-Niclos, Jonny Hertzog, Carolina Uggenti, Marie Legendre, Stéphanie Chhun, Caroline Thumerelle, Luis Seabra, Marie-Louise Frémond, Vincent Bondet, Bénédicte Neven, Joseph A. Marsh, Marie Wislez, Catherine McDougall, Marine Depp, Jan Rehwinkel, Gillian I. Rice, Aurore Coulomb L'Hermine, Yanick J. Crow, Lucienne Chatenoud, Melvin Le Bihan, Thierry Jo Molina, Karen J. Mackenzie, Alice Lepelley, Edwin Carter, Jonathan Marey, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Radcliffe Department of Medicine [Oxford], University of Oxford [Oxford], Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Royal Hospital for Sick Children [Edinburgh], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de pathologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Service de pneumologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Royal Infirmary of Edinburgh, Département de Pathologie [CHU Necker], Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-CHU Necker - Enfants Malades [AP-HP], Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), M.-L. Frémond received a grant from the Institut National de la Santé et de la Recherche Médicale (000427993) and acknowledges La Fondation Square. Y.J. Crow acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs), and a state subsidy managed by the Agence Nationale de la Recherche under the 'Investments for the Future' program (ANR-10-IAHU-01). Y.J. Crow and D. Duffy acknowledge the Agence Nationale de la Recherche (grant CE17001002). J.A. Marsh is supported by a Medical Research Council Career Development Award (MR/M02122X/1) and is a Lister Institute of Preventive Medicine Research Prize Fellow. N. Manel was supported by LABEX DCBIOL (ANR-10-IDEX-0001-02 PSL* and ANR-11-LABX-0043), ANR-17-CE15-0025-01, ANR-18-CE92-0022-01, Fondation BMS, Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ECTZ71745), Sidaction (VIH2016126002), and Ile-de-France Emergence. M. Le Bihan received a doctoral fellowship from Ile-de-France ARDoc. The project was supported by MSDAVENIR (Devo-Decode Project)., We thank Immunoqure AG for provision of antibodies for the Simoa assay., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-17-CE15-0025,STINGCHECK,Mécanismes des points de contrôle du senseur de l'immunité innée STING(2017), ANR-18-CE92-0022,cGAS-Vac,Analyses fonctionnelles de la voie cGAS/STING au cours d'infections bactériennes et infections virales et implications pour le développement de vaccins innovants(2018), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Oxford, Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), UF de Génétique moléculaire [CHU Trousseau], Service de Pneumologie pédiatrique [CHU Trousseau], Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Mécanismes des points de contrôle du senseur de l'immunité innée STING - - STINGCHECK2017 - ANR-17-CE15-0025 - AAPG2017 - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Analyses fonctionnelles de la voie cGAS/STING au cours d'infections bactériennes et infections virales et implications pour le développement de vaccins innovants - - cGAS-Vac2018 - ANR-18-CE92-0022 - AAPG2018 - VALID, and Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID
Subjects: 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Protein subunit, Immunology, Mutant, Biology, medicine.disease_cause, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Interferon, medicine, Immunology and Allergy, Gene silencing, Mutation, HEK 293 cells, Golgi apparatus, eye diseases, 3. Good health, Cell biology, Sting, 030104 developmental biology, 030220 oncology & carcinogenesis, symbols, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.drug
Abstract: International audience; Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.
Published: 2020

35. List of Contributors

Author: Jakub Abramson, S. Sohail Ahmed, Marco A. Alba, Youssif M. Ali, Julian L. Ambrus, Agnes Andersson Svärd, Martin Aringer, Shervin Assassi, Thanda Aung, Ilya Ayzenberg, Robert N. Barker, Alan G. Baxter, Corrado Betterle, Stanca A. Birlea, Niklas K. Björkström, Paul A. Blair, Stephan Blüml, Xavier Bosch, Robert A. Brodsky, Yenan T. Bryceson, Patrick R. Burkett, James B. Bussel, Roberto Caricchio, Livia Casciola-Rosen, Patrizio Caturegli, Benjamin Chaigne-Delalande, Paulina Chalan, Lucienne Chatenoud, Philip L. Cohen, Megan A. Cooper, Ken Coppieters, Ronald G. Crystal, Donna A. Culton, Valentina Damato, Anne Davidson, Lorenzo Delfino, Peter J. Delves, Giulia Di Dalmazi, Betty Diamond, Luis A. Diaz, Ronald J. Falk, Marvin J. Fritzler, Stefania Gallucci, Sapna Gangaputra, Brian Gelbman, M. Eric Gershwin, Igal Gery, Daniel R. Getts, Ralf Gold, Yael Goldfarb, Jing Gong, Siamon Gordon, Jörg J. Goronzy, Judith M. Greer, Vanesa A. Guazzone, Luiza Guilherme, David A. Hafler, Bevra H. Hahn, Abdel Rahim A. Hamad, Hideaki Hamano, Leonard C. Harrison, Dirk Homann, Eystein S. Husebye, J. Charles Jennette, Richard J. Jones, Margaret A. Jordan, Jorge Kalil, Shigeyuki Kawa, Ziya Kaya, Christian W. Keller, Nicholas J.C. King, Maleewan Kitcharoensakkul, Kendo Kiyosawa, Christoph Königs, Mitchell Kronenberg, Vijay K. Kuchroo, Arian Laurence, Eun-Ju Lee, Helmar C. Lehmann, Åke Lernmark, Ida Lindbladh, Zhi Liu, Hans-Gustaf Ljunggren, Claudio Lunardi, Knut E.A. Lundin, Jan D. Lünemann, Michael P.T. Lunn, Livia Lustig, Charles R. Mackay, Ian R. Mackay, Clara Malattia, Luisa Martinez-Pomares, Alberto Martini, Claudia Mauri, Pamela A. McCombe, Fritz Melchers, Giorgina Mieli-Vergani, Frederick W. Miller, Stephen D. Miller, Masayuki Mizui, Jenny Mjösberg, Christian Münz, Jagtar Singh Nijjar, David A. Norris, Kristine Oleinika, Joost J. Oppenheim, Mathias Pawlak, Cristina Peligero-Cruz, Anneli Peters, Pärt Peterson, Kalliopi Pitarokoili, Fabio Presotto, Antonio Puccetti, Hamid Rabb, Patricia Raczek, M. Jubayer Rahman, Manuel Ramos-Casals, Noel R. Rose, Antony Rosen, Mohanraj Sadasivam, Adam Schiffenbauer, Wilhelm J. Schwaeble, H. Nida Sen, Marc Serota, Kazim A. Sheikh, Yehuda Shoenfeld, Ora Shovman, Joachim Sieper, Arthur M. Silverstein, Robert B. Sim, Kenneth G C Smith, Josef S. Smolen, Ludvig M. Sollid, Alanna Spiteri, Lawrence Steinman, John H. Stone, Uta Syrbe, Ami Tamhaney, Atsushi Tanaka, Veena Taneja, Kristin V. Tarbell, Elisa Tinazzi, Benedict K. Tiong, Ban-Hock Toh, George C. Tsokos, Kenneth S.K. Tung, John Varga, Diego Vergani, Mark A. Vickers, Stuart Viegas, Angela Vincent, Matthias von Herrath, Anthony P. Weetman, Joel V. Weinstock, John M. Wentworth, Sarah Wesley, Cornelia M. Weyand, Gerhard Wingender, Michael W. Winter, Renato Zanchetta, and Moncef Zouali
Published: 2020

36. Emerging Biological and Molecular Therapies in Autoimmune Disease

Author: Lucienne Chatenoud
Subjects: Autoimmune disease, medicine.drug_class, business.industry, medicine.medical_treatment, Immunosuppression, Immunotherapy, medicine.disease, medicine.disease_cause, Monoclonal antibody, Autoimmunity, Cell therapy, Immune system, Immunology, medicine, Receptor, business
Abstract: The field of immunotherapy metamorphosed with the development of monoclonal antibodies and fusion proteins targeting specialized receptors of immune cells or cytokines and of bioengineering of cell receptors to improve cell therapy approaches. Autoimmunity is probably one of the fields that benefited the most from these new therapies that very significantly impacted the modalities of patient’s care. Here we shall discuss agents which constitute major disease-modifying drugs for the treatment of chronic invalidating autoimmune diseases and distinguish strategies that globally depress immune responses from those that have potential to selectively target the pathogenic autoimmune response over long term in absence of chronic immunosuppression, in other words, strategies promoting “operational tolerance.” We shall also discuss new avenues for autoantigen-specific therapy and cell therapies emerging from antigen receptor gene–modified T cells.
Published: 2020

37. Chronic Disseminated Candidiasis During Hematological Maligancies: An Immune Reconstitution Inflammatory Syndrome with Expansion of Pathogen-Specific TH1 T Cells

Author: Maria Pilar Gallego Hernanz, Olivier Lortholary, Lucienne Chatenoud, Sophie Candon, Blandine Rammaert, Anne Perrine Foray, Baptiste Moreira, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pharmacologie des anti-infectieux (PHAR), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), The study was funded by a grant from Programme Hospitalier de Recherche Clinique - PHRC 2012 of the Ministry of Health (grant number AOM12047 to BR)., Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], CHU Necker - Enfants Malades [AP-HP], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Neutropenia, [SDV]Life Sciences [q-bio], Inflammation, Systemic inflammation, 03 medical and health sciences, Interferon-gamma, Immune system, Immune reconstitution inflammatory syndrome, Interferon, Immune Reconstitution Inflammatory Syndrome, medicine, Immunology and Allergy, Humans, Candidiasis, Invasive, Prospective Studies, 030304 developmental biology, Aged, Interferon gamma, 0303 health sciences, 030306 microbiology, business.industry, Middle Aged, Th1 Cells, medicine.disease, Neutrophilia, 3. Good health, Invasive candidiasis, Interleukin 10, Infectious Diseases, Case-Control Studies, Hematologic Neoplasms, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, business, CD8, medicine.drug
Abstract: Background Chronic disseminated candidiasis (CDC) is a rare disease that mostly occurs after chemotherapy-induced prolonged neutropenia in patients with hematological malignancies. It is believed to ensue from Candida colonization, breach of the intestinal epithelial barrier, and venous translocation to organs. Fungal blood or liver biopsy cultures are generally negative, suggesting the absence of an ongoing invasive fungal disease. Methods To unravel the contribution of the immune system to CDC pathogenesis, we undertook a prospective multicentric exploratory study in 44 CDC patients at diagnosis and 44 matched controls. Results Analysis of Candida-specific T-cell responses using enzyme-linked immunospot assays revealed higher numbers of interferon (IFN)γ-producing T cells reactive to mp65 or candidin in 27 CDC cases compared with 33 controls. Increased plasma levels of soluble CD25, interleukin (IL)-6, IL-1β, tumor necrosis factor-α, and IL-10 and lower levels of IL-2 were observed in CDC patients versus controls. Neutrophilia and higher levels of CD4 and CD8 T-cell activation were found in CDC patients as well as increased proportions of CXCR3-expressing TCRγδ +Vδ2+ cells. Conclusions The expansion of Candida-specific IFNγ-producing T cells together with features of T-cell activation and systemic inflammation identified here support the view that CDC belongs to the broad spectrum of fungal-associated immune reconstitution inflammatory syndromes.
Published: 2019

38. Circulating IL-17-producing mucosal-associated invariant T cells (MAIT) are associated with symptoms in children with asthma

Author: Céline Dietrich, Jacques de Blic, Guillaume Lezmi, Lucienne Chatenoud, Rola Abou Taam, Maria Leite-de-Moraes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Référence des Maladies Héréditaires du Métabolisme de l'Enfant et de l'Adulte [CHU Necker] (MaMEA Necker), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Laboratory of Immunoregulation and Immunopathology [Paris], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), 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)-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), Service de Pneumologie Allergologie [CHU Necker], Cytokines, hématopoïèse et réponse immune (CHRI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: Male, 0301 basic medicine, Immunology, Mucosal associated invariant T cell, Lymphocyte Activation, Mucosal-Associated Invariant T Cells, Flow cytometry, Cohort Studies, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Wheeze, medicine, Humans, Immunology and Allergy, Lymphocyte Count, Child, ComputingMilieux_MISCELLANEOUS, Asthma, medicine.diagnostic_test, business.industry, Interleukin-17, MAIT Cells, medicine.disease, 3. Good health, 030104 developmental biology, Cohort, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Interleukin 17, medicine.symptom, business, 030215 immunology
Abstract: IL-17 and mucosal-associated invariant T (MAIT) cells have been involved in asthma pathogenesis. However, IL-17-producing MAIT cells (MAIT-17) were not evidenced. We aimed to determine whether circulating MAIT-17 were detectable in children with asthma, and whether they correlated with asthma symptoms or lung function. Children from the SPASM cohort of preschoolers with severe wheeze were reassessed for asthma at school age, and categorized as exacerbators (1 or more severe exacerbations in the previous 12months) or non-exacerbators. Nineteen children (10.9years) were included (9 non-exacerbators, 10 exacerbators). Circulating MAIT-17 were detected by flow cytometry. Their frequency was higher in exacerbators than in non-exacerbators (1.9 [1.01-3.55] vs 0.58 [0.46-1.15], p0.01). MAIT-17 correlated with the number of severe exacerbations (r=0.68, p0.001), and correlated negatively with the ACT score (r=-0.55, p=0.01). In summary, MAIT-17 are present in children with asthma and associated with asthma symptoms.
Published: 2018

39. Rapid and Safe T Cell Immune Reconstitution By T Cell Progenitor Injection Following Haploidentical Transplantation for Severe Combined Immunodeficiency (SCID)

Author: Alessandra Magnani, Lucienne Chatenoud, Capucine Picard, Laurence Vendrame, Isabelle André, Martin Castelle, Tayebeh-Shabi Soheili, Despina Moshous, Pierre Gaudeaux, Benjamin Fournier, Sarah Winter, Elisa Magrin, Marina Cavazzana, Laura E. Simons, and Bénédicte Neven
Subjects: Severe combined immunodeficiency, Haploidentical transplantation, business.industry, T cell, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, medicine.anatomical_structure, Immune system, medicine, business, Progenitor
Abstract: Severe Combined Immunodeficiencies (SCID) are defined by a complete absence of T lymphocytes in the blood and lymphoid organs, with variable defects in other WBC subsets depending on the gene defect. From a clinical perspective SCIDs are characterized by early development of life-threatening infections accounting for early death if untreated. The treatment of choice is allogeneic HSCT with very high success rates if a HLA identical sibling (MRD) or unrelated donor (MUD) is used. However, due to the scarcity of matched-related donors, SCID can benefit from haploidentical HSCT. In contrast to the continuous improvement of HLA compatible donor transplantations, no significant improvements have been obtained over the last twenty years for haploidentical HSCT. The profound immunodeficiency during the first months following haploidentical HSCT exposes patients to opportunistic viral, bacterial and fungal infections, which account for approximately 30-40% of the transplant related mortality (TRM). The rapid restoration of the T-cell compartment is the main aim of stem cell therapy in this setting. To this end we have recently set up a phase I/II clinical trial (ClinicalTrials.gov Identifier: NCT03879876) aiming to accelerate the immune reconstitution by injection of ex vivo generated Human T lymphoid progenitors (ProTcell TM) following haploidentical HSCT. T cell progenitors in this trial are generated in vitro within 7 days from mobilized peripheral blood (mPB) CD34 + hematopoietic stem and precursor cells (HSPCs) using our Notch ligand Delta-like 4 GMP culture platform so called SMART Immune's SMART101 product. This open-label, non-randomized study evaluates safety and efficacy of the SMART101 injection following CD34 + selected, haploidentical HSCT in SCID patients and is designed as a dose-escalation study comprising 6 doses of the SMART101 product obtained from the patient's haploidentical stem cell graft. The aim of this protocol is to define the highest efficacy dose without any toxicity. The conditioning regimen is based on Busulfan and Fludarabine according to IE-WP/EBMT guidelines with upfront administration of ATG to prevent graft rejection. Tight monitoring of ATG serum levels is applied in order to assure injection of SMART101 when ATG is below the lymphotoxicity threshold. Here we report the results of the first two SCID patients. P1 presented a homozygous Artemis deficiency. At diagnosis he had an ALC of 341/µl, with complete absence of T cells (CD3 + < 4/µl, CD4 + < 1/µl, CD8 + < 2/µl) and B cells (CD19 + 0/µl). NK cells were present in the normal range for age (CD16 +CD56 + 331/µl). In the absence of an HLA compatible donor, the patient`s father was chosen as haploidentical stem cell donor. P1 received upfront ATG (5 mg /kg total dose), Busulfan (AUC of 16058 microM.min) and Fludarabine (160 mg/m²). He received Defibrotide prophylaxis from D0 until D+21, as well as Ursodeoxycholic acid until D+80. The CD34 + immunoselected graft contained 1.04 x 10 8 nucleated cells/kg with 24.15 x10 6 CD34 + cells/kg and 4000 CD3 + cells/kg on D0. After ATG monitoring 0.12x10 6 Smart101 cells were administered at D+14 post- HSCT. In the follow-up P1 didn't develop any acute or chronic SAEs, no acute or chronic GVHD, and no infection. He was discharged at D+121 post HSCT. The day +100 post transplantation CD4 + cell count/microliter exceeded 10 times the CD4 + count of our historical cohort of RAG1/2 or Artemis deficient patients transplanted with haploidentical HSCT alone following the same conditioning regimen. At 6 months post HSCT this difference remains important (851 versus 300 CD4 + cells/µl); Ig replacement therapy could be stopped as early as 9 months post transplantation and vaccinations have been started. At last follow up; almost 14 months post HSCT P1 is alive and well. P2 had an undefined molecular SCID diagnosis. She has been treated with the same conditioning regimen and received the second dose of 0.2x10 6 CD7 + cells, but unfortunately died from severe VOD emphasizing the need to replace chemotherapy with less toxic myeloablative agents. The preliminary results obtained after injection of Human T lymphoid progenitors in P1 are encouraging. While deserving confirmation in larger numbers of patients they could represent an important step forward in improving the outcome of haploidentical HSCT for SCID. Disclosures Cavazzana: Smart Immune: Other: co-founder.
Published: 2021

40. Oral histone deacetylase inhibitor synergises with T cell targeted immunotherapy to preserve beta cell metabolic function and induce stable remission of new-onset autoimmune diabetes in NOD mice

Author: Sylvaine You, Fabrice Valette, Mattias S. Dahllöf, Alix Besançon, Thomas Mandrup-Poulsen, Lucienne Chatenoud, and Tania Goncalves
Subjects: Male, 0301 basic medicine, Combination therapy, T-Lymphocytes, Endocrinology, Diabetes and Metabolism, Interleukin-1beta, Administration, Oral, Pharmacology, Biology, Antibodies, Monoclonal, Humanized, medicine.disease_cause, Autoimmunity, Interferon-gamma, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Mice, Inbred NOD, Insulin-Secreting Cells, Diabetes mellitus, Internal Medicine, medicine, Animals, Givinostat, Cells, Cultured, NOD mice, Mice, Inbred BALB C, Type 1 diabetes, Interleukin-6, Tumor Necrosis Factor-alpha, Otelixizumab, Flow Cytometry, medicine.disease, Interleukin-10, Histone Deacetylase Inhibitors, Diabetes Mellitus, Type 1, 030104 developmental biology, chemistry, Immunology, Female, Immunotherapy, Insulitis, 030215 immunology, medicine.drug
Abstract: Combination therapy targeting the major actors involved in the immune-mediated destruction of pancreatic beta cells appears to be an indispensable approach to treat type 1 diabetes effectively. We hypothesised that the combination of an orally active pan-histone deacetylase inhibitor (HDACi: givinostat) with subtherapeutic doses of CD3 antibodies may provide ideal synergy to treat ongoing autoimmunity. NOD mice transgenic for the human CD3e (also known as CD3E) chain (NOD-huCD3e) were treated for recent-onset diabetes with oral givinostat, subtherapeutic doses of humanised CD3 antibodies (otelixizumab, 50 μg/day, 5 days, i.v.) or a combination of both drugs. Disease remission, metabolic profiles and autoreactive T cell responses were analysed in treated mice. We demonstrated that givinostat synergised with otelixizumab to induce durable remission of diabetes in 80% of recently diabetic NOD-huCD3e mice. Remission was obtained in only 47% of mice treated with otelixizumab alone. Oral givinostat monotherapy did not reverse established diabetes but reduced the in situ production of inflammatory cytokines (IL-1β, IL-6, TNF-α). Importantly, the otelixizumab + givinostat combination strongly improved the metabolic status of NOD-huCD3e mice; the mice recovered the capacity to appropriately produce insulin, control hyperglycaemia and sustain glucose tolerance. Finally, diabetes remission induced by the combination therapy was associated with a significant reduction of insulitis and autoantigen-specific CD8+ T cell responses. HDACi and low-dose CD3 antibodies synergised to abrogate in situ inflammation and thereby improved pancreatic beta cell survival and metabolic function leading to long-lasting diabetes remission. These results support the therapeutic potential of protocols combining these two drugs, both in clinical development, to restore self-tolerance and insulin independence in type 1 diabetes.
Published: 2017

41. Mucosal administration of CD3-specific monoclonal antibody inhibits diabetes in NOD mice and in a preclinical mouse model transgenic for the CD3 epsilon chain

Author: Fabrice Valette, Chantal Kuhn, Francisco J. Quintana, Rafael M. Rezende, Lucienne Chatenoud, Howard L. Weiner, and Andre Pires da Cunha
Subjects: 0301 basic medicine, CD3 Complex, medicine.drug_class, Regulatory T cell, medicine.medical_treatment, CD3, Immunology, Mice, Transgenic, Nod, Lymphocyte Activation, Protective Agents, Monoclonal antibody, T-Lymphocytes, Regulatory, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Mice, Inbred NOD, Transforming Growth Factor beta, In vivo, Immune Tolerance, medicine, Administration, Mucosal, Animals, Immunology and Allergy, Immunity, Mucosal, NOD mice, Autoimmune disease, biology, Antibodies, Monoclonal, Immunotherapy, medicine.disease, Interleukin-10, Disease Models, Animal, Diabetes Mellitus, Type 1, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Female, 030215 immunology
Abstract: CD3-specific monoclonal antibody (mAb) treats autoimmune disease in animal models and has shown promise in clinical trials of type 1 diabetes. Whereas intravenous administration of CD3-specific mAb acts primarily by transient depletion of activated effector T cells, oral CD3-specific mAb acts primarily by the induction Tregs. We investigated whether oral CD3-specific mAb inhibits disease in non obese diabetic (NOD) mice that spontaneously develop autoimmune diabetes, closely resembling human type 1 diabetes. We found that oral CD3-specific mAb treatment delayed onset and reduced incidence of diabetes in NOD mice, inducing changes in both effector and regulatory T cell compartments. The therapeutic effect was associated with decreased T cell proliferation, decreased IFNγ and IL-17 production, and increased TGF-β and IL-10 production in vitro. In vivo transfer experiments demonstrated that oral CD3-specific mAb decreased diabetogenicity of effector T cells and increased the function of regulatory T cells. Oral OKT3, a monoclonal antibody specific for human CD3 had equivalent effects in transgenic NOD mice expressing the human CD3 epsilon chain which serves as a preclinical model for testing human CD3-specific mAb. These results suggest that oral CD3-specific mAb has the potential for treating autoimmune diabetes in humans.
Published: 2017

42. Revisiting autoimmune gastritis in children and adolescents with type 1 diabetes

Author: Jean-Philippe Jais, Benedicte Michaud, Lucienne Chatenoud, Jean-Jacques Robert, Alix Besançon, Michel Polak, Jacques Beltrand, and Tania Goncalves
Subjects: Type 1 diabetes, medicine.medical_specialty, medicine.diagnostic_test, Autoimmune Gastritis, Atrophic gastritis, Anemia, business.industry, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Iron deficiency, medicine.disease, Autoimmune thyroiditis, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Iron-deficiency anemia, Internal medicine, Pediatrics, Perinatology and Child Health, Internal Medicine, medicine, Serum iron, 030211 gastroenterology & hepatology, business
Abstract: Objective Assess the frequency of anti-H+ /K+ adenosine triphosphatase (ATPase) autoantibodies (AAB) and symptoms of autoimmune gastritis in children and adolescents with type 1 diabetes (T1D). Research design and methods Anti-H+ /K+ ATPase AAB were measured in 402 children and adolescents (210 boys and 192 girls, 11.1 ± 4.5 years) treated for T1D (screened positive for β-cell AAB), along with search of symptoms of anemia (hemoglobin, serum iron, and ferritin levels) and gastric pain. The AAB specific for thyroperoxydase, thyroglobulin, and transglutaminase were also measured. Results Anti-H+ /K+ ATPase AAB were present in 6.5% of children. Their frequency increased with age: 4% at 10 years, 10% at 15 years, and 20% at 20 years. Iron deficiency (45% vs 3.8%), iron deficiency anemia (36% vs 3.8%), antithyroid AAB (24% vs 9.7%), and family history of Graves' disease (25% vs 5.6%) were more frequent in patients with anti-H+ /K+ ATPase AAB. Two patients, a 13-year-old girl and a 11-year-old boy, experienced symptoms (iron deficiency anemia and epigastric pain) which led to diagnosis of autoimmune gastritis confirmed upon fibroscopy. Both showed high levels of anti-H+ /K+ ATPase AAB and atrophic gastritis. Conclusions Autoimmune gastritis presents an age-dependent frequency in children and adolescents with T1D but is rarely symptomatic. Screening for anti-H+ /K+ ATPase AAB should thus target patients with iron deficiency, anemia, epigastralgia, autoimmune thyroiditis, or age over 15 years.
Published: 2016

43. Antibody Therapeutics: Application to Autoimmunity

Author: Lucienne Chatenoud
Subjects: biology, business.industry, Immunology, biology.protein, Medicine, Antibody, business, medicine.disease_cause, Autoimmunity
Published: 2019

44. Human peripheral blood DNAM-1

Author: Kimberley A, Stannard, Sébastien, Lemoine, Nigel J, Waterhouse, Frank, Vari, Lucienne, Chatenoud, Maher K, Gandhi, Ludovic, Martinet, Mark J, Smyth, and Camille, Guillerey
Subjects: Antigens, Differentiation, T-Lymphocyte, Killer Cells, Natural, genetic structures, Immunobiology and Immunotherapy, Humans, chemical and pharmacologic phenomena, Cell Differentiation, sense organs, Lymphoma, Large B-Cell, Diffuse, Hodgkin Disease, CD56 Antigen, Neoplasm Proteins
Abstract: Natural killer (NK) cells are a heterogeneous population of innate lymphocytes whose potent anticancer properties make them ideal candidates for cellular therapeutic application. However, our lack of understanding of the role of NK cell diversity in antitumor responses has hindered advances in this area. In this study, we describe a new CD56(dim) NK cell subset characterized by the lack of expression of DNAX accessory molecule-1 (DNAM-1). Compared with CD56(bright) and CD56(dim)DNAM-1(pos) NK cell subsets, CD56(dim)DNAM-1(neg) NK cells displayed reduced motility, poor proliferation, lower production of interferon-γ, and limited killing capacities. Soluble factors secreted by CD56(dim)DNAM-1(neg) NK cells impaired CD56(dim)DNAM-1(pos) NK cell–mediated killing, indicating a potential inhibitory role for the CD56(dim)DNAM-1(neg) NK cell subset. Transcriptome analysis revealed that CD56(dim)DNAM-1(neg) NK cells constitute a new mature NK cell subset with a specific gene signature. Upon in vitro cytokine stimulation, CD56(dim)DNAM-1(neg) NK cells were found to differentiate from CD56(dim)DNAM-1(pos) NK cells. Finally, we report a dysregulation of NK cell subsets in the blood of patients diagnosed with Hodgkin lymphoma and diffuse large B-cell lymphoma, characterized by decreased CD56(dim)DNAM-1(pos)/CD56(dim)DNAM-1(neg) NK cell ratios and reduced cytotoxic activity of CD56(dim)DNAM-1(pos) NK cells. Altogether, our data offer a better understanding of human peripheral blood NK cell populations and have important clinical implications for the design of NK cell–targeting therapies.
Published: 2018

45. Understanding Pathogenesis and Care Challenges of Immune Reconstitution Inflammatory Syndrome in Fungal Infections

Author: Olivier Lortholary, Claire Aguilar, Sarah Dellière, Blandine Rammaert, Romain Guery, Lucienne Chatenoud, Fanny Lanternier, Sophie Candon, Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pharmacologie des anti-infectieux (PHAR), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris], and TAN, Yossan-Var
Subjects: 0301 basic medicine, Microbiology (medical), 030106 microbiology, Cryptococcus, fungal immunity, Plant Science, Review, urologic and male genital diseases, Pathogenesis, 03 medical and health sciences, Immune system, Immune reconstitution inflammatory syndrome, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Histoplasma, medicine, Iris (anatomy), mycoses, lcsh:QH301-705.5, Ecology, Evolution, Behavior and Systematics, Aspergillus, invasive fungal infections, biology, business.industry, urogenital system, fungi, medicine.disease, biology.organism_classification, immune reconstitution inflammatory syndrome, 3. Good health, medicine.anatomical_structure, lcsh:Biology (General), Immunology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Etiology, business
Abstract: Immune deficiency of diverse etiology, including human immunodeficiency virus (HIV), antineoplastic agents, immunosuppressive agents used in solid organ recipients, immunomodulatory therapy, and other biologics, all promote invasive fungal infections. Subsequent voluntary or unintended immune recovery may induce an exaggerated inflammatory response defining immune reconstitution inflammatory syndrome (IRIS), which causes significant mortality and morbidity. Fungal-associated IRIS raises several diagnostic and management issues. Mostly studied with Cryptococcus, it has also been described with other major fungi implicated in human invasive fungal infections, such as Pneumocystis, Aspergillus, Candida, and Histoplasma. Furthermore, the understanding of IRIS pathogenesis remains in its infancy. This review summarizes current knowledge regarding the clinical characteristics of IRIS depending on fungal species and existing strategies to predict, prevent, and treat IRIS in this patient population, and tries to propose a common immunological background to fungal IRIS.
Published: 2018

46. Efficacy of JAK1/2 inhibition in the treatment of chilblain lupus due to TREX1 deficiency

Author: Marie-Louise Frémond, Aurélia Carbasse, Bénédicte Neven, Coralie Briand, Yanick J. Crow, Lucienne Chatenoud, Darragh Duffy, Vincent Bondet, Gillian I. Rice, Didier Bessis, Stéphane Blanche, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Manchester [Manchester], Immunobiologie des Cellules dendritiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Edinburgh, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), and ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016)
Subjects: 0301 basic medicine, Ruxolitinib, Immunology, Encephalopathy, Inflammation, General Biochemistry, Genetics and Molecular Biology, rehabilitation, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Downregulation and upregulation, Interferon, medicine, Immunology and Allergy, 030203 arthritis & rheumatology, Lupus erythematosus, Janus kinase 1, treatment, business.industry, medicine.disease, 3. Good health, 030104 developmental biology, Tyrosine kinase 2, inflammation, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, business, medicine.drug
Abstract: The type I interferonopathies, Mendelian disorders characterised by constitutive upregulation of the type I interferon (IFN) pathway, are associated with a spectrum of phenotypes particularly involving the brain and the skin.1 Mutations in the 3′−5′ DNA exonuclease TREX1 were the first described cause of the severe encephalopathy Aicardi-Goutieres syndrome (AGS),2 of which acral vasculitic lesions are a well-recognised feature. Familial chilblain lupus (FCL) is the name given where such lesions occur in the absence of neurological disease.3 TREX1 dysfunction, due to biallelic loss of function or dominant negative heterozygous mutations, is postulated to lead to aberrant immune recognition of self-nucleic acids inducing the production of type I IFNs. These potent cytokines drive the expression of IFN-stimulated genes (ISGs) through the engagement of a common receptor and the subsequent activation of Janus kinase 1 (JAK1) and tyrosine kinase 2. We describe, to our knowledge for the first time, the efficacy of the JAK1/2 inhibitor ruxolitinib in a patient with TREX1-related skin disease. Parental consent was obtained for the use of ruxolitinib on a compassionate basis. The patient carried a previously recorded dominant negative heterozygous mutation in TREX1 (c.52G>A, …
Published: 2018

47. Efficacy of Rituximab in Refractory Generalized anti-AChR Myasthenia Gravis

Author: Olivier Boyer, Yves Allenbach, Océane Landon-Cardinal, Lucienne Chatenoud, Emmanuelle Salort-Campana, Bruno Eymard, Olivier Benveniste, Nicholas Heming, Diane Friedman, Pascal Laforêt, Marguerite Guiguet, Tarek Sharshar, Fabienne Jouen, Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Hôpital Raymond Poincaré [AP-HP], Epidémiologie, Systèmes d'Information, Modélisation, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Thérapie des maladies du muscle strié, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Raymond Poincaré [Garches], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Adult, Male, Vital capacity, medicine.medical_specialty, Exacerbation, [SDV]Life Sciences [q-bio], Health Status, Pilot Projects, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Refractory, Internal medicine, Myasthenia Gravis, medicine, Clinical endpoint, Humans, Immunologic Factors, Receptors, Cholinergic, Respiratory system, ComputingMilieux_MISCELLANEOUS, Acetylcholine receptor, Autoantibodies, Muscle Weakness, business.industry, Middle Aged, medicine.disease, Myasthenia gravis, 3. Good health, Respiratory Function Tests, 030104 developmental biology, Treatment Outcome, Neurology, Quality of Life, Rituximab, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract: Background Several retrospective case series have suggested rituximab (RTX) might improve patients with refractory Myasthenia Gravis (MG). Objective In this study, we aimed to evaluate prospectively the efficacy of RTX on muscle function in refractory generalized anti-acetylcholine receptor (AChR) MG patients. Methods Enrolled patients received 1 g of RTX at day 0, day 14, and 6-month follow-up (M6). The primary endpoint was improvement of muscle function at 12-month (M12) based on myasthenic muscle score (MMS). Secondary endpoints were an improvement of the MG Foundation of America Postintervention Status (MGFA-PIS), respiratory forced vital capacity, occurrences of acute MG exacerbation and requirement of associated immunosuppressants and immunomodulatory agents. Results Twelve patients were enrolled, and 11 completed the study. Only a single patient presented an improvement of at least 20 points on MMS at M12, although 2 patients displayed an increase of at least 18 points at M12. MGFA-PIS had improved in 55% of patients by M12. The clinical improvement was not associated with a reduction of immunosuppressant burden. Conclusions These results provide data on the effect of RTX in patients with severe, refractory anti-AChR Abs generalized MG. Even though primary outcome was only reached in a single patient at M12, a beneficial effect of RTX on muscle function was seen in half of the patients at M12 and persisted in a third of patients at M18.
Published: 2018

48. Differential Impact of T-bet and IFNγ on Pancreatic Islet Allograft Rejection

Author: Alix Besançon, Emilie Panafieu, Fabrice Valette, Sylvaine You, Lucienne Chatenoud, Tania Goncalves, and Zeynep Demir
Subjects: 0301 basic medicine, Graft Rejection, Adoptive cell transfer, Time Factors, T-Lymphocytes, Islets of Langerhans Transplantation, 03 medical and health sciences, Interferon-gamma, Islets of Langerhans, 0302 clinical medicine, Immunity, Medicine, Animals, Transcription factor, Differential impact, Mice, Knockout, Transplantation, geography, Immunity, Cellular, Mice, Inbred BALB C, geography.geographical_feature_category, Graft rejection, business.industry, Graft Survival, Islet, Allografts, Phenotype, Adoptive Transfer, Mice, Inbred C57BL, 030104 developmental biology, Allograft rejection, Immunology, Female, business, T-Box Domain Proteins, 030215 immunology
Abstract: T cell-mediated graft rejection is mostly correlated with potent Th1 responses. However, because IFNγ mice reject their graft as efficiently as wild-type (WT) mice, the exact contribution of IFNγ and its transcription factor T-bet remains a matter of debate. Here, we address this question in the context of pancreatic islet allograft to better inform the molecular pathways that hampers islet survival in vivo.Pancreatic islets from BALB/c mice were transplanted in WT, IFNγ, or T-bet C57BL/6 mice. Graft survival and the induction of effector and cytotoxic T-cell responses were monitored.Rejection of fully mismatched islet allografts correlated with high expression of both IFNγ and T-bet in WT recipients. However, allogeneic islets were permanently accepted in T-bet mice, in contrast to IFNγ hosts. Long-term survival correlated with decreased CD4 and CD8 T-cell infiltrates, drastically reduced donor-specific IFNγ and tumor necrosis factor tumor necrosis factor α responses and very low expression of the cytotoxic markers granzyme B, perforin, and FasLigand. In addition, in vitro and in vivo data pointed to an increased susceptibility of T-bet CD8 T cell to apoptosis. These observations were not reported in IFNγ mice, which have set up compensatory effector mechanisms comprising an increased expression of the transcription factor Eomes and cytolytic molecules as well as tumor necrosis factor α-mediated but not IL-4 nor IL-17-mediated allogeneic responses.Anti-islet T-cell responses require T-bet but not IFNγ-dependent programs. Our results provide new clues on the mechanisms dictating islet rejection and may help refine the therapeutic/immunosuppressive regimens applied in diabetic patients receiving islets or pancreas allografts.
Published: 2018

49. Deficiency of immunoregulatory indoleamine 2,3-dioxygenase 1 in juvenile diabetes

Author: Giada Mondanelli, Susanna Esposito, Giovanni De Giorgi, Dietmar Fuchs, M. C. Matteoli, Cinzia Antognelli, Matteo Puccetti, Luc Pilotte, Alessandra Ferretti, Maria Giulia Berioli, Benoît Van den Eynde, Marco Cappa, Davide Matino, Raffaella Scattoni, Roberta Bianchi, Cristina Cunha, Vincenzo Nicola Talesa, Paolo Puccetti, Alberto Verrotti, Elisa Albini, Luigina Romani, Maria Teresa Pallotta, Francesca Fallarino, Alberta Iacono, Silvio Bicciato, Ciriana Orabona, Ursula Grohmann, Sonia Toni, Giulia Ceccarini, Carmine Vacca, Agostinho Carvalho, Lucienne Chatenoud, Claudia Volpi, Maria Laura Belladonna, Manuel C. Lemos, [et al.], and Universidade do Minho
Subjects: 0301 basic medicine, endocrine system diseases, Autoimmunity, medicine.disease_cause, Immune tolerance, Mice, chemistry.chemical_compound, Mice, Inbred NOD, immune system diseases, Child, Indoleamine 2,3-dioxygenase, NOD mice, Diabetes, Tryptophan, General Medicine, 3. Good health, Amino acid metabolism, Immunology, Immunotherapy, Cytokines, Female, Research Article, endocrine system, Antibodies, Monoclonal, Humanized, Polymorphism, Single Nucleotide, Peripheral blood mononuclear cell, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, Tocilizumab, Diabetes mellitus, Immune Tolerance, medicine, Animals, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Genetic Association Studies, Type 1 diabetes, Science & Technology, business.industry, nutritional and metabolic diseases, medicine.disease, Receptors, Interleukin-6, Mice, Inbred C57BL, Disease Models, Animal, Diabetes Mellitus, Type 1, 030104 developmental biology, chemistry, Multivariate Analysis, Leukocytes, Mononuclear, business
Abstract: A defect in indoleamine 2,3-dioxygenase 1 (IDO1), which is responsible for immunoregulatory tryptophan catabolism, impairs development of immune tolerance to autoantigens in NOD mice, a model for human autoimmune type 1 diabetes (T1D). Whether IDO1 function is also defective in T1D is still unknown. We investigated IDO1 function in sera and peripheral blood mononuclear cells (PBMCs) from children with T1D and matched controls. These children were further included in a discovery study to identify SNPs in IDO1 that might modify the risk of T1D. T1D in children was characterized by a remarkable defect in IDO1 function. A common haplotype, associated with dysfunctional IDO1, increased the risk of developing T1D in the discovery and also confirmation studies. In T1D patients sharing such a common IDO1 haplotype, incubation of PBMCs in vitro with tocilizumab (TCZ) - an IL-6 receptor blocker - would, however, rescue IDO1 activity. In an experimental setting with diabetic NOD mice, TCZ was found to restore normoglycemia via IDO1-dependent mechanisms. Thus, functional SNPs of IDO1 are associated with defective tryptophan catabolism in human T1D, and maneuvers aimed at restoring IDO1 function would be therapeutically effective in at least a subgroup of T1D pediatric patients., The authors wish to thank patients and subjects who participated in this study, as well as nurses and staff of the Pediatric Clinic of S. Maria della Misericordia Hospital (Perugia), Juvenile Diabetes Center-Anna Meyer Children's Hospital (Florence), Unit of Endocrinology and Diabetes-'Bambino Gesu' Children's Hospital (Rome), Hopital Necker-Enfants Malades (Paris), and Diabetes and Metabolism Service-University Hospital Centre of Coimbra (Coimbra). The authors wish also to thank Roberto Gerli for the gift of TCZ, Giovanni Ricci for histologies, and Francisco Carrilho and Eduarda Coutinho for providing and processing, respectively, DNA samples from the Portuguese cohorts. This work was supported by the European Research Council (338954-DIDO to UG) and, in part, by Associazione per l'Aiuto ai Giovani con Diabete Italia e dell'Umbria (to UG) and the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013 to AC) and the Fundacao para a Ciencia e Tecnologia (contracts IF/00735/2014 to AC, and SFRH/BPD/96176/2013 to CC)., info:eu-repo/semantics/publishedVersion
Published: 2018

50. Regulation of the β-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis

Author: Yama Osmai, Lisa Perruzza, Mattias S. Dahllöf, Dan Ploug Christensen, Alexander Aivazidis, Morten Lundh, Kathrine Kronberg Jakobsen, Mirwais Osmai, Björn Tyrberg, Thomas Mandrup-Poulsen, Morten Fog-Tonnesen, Seyed Mojtaba Ghiasi, Lucienne Chatenoud, Michala Prause, and Fabio Grassi
Subjects: 0301 basic medicine, Programmed cell death, Inflammasomes, Interleukin-1beta, Apoptosis, Biochemistry, Histone Deacetylases, Cell Line, 03 medical and health sciences, Young Adult, Endocrinology, Downregulation and upregulation, NLRC4, Stress, Physiological, Insulin-Secreting Cells, Insulin Secretion, medicine, Extracellular, Animals, Humans, RNA, Messenger, Autocrine signalling, Molecular Biology, Cell Death, Chemistry, Purinergic receptor, JNK Mitogen-Activated Protein Kinases, Inflammasome, Middle Aged, Lipids, Cell biology, Rats, CARD Signaling Adaptor Proteins, 030104 developmental biology, Glucose, Cytoprotection, Potassium, Cytokines, Female, Receptors, Purinergic P2X7, medicine.drug
Abstract: β-Cells may be a source of IL-1β that is produced as inactive pro-IL-1β and processed into biologically-active IL-1β by enzymatic cleavage mediated by the NLRP1-, NLRP3- and NLRC4-inflammasomes. Little is known about the β-cell inflammasomes. NLRP1-expression was upregulated in islet-cells from T2D-patients and by IL-1β+IFNγ in INS-1 cells in a histone-deacetylase dependent manner. NLRP3 was downregulated by cytokines in INS-1 cells. NLRC4 was barely expressed and not regulated by cytokines. High extracellular K+ reduced cytokine-induced apoptosis and NO production and restored cytokine-inhibited accumulated insulin-secretion. Basal inflammasome expression was JNK1-3 dependent. Knock-down of the ASC interaction domain common for NLRP1 and 3 improved insulin secretion and ameliorated IL-1β and/or glucolipotoxicity-induced cell death and reduced cytokine-induced NO-production. Broad inflammasome-inhibition, but not NLRP3-selective inhibition, protected against IL-1β-induced INS-1 cell-toxicity. We suggest that IL-1β causes β-cell toxicity in part by NLRP1 mediated caspase-1-activation and maturation of IL-1β leading to an autocrine potentiation loop.
Published: 2018

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