97 results on '"Klatzmann, David"'
Search Results
2. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases.
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Klatzmann, David and Abbas, Abul K.
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INTERLEUKIN-2 , *AUTOIMMUNE disease treatment , *INFLAMMATORY bowel disease treatment , *CELL proliferation , *CELL differentiation , *THERAPEUTICS - Abstract
Depletion of regulatory T (TReg) cells in otherwise healthy individuals leads to multi-organ autoimmune disease and inflammation. This indicates that in a normal immune system, there are self-specific effector T cells that are ready to attack normal tissue if they are not restrained by TReg cells. The data imply that there is a balance between effector T cells and TReg cells in health and suggest a therapeutic potential of TReg cells in diseases in which this balance is altered. Proof-of-concept clinical trials, now supported by robust mechanistic studies, have shown that low-dose interleukin-2 specifically expands and activates TReg cell populations and thus can control autoimmune diseases and inflammation. [ABSTRACT FROM AUTHOR]
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- 2015
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3. State-Transition Diagrams for Biologists.
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Bersini, Hugues, Klatzmann, David, Six, Adrien, and Thomas-Vaslin, Véronique
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BIOLOGISTS , *UNIFIED modeling language , *COMPUTER software , *DIFFERENTIAL equations , *MATHEMATICAL models , *THYMOCYTES - Abstract
It is clearly in the tradition of biologists to conceptualize the dynamical evolution of biological systems in terms of statetransitions of biological objects. This paper is mainly concerned with (but obviously not limited too) the immunological branch of biology and shows how the adoption of UML (Unified Modeling Language) state-transition diagrams can ease the modeling, the understanding, the coding, the manipulation or the documentation of population-based immune software model generally defined as a set of ordinary differential equations (ODE), describing the evolution in time of populations of various biological objects. Moreover, that same UML adoption naturally entails a far from negligible representational economy since one graphical item of the diagram might have to be repeated in various places of the mathematical model. First, the main graphical elements of the UML state-transition diagram and how they can be mapped onto a corresponding ODE mathematical model are presented. Then, two already published immune models of thymocyte behavior and time evolution in the thymus, the first one originally conceived as an ODE population-based model whereas the second one as an agent-based one, are refactored and expressed in a state-transition form so as to make them much easier to understand and their respective code easier to access, to modify and run. As an illustrative proof, for any immunologist, it should be possible to understand faithfully enough what the two software models are supposed to reproduce and how they execute with no need to plunge into the Java or Fortran lines. [ABSTRACT FROM AUTHOR]
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- 2012
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4. CD4+CD25+ regulatory/suppressor T cells prevent allogeneic fetus rejection in mice
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Darasse-Jèze, Guillaume, Klatzmann, David, Charlotte, Frédéric, Salomon, Benoît L., and Cohen, José L.
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CD antigens , *T cells , *STEM cells , *AUTOANTIBODIES - Abstract
Abstract: Recent evidences indicate that naturally occurring CD4+CD25+ regulatory/suppressor T cells (Treg) regulate not only autoimmunity, but also alloreactivity. In mice, they notably control tolerance to allogeneic transplants and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Here, we studied the role of Treg in maternal tolerance to fetuses, i.e. natural semi-allogeneic grafts. We show that semi-allogeneic pregnancies in mice induce an expansion of Treg, but not of activated CD4+ and CD8+ T cells, in para-aortic lymph nodes draining fetal antigens. The treatment of female mice with an anti-CD25 antibody before mating results in depletion of Treg and expansion of activated CD4+ and CD8+ T cells solely in the draining lymph nodes, ultimately leading to fetus rejection. These observations were not made in the context of syngeneic pregnancies. Thus, Treg play a major role in maternal–fetal tolerance. [Copyright &y& Elsevier]
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- 2006
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5. In situ transduction of stromal cells and thymocytes upon intrathymic injection of lentiviral vectors.
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Marodon, Gilles and Klatzmann, David
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GENETIC transduction , *T cell differentiation , *ANTIGENS , *GENE expression , *GREEN fluorescent protein , *PROTEINS , *INFLUENZA viruses - Abstract
Background: The thymus is the primary site for T-cell development and induction of self-tolerance. Previous approaches towards manipulation of T-cell differentiation have used intrathymic injection of antigens, as proteins, cells or adenoviruses, leading to transient expression of the foreign protein. Lentiviral vectors, due to their unique ability to integrate into the genome of quiescent cells, may be best suited for long-term expression of a transgene in the thymus. Results: Young adult mice were injected in the thymus with lentiviral vectors expressing eGFP or the hemaglutinin of the Influenza virus under the control of the ubiquitous phospho glycerate kinase promoter. Thymi were examined 5 to 90 days thereafter directly under a UV-light microscope and by flow cytometry. Intrathymic injection of lentiviral vectors predominantly results in infection of stromal cells that could be detected for at least 3 months. Importantly, hemaglutinin expression by thymic stromal cells mediated negative selection of thymocytes expressing the cognate T-cell receptor. In addition and despite the low multiplicity of infection, transduced thymocytes were also detected, even 30 days after injection. Conclusions: Our results demonstrate that intrathymic delivery of a lentiviral vector is an efficient means for stable expression of a foreign gene in the thymus. This new method of gene delivery may prove useful for induction of tolerance to a specific antigen and for gene therapy of severe combined immunodeficiencies. [ABSTRACT FROM AUTHOR]
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- 2004
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6. Interleukin-2 and regulatory T cells in rheumatic diseases.
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Kolios, Antonios G. A., Tsokos, George C., and Klatzmann, David
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REGULATORY T cells , *AUTOIMMUNE diseases , *SYSTEMIC lupus erythematosus , *RHEUMATISM , *THERAPEUTICS , *CELL communication , *INTERLEUKIN-2 , *RHEUMATISM treatment - Abstract
Failure of regulatory T (Treg) cells to properly control immune responses leads invariably to autoimmunity and organ damage. Decreased numbers or impaired function of Treg cells, especially in the context of inflammation, has been documented in many human autoimmune diseases. Restoration of Treg cell fitness and/or expansion of their numbers using low-dose natural IL-2, the main cytokine driving Treg cell survival and function, has demonstrated clinical efficacy in early clinical trials. Genetically modified IL-2 with an extended half-life and increased selectivity for Treg cells is now in clinical development. Administration of IL-2 combined with therapies targeting other pathways involved in the expression of autoimmune diseases should further enhance its therapeutic potential. Ongoing clinical efforts that capitalize on the early clinical success of IL-2 treatment should bring the use of this cytokine to the forefront of biological treatments for autoimmune diseases. [ABSTRACT FROM AUTHOR]
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- 2021
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7. Abnormal neutrophil-to-lymphocyte ratio in children with autism spectrum disorder and history of maternal immune activation.
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Ellul, Pierre, Maruani, Anna, Peyre, Hugo, Vantalon, Valérie, Hoareau, Daphnée, Tiercelin, Hugo, Rosenzwajg, Michelle, Klatzmann, David, and Delorme, Richard
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MATERNAL immune activation , *CHILDREN with autism spectrum disorders , *NEUTROPHIL lymphocyte ratio , *FIRST trimester of pregnancy , *AUTISM spectrum disorders , *SECOND trimester of pregnancy - Abstract
Maternal immune activation (MIA), related to autoimmune/inflammatory diseases or acute infections, during the two first trimesters of pregnancy is a risk factor for autism spectrum disorders (ASD) in offspring. In mice, MIA has a long-term impact on offspring's immune equilibrium resulting in a pro-inflammatory phenotype. We therefore hypothesized that children with ASD and a history of MIA could display a similar phenotype specifically assessed by a higher neutrophil to lymphocyte ratio (NLR). In this study, we used a retrospective sample of 231 dyads involving children with ASD and their mothers. Among ASD patients, 12% had a history of MIA. The multivariate analysis revealed a significant association between NLR in children with ASD and maternal history of MIA (F = 2.27, p = 0.03). Using a categorical approach, we observed an abnormal NLR (over 3) in 7.4% of children with ASD MIA+ compared to 1.9% for MIA−. Our study supports the hypothesis suggesting an impact of MIA on the risk of ASD. Further studies could contribute to the development of biomarkers in MIA+ ASD and enable the development of targeted immunomodulatory therapies. [ABSTRACT FROM AUTHOR]
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- 2023
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8. Particulate antigens administrated by intranasal and intravaginal routes in a prime-boost strategy improve HIV-specific TFH generation, high-quality antibodies and long-lasting mucosal immunity.
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Vazquez, Thomas, Torrieri-Damard, Léa, Pitoiset, Fabien, Levacher, Béatrice, Vigneron, James, Mayr, Luzia, Brimaud, Faustine, Bonnet, Benjamin, Moog, Christiane, Klatzmann, David, and Bellier, Bertrand
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HUMORAL immunity , *ANTIGENS , *T helper cells , *IMMUNITY , *IMMUNOGLOBULINS , *HUMAN body - Abstract
[Display omitted] Mucosal surfaces serve as the primary entry points for pathogens such as SARS- CoV-2 coronavirus or HIV in the human body. Mucosal vaccination plays a crucial role to successfully induce long-lasting systemic and local immune responses to confer sterilizing immunity. However, antigen formulations and delivery methods must be properly selected since they are decisive for the quality and the magnitude of the elicited immune responses in mucosa. We investigated the significance of using particulate antigen forms for mucosal vaccination by comparing VLP- or protein- based vaccines in a mouse model. Based on a mucosal prime-boost immunization protocol combining (i) HIV- pseudotyped recombinant VLPs (HIV-VLPs) and (ii) plasmid DNA encoding HIV- VLPs (pVLPs), we demonstrated that combination of intranasal primes and intravaginal boosts is optimal to elicit both humoral and cellular memory responses in mucosa. Interestingly, our results show that in contrast to proteins, particulate antigens induce high-quality humoral responses characterized by a high breadth, long-term neutralizing activity and cross-clade reactivity, accompanying with high T follicular helper cell (T FH) response. These results underscore the potential of a VLP-based vaccine in effectively instigating long-lasting, HIV-specific immunity and point out the specific role of particulate antigen form in driving high-quality mucosal immune responses. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Reduction of Neutrophil Activation by Phosphodiesterase 4 Blockade in Behçet's Disease.
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Le Joncour, Alexandre, Régnier, Paul, Maciejewski‐Duval, Anna, Charles, Erwan, Barete, Stéphane, Fouret, Pierre, Rosenzwajg, Michelle, Klatzmann, David, Cacoub, Patrice, and Saadoun, David
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SMALL molecules , *BIOMARKERS , *DRUG efficacy , *FLOW cytometry , *BEHCET'S disease , *INVESTIGATIONAL drugs , *NEUTROPHILS , *CELLULAR signal transduction , *FLUORESCENT antibody technique , *GENES , *RESEARCH funding , *REACTIVE oxygen species , *PHOSPHODIESTERASE inhibitors , *PHARMACODYNAMICS , *EVALUATION - Abstract
Objective: Behçet's disease (BD) is a systemic vasculitis with inflammatory lesions mediated by cytotoxic T cells and neutrophils. Apremilast, an orally available small‐molecule drug that selectively inhibits phosphodiesterase 4 (PDE4), has been recently approved for the treatment of BD. We aimed to investigate the effect of PDE4 inhibition on neutrophil activation in BD. Methods: We studied surface markers and reactive oxygen species (ROS) production by flow cytometry, and neutrophil extracellular traps (NETs) production and molecular signature of neutrophils by transcriptome analysis before and after PDE4 inhibition. Results: Activation surface markers (CD64, CD66b, CD11b, and CD11c), ROS production, and NETosis were up‐regulated in BD patient neutrophils compared to healthy donor neutrophils. Transcriptome analysis revealed 1,021 significantly dysregulated neutrophil genes between BD patients and healthy donors. Among dysregulated genes, we found a substantial enrichment for pathways linked to innate immunity, intracellular signaling, and chemotaxis in BD. Skin lesions of BD patients showed increased infiltration of neutrophils that colocalized with PDE4. Inhibition of PDE4 by apremilast strongly inhibited neutrophil surface activation markers as well as ROS production, NETosis, and genes and pathways related to innate immunity, intracellular signaling, and chemotaxis. Conclusion: We highlight key biologic effects of apremilast on neutrophils in BD. [ABSTRACT FROM AUTHOR]
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- 2023
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10. Human thymopoiesis produces polyspecific CD8+ α/β T cells responding to multiple viral antigens.
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Quiniou, Valentin, Barennes, Pierre, Mhanna, Vanessa, Stys, Paul, Vantomme, Helene, Zhicheng Zhou, Martina, Federica, Coatnoan, Nicolas, Barbie, Michele, Hang-Phuong Pham, Clémenceau, Béatrice, Vie, Henri, Shugay, Mikhail, Six, Adrien, Brandao, Barbara, Mallone, Roberto, Mariotti-Ferrandiz, Encarnita, and Klatzmann, David
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VIRAL antigens , *T cells , *GENE rearrangement , *T cell receptors , *IMMUNE response , *CD8 antigen - Abstract
T-cell receptors (TCRs) are formed by stochastic gene rearrangements, theoretically generating >1019 sequences. They are selected during thymopoiesis, which releases a repertoire of about 108 unique TCRs per individual. How evolution shaped a process that produces TCRs that can effectively handle a countless and evolving set of infectious agents is a central question of immunology. The paradigm is that a diverse enough repertoire of TCRs should always provide a proper, though rare, specificity for any given need. Expansion of such rare T cells would provide enough fighters for an effective immune response and enough antigen-experienced cells for memory. We show here that human thymopoiesis releases a large population of clustered CD8+ T cells harboring α/β paired TCRs that (i) have high generation probabilities and (ii) a preferential usage of some V and J genes, (iii) which CDR3 are shared between individuals, and (iv) can each bind and be activated by multiple unrelated viral peptides, notably from EBV, CMV, and influenza. These polyspecific T cells may represent a first line of defense that is mobilized in response to infections before a more specific response subsequently ensures viral elimination. Our results support an evolutionary selection of polyspecific α/β TCRs for broad antiviral responses and heterologous immunity. [ABSTRACT FROM AUTHOR]
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- 2023
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11. T cells and autoimmune kidney disease.
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Suárez-Fueyo, Abel, Bradley, Sean J., Klatzmann, David, Tsokos, George C., and Suárez-Fueyo, Abel
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REJUVENESCENCE (Botany) , *KIDNEY diseases , *LYMPHOCYTES , *T cells , *PLANT growth , *ANIMALS , *AUTOANTIBODIES , *CYTOKINES , *GLOMERULONEPHRITIS , *IMMUNITY , *INFLAMMATION , *SYSTEMIC lupus erythematosus , *PHYSIOLOGY - Abstract
Glomerulonephritis is traditionally considered to result from the invasion of the kidney by autoantibodies and immune complexes from the circulation or following their formation in situ, and by cells of the innate and the adaptive immune system. The inflammatory response leads to the proliferation and dysfunction of cells of the glomerulus, and invasion of the interstitial space with immune cells, resulting in tubular cell malfunction and fibrosis. T cells are critical drivers of autoimmunity and related organ damage, by supporting B-cell differentiation and antibody production or by directly promoting inflammation and cytotoxicity against kidney resident cells. T cells might become activated by autoantigens in the periphery and become polarized to secrete inflammatory cytokines before entering the kidney where they have the opportunity to expand owing to the presence of costimulatory molecules and activating cytokines. Alternatively, naive T cells could enter the kidney where they become activated after encountering autoantigen and expand locally. As not all individuals with a peripheral autoimmune response to kidney antigens develop glomerulonephritis, the contribution of local kidney factors expressed or produced by kidney cells is probably of crucial importance. Improved understanding of the biochemistry and molecular biology of T cells in patients with glomerulonephritis offers unique opportunities for the recognition of treatment targets for autoimmune kidney disease. [ABSTRACT FROM AUTHOR]
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- 2017
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12. Erratum to “CD4+CD25+ regulatory/suppressor T cells prevent allogeneic fetus rejection in mice” [Immunol. Lett. 102 (1) (2005) 106–109]
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Darrasse-Jèze, Guillaume, Klatzmann, David, Charlotte, Frédéric, Salomon, Benoît L., and Cohen, José L.
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- 2006
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13. The Tsallis generalized entropy enhances the interpretation of transcriptomics datasets.
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Dérian, Nicolas, Pham, Hang-Phuong, Nehar-Belaid, Djamel, Tchitchek, Nicolas, Klatzmann, David, Eric, Vicaut, and Six, Adrien
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ENTROPY , *TRANSCRIPTOMES - Abstract
Background: Identifying differentially expressed genes between experimental conditions is still the gold-standard approach to interpret transcriptomic profiles. Alternative approaches based on diversity measures have been proposed to complement the interpretation of such datasets but are only used marginally. Methods: Here, we reinvestigated diversity measures, which are commonly used in ecology, to characterize mice pregnancy microenvironments based on a public transcriptome dataset. Mainly, we evaluated the Tsallis entropy function to explore the potential of a collection of diversity measures for capturing relevant molecular event information. Results: We demonstrate that the Tsallis entropy function provides additional information compared to the traditional diversity indices, such as the Shannon and Simpson indices. Depending on the relative importance given to the most abundant transcripts based on the Tsallis entropy function parameter, our approach allows appreciating the impact of biological stimulus on the inter-individual variability of groups of samples. Moreover, we propose a strategy for reducing the complexity of transcriptome datasets using a maximation of the beta diversity. Conclusions: We highlight that a diversity-based analysis is suitable for capturing complex molecular events occurring during physiological events. Therefore, we recommend their use through the Tsallis entropy function to analyze transcriptomics data in addition to differential expression analyses. [ABSTRACT FROM AUTHOR]
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- 2022
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14. Anakinra reduces lung inflammation in experimental acute lung injury.
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Engeroff, Paul, Belbézier, Aude, Monsel, Antoine, and Klatzmann, David
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PNEUMONIA , *ANAKINRA , *ADULT respiratory distress syndrome , *LUNG injuries , *KILLER cells - Abstract
Introduction: Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury (ALI) resulting in life‐threatening hypoxaemia. Although ARDS can be caused by a variety of pathogens or major trauma, it is best known as the major cause of mortality in COVID‐19 patients. Since ARDS is often associated with dysregulated inflammatory immune responses, immunomodulatory approaches represent a possible treatment option. The objective of this study was to evaluate the therapeutic potential of interleukin (IL)‐1 blockade using Anakinra in a mouse model of lipopolysaccharide (LPS)‐induced ALI. Methods: We evaluated the effects of a daily subcutaneous Anakinra treatment in a mouse model of LPS‐induced ALI. We monitored body weight to assess the general health status of the mice. Two days after ALI induction, we evaluated the inflammatory cytokine MIP‐2 as well as protein levels in bronchoalveolar lavage (BAL) fluids. Two and nine days after ALI induction, we evaluated infiltrating leukocytes in BAL fluid and lung tissue. Results: Anakinra treatment reduced ALI‐induced weight loss compared to nontreated groups. At Day 2, Anakinra treatment reduced levels of MIP‐2 and protein in BAL fluids and reduced frequencies of NK cells and neutrophils in the lung tissue. Nine days after ALI induction, Anakinra treated mice displayed reduced levels of neutrophils and alveolar macrophages in BAL fluids. Conclusions: IL‐1 blockade using Anakinra reduced classical hallmarks of inflammation in a mouse model of ALI. Our data support ongoing and future research on the evaluation of Anakinra as a potential treatment option in ARDS. [ABSTRACT FROM AUTHOR]
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- 2022
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15. Reply: Beneficial effect of interleukin-2-based immunomodulation in Alzheimer-like pathology.
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Alves, Sandro, Churlaud, Guillaume, Klatzmann, David, and Cartier, Nathalie
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INTERLEUKIN-2 , *ALZHEIMER'S disease treatment , *ALZHEIMER'S disease prevention , *THERAPEUTICS , *ALZHEIMER'S disease , *AMYLOIDOSIS , *ANIMAL experimentation , *COMPARATIVE studies , *RESEARCH methodology , *MEDICAL cooperation , *MEMORY , *MICE , *RESEARCH , *EVALUATION research ,IMMUNE system physiology - Published
- 2017
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16. Beneficial Role of Rapamycin in Experimental Autoimmune Myositis.
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Prevel, Nicolas, Allenbach, Yves, Klatzmann, David, Salomon, Benoit, and Benveniste, Olivier
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RAPAMYCIN , *AUTOIMMUNE diseases , *MYOSITIS , *T cells , *IMMUNOSUPPRESSIVE agents , *TRANSPLANTATION of organs, tissues, etc. - Abstract
Introduction: We developed an experimental autoimmune myositis (EAM) mouse model of polymyositis where we outlined the role of regulatory T (Treg) cells. Rapamycin, this immunosuppressant drug used to prevent rejection in organ transplantation, is known to spare Treg. Our aim was to test the efficacy of rapamycin in vivo in this EAM model and to investigate the effects of the drug on different immune cell sub-populations. Methods: EAM is induced by 3 injections of myosin emulsified in CFA. Mice received rapamycin during 25 days starting one day before myosin immunization (preventive treatment), or during 10 days following the last myosin immunization (curative treatment). Results: Under preventive or curative treatment, an increase of muscle strength was observed with a parallel decrease of muscle inflammation, both being well correlated (R2 = −0.645, p<0.0001). Rapamycin induced a general decrease in muscle of CD4 and CD8 T cells in lymphoid tissues, but spared B cells. Among T cells, the frequency of Treg was increased in rapamycin treated mice in draining lymph nodes (16.9±2.2% vs. 9.3±1.4%, p<0.001), which were mostly activated regulatory T cells (CD62LlowCD44high: 58.1±5.78% vs. 33.1±7%, treated vs. untreated, p<0.001). In rapamycin treated mice, inhibition of proliferation (Ki-67+) is more important in effector T cells compared to Tregs cells (p<0.05). Furthermore, during preventive treatment, rapamycin increased the levels of KLF2 transcript in CD44low CD62Lhigh naive T cell and in CD62Llow CD44high activated T cell. Conclusions: Rapamycin showed efficacy both as curative and preventive treatment in our murine model of experimental myositis, in which it induced an increase of muscle strength with a parallel decrease in muscle inflammation. Rapamycin administration was also associated with a decrease in the frequency of effector T cells, an increase in Tregs, and, when administered as preventive treatment, an upregulation of KFL2 in naive and activated T cells. [ABSTRACT FROM AUTHOR]
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- 2013
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17. Regulatory T lymphocytes/Th17 lymphocytes imbalance in autism spectrum disorders: evidence from a meta-analysis.
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Ellul, Pierre, Rosenzwajg, Michelle, Peyre, Hugo, Fourcade, Gwladys, Mariotti-Ferrandiz, Encarnita, Trebossen, Vincent, Klatzmann, David, and Delorme, Richard
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REGULATORY T cells , *AUTISM spectrum disorders , *LYMPHOCYTE subsets , *PATHOLOGICAL physiology , *LYMPHOCYTES - Abstract
Background: Immune system dysfunction has been proposed to play a critical role in the pathophysiology of autism spectrum disorders (ASD). Conflicting reports of lymphocyte subpopulation abnormalities have been described in numerous studies of patients with ASD. To better define lymphocytes abnormalities in ASD, we performed a meta-analysis of the lymphocyte profiles from subjects with ASD. Methods: We used the PRISMA recommendations to query PubMed, Embase, PsychoINFO, BIOSIS, Science Direct, Cochrane CENTRAL, and Clinicaltrials.gov for terms related to clinical diagnosis of ASD and to lymphocytes' populations. We selected studies exploring lymphocyte subpopulations in children with ASD. The search protocol has been registered in the international Prospective Register of Systematic Reviews (CRD42019121473). Results: We selected 13 studies gathering 388 ASD patients and 326 healthy controls. A significant decrease in the CD4+ lymphocyte was found in ASD patients compared to controls [− 1.51 (95% CI − 2.99; − 0.04) p = 0.04] (I2 = 96% [95% CI 94.6, 97.7], p < 0.01). No significant difference was found for the CD8+ T, B and natural killer lymphocytes. Considering the CD4+ subpopulation, there was a significant decrease in regulatory T lymphocytes (Tregs) in ASD patients (n = 114) compared to controls (n = 107) [− 3.09 (95% CI − 4.41; − 1.76) p = 0.0001]; (I2 = 90.9%, [95% CI 76.2, 96.5], p < 0.0001) associated with an increase oin the Th17 lymphocytes (ASD; n = 147 controls; n = 128) [2.23 (95% CI 0.79; 3.66) p = 0,002] (I2 = 95.1% [95% CI 90.4, 97.5], p < 0.0001). Limitations: Several factors inducing heterogeneity should be considered. First, differences in the staining method may be responsible for a part in the heterogeneity of results. Second, ASD population is also by itself heterogeneous, underlying the need of studying sub-groups that are more homogeneous. Conclusion: Our meta-analysis indicates defects in CD4+ lymphocytes, specifically decrease oin Tregs and increase in Th17 in ASD patients and supports the development of targeted immunotherapies in the field of ASD. [ABSTRACT FROM AUTHOR]
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- 2021
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18. Fever during pregnancy as a risk factor for neurodevelopmental disorders: results from a systematic review and meta-analysis.
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Antoun, Stephanie, Ellul, Pierre, Peyre, Hugo, Rosenzwajg, Michelle, Gressens, Pierre, Klatzmann, David, and Delorme, Richard
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NEURAL development , *FEVER , *MATERNAL immune activation , *PREGNANCY , *MATERNAL exposure - Abstract
Background: Fever during pregnancy is a relatively common and most often trivial event. However, under specific conditions, it could affect significantly fetal brain development. Few studies, with inconsistent results, investigated whether fever, regardless the pathogen, could represent a risk factor for neurodevelopmental disorders (NDD) in the offspring. We aimed to explore further this question by performing a systematic review and meta-analysis. Methods: Peer-reviewed studies exploring the occurrence of NDD in offspring after a fetal exposure to maternal fever were included. We specifically considered the impact of fever severity and duration, taking into consideration some confounding variables such as the use of antipyretic during pregnancy, the trimester in which the fever arose, the maternal age or smoking at time of gestation. MEDLINE, EMBASE, PsycINFO, Cochrane and Web of Science were searched without language restriction. PRISMA recommendations were followed. Odds ratio (OR) were pooled using random-effects meta-analysis. Heterogeneity in effect size across studies was studied using random-effects meta-regression analysis. (PROSPERO CRD42020182801). Results: We finally considered ten studies gathering a total of 10,304 children with NDD. Among them, 1394 were exposed to fever during pregnancy. The selected studies were divided into 5 case–control studies and 5 cohort studies. Maternal exposure to fever during pregnancy increased the risk of NDD in offspring with an OR of 1.24 [95% CI: 1.12–1.38]. Secondary analysis revealed an increased risk for NDD when fever occurred during the first trimester of gestation [OR 1.13–95% CI: 1.02–1.26]. Limitations: We excluded studies that considered infections with no evidence of fever. Another potential limitation may be the possible heterogeneity between study designs (cohorts and case–control). Conclusion: Additional evidence supported the association between fever during pregnancy and increased risk for NDD in offspring. Careful monitoring should be considered for children born from mothers with a febrile episode during pregnancy (specifically during the first trimester). [ABSTRACT FROM AUTHOR]
- Published
- 2021
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19. Transgene amplification and persistence after delivery of retroviral vector and packaging functions with E1/E4-deleted adenoviruses.
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Torrent, Christophe, Jullien, Carole, Klatzmann, David, Perricaudet, Michel, and Yeh, Patrice
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GENE amplification , *RETROVIRUSES , *ADENOVIRUSES , *GENE therapy - Abstract
Adenovirus DNA is rapidly lost in actively dividing cells. In addition, first-generation (E1-defective) vectors trigger a strong cytotoxicity that impairs the duration of transgene expression. To solve these issues, we have developed a chimeric vector system that uses E1/E4 doubly defective adenoviruses for efficient production of infectious retroviral vectors. The retroviral vector sequences and packaging functions were split into two E1/E3/E4-deleted adenoviral vectors: the Moloney murine leukemia virus gag-pol cistron was expressed from the human EF1 α (elongation factor) promoter (AdGAG/POL), whereas the thymidine kinase transgene, embedded in a retroviral vector context, and an amphotropic retroviral envelope cassette were included within a second adenovirus (AdTK/ENV). This chimeric vector system was evaluated with a special emphasis on recombinant retrovirus production in vitro, as well as transgene amplification and persistence in vivo. Retrovirus titers of >10[sup 5] infectious units/mL were routinely obtained in W162 cells coinfected with both recombinant adenoviruses. Long-term transgene persistence (up to 3 months) was demonstrated in vitro in two different cell lines coinfected with AdGAG/POL and AdTK/ENV, and correlated with the detection of specific provirus sequences. A 10- to 50-fold transgene amplification also was demonstrated in an in vivo tumor model infected with the Ad/Rt chimeric vector system. The chimeric vector system described herein combines the efficiency of gene delivery by recombinant adenoviruses with the integrative properties of infectious retroviral vectors. This versatile vector system may open up new avenues for efficient production of oncogenic, but also non-oncogenic, retroviruses from cells of non-murine origin. [ABSTRACT FROM AUTHOR]
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- 2000
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20. Low dose IL-2 in patients with steroid-dependent dysimmune manifestations associated with myelodysplastic syndromes: a three-case report.
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Corfmat, Marion, Willekens, Christophe, Vinit, Julien, Bussone, Guillaume, Fenaux, Pierre, Fain, Olivier, Klatzmann, David, Mekinian, Arsene, Comont, Thibault, and malignancies), MINHEMON (French network of dysimmune disorders associated to hematological
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STEROID drugs , *MYELODYSPLASTIC syndromes , *DISEASE progression , *INTERLEUKIN-2 , *SYSTEMIC inflammatory response syndrome , *TREATMENT effectiveness , *IMMUNOLOGIC diseases , *T cells , *DRUG side effects , *DISEASE complications , *SYMPTOMS , *EVALUATION - Abstract
Objectives Systemic inflammatory and autoimmune diseases can be associated with myelodysplastic syndromes. Current treatments (steroids, immunosuppressive agents, biologics) are unsatisfactory because of their low response rate, dependence or adverse events. We aimed at evaluating the effects of low doses of IL-2 (ld-IL2) as a regulatory T-cell inducer in this context. Methods We treated three patients with ld-IL2 with myelodysplastic syndromes and an associated dysimmune disorder (polymyalgia rheumatic, relapsing polychondritis associated with Sweet's syndrome and vasculitis with cutaneous and joint involvement, respectively). All three patients were dependent on steroids and refractory to biologics or azacitidine. They received doses of 1–1.5 million units of proleukin/day during 5 days and then every fortnight. Results The treatment led to a clinical improvement and steroid sparing in 2/3 patients with no serious adverse events, and no progression of the disease. Conclusion Our results support the investigation of ld-IL2 in MDS associated with immune disorders in controlled clinical studies. [ABSTRACT FROM AUTHOR]
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- 2021
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21. Impaired Activated/Memory Regulatory T Cell Clonal Expansion Instigates Diabetes in NOD Mice.
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Mhanna, Vanessa, Fourcade, Gwladys, Barennes, Pierre, Quiniou, Valentin, Pham, Hang P., Ritvo, Paul-Gydeon, Brimaud, Faustine, Gouritin, Bruno, Churlaud, Guillaume, Six, Adrien, Mariotti-Ferrandiz, Encarnita, and Klatzmann, David
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REGULATORY T cells , *CLONE cells , *T cells , *MICE , *LABORATORY mice , *RESEARCH , *INTERLEUKIN-2 , *ANIMAL experimentation , *RESEARCH methodology , *CELL receptors , *TYPE 1 diabetes , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies - Abstract
Regulatory T cell (Treg) insufficiency licenses the destruction of insulin-producing pancreatic β-cells by autoreactive effector T cells (Teffs), causing spontaneous autoimmune diabetes in NOD mice. We investigated the contribution to diabetes of the T-cell receptor (TCR) repertoires of naive regulatory T cells (nTregs), activated/memory Tregs (amTregs), and CD4+ Teffs from prediabetic NOD mice and normal C57BL/6 (B6) mice. NOD mice amTreg and Teff repertoire diversity was unexpectedly higher than that of B6 mice. This was due to the presence of highly expanded clonotypes in B6 amTregs and Teffs that were largely lost in their NOD counterparts. Interleukin-2 (IL-2) administration to NOD mice restored such amTreg clonotype expansions and prevented diabetes development. In contrast, IL-2 administration only led to few or no clonotype expansions in nTregs and Teffs, respectively. Noteworthily, IL-2-expanded amTreg and nTreg clonotypes were markedly enriched in islet-antigen specific TCRs. Altogether, our results highlight the link between a reduced clonotype expansion within the activated Treg repertoire and the development of an autoimmune disease. They also indicate that the repertoire of amTregs is amenable to rejuvenation by IL-2. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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22. Benchmarking of T cell receptor repertoire profiling methods reveals large systematic biases.
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Barennes, Pierre, Quiniou, Valentin, Shugay, Mikhail, Egorov, Evgeniy S., Davydov, Alexey N., Chudakov, Dmitriy M., Uddin, Imran, Ismail, Mazlina, Oakes, Theres, Chain, Benny, Eugster, Anne, Kashofer, Karl, Rainer, Peter P., Darko, Samuel, Ransier, Amy, Douek, Daniel C., Klatzmann, David, and Mariotti-Ferrandiz, Encarnita
- Abstract
Monitoring the T cell receptor (TCR) repertoire in health and disease can provide key insights into adaptive immune responses, but the accuracy of current TCR sequencing (TCRseq) methods is unclear. In this study, we systematically compared the results of nine commercial and academic TCRseq methods, including six rapid amplification of complementary DNA ends (RACE)-polymerase chain reaction (PCR) and three multiplex-PCR approaches, when applied to the same T cell sample. We found marked differences in accuracy and intra- and inter-method reproducibility for T cell receptor α (TRA) and T cell receptor β (TRB) TCR chains. Most methods showed a lower ability to capture TRA than TRB diversity. Low RNA input generated non-representative repertoires. Results from the 5′ RACE-PCR methods were consistent among themselves but differed from the RNA-based multiplex-PCR results. Using an in silico meta-repertoire generated from 108 replicates, we found that one genomic DNA-based method and two non-unique molecular identifier (UMI) RNA-based methods were more sensitive than UMI methods in detecting rare clonotypes, despite the better clonotype quantification accuracy of the latter. A comparison of T cell receptor repertoire profiling methods shows substantial differences in their outputs. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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23. Immunomodulatory role of Interleukin-33 in large vessel vasculitis.
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Desbois, Anne-Claire, Cacoub, Patrice, Leroyer, Aurélie S., Tellier, Edwige, Garrido, Marlène, Maciejewski-Duval, Anna, Comarmond, Cloé, Barete, Stéphane, Arock, Michel, Bruneval, Patrick, Launay, Jean-Marie, Fouret, Pierre, Blank, Ulrich, Rosenzwajg, Michelle, Klatzmann, David, Jarraya, Mohamed, Cluzel, Philippe, Koskas, Fabien, Kaplanski, Gilles, and Saadoun, David
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INTERLEUKIN-33 , *NATURAL immunity , *CYTOKINES , *T cells , *REVERSE transcriptase polymerase chain reaction - Abstract
The mechanisms regulating inflammation in large vessels vasculitis (LVV) are poorly understood. Interleukin 33 (IL-33) has been shown to license innate and adaptive immunity by enhancing Th2 cytokines production. We aimed to examine the role of IL-33 in the immunomodulation of T cell activation in LVV. T cell homeostasis and cytokines production were determined in peripheral blood from 52 patients with giant cell arteritis (GCA) and 50 healthy donors (HD), using Luminex assay, flow cytometry, quantitative RT-PCR and by immunofluorescence analysis in inflammatory aorta lesions. We found increased level of IL-33 and its receptor ST2/IL-1R4 in the serum of patient with LVV. Endothelial cells were the main source of IL-33, whereas Th2 cells, Tregs and mast cells (MC) express ST2 in LVV vessels. IL-33 had a direct immunomodulatory impact by increasing Th2 and Tregs. IL-33 and MC further enhanced Th2 and regulatory responses by inducing a 6.1 fold increased proportion of Tregs (p = 0.008). Stimulation of MC by IL-33 increased indoleamine 2 3-dioxygenase (IDO) activity and IL-2 secretion. IL-33 mRNA expression was significantly correlated with the expression of IL-10 and TGF-β within aorta inflammatory lesions. To conclude, our findings suggest that IL-33 may exert a critical immunoregulatory role in promoting Tregs and Th2 cells in LVV. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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24. Pre-treatment with IL2 gene therapy alleviates Staphylococcus aureus arthritis in mice.
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Bergmann, Berglind, Fei, Ying, Jirholt, Pernilla, Hu, Zhicheng, Bergquist, Maria, Ali, Abukar, Lindholm, Catharina, Ekwall, Olov, Churlaud, Guillaume, Klatzmann, David, Jin, Tao, and Gjertsson, Inger
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GENE therapy , *STAPHYLOCOCCUS aureus , *SUPPRESSOR cells , *ARTHRITIS , *JOINT diseases - Abstract
Background: Staphylococcus aureus (S. aureus) arthritis is one of the most detrimental joint diseases known and leads to severe joint destruction within days. We hypothesized that the provision of auxiliary immunoregulation via an expanded compartment of T regulatory cells (Tregs) could dampen detrimental aspects of the host immune response whilst preserving its protective nature. Administration of low-dose interleukin 2 (IL2) preferentially expands Tregs, and is being studied as a treatment choice in several autoimmune conditions. We aimed to evaluate the role of IL2 and Tregs in septic arthritis using a well-established mouse model of haematogenously spred S. aureus arthritis.Methods: C57BL/6 or NMRI mice we intravenously (iv) injected with a defined dose of S. aureus LS-1 or Newman and the role of IL2 and Tregs were assessed by the following approaches: IL2 was endogenously delivered by intraperitoneal injection of a recombinant adeno-associated virus vector (rAAV) before iv S. aureus inoculation; Tregs were depleted before and during S. aureus arthritis using antiCD25 antibodies; Tregs were adoptively transferred before induction of S. aureus arthritis and finally, recombinant IL2 was used as a treatment starting day 3 after S. aureus injection. Studied outcomes included survival, weight change, bacterial clearance, and joint damage.Results: Expansion of Tregs induced by IL2 gene therapy prior to disease onset does not compromise host resistance to S. aureus infection, as the increased proportions of Tregs reduced the arthritis severity as well as the systemic inflammatory response, while simultaneously preserving the host's ability to clear the infection.Conclusions: Pre-treatment with IL2 gene therapy dampens detrimental immune responses but preserves appropriate host defense, which alleviates S. aureus septic arthritis in a mouse model. [ABSTRACT FROM AUTHOR]- Published
- 2020
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25. T regulatory cells activation and distribution are modified in critically ill patients with acute respiratory distress syndrome: A prospective single-centre observational study.
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Halter, Sebastien, Aimade, Lucrèce, Barbié, Michèle, Brisson, Hélène, Rouby, Jean-Jacques, Langeron, Olivier, Klatzmann, David, Rosenzwajg, Michelle, and Monsel, Antoine
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ADULT respiratory distress syndrome , *SUPPRESSOR cells , *CRITICALLY ill , *INTENSIVE care units - Abstract
Acute respiratory distress syndrome (ARDS) is a common and fatal inflammatory condition. Whether T regulatory cells (Tregs) are beneficial or detrimental remains controversial, and longitudinal studies are lacking. Phenotyping of Tregs activation markers has been poorly reported. We aimed to evaluate quantitative and functional alterations in blood and bronchoalveolar Treg phenotype of ARDS patients. We performed a single-centre observational study in a French intensive care unit. The study enrolled 60 ARDS and 45 non-ARDS patients. Patients under 18 years old or with immunosuppression (native or acquired) were excluded. Tregs phenotypes were assessed by flow cytometry, while cytokines were measured by multiplex-based assays in blood and bronchoalveolar samples collected over 3 weeks after the onset of ARDS. Blood Tregs/CD4+ percentage (median %, 25–75% interquartile) was higher in ARDS patients than in non-ARDS patients: 12.1% [9.0–16.0] versus 9.9% [8.1–12.6], P = 0.01. Alveolar Tregs/CD4+ percentage was lower in ARDS patients than in non-ARDS patients: 10.4% [6.3–16.6] versus 16.2% [12.4–21.1], P = 0.03. In ARDS patients, Tregs activation was reduced in the blood and increased in the alveolus, compared to non-ARDS patients. ROC analysis revealed a threshold of 10.4% for the Tregs/CD4+ percentage in the blood collected within the first week of ARDS to discriminate between survivors and non-survivors (sensitivity: 75%; specificity 76%; area under the curve [95% confidence interval]: 0.72 [0.5–0.9]). Quantitative and functional alterations in Treg phenotype were observed in patients with ARDS. Whether rebalancing Tregs phenotype with therapeutic interventions would be beneficial deserves further investigations. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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26. TLR9 signalling in HCV-associated atypical memory B cells triggers Th1 and rheumatoid factor autoantibody responses.
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Comarmond, Cloé, Lorin, Valérie, Marques, Cindy, Maciejewski-Duval, Anna, Joher, Nizar, Planchais, Cyril, Touzot, Maxime, Biard, Lucie, Hieu, Thierry, Quiniou, Valentin, Desbois, Anne-Claire, Rosenzwajg, Michelle, Klatzmann, David, Cacoub, Patrice, Mouquet, Hugo, and Saadoun, David
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B cells , *TH1 cells , *RHEUMATOID factor , *SUPPRESSOR cells , *ANTIBODY diversity , *PAIN tolerance - Abstract
• TLR9 activation of atypical memory B cells (AtM) has a central role in breaking tolerance in patients with HCV-CV. • TLR9 signaling on AtMs stimulates proliferation and activation of effector Th1 cells by secreting TNFα. • Rheumatoid factors produced by AtMs recognized distinct IgG-Fc epitopes and did not cross-react against HCV proteins. • AtMs largely disappear after antigen removal by DAA therapy. Hepatitis C virus (HCV) infection contributes to the development of autoimmune disorders such as cryoglobulinaemia vasculitis (CV). However, it remains unclear why only some individuals with HCV develop HCV-associated CV (HCV-CV). HCV-CV is characterized by the expansion of anergic CD19+CD27+CD21low/− atypical memory B cells (AtMs). Herein, we report the mechanisms by which AtMs participate in HCV-associated autoimmunity. The phenotype and function of peripheral AtMs were studied by multicolour flow cytometry and co-culture assays with effector T cells and regulatory T cells in 20 patients with HCV-CV, 10 chronically HCV-infected patients without CV and 8 healthy donors. We performed gene expression profile analysis of AtMs stimulated or not by TLR9. Immunoglobulin gene repertoire and antibody reactivity profiles of AtM-expressing IgM antibodies were analysed following single B cell FACS sorting and expression-cloning of monoclonal antibodies. The Tbet+CD11c+CD27+CD21− AtM population is expanded in patients with HCV-CV compared to HCV controls without CV. TLR9 activation of AtMs induces a specific transcriptional signature centred on TNFα overexpression, and an enhanced secretion of TNFα and rheumatoid factor-type IgMs in patients with HCV-CV. AtMs stimulated through TLR9 promote type 1 effector T cell activation and reduce the proliferation of CD4+CD25hiCD127−/lowFoxP3+ regulatory T cells. AtM expansions display intraclonal diversity with immunoglobulin features of antigen-driven maturation. AtM-derived IgM monoclonal antibodies do not react against ubiquitous autoantigens or HCV antigens including NS3 and E2 proteins. Rather, AtM-derived antibodies possess rheumatoid factor activity and target unique epitopes on the human IgG-Fc region. Our data strongly suggest a central role for TLR9 activation of AtMs in driving HCV-CV autoimmunity through rheumatoid factor production and type 1 T cell responses. B cells are best known for their capacity to produce antibodies, which often play a deleterious role in the development of autoimmune diseases. During chronic hepatitis C, self-reactive B cells proliferate and can be responsible for autoimmune symptoms (arthritis, purpura, neuropathy, renal disease) and/or lymphoma. Direct-acting antiviral therapy clears the hepatitis C virus and eliminates deleterious B cells. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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27. Children with a history of both maternal immune activation and prematurity are not at increased risk of ADHD symptoms.
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Ellul, Pierre, Wallez, Solène, Acquaviva, Eric, Rosenzwajg, Michelle, Klatzmann, David, Delorme, Richard, and Melchior, Maria
- Abstract
Maternal autoimmune diseases (AID) are risk factors for Attention Deficit Hyperactivity Disorder (ADHD). Animal studies suggest that maternal immune activation (MIA) is a disease primer for ADHD, with second environmental factor precipitating the onset of the disease. Prematurity is also a major risk factor for ADHD. In this study, we sought to explore the interaction between parental AID and prematurity on ADHD risk in a community sample. Children of AID parents born prematurely appeared at increased odds of ADHD but these two risk factors do not appear to be additive (OR 1.39 [95 CI 0.75; 2.46]). Longitudinal studies with larger numbers of participants are needed. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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28. 14:50-15:10 On Tregs, IL-2 and pregnancy.
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Florez, Laura, Rosenzwajg, Michelle, Mekinian, Arsene, and Klatzmann, David
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REGULATORY T cells , *RECURRENT miscarriage , *FETAL development , *PREGNANCY - Abstract
Regulatory T cells (Treg) play a key and at least dual role in successful pregnancy. Experimental Treg depletion in mice leads to increased fetus loss as well as decreased fetus growth. Fetus loss is explained by the key suppressive role of Tregs in maternal-fetal tolerance. Fetus growth restriction is explained by a newly discovered trophic function of a previously undescribed population of uterine resident Tregs. These observations suggest that boosting Tregs may prevent recurrent spontaneous abortion. As we showed that low-dose interleukin-2 (IL-2 LD) is selectively boosting Tregs, and thus improving various immune condition related to a Treg insufficiency, we initiated an open clinical trial of IL-2 LD in women with recurrent spontaneous abortion of presumably immunological cause. We will present the rationale and the early clinical results of this study. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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29. 14:10-14:30 Dendritic cells and Tregs interplay at the maternal-fetal interface.
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Darrasse-Jèze, Guillaume, Ghouma, Myriam, Laboureur, Rebecca, Podsypanina, Katrina, Mékinian, Arsène, Lédée, Nathalie, and Klatzmann, David
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DENDRITIC cells , *REGULATORY T cells , *EMBRYO implantation , *PREGNANCY outcomes , *RECURRENT miscarriage - Abstract
Successful pregnancies depend on maternal-fetal tolerance. Understanding the immune mechanisms of infertility and recurrent miscarriage is mandatory to improve care. We previously established that maternal CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) are necessary to protect the fetus from maternal immune response (1). We also discovered that self-specific thymic-derived Tregs accumulate in the uterus-draining lymph nodes (LNs) and uterus and protect embryos at implantation (2, 3). These cells are dependent on antigen-presenting cells and especially on dendritic cells (DCs), the immune sentinels that capture, process and present self and foreign antigens to T cells in order to initiate immune response or promote immune tolerance depending on the context. Unfortunately, little is known about the DCs of the maternofetal interface and their role in normal or pathological pregnancy. We examined the dynamics of Dendritic Cells (DCs) subsets from pregnant and non-pregnant mice and humans during normal or pathological pregnancies, and we investigated the consequences of DCs deficiency on pregnancy in genetically-modified mice and in humans. We show how DCs influence the homeostasis of Treg cells as well as the homeostasis of Natural Killer (NK) cells during pregnancy. We also show and discuss how the modulation of the homeostasis of specific DC subsets affects the outcome of pregnancy and can be used to cure implantation failure and multiple miscarriages. Our results may help to improve prenatal diagnosis and serve as a foundation for designing innovative biotherapies for patients with infertility problems and multiple miscarriages. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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30. Comparison of Dendritic Cell Activation by Virus-Based Vaccine Delivery Vectors Emphasizes the Transcriptional Downregulation of the Oxidative Phosphorylation Pathway.
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Tsitoura, Eliza, Kazazi, Dorothea, Oz-Arslan, Devrim, Sever, Elif Arik, Khalili, Shirin, Vassilaki, Niki, Aslanoglou, Elina, Dérian, Nicolas, Six, Adrien, Sezerman, Osman Ugur, Klatzmann, David, and Mavromara, Penelope
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OXIDATIVE phosphorylation , *DENDRITIC cells , *VACCINES , *VIRUS-like particles , *DOWNREGULATION , *CELL membranes - Abstract
Antigen delivery platforms based on engineered viruses or virus-like particles are currently developed as vaccines against infectious diseases. As the interaction of vaccines with dendritic cells (DCs) shapes the immunological response, we compared the interaction of a range of virus-based vectors and virus-like particles with DCs in a murine model of systemic administration and transcriptome analyses of splenic DCs. The transcriptome profiles of DCs separated the vaccine vectors into two distinct groups characterized by high- and low-magnitude differential gene expression, which strongly correlated with (1) the surface expression of costimulatory molecules CD40, CD83, and CD86 on DCs, and (2) antigen-specific T-cell responses. Pathway analysis using PANOGA (Pathway and Network-Oriented GWAS Analysis) revealed that the JAK/STAT pathway was significantly activated by both groups of vaccines. In contrast, the oxidative phosphorylation pathway was significantly downregulated only by the high-magnitude DC-stimulating vectors. A gene signature including exclusively chemokine-, cytokine-, and receptor-related genes revealed a vector-specific pattern. Overall, this in vivo DC stimulation model demonstrated a strong relationship between the levels of induced DC maturation and the intensity of T-cell-specific immune responses with a distinct cytokine/chemokine profile, metabolic shifting, and cell surface expression of maturation markers. It could represent an important tool for vaccine design. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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31. High-resolution repertoire analysis reveals a major bystander activation of Tfh and Tfr cells.
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Ritvo, Paul-Gydeon, Saadawi, Ahmed, Barennes, Pierre, Quiniou, Valentin, Chaara, Wahiba, El Soufi, Karim, Bonnet, Benjamin, Six, Adrien, Shugay, Mikhail, Mariotti-Ferrandiz, Encarnita, and Klatzmann, David
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T cells , *T helper cells , *LYMPHOCYTES , *FOLLICULAR dendritic cells , *ANTIGEN presenting cells - Abstract
T follicular helper (Tfh) and regulatory (Tfr) cells are terminally differentiated cells found in germinal centers (GCs), specialized secondary lymphoid organ structures dedicated to antibody production. As such, follicular T (Tfol) cells are supposed to be specific for immunizing antigens, which has been reported for Tfh cells but is debated for Tfr cells. Here, we used high-throughput T cell receptor (TCR) sequencing to analyze the repertoires of Tfh and Tfr cells, at homeostasis and after immunization with self- or foreign antigens. We observed that, whatever the conditions, Tfh and Tfr cell repertoires are less diverse than those of effector T cells and Treg cells of the same tissues; surprisingly, these repertoires still represent thousands of different sequences, even after immunization with a single antigen that induces a 10-fold increase in Tfol cell numbers. Thorough analysis of the sharing and network of TCR sequences revealed that a specific response to the immunizing antigen can only, but hardly, be detected in Tfh cells immunized with a foreign antigen and Tfr cells immunized with a self-antigen. These antigen-specific responses are obscured by a global stimulation of Tfh and Tfr cells that appears to be antigen-independent. Altogether, our results suggest a major bystander Tfol cell activation during the immune response in the GCs. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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32. Retrovirus-Based Virus-Like Particle Immunogenicity and Its Modulation by Toll-Like Receptor Activation.
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Pitoiset, Fabien, Vazquez, Thomas, Levacher, Beatrice, Nehar-Belaid, Djamel, Dérian, Nicolas, Vigneron, James, Klatzmann, David, and Bellier, Bertrand
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VIRUS-like particles , *IMMUNOGENETICS , *IMMUNE response , *RETROVIRUS genetics , *TOLL-like receptors - Abstract
Retrovirus-derived virus-like particles (VLPs) are particularly interesting vaccine platforms, as they trigger efficient humoral and cellular immune responses and can be used to display heterologous antigens. In this study, we characterized the intrinsic immunogenicity of VLPs and investigated their possible adjuvantization by incorporation of Toll-like receptor (TLR) ligands. We designed a noncoding single-stranded RNA (ncRNA) that could be encapsidated by VLPs and induce TLR7/8 signaling. We found that VLPs efficiently induce in vitro dendritic cell activation, which can be improved by ncRNA encapsidation (ncRNAVLPs). Transcriptome studies of dendritic cells harvested from the spleens of immunized mice identified antigen presentation and immune activation as the main gene expression signatures induced by VLPs, while TLR signaling and Th1 signatures characterize ncRNAVLPs. In vivo and compared with standard VLPs, ncRNAVLPs promoted Th1 responses and improved CD8+ T cell proliferation in a MyD88-dependent manner. In an HIV vaccine mouse model, HIV-pseudotyped ncRNAVLPs elicited stronger antigen-specific cellular and humoral responses than VLPs. Altogether, our findings provide molecular evidence for a strong vaccine potential of retrovirus-derived VLPs that can be further improved by harnessing TLR-mediated immune activation. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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33. Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: results from the AGENT-HF randomized phase 2 trial.
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Hulot, Jean-Sébastien, Salem, Joe-Elie, Redheuil, Alban, Collet, Jean-Philippe, Varnous, Shaida, Jourdain, Patrick, Logeart, Damien, Gandjbakhch, Estelle, Bernard, Claude, Hatem, Stéphane N., Isnard, Richard, Cluzel, Philippe, Le Feuvre, Claude, Leprince, Pascal, Hammoudi, Nadjib, Lemoine, François M., Klatzmann, David, Vicaut, Eric, Komajda, Michel, and Montalescot, Gilles
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ENDOPLASMIC reticulum , *GENETIC transformation , *HEART failure , *CARDIAC imaging , *SARCOPLASMIC reticulum , *ADENOSINE triphosphatase , *DRUG therapy for heart diseases , *HEART disease diagnosis , *CARRIER proteins , *COMPARATIVE studies , *CORONARY arteries , *GENE therapy , *HEART diseases , *RESEARCH methodology , *MEDICAL cooperation , *RESEARCH , *EVALUATION research , *VENTRICULAR remodeling , *RANDOMIZED controlled trials , *TREATMENT effectiveness , *BLIND experiment , *INTRA-arterial infusions - Abstract
Aims: Restoration of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2a) activity through gene transfer improved cardiac function in experimental and pilot studies in humans with heart failure. The AGENT-HF (NCT01966887) trial investigated the impact of adeno-associated virus (AAV1)/SERCA2a on ventricular remodelling using multimodality non-invasive cardiac imaging.Methods and Results: AGENT-HF was a single centre, randomized, double-blind, placebo-controlled trial in adult patients with NYHA class III-IV ischaemic or non-ischaemic heart failure and left ventricular ejection fraction ≤35%. Eligible patients were randomized to receive a single intracoronary infusion of either 1 × 1013 DNase-resistant particles of AAV1/SERCA2a or placebo. The primary endpoint was change in left ventricular end-systolic volume (LVESV), measured by cardiac computed tomography at 6 month follow-up. We planned to include 40 patients but the trial was terminated prematurely as the sponsor suspended further enrolment following neutral results of the CUPID-2 outcome trial. At the time of termination, nine patients were randomized with five patients infused with AAV1/SERCA2a and four with placebo. At 6 months, LVESV was increased in both groups compared with baseline: median (interquartile range) in AAV1/SERCA2a vs. placebo: 13 (13;14) mL vs. 3.5 (-36;36) mL, P = 0.74, with a mean difference between groups of 11.4 mL in favour of placebo. No safety issues were noted.Conclusion: AGENT-HF failed to demonstrate any improvement in ventricular remodelling in response to AAV1/SERCA2a at the dose studied. However, because of premature termination, the study was underpowered to demonstrate an effect of AAV1/SERCA2a and these data should be interpreted with caution. [ABSTRACT FROM AUTHOR]- Published
- 2017
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- View/download PDF
34. Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: results from the AGENT-HF randomized phase 2 trial.
- Author
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Hulot, Jean-Sébastien, Salem, Joe-Elie, Redheuil, Alban, Collet, Jean-Philippe, Varnous, Shaida, Jourdain, Patrick, Logeart, Damien, Gandjbakhch, Estelle, Bernard, Claude, Hatem, Stéphane N., Isnard, Richard, Cluzel, Philippe, Le Feuvre, Claude, Leprince, Pascal, Hammoud, Nadjib, Lemoine, François M., Klatzmann, David, Vicaut, Eric, Komajda, Michel, and Montalescot, Gilles
- Subjects
- *
HEART radiography , *HEART failure treatment , *CARRIER proteins , *COMPUTED tomography , *DNA viruses , *GENE therapy , *CARDIAC patients , *PROTEINS , *STATISTICAL sampling , *VENTRICULAR remodeling , *RANDOMIZED controlled trials , *TREATMENT effectiveness , *BLIND experiment , *DESCRIPTIVE statistics , *STROKE volume (Cardiac output) , *VENTRICULAR ejection fraction - Abstract
Aims Restoration of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2a) activity through gene transfer improved cardiac function in experimental and pilot studies in humans with heart failure. The AGENT-HF (NCT01966887) trial investigated the impact of adeno-associated virus (AAV1)/SERCA2a on ventricular remodelling using multimodality non-invasive cardiac imaging. Methods and results AGENT-HF was a single centre, randomized, double-blind, placebo-controlled trial in adult patients with NYHA class III-IV ischaemic or non-ischaemic heart failure and left ventricular ejection fraction ≤35%. Eligible patients were randomized to receive a single intracoronary infusion of either 1 × 1013 DNase-resistant particles of AAV1/SERCA2a or placebo. The primary endpoint was change in left ventricular end-systolic volume (LVESV), measured by cardiac computed tomography at 6 month follow-up. We planned to include 40 patients but the trial was terminated prematurely as the sponsor suspended further enrolment following neutral results of the CUPID-2 outcome trial. At the time of termination, nine patients were randomized with five patients infused with AAV1/SERCA2a and four with placebo. At 6 months, LVESV was increased in both groups compared with baseline: median (interquartile range) in AAV1/SERCA2a vs. placebo: 13 (13;14) mL vs. 3.5 (-36;36) mL, P = 0.74, with a mean difference between groups of 11.4 mL in favour of placebo. No safety issues were noted Aims Restoration of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2a) activity through gene transfer improved cardiac function in experimental and pilot studies in humans with heart failure. The AGENT-HF (NCT01966887) trial investigated the impact of adeno-associated virus (AAV1)/SERCA2a on ventricular remodelling using multimodality non-invasive cardiac imaging. Methods and results AGENT-HF was a single centre, randomized, double-blind, placebo-controlled trial in adult patients with NYHA class III-IV ischaemic or non-ischaemic heart failure and left ventricular ejection fraction ≤35%. Eligible patients were randomized to receive a single intracoronary infusion of either 1 × 1013 DNase-resistant particles of AAV1/SERCA2a or placebo. The primary endpoint was change in left ventricular end-systolic volume (LVESV), measured by cardiac computed tomography at 6 month follow-up. We planned to include 40 patients but the trial was terminated prematurely as the sponsor suspended further enrolment following neutral results of the CUPID-2 outcome trial. At the time of termination, nine patients were randomized with five patients infused with AAV1/SERCA2a and four with placebo. At 6 months, LVESV was increased in both groups compared with baseline: median (interquartile range) in AAV1/SERCA2a vs. placebo: 13 (13;14) mL vs. 3.5 (-36;36) mL, P = 0.74, with a mean difference between groups of 11.4 mL in favour of placebo. No safety issues were noted. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
35. The early pregnancy placenta foreshadows DNA methylation alterations of solid tumors.
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Nordor, Akpéli V., Nehar-Belaid, Djamel, Richon, Sophie, Klatzmann, David, Bellet, Dominique, Dangles-Marie, Virginie, Fournier, Thierry, and Aryee, Martin J.
- Published
- 2017
- Full Text
- View/download PDF
36. Regulatory T Cell Therapy for Uveitis: A New Promising Challenge.
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Foussat, Arnaud, Gregoire, Sylvie, Clerget-Chossat, Nathalie, Terrada, Celine, Asnagli, Hélène, Lemoine, François M., Klatzmann, David, LeHoang, Phuc, Forte, Miguel, Bodaghi, Bahram, Asnagli, Hélène, and Lemoine, François M
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T cells , *UVEITIS treatment , *AUTOIMMUNE diseases , *IMMUNOSUPPRESSION , *CLINICAL trials , *THERAPEUTICS , *UVEITIS - Abstract
Uveitis is a sight-threatening primary intraocular inflammation of various origins in mainly young and active patients. Due to the absence of biomarkers in most of the cases, the current treatment of noninfectious entities remains nonspecific, using corticosteroids, conventional immunosuppressors, and more recently biological agents. Identification of regulatory T cells in different models of autoimmune uveitis together with the evaluation of this important subpopulation in different entities paved the way for new therapeutic strategies, in addition to exclusive pharmaceutical approaches. Upregulation of regulatory T cells induced by biological agents has been recently highlighted. Development of cell therapy in autoimmune diseases is at its stammering needing more experimental data and robust clinical trials to demonstrate safety and efficacy before larger developments. Specific or polyclonal Tregs may be used, but it is of utmost importance to determine the method of selection, the level of activation, and the route of administration. Mastering immune cell therapy remains a challenging goal in patients with autoimmune diseases, but it may significantly enlarge our therapeutic possibilities in severe and refractory situations. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
37. Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer's disease mice.
- Author
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Alves, Sandro, Churlaud, Guillaume, Audrain, Mickael, Michaelsen-Preusse, Kristin, Fol, Romain, Souchet, Benoit, Braudeau, Jérôme, Korte, Martin, Klatzmann, David, and Cartier, Nathalie
- Subjects
- *
INTERLEUKINS , *ALZHEIMER'S disease , *SYNAPSES , *MEMORY disorders , *LABORATORY mice - Abstract
Interleukin-2 (IL-2)-deficient mice have cytoarchitectural hippocampal modifications and impaired learning and memory ability reminiscent of Alzheimer's disease. IL-2 stimulates regulatory T cells whose role is to control inflammation. As neuroinflammation contributes to neurodegeneration, we investigated IL-2 in Alzheimer's disease. Therefore, we investigated IL-2 levels in hippocampal biopsies of patients with Alzheimer's disease relative to age-matched control individuals. We then treated APP/PS1ΔE9 mice having established Alzheimer's disease with IL-2 for 5 months using single administration of an AAV-IL-2 vector. We first found decreased IL-2 levels in hippocampal biopsies of patients with Alzheimer's disease. In mice, IL-2-induced systemic and brain regulatory T cells expansion and activation. In the hippocampus, IL-2 induced astrocytic activation and recruitment of astrocytes around amyloid plaques, decreased amyloid-β42/40 ratio and amyloid plaque load, improved synaptic plasticity and significantly rescued spine density. Of note, this tissue remodelling was associated with recovery of memory deficits, as assessed in the Morris water maze task. Altogether, our data strongly suggest that IL-2 can alleviate Alzheimer's disease hallmarks in APP/PS1ΔE9 mice with established pathology. Therefore, this should prompt the investigation of low-dose IL-2 in Alzheimer's disease and other neuroinflammatory/neurodegenerative disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
38. Narcolepsy Type 1 Is Associated with a Systemic Increase and Activation of Regulatory T Cells and with a Systemic Activation of Global T Cells.
- Author
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Lecendreux, Michel, Churlaud, Guillaume, Pitoiset, Fabien, Regnault, Armelle, Tran, Tu Anh, Liblau, Roland, Klatzmann, David, and Rosenzwajg, Michelle
- Subjects
- *
NARCOLEPSY , *T cells , *OREXINS , *DISEASE susceptibility , *CELL populations - Abstract
Narcolepsy is a rare neurologic disorder characterized by excessive daytime sleepiness, cataplexy and disturbed nocturnal sleep patterns. Narcolepsy type 1 (NT1) has been shown to result from a selective loss of hypothalamic hypocretin-secreting neurons with patients typically showing low CSF-hypocretin levels (<110 pg/ml). This specific loss of hypocretin and the strong association with the HLA-DQB1*06:02 allele led to the hypothesis that NT1 could be an immune-mediated pathology. Moreover, susceptibility to NT1 has recently been associated with several pathogens, particularly with influenza A H1N1 virus either through infection or vaccination. The goal of this study was to compare peripheral blood immune cell populations in recent onset pediatric NT1 subjects (post or non-post 2009-influenza A H1N1 vaccination) to healthy donors. We demonstrated an increased number of central memory CD4+ T cells (CD62L+ CD45RA-) associated to an activated phenotype (increase in CD69 and CD25 expression) in NT1 patients. Percentage and absolute count of regulatory T cells (Tregs) in NT1 patients were increased associated with an activated phenotype (increase in GITR and LAP expression), and of activated memory phenotype. Cytokine production by CD4+ and CD8+ T cells after activation was not modified in NT1 patients. In H1N1 vaccinated NT1 patients, absolute counts of CD3+, CD8+ T cells, and B cells were increased compared to non-vaccinated NT1 patients. These results support a global T cell activation in NT1 patients and thus support a T cell-mediated autoimmune origin of NT1, but do not demonstrate the pathological role of H1N1 prophylactic vaccination. They should prompt further studies of T cells, particularly of Tregs (such as suppression and proliferation antigen specific assays, and also T-cell receptor sequencing), in NT1. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
39. Low-Dose IL-2 Induces Regulatory T Cell-Mediated Control of Experimental Food Allergy.
- Author
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Bonnet, Benjamin, Vigneron, James, Levacher, Béatrice, Vazquez, Thomas, Pitoiset, Fabien, Brimaud, Faustine, Churlaud, Guillaume, Klatzmann, David, and Bellier, Bertrand
- Subjects
- *
FOOD allergy , *ALLERGENS , *IMMUNOREGULATION , *IMMUNOSUPPRESSION , *AUTOIMMUNE diseases - Abstract
Regulatory T cells (Tregs) are pivotal for maintenance of immune self-tolerance and also regulate immune responses to exogenous Ags, including allergens. Both decreased Treg number and function have been reported in allergic patients, offering new therapeutic perspectives. We previously demonstrated that Tregs can be selectively expanded and activated by low doses of IL-2 (ld-IL-2) inducing immunoregulation without immunosuppression and established its protective effect in autoimmune diseases. In this study, we evaluated the ability of ld-IL-2 to control allergy in an experimental model of food allergy. Ld-IL-2 induced Treg expansion and activation that elicited protection against clinical manifestations of food allergy in two mouse models with OVA and peanut. This clinical effect was lost in Treg-depleted mice, demonstrating the major contribution of Tregs in ld-IL-2 efficacy. Mechanistic studies further indicated that protection fromallergy could be explained by a Treg-dependent local modification of the Th1/Th2 balance and an inhibition ofmast cell recruitment and activation. Preventive and therapeutic effects of ld-IL-2 were observed over a 7-mo-period, highlighting its long-term efficacy. This study demonstrated that ld-IL-2 is efficient to prevent and to treat allergic immune responses, and thus represents a promising therapeutic strategy for managing allergic diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
40. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases.
- Author
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Dragin, Nadine, Bismuth, Jacky, Cizeron-Clairac, Géraldine, Biferi, Maria Grazia, Berthault, Claire, Serraf, Alain, Nottin, Rémi, Klatzmann, David, Cumano, Ana, Barkats, Martine, Le Panse, Rozen, and Berrih-Aknin, Sonia
- Subjects
- *
ANTI-estrogenic diet , *ESTROGEN replacement therapy , *DIMORPHISM (Biology) , *MESSENGER RNA , *PROTEIN analysis , *PROTEIN metabolism , *ANIMALS , *AUTOIMMUNE diseases , *CELL culture , *DNA , *ESTROGEN , *GENES , *HUMAN reproduction , *MICE , *PROTEINS , *THYMUS , *TRANSCRIPTION factors , *DNA methylation - Abstract
Autoimmune diseases affect 5% to 8% of the population, and females are more susceptible to these diseases than males. Here, we analyzed human thymic transcriptome and revealed sex-associated differences in the expression of tissue-specific antigens that are controlled by the autoimmune regulator (AIRE), a key factor in central tolerance. We hypothesized that the level of AIRE is linked to sexual dimorphism susceptibility to autoimmune diseases. In human and mouse thymus, females expressed less AIRE (mRNA and protein) than males after puberty. These results were confirmed in purified murine thymic epithelial cells (TECs). We also demonstrated that AIRE expression is related to sexual hormones, as male castration decreased AIRE thymic expression and estrogen receptor α-deficient mice did not show a sex disparity for AIRE expression. Moreover, estrogen treatment resulted in downregulation of AIRE expression in cultured human TECs, human thymic tissue grafted to immunodeficient mice, and murine fetal thymus organ cultures. AIRE levels in human thymus grafted in immunodeficient mice depended upon the sex of the recipient. Estrogen also upregulated the number of methylated CpG sites in the AIRE promoter. Together, our results indicate that in females, estrogen induces epigenetic changes in the AIRE gene, leading to reduced AIRE expression under a threshold that increases female susceptibility to autoimmune diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
41. Early Transcriptome Signatures from Immunized Mouse Dendritic Cells Predict Late Vaccine-Induced T-Cell Responses.
- Author
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Dérian, Nicolas, Bellier, Bertrand, Pham, Hang Phuong, Tsitoura, Eliza, Kazazi, Dorothea, Huret, Christophe, Mavromara, Penelope, Klatzmann, David, and Six, Adrien
- Subjects
- *
DENDRITIC cells , *GENETIC transcription , *VACCINATION , *T cells , *INTERFERON inducers - Abstract
Systems biology offers promising approaches for identifying response-specific signatures to vaccination and assessing their predictive value. Here, we designed a modelling strategy aiming to predict the quality of late T-cell responses after vaccination from early transcriptome analysis of dendritic cells. Using standardized staining with tetramer, we first quantified antigen-specific T-cell expansion 5 to 10 days after vaccination with one of a set of 41 different vaccine vectors all expressing the same antigen. Hierarchical clustering of the responses defined sets of high and low T cell response inducers. We then compared these responses with the transcriptome of splenic dendritic cells obtained 6 hours after vaccination with the same vectors and produced a random forest model capable of predicting the quality of the later antigen-specific T-cell expansion. The model also successfully predicted vector classification as low or strong T-cell response inducers of a novel set of vaccine vectors, based on the early transcriptome results obtained from spleen dendritic cells, whole spleen and even peripheral blood mononuclear cells. Finally, our model developed with mouse datasets also accurately predicted vaccine efficacy from literature-mined human datasets. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
42. Treatment of Uveitis by In Situ Administration of Ex Vivo-Activated Polyclonal Regulatory T Cells.
- Author
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Grégoire, Sylvie, Terrada, Celine, Martin, Gaelle H., Fourcade, Gwladys, Baeyens, Audrey, Marodon, Gilles, Fisson, Sylvain, Billiard, Fabienne, Lucas, Bruno, Tadayoni, Ramin, Behar-Cohen, Francine, Levacher, Béatrice, Galy, Anne, LeHoang, Phuc, Klatzmann, David, Bodaghi, Bahram, and Salomon, Benoit L.
- Subjects
- *
SUPPRESSOR cells , *T cells , *UVEITIS , *INTERLEUKIN-10 , *REACTIVE oxygen species , *LABORATORY mice - Abstract
CD4+CD25+Foxp3+ regulatory T (Treg) cell therapy is a promising approach for the treatment of autoimmune diseases. To be effective, Treg cells should be in an activated state in the target tissue. This can be achieved by systemic administration of Ag-specific Treg cells, which are difficult to produce in conditions that can be translated to the clinic. In this paper, we propose an alternative approach consisting of in situ injection of preactivated polyclonal Treg cells that would exert bystander suppression in the target tissue. We show that polyclonal Treg cells suppressed uveitis in mice as efficiently as Ag-specific Treg cells but only when preactivated and administered in the vitreous. Uveitis control was correlated with an increase of IL-10 and a decrease of reactive oxygen species produced by immune cell infiltrates in the eye. Thus, our results reveal a new mechanism of Treg cell-mediated suppression and a new Treg cell therapy approach. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
43. A TCRβ Repertoire Signature Can Predict Experimental Cerebral Malaria.
- Author
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Mariotti-Ferrandiz, Encarnita, Pham, Hang-Phuong, Dulauroy, Sophie, Gorgette, Olivier, Klatzmann, David, Cazenave, Pierre-André, Pied, Sylviane, and Six, Adrien
- Subjects
- *
CEREBRAL malaria , *T cells , *STIMULUS & response (Biology) , *DISEASE relapse , *MOLECULAR cloning , *LABORATORY mice , *THERAPEUTICS , *PHYSIOLOGY - Abstract
Cerebral Malaria (CM) is associated with a pathogenic T cell response. Mice infected by P. berghei ANKA clone 1.49 (PbA) developing CM (CM+) present an altered PBL TCR repertoire, partly due to recurrently expanded T cell clones, as compared to non-infected and CM- infected mice. To analyse the relationship between repertoire alteration and CM, we performed a kinetic analysis of the TRBV repertoire during the course of the infection until CM-related death in PbA-infected mice. The repertoires of PBL, splenocytes and brain lymphocytes were compared between infected and non-infected mice using a high-throughput CDR3 spectratyping method. We observed a modification of the whole TCR repertoire in the spleen and blood of infected mice, from the fifth and the sixth day post-infection, respectively, while only three TRBV were significantly perturbed in the brain of infected mice. Using multivariate analysis and statistical modelling, we identified a unique TCRβ signature discriminating CM+ from CTR mice, enriched during the course of the infection in the spleen and the blood and predicting CM onset. These results highlight a dynamic modification and compartmentalization of the TCR diversity during the course of PbA infection, and provide a novel method to identify disease-associated TCRβ signature as diagnostic and prognostic biomarkers. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
44. Regulatory T Cells Orchestrate Similar Immune Evasion of Fetuses and Tumors in Mice.
- Author
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Nehar-Belaid, Djamel, Courau, Tristan, Dérian, Nicolas, Ruocco, Maria Grazia, Klatzmann, David, and Florez, Laura
- Subjects
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T cells , *PREGNANCY , *EMBRYOS , *TUMORS , *FETUS , *LABORATORY mice - Abstract
Embryos and tumors are both masses of dividing cells expressing foreign Ags, but they are not rejected by the immune system. We hypothesized that similar tolerogenic mechanisms prevent their rejection. Global comparison of fetal and tumor microenvironments through transcriptomics in mice revealed strikingly similar and dramatic decreases in expression of numerous immune-related pathways, including Ag presentation and T cell signaling. Unsupervised analyses highlighted the parallel kinetics and similarities of immune signature downregulation, from the very first days after tumor or embryo implantation. Besides upregulated signatures related to cell proliferation, the only significant signatures shared by the two conditions across all biological processes and all time points studied were downmodulated immune response signatures. Regulatory T cell depletion completely reverses this immune downmodulation to an immune upregulation that leads tofetal or tumor immune rejection. We propose that evolutionarily selected mechanisms that protect mammalian fetuses from immune attack are hijacked to license tumor development. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
45. Calpains Released by T Lymphocytes Cleave TLR2 To Control IL-17 Expression.
- Author
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Perez, Joëlle, Dansou, Boris, Hervé, Roxane, Levi, Charlène, Tamouza, Houda, Vandermeersch, Sophie, Demey-Thomas, Emmanuelle, Haymann, Jean-Philippe, Zafrani, Lara, Klatzmann, David, Boissier, Marie-Christophe, Letavernier, Emmanuel, and Baud, Laurent
- Subjects
- *
CALPAIN genetics , *T cells , *GENE expression , *INTERLEUKIN-17 , *EXTRACELLULAR matrix proteins , *IMMUNOREGULATION - Abstract
Calpains are intracellular proteases that play a key role in inflammation/immunity. Rare studies show that they are partially externalized. However, the mechanism of this secretion and the functions of exteriorized calpains remain poorly understood. In this study, we found that mouse and human lymphocytes secreted calpains through an ABCA1-driven process. In turn, extracellular calpains inhibited IL-17A expression. We were able to attribute this function to a cleavage of the TLR2 extracellular domain, which prevented TLR2-induced transcription of molecules essential for IL-17A induction. Calpain exteriorization and TLR2 cleavage were critical for the control of IL-17A expression by low doses of IL-2. By using newly developed transgenic mice in which extracellular calpains are specifically inactivated, we provide evidence for the relevance of calpain externalization in vivo in regulating IL-17A expression and function in experimental sterile peritonitis and autoimmune arthritis, respectively. Thus, this study identifies calpain exteriorization as a potential target for immune modulation. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
46. Regulatory T-cell development and function are impaired in mice lacking membrane expression of full length intercellular adhesion molecule-1.
- Author
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Gottrand, Gaëlle, Courau, Tristan, Thomas‐Vaslin, Véronique, Prevel, Nicolas, Vazquez, Thomas, Ruocco, Maria Grazia, Lambrecht, Benedicte, Bellier, Bertrand, Colombo, Bruno M., and Klatzmann, David
- Subjects
- *
CD54 antigen , *T cells , *CELLULAR control mechanisms , *IMMUNE response , *THYMOCYTES , *LABORATORY mice - Abstract
Tofurther investigate the contribution of intercellular adhesion molecule- 1 (ICAM-1) to adaptive immune responses, we analysed T-cell development and function in mice lacking full-length ICAM-1 (ICAM-1tm1Jcgr). Compared with wild-type (ICAM-1WT) mice, ICAM-1tm1Jcgr mice have impaired thymocyte development. Proportions and numbers of double negative, double positive, mature CD4+ and CD8+ thymocytes, as well as of regulatory T (Treg) cells were also significantly decreased. In the periphery, ICAM-1tm1Jcgr mice had significantly decreased proportions and numbers of naive and activated/memory CD4+ and CD8+ T cells, as well as of Treg cells, in lymph nodes but not in the spleen. In vitro activation of CD4+ and CD8+ T cells from ICAM-1tm1Jcgr mice with anti-CD3 antibodies and antigen-presenting cells (APCs) resulted in a significantly weaker proliferation, whereas proliferation induced with anti-CD3 and anti-CD28 antibody-coated beads was normal. In vivo immunization of ICAM-1tm1Jcgr mice resulted in normal generation of specific effector and memory immune responses that protect against a viral challenge. However, contrary to ICAM-1WT mice, immunization-induced specific effectors could not eradicate immunogen-expressing tumours. Treg cells from ICAM-1tm1Jcgr mice have abnormal activation and proliferation induced by anti-CD3 antibody and APCs, and have markedly decreased suppressive activity in vitro. In contrast to ICAM-1WT mice, they were unable to control experimentally induced colitis in vivo. Hence, our results further highlight the pleiotropic role of ICAM-1 in T-cell-dependent immune responses, with a major role in Treg cell development and suppressive function. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
47. Selective IL-2 Responsiveness of Regulatory T Cells Through Multiple Intrinsic Mechanisms Supports the Use of Low-Dose IL-2 Therapy in Type 1 Diabetes.
- Author
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Aixin Yu, Snowhite, Isaac, Vendrame, Francesco, Rosenzwajg, Michelle, Klatzmann, David, Pugliese, Alberto, and Malek, Thomas R.
- Subjects
- *
INTERLEUKIN-2 , *TYPE 1 diabetes , *GLUCOSE intolerance , *T cells , *DIABETES , *IMMUNOLOGY - Abstract
Low-dose interleukin-2 (IL-2) inhibited unwanted immune responses in several clinical settings and is currently being tested in patients with type 1 diabetes (T1D). Low-dose IL-2 selectively targets regulatory T cells (Tregs), but the mechanisms underlying this selectivity are poorly understood. We show that IL-2-dependent STAT5 activation in Tregs from healthy individuals and patients with T1D occurred at an ~10-fold lower concentration of IL-2 than that required by T memory (TM) cells or by in vitro-activated T cells. This selective Treg responsiveness is explained by their higher expression of IL-2 receptor subunit α (IL-2Rα) and γ chain and also endogenous serine/threonine phosphatase protein phosphates 1 and/or 2A activity. Genome-wide profiling identified an IL-2-dependent transcriptome in human Tregs. Quantitative assessment of selected targets indicated that most were optimally activated by a 100-fold lower concentration of IL-2 in Tregs versus CD4+ TM cells. Two such targets were selectively increased in Tregs from T1D patients undergoing low-dose IL-2 therapy. Thus, human Tregs possess an IL-2-dependent transcriptional amplification mechanism that widens their selective responses to low IL-2. Our findings support a model where low-dose IL-2 selectively activates Tregs to broadly induce their IL-2/IL-2R gene program and provide a molecular underpinning for low-dose IL-2 therapy to enhance Tregs for immune tolerance in T1D. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
48. Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in T1D patients.
- Author
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Rosenzwajg, Michelle, Churlaud, Guillaume, Mallone, Roberto, Six, Adrien, Dérian, Nicolas, Chaara, Wahiba, Lorenzon, Roberta, Long, S. Alice, Buckner, Jane H., Afonso, Georgia, Pham, Hang-Phuong, Hartemann, Agnès, Yu, Aixin, Pugliese, Alberto, Malek, Thomas R., and Klatzmann, David
- Subjects
- *
AUTOIMMUNE diseases , *INTERLEUKIN-2 , *DRUG dosage , *GENETIC regulation , *T cells , *MILIEU therapy , *PATIENTS - Abstract
Most autoimmune diseases (AID) are linked to an imbalance between autoreactive effector T cells (Teffs) and regulatory T cells (Tregs). While blocking Teffs with immunosuppression has long been the only therapeutic option, activating/expanding Tregs may achieve the same objective without the toxicity of immunosuppression. We showed that low-dose interleukin-2 (ld-IL-2) safely expands/activates Tregs in patients with AID, such HCV-induced vasculitis and Type 1 Diabetes (T1D). Here we analyzed the kinetics and dose-relationship of IL-2 effects on immune responses in T1D patients. Ld-IL-2 therapy induced a dose-dependent increase in CD4 + Foxp3 + and CD8 + Foxp3 + Treg numbers and proportions, the duration of which was markedly dose-dependent. Tregs expressed enhanced levels of activation markers, including CD25, GITR, CTLA-4 and basal pSTAT5, and retained a 20-fold higher sensitivity to IL-2 than Teff and NK cells. Plasma levels of regulatory cytokines were increased in a dose-dependent manner, while cytokines linked to Teff and Th17 inflammatory cells were mostly unchanged. Global transcriptome analyses showed a dose-dependent decrease in immune response signatures. At the highest dose, Teff responses against beta-cell antigens were suppressed in all 4 patients tested. These results inform of broader changes induced by ld-IL-2 beyond direct effects on Tregs, and relevant for further development of ld-IL-2 for therapy and prevention of T1D, and other autoimmune and inflammatory diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
49. Interleukin-5-producing group 2 innate lymphoid cells control eosinophilia induced by interleukin-2 therapy.
- Author
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Van Gool, Frédéric, Molofsky, Ari B., Morar, Malika M., Rosenzwajg, Michelle, Hong-Erh Liang, Klatzmann, David, Locksley, Richard M., and Bluestone, Jeffrey A.
- Subjects
- *
INTERLEUKIN-5 , *LYMPHOKINES , *LYMPHOID tissue , *EOSINOPHILIA , *INTERLEUKIN-2 , *INTERLEUKINS - Abstract
Interleukin (IL)-2 promotes regulatory T-cell development and function, and treatment with IL-2 is being tested as therapy for some autoimmune diseases. However, patients receiving IL-2 treatment also experience eosinophilia due to an unknown mechanism. Here, we show that patients receiving low-dose IL-2 have elevated levels of serum IL-5, and this correlates with their degree of eosinophilia. In mice, low-dose IL-2-anti-IL-2 antibody complexes drove group 2 innate lymphoid cells (ILC2) to produce IL-5 and proliferate. Using genetic approaches in mice, we demonstrate that activation of ILC2 was responsible for the eosinophilia observed with IL-2 therapy. These observations reveal a novel cellular network that is activated during IL-2 treatment. A better understanding of the cross talk between these cell populations may lead to more effective targeting of IL-2 to treat autoimmune disease. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
50. Interferon signature in giant cell arteritis aortitis.
- Author
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Vieira, Matheus, Régnier, Paul, Maciejewski-Duval, Anna, Le Joncour, Alexandre, Darasse-Jèze, Guillaume, Rosenzwajg, Michelle, Klatzmann, David, Cacoub, Patrice, and Saadoun, David
- Subjects
- *
GIANT cell arteritis , *TYPE I interferons , *AORTITIS , *INTERFERONS , *T cells , *BLOOD collection - Abstract
Molecular mechanisms underlying large-vessel involvement in giant cell arteritis (LV-GCA) are largely unknown. Herein, we explore the critical involvement of pro-inflammatory signaling pathways in both aorta and T cells from patients with LV-GCA. We analyzed transcriptome and interferon gene signature in inflamed aortas from LV-GCA patients and compared them to non-inflammatory control aorta. Differential transcriptomic analyses of circulating CD4+ and CD8+ T cells were also performed between patients with active GCA (not under any immunosuppressants or corticosteroid doses higher than 10 mg/day by the time of blood collection) and healthy donors. Interferon-alpha serum levels were measured using ultra-sensitive technique (HD-X Simoa Planar Technology) in GCA patients according to disease activity status. Transcriptomic analyses revealed 1042, 1479 and 2075 significantly dysregulated genes for aortas, CD4+ and CD8+ cells from LV-GCA patients, respectively, as compared to controls. A great enrichment for pathways linked to interferons (type I, II and III), JAK/STAT signaling, cytokines and chemokines was seen across aortas and circulating T cells. A type I interferon signature was identified as significantly upregulated in the aorta of patients with LV-GCA, notably regarding EPSTI1 and IFI44L genes. STAT3 was significantly upregulated in both aorta and T cells and appeared as central in related gene networks from LV-GCA patients. Interferon-alpha serum levels were higher in patients with active GCA when compared to those in remission (0.024 vs. 0.011 pg/mL; p = 0.028). LV-GCA presents a clear type I interferon signature in aortas, which paves the way for tailored therapeutical targeting. • Aortas from LV-GCA patients are enriched with type I interferon signature. • JAK/STAT pathway seems key in disease mechanisms, notably regarding STAT3. • Interferon-alpha serum levels may be associated with disease activity. • Upregulated signaling pathways in LV-GCA paves the way for therapeutical targeting. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
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