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11 Projects, page 1 of 3
  • Funder: ANR Project Code: ANR-14-ACHN-0008
    Funder Contribution: 499,445 EUR
    Partners: Inserm

    Autoimmune diseases represent an increasing burden on global health, with a steadily rising incidence and a consistent association with chronic illness and premature death. Despite this, therapy often relies on non-specific and potentially toxic immunosuppression, which carries its own morbidity. The recent development of antibody-mediated therapies has shown great promise for the treatment of several autoimmune diseases demonstrating that the development of specifically targeted therapies is the way forward for the treatment of these disabling conditions. Autoimmune disease are complex conditions characterized by a deregulation of the immune system that can implicate several cell types including B and T cells and affect different organs. Thus, we need to gain a better insight into the biology of the cells involved in these pathologies if we are to design and develop safer and more efficient therapies. The proposal AUTO-PLASMO focuses on plasma cells - the cells that are responsible for antibody production within the adaptive immune system. Plasma cells play an essential protective role against infection but they are also implicated in the pathology of several autoimmune diseases including systemic lupus erythematosus via secretion of pathologic autoantibodies. Despite their essential role in health and disease, how plasma cells are generated, survive and secrete antibodies is still not fully elucidated. Moreover, plasma cells are resistant to most therapies currently used to treat autoimmune disease. There is thus a knowledge gap that needs to be filled in order to offer new therapeutic options for the control or elimination of this cell subset. _x000D_ This question forms the core of this research project that is divided in three complementary axes:_x000D_ -Identification of new regulators of plasma cell survival and antibody secretion in health and disease._x000D_ -Analysis of plasma cell phenotypic and functional heterogeneity in health and disease._x000D_ -Characterization of plasma cell survival and migration in inflamed tissue in systemic lupus erythematosus._x000D_ These three axes form an integrative approach combining basic immunology techniques with innovative single-cell methods to study plasma cell function and survival in health and disease, which in turn could facilitate the identification and validation of new therapies that target this cell subset._x000D_ _x000D_ _x000D_

  • Funder: ANR Project Code: ANR-19-CE15-0019
    Funder Contribution: 345,762 EUR
    Partners: Inserm

    Plasma cells and the antibodies they secrete are essential for long-term protective immune responses and tissue homeostasis. However, they can also contribute to the pathology of numerous inflammatory and autoimmune conditions. Despite their relevance in health and disease, the mechanisms underlying antibody production and secretion are still poorly understood. This is an essential question as a better characterization of the involved molecular actors may pave the way to improved antibody production, and to the development of new therapies for antibody-driven diseases. Preliminary data obtained in our laboratory showed that the Sec22b SNARE is essential for antibody secretion but also for plasma cell maturation. Using a conditional mouse model we observed in absence of Sec22b in the B cell lineage an almost complete lack of circulating antibodies and a dramatic decrease in the number of plasma cells in the spleen and the bone marrow. We now plan to use this model to address how Sec22b affects plasma cell fitness and antibody secretion. In parallel we will determine the impact of such defects on the normal and pathological humoral immune response and on tissue homeostasis, in particular in the BM. Collectively, this project should bring new lights on the molecular mechanisms underlying antibody secretion by plasma cells, a key process with huge relevance both at the therapeutic and at the industrial levels but largely overlooked so far. Moreover, our model will allow us to study with great details the impact of plasma cells and antibodies on homeostasis and inflammation at the tissue and organism level.

  • Funder: ANR Project Code: ANR-16-ECVD-0002
    Funder Contribution: 249,912 EUR
    Partners: Inserm

    EXPERT is an interdisciplinary program involving 6 European nations exploiting the power of RNA biology_x000D_ to fight age-related heart failure (HF). EXPERT will identify pathways of age-related HF and will explore_x000D_ non-coding RNA (ncRNA)-mediated regulatory pathways of the human genome, instead of the traditional_x000D_ focus on protein-coding genes. EXPERT uses innovative genetic models, ncRNA gender-specific_x000D_ theranostic approaches, and clinical/population-based cohorts to explore age-related HF. The project will_x000D_ lead to novel diagnostic and therapeutic strategies for treatment of HF and other cardiovascular alterations,_x000D_ such as atherosclerosis and myocardial infarction._x000D_ EXPERT will a) validate pathways of pathologic cardiac ageing to develop therapeutic ncRNA-based_x000D_ strategies, b) identify an age-specific pattern of circulating ncRNA to predict future cardiac events/death._x000D_ The specific objectives are to:_x000D_ i. Generate a cell-type specific ncRNA blueprint of the ageing heart._x000D_ ii. Study ncRNA regulation in cardiac ageing upon interference with cardiac stress leading to HF._x000D_ iii. Validate important age-related cardiovascular pathways by testing ncRNA interventions in small_x000D_ and large animal models._x000D_ iv. Define the predictive value of circulating age-related ncRNAs in clinical and population-based_x000D_ cohorts._x000D_ To reach these objectives we will perform:_x000D_ i. Experimental studies on existing and/or de novo-generated in vitro/in vivo models of ageing._x000D_ ii. Clinical studies, stratifying the risk of developing atherosclerosis, cardiac events and death, in_x000D_ large-scale population- and patient-based cohorts.

  • Funder: ANR Project Code: ANR-16-COEN-0007
    Funder Contribution: 313,600 EUR
    Partners: Institut Pasteur de Lille, U1167, Inserm
  • Funder: ANR Project Code: ANR-14-CE14-0030
    Funder Contribution: 509,889 EUR

    Although the news that life expectancy in France has nearly doubled over the last century is a reflection of the positive impact of medical knowledge and disease control, there is a consequent burden to society. Elderly people have an increased rate of severe infection, autoimmune disease or cancer as compared to younger individuals, resulting in a significant reduction in their quality of life and ever increasing medical costs. Disease in the elderly is likely related to an age-related decline of the immune system homeostasis. Growing evidence indicates that advanced age is indeed associated with a variety of phenotypic and functional alterations of the cells and organs of the immune system, referred to as immune aging or immunosenescence. Alterations of the ability to respond to new antigens may explain the reduced vaccine efficacy observed in old people. This project is predicated on the belief that understanding immune aging is a public health priority, with broad implications in prevention of infectious diseases, and optimization of vaccine efficacy in the elderly._x000D_ _x000D_ Cellular immunity, which is mediated by CD8+ and CD4+ T cells, is critically important in the host response to various pathogens, and the control of cells undergoing malignant transformation. However, with increasing age, the T cell compartment is biased towards increasing proportions of highly differentiated oligoclonal memory populations, with short telomeres and limited proliferative capacity, considered to be approaching replicative senescence. There is also evidence that aging compromises the functional capacity of dendritic cells. Together, these age-related changes may limit the capacity of the cellular immunity to effectively mount responses specific to new antigenic determinants, such as those associated with emerging strains of influenza virus or emerging tumor cells. Although it is clear that detectable antigen-specific T cells can be induced safely in humans by vaccination, the challenge is now to improve vaccine immunogenicity and efficacy in elderly._x000D_ _x000D_ The naïve T cell compartment represents the primary resource for the induction of T cell responses. Although it is established that age-related thymic involution is associated with a reduced production in naïve T cells, the precise attributes of naïve T cells themselves in elderly remain largely uncharacterized. Our hypothesis is that the quantitative and qualitative decline of the naïve T cell compartment with advanced age results in a suboptimal capacity to prime effective antigen specific T cell responses. The objectives of our project are therefore to perform a comprehensive characterization of naïve CD8+ and CD4+ T cells in the elderly, and thymectomized young adults who present evidence of premature aging, examining ways to improve the initiation of de novo T cell responses – ultimately helping to define strategies aimed at enhancing the efficacy of T cell based vaccination in these populations. To this end, we propose to apply original and state-of-the-art analytical approaches, currently developed by our groups, to generate relevant information on the quantitative and qualitative attributes of naïve CD8+ and CD4+ T cells and their ability to mount effective T cell responses from blood samples. We will directly test the effect of potential adjuvants that could favor the induction of T cell responses in the targeted populations. Additionally, our optimized immune monitoring strategies will be assessed for their use as in vitro diagnostic tools that can support future vaccine studies. Our combined expertise will ensure efficient translation of cutting-edge immunologic concepts. In sum, our understanding of the decline of immune competence with advanced age in humans will support the development of new diagnostic tools and the execution of clinical studies to improve vaccination and adjuvant formulation.