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Human Immunology, Pathophysiology and Immunotherapy / Immunologie humaine, physiopathologie & immunithérapie

Human Immunology, Pathophysiology and Immunotherapy / Immunologie humaine, physiopathologie & immunithérapie

9 Projects, page 1 of 2
  • Funder: French National Research Agency (ANR) Project Code: ANR-21-CE17-0066
    Funder Contribution: 597,454 EUR

    We recently identified by investigating a Mendelian psoriasis model a new mutatioon of a gene encoding a protein involved in skin immune responses, which leads to a constitutive activation of the related signaling pathway. By gathering a consortium with high level complementary expertises, we plan not only to demonstrate the pathogenicity of this mutation in psoriasis, but also to identify robust immunogenetic biomarkers applicable in practice to better predict the clinical response to different therapies, allowing to design innovative precision medical approaches, which would bring multiple benefits for patients affected with this chronic inflammatory disease still associated with high rates of loss of efficacy in real life, including for the most effective treatments to date.

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  • Funder: French National Research Agency (ANR) Project Code: ANR-20-COV1-0001
    Funder Contribution: 114,728 EUR

    SARS-CoV-2 infection can result in severe disease characterised by systemic inflammation, acute respiratory distress syndrome and lung injury, leading to morbidity and mortality caused by lung damage, inflammation and pneumonia. Such COVID-19 patients require hospitalisation in intensive care units and present a major concern in the current epidemics. Deregulation in the distribution of immune cell populations is suggested to be a major player in the disease severity. COVID-19 patients are characterised by lymphopenia and elevated serum levels of pro-inflammatory cytokines. Important progress has already been made in describing the cellular composition featuring COVID-19 patient blood. However, the rarity of some populations that play major roles in immune regulation precludes their analysis, unless a dedicated and integrated approach would combine clinical, immunological and technological frameworks. Along this line, in this project we aim to put special emphasis on antigen-presenting cell subset diversity, the underlying molecular and functional features, and cellular networks they engage in the context of severe SARS-CoV-2 infection. Our project has the potential to result in a significant clinical impact for future management of COVID-19 disease, in the form of novel therapeutic targets, and biomarker-driven treatment strategies.

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  • Funder: French National Research Agency (ANR) Project Code: ANR-19-CE14-0018
    Funder Contribution: 400,660 EUR

    The Epi-Dev project will investigate the epigenetic and transcriptional mechanisms underlying lymphoid lineage specification in mammals. Our consortium will use a comparative human/mouse experimental strategy combining functional analyses and high throughput transcriptomic and epigenomic studies. Human studies will aim to investigate the bases of lymphoid priming in multipotent progenitors and to characterize the signaling pathways and gene networks driving the differential emergence of IL7 receptor (CD127) positive or negative lymphoid progenitors. Mouse studies conducted in parallel will also aim to dissect lymphoid priming and subsequent lymphoid diversification in the fetal liver. Single-cell comparative transcriptomics will then be used to define the developmental trajectories of human and mouse lymphoid progenitors. Overall, the Epi-Dev project will provide a roadmap of the early steps of lymphoid differentiation and will distinguish species-specific regulatory mechanisms from those that have been conserved through evolution. Ultimately, this project will contribute to a better understanding of the developmental plasticity and functional properties of the cells from which hematological malignancies originate and help unravel the perturbations of lymphoid differentiation associated with pathologic conditions and aging.

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  • Funder: French National Research Agency (ANR) Project Code: ANR-20-CE18-0033
    Funder Contribution: 268,071 EUR

    Inflammatory dermatoses include two multifactorial pathologies, psoriasis and atopic dermatitis, with a very high global prevalence in the world. Current treatments, topical or systemic, are often partially effective as targeting only one component of the disease (either immune system or epidermal inflammation). Our project focuses on a new Pickering emulsion composed of PLGA nanoparticles encapsulating an immunosuppressive drug (i.e. tacrolimus or ciclosporin A) and stabilizing an oily phase containing an anti-inflammatory drug (calcitriol) that can regulate epidermal activation and proliferation. The project aims to establish the proof of concept of the activity of these new topical emulsions as a new unique and innovative topical treatment for inflammatory dermatoses, by investigating its efficacy through, on the one hand, in vitro experiments on cutaneous and immune isolated cells as well as on skin explants from healthy donors or from lesions from patients, and on the another hand, in vivo experiments in a preclinical study conducted in a mouse model dedicated to mimic either psoriasis or atopic dermatitis. In the future, a phase I clinical study of the topical application of the Pickering emulsions might be assessed in collaboration with industrial partners, knowing that the active substances co-encapsulated within the emulsions are already administered to humans and that the use of PLGA NP has been validated by the FDA and the EMA. For conducting these main objectives in the best way, a thorough physical chemistry study is necessary to clarify the emulsion physico-chemical properties and the stabilization mechanism of the water/oil interface, to the benefit of pharmaceutical applications.

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  • Funder: French National Research Agency (ANR) Project Code: ANR-22-CE17-0027
    Funder Contribution: 534,548 EUR

    Adoptive cellular immunotherapy has emerged as a fascinating approach to prevent and/or limit graft-versus-host disease (GVHD), a major source of morbidity and mortality following allogeneic transplantation. To date however, the most appropriate regulatory population to use remains elusive. Human mucosal associated invariant T cells (MAITs) are unconventional T cells very abundant in barrier tissues and blood, which express a semi-invariant TCR recognizing microbial-derived riboflavin derivatives presented by the highly conserved MR1 molecule. MAITs exhibit potent TCR-dependent and -independent effector functions in response to homeostatic perturbations. Recent studies have also revealed the tissue repair and regulatory capacities of MAITs, but the mechanisms involved in these new functions are hardly explored. We recently demonstrated that MAITs lack alloreactive potential and do not contribute to GVHD tissue lesions, prompting us to exploit their regulatory potential for adoptive cell therapy in allogeneic settings. Our program has three specific objectives: 1/ to characterize the MAIT regulatory mechanisms in vitro in a mixed lymphocyte reaction (MLR) model using transcriptomic, deep phenotyping and live microscopy, 2/ to confirm the mechanisms sustaining the protective role of human MAITs in vivo in a xenogenic GVHD model, and 3/ to validate the identified molecule(s) using gene-edited MAITs or specific antagonists. A main challenge of our project will be to determine if MAITs perform dual effector and regulatory functions depending on the inflammatory context. Our results should allow considering human MAITs as universal, off-the-shelf therapeutic tools to control GVHD or other inflammatory mucosal diseases.

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