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Sophie Ugloni
Head of the lab 'Neural regulation of Immunity' Centre d'Immunologie de Marseille Luminy Parc Scientifique et technologique de Luminy
Title : Neuroimmune crosstalk in the skin
Abstract : The survival of living organisms depends on their capacity to develop mechanisms of defense against environmental challenges causing tissue damage and infections. These protective functions involve both the immune and nervous systems, which have traditionally been considered independent. However, the nervous system has recently been shown to regulate immune functions. Pain is one of the major signs of inflammation. Following injury or infection, inflammatory mediators activate nociceptive sensory neurons in tissues. These neurons transmit the signal to the brain, eliciting pain. They also release a number of mediators directly at the site of injury, modulating local immune responses. We recently demonstrated a key role for subsets of sensory neurons in limiting inflammation and promoting macrophage tissue-repair functions in the skin. The sensory nervous system also regulates the adaptive immune response to Herpes simplex virus type 1 (HSV-1) infection. We are exploring the molecular and cellular basis of these neuro-immune regulations and the potential therapeutic value of our findings for the treatment of inflammatory diseases.
Homaira Nawabi
Head of the GIN team « Central nervous system : development to regeneration »
Grenoble Institute of Neuroscience
Title : Adult axon guidance to reform a functionnal circuit in the visual system
Abstract : Impairment of the CNS often affects vital functions such as vision, in the case of glaucoma, or motor function, in the cases of multiple sclerosis or spinal cord injuries. Most of the patients suffering from CNS injuries must endure irreversible disabilities as a result of these insults. Moreover, injuries to the spinal cord often affect young adults, who will have to deal with severe disabilities for the rest of their lives. The main cause for a lack of efficient treatment is that unlike young neurons, mature neurons from the CNS lose the ability to regenerate their axons after injury. Thus understanding the detailed mechanisms of neuronal growth, repair and functional recovery remains not only one of the greatest questions of neurobiology but represents also a major challenge for public health and society.
Guidance of regenerative fibers
Manipulating extrinsic factors failed to reach the expected regeneration. However modulating intrinsic pathways has shown promising results. Particularly, our work demonstrated that the simultaneous activation of mTOR, JAK/STAT and c-myc pathways allows exceptional regeneration with axons close to their targets. However it also exacerbates previously described phenomenon of misguidance with potential aberrant circuit formation. In this context, we address the yet unexplored problem of the guidance of regenerating axons in adults in order to promote the formation of a functional new circuit after injury.
Mechanisms to promote regeneration
The absence of treatment to overcome CNS regenerative failure is pointing out our lack of knowledge in the detailed mechanisms of neuronal growth, repair and their fine-tuning during development and injury. We believe that the translation machinery holds the key to unlock the regenerative failure of central nervous system.
Bruno Silva-Santos
Professor & Director of Immuno-Oncology, Faculdade de Medicina da Universidade de Lisboa;
Group Leader & Vice-Director, Instituto de Medicina Molecular João Lobo Antunes.
Title : Delta One T cells: a new adoptive cell therapy for cancer
Abstract : Adoptive cell therapy is perceived as the most promising avenue for immunotherapy of leukemias. Although already implemented in the clinic as an autologous treatment for B-cell malignancies, around 50% of the patients relapse at 1-year post-treatment. T cell “fitness” is perceived as critical to prolong the persistence and activity of the adoptively transferred product. Allogeneic T cells from healthy donors are a very attractive option, less dysfunctional or exhausted than autologous patient-derived T-cells, and enabling an “off-the-shelf” therapy. We have developed Delta One T cells (DOT cells) as an allogeneic cellular product based on MHC/HLA-independent Vd1+ gd T-cells from the peripheral blood of healthy donors, and demonstrated their potent anti-leukemic activity in pre-clinical models of Acute Myeloid Leukemia (AML), the most aggressive hematological malignancy. We have further dissected the (endogenous) molecular mechanisms of AML targeting by DOT cells; and enhanced their efficacy through (exogenous) Chimeric Antigen Receptor (CAR) transduction. Thus, using CRISPR/ Cas9-mediated gene editing and antibody-mediated receptor blockade, we showed that the NK-cell receptor, DNAM-1, is a critical determinant of DOT-cell recognition through interactions with its ligands, PVR and Nectin-2, on AML cells. Moreover, using a 4-1BB-based and CD123-directed CAR (CAR123), we have enhanced the intrinsic capacity of DOT cells to eliminate AML cell lines and primary samples both in vitro and in vivo. Strikingly, IL-15 infusions increased single-dose CAR123-DOT persistence in a patient-derived xenograft model, sustaining their anti-leukemic efficacy as demonstrated upon tumor re-challenge in vivo. Our work supports the clinical application of DOT-based cellular products as next-generation allogeneic therapies of cancer, which we are now exploring in the context of solid tumors.
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