Une nouvelle biothérapie dans le traitement de la sclérose en plaques (le natalizumab)

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Immunothérapie et cancer du sein (exemple d'une approche vaccinale utilisant l'antigène tumoral Tn)

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Contribution à l'étude des fonctions de la molécule d'hadérence endothéliale CD146

Mon travail de thèse représente une contribution à l étude des fonctions de CD146, puisque j ai développé des souris CD146 knock-out, identifié un ligand pour CD146 et montré une différence d expression leucocytaire de CD146 entre l homme et la souris. Les souris CD146 KO sont viables et fertiles. Le phénotype de ces souris pour l implication de CD146 dans le développement vasculaire et la transmigration leucocytaire ou tumorale est en cours d évaluation. A la recherche d un ligand de la mucine CD146/Muc18, j ai pu montré que la galectine 1 était capable d interagir directement avec la partie extracellulaire de CD146. Cette interaction est dépendante des sucres et affiche un KD de 3.10-7 M. Cette association n est retrouvée in vivo que lors de condition pro-inflammatoire et sur des cellules endothéliales non confluentes. Elle semble impliquée dans la survie des cellules endothéliales. Bien que n étant pas exprimée sur les cellules NK humaines, la production de nouveaux anticorps monoclonaux a permis de montrer que CD146 l est sur celles d origine murine. Plus qu un marqueur spécifique de ces cellules au sein des lymphocytes, le niveau d expression de CD146 détermine la maturité de ces cellules.Increasing knowledge of CD146 functions has been the aim of my PhD. To address this issue, a CD146 knock-out mice was generated, one ligand was identified and a new differential expression of CD146 on leukocyte between human and mice was demonstrated. KO mice are viable and fertile. Involvement of CD146 during the vascular development, the leukocyte transmigration and metastatic ability of tumor cells are actually in process. Looking for a ligand of the mucin CD146/ MUC18, I showed that galectin-1 is able to interact directly with the extracellular part of CD146. This interaction is dependant of CD146 s sugar ramifications and the KD is 3.10-7 M. In vivo, this interaction only occurs in inflammatory conditions on non-confluent endothelial cells and seems to be implicated in endothelial cell survival. Conversely to human NK cells, the generation of a new set of monoclonal anibody allowed us to prove that mouse NK cells do express CD146. Indeed this expression increases during NK cell maturation and is restricted to NK cells among mouse lymphocytes.AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

CD146 mediates VEGF-induced melanoma cell extravasation through FAK activation

International audienc

Soluble CD146 displays angiogenic properties and promotes neovascularization in experimental hind-limb ischemia

International audienceCD146, an endothelial molecule involved in permeability and monocyte transmigration, has recently been reported to promote vessel growth. As CD146 is also detectable as a soluble form (sCD146), we hypothesized that sCD146 could stimulate angiogenesis. Experiments of Matrigel plugs in vivo showed that sCD146 displayed chemotactic activity on endogenous endothelial cells, and exogenously injected late endothelial progenitor cells (EPCs). Recruited endothelial cells participated in formation of vascular-like structures. In vitro, sCD146 enhanced angiogenic properties of EPCs, with an increased cell migration, proliferation, and capacity to establish capillary-like structures. Effects were additive with those of vascular endothelial growth factor (VEGF), and sCD146 enhanced VEGFR2 expression and VEGF secretion. Consistent with a proangiogenic role, gene expression profiling of sCD146-stimulated EPCs revealed an up-regulation of endothelial nitric oxide synthase, urokinase plasminogen activator, matrix metalloproteinase 2, and VEGFR2. Silencing membrane-bound CD146 inhibited responses. The potential therapeutic interest of sCD146 was tested in a model of hind limb ischemia. Local injections of sCD146 significantly reduced auto-amputation, tissue necrosis, fibrosis, inflammation, and increased blood flow. Together, these findings establish that sCD146 displays chemotactic and angiogenic properties and promotes efficient neovascularization in vivo. Recombinant human sCD146 might thus support novel strategies for therapeutic angiogenesis in ischemic diseases

Tuning of natural killer cell reactivity by NKp46 and Helios calibrates T cell responses.

International audienceNatural killer (NK) cells are lymphocytes involved in antimicrobial and antitumoral immune responses. Using N-ethyl-N-nitrosourea mutagenesis in mice, we identified a mutant with increased resistance to viral infections because of the presence of hyperresponsive NK cells. Whole-genome sequencing and functional analysis revealed a loss-of-function mutation in the Ncr1 gene encoding the activating receptor NKp46. The down-regulation of NK cell activity by NKp46 was associated with the silencing of the Helios transcription factor in NK cells. NKp46 was critical for the subsequent development of antiviral and antibacterial T cell responses, which suggests that the regulation of NK cell function by NKp46 allows for the optimal development of adaptive immune responses. NKp46 blockade enhanced NK cell reactivity in vivo, which could enable the design of immunostimulation strategies in humans

Integrative study of pandemic A/H1N1 influenza infections: design and methods of the CoPanFlu-France cohort

Abstract Background The risk of influenza infection depends on biological characteristics, individual or collective behaviors and the environmental context. The Cohorts for Pandemic Influenza (CoPanFlu) France study was set up in 2009 after the identification of the novel swine-origin A/H1N1 pandemic influenza virus. This cohort of 601 households (1450 subjects) representative for the general population aims at using an integrative approach to study the risk and characteristics of influenza infection as a complex combination of data collected from questionnaires regarding sociodemographic, medical, behavioral characteristics of subjects and indoor environment, using biological samples or environmental databases. Methods/Design Households were included between December 2009 and July 2010. The design of this study relies on systematic follow-up visits between influenza seasons and additional visits during influenza seasons, when an influenza-like illness is detected in a household via an active surveillance system. During systematic visits, a nurse collects individual and environmental data on questionnaires and obtains blood samples from all members of the household. When an influenza-like-illness is detected, a nurse visits the household three times during the 12 following days, and collects data on questionnaires regarding exposure and symptoms, and biological samples (including nasal swabs) from all subjects in the household. The end of the follow-up period is expected in fall 2012. Discussion The large amount of data collected throughout the follow-up will permit a multidisciplinary study of influenza infections. Additional data is being collected and analyzed in this ongoing cohort. The longitudinal analysis of these households will permit integrative analyses of complex phenomena such as individual, collective and environmental risk factors of infection, routes of transmission, or determinants of the immune response to infection or vaccination.</p

3MO - Comprehensive biomarkers (BMs) analysis to predict efficacy of PD1/L1 immune checkpoint inhibitors (ICIs) in combination with chemotherapy: a subgroup analysis of the Precision Immuno-Oncology for advanced Non-Small CEll Lung CancER (PIONeeR) trial

International audienc