Ganglion lymphatique | EPFL Graph Search

Les ganglions lymphatiques (dits « lymphonœuds » ou encore « nœuds lymphatiques » dans la nomenclature internationale, traduction du latin nodi lymphatici) sont des petits amas réniformes dont la taille varie de l'un à l'autre. On en dénombre chez l'humain environ 800, pour une masse totale de . Ils sont le lieu de prolifération et de différenciation des cellules immunitaires. Le premier rôle des vaisseaux lymphatiques est d’amener un antigène (dans la grande majorité des cas issu d’un pathogène) du tissu jusqu’aux ganglions, afin d’activer la réponse immunitaire spécifique des lymphocytes T et B. Localisation Les ganglions lymphatiques sont situés le long du réseau lymphatique, regroupés en certains points « stratégiques » :

les réseaux profonds : au niveau de l’abdomen, du thorax, du cou, etc. ;
les réseaux superficiels : aux niveaux inguinal, axillaire, occipital, cervical, etc. Les ganglions font partie du tissu lymphoïde ; tissu important, structuré en résea

Elucidating the mechanisms of paclitaxel-loaded-nanoparticle-induced immune response

Efthymia Vokali

Dentritic cells (DC) are the most potent antigen-presenting cells and play a key role in the induction of effective immune responses, suggesting a novel target for anti-tumor immunotherapy. Paclitaxel (PXL) is a widely used chemotherapeutic, initially characterized as a mitotic inhibitor, that has been shown to enhance maturation and function of DCs as well as up-regulate the production of inflammatory cytokines. Thus, modulation of DC function by the approved-for-human-use PXL could constitute a novel approach for reshaping immune responses against a tumor. For targeted delivery of PXL to DCs in the lymph nodes (LNs), where they are present in high concentrations and apt for antigen uptake, poly(propylene) sulfide core nanopatricles (NPs) developed by our laboratory have been used. PXL loaded-NP (PXL-NP) treatment induces massive immune cell infiltration into the draining LN 24h after intradermal injection of PXL-NPs in mice, suggesting that PXL-NP treatment induces a local and robust immune response (Thomas et al., in preparation). We hypothesized that this effect stems directly from the action of PXL-NPs on LN-resident DCs. We demonstrate that PXL-NPs are able to induce maturation and cytokine production in murine and human DCs in vitro, which may explain the in vivo observations of robust cell recruitment to the draining LN and generation of adaptive immune responses. Furthermore, the striking cell infiltration in the LN upon PXL-NP treatment was abrogated in complement protein 3 (C3) knockout mice in vivo (Thomas et al. in preparation). Interestingly, we show that the presence of C3 regulates IL-12p40 expression and, in turn, plays a crucial role in the activation of mature, functional DCs in response to PXL-NPs. Thus, the absence of functional DCs in case of C3 deficiency might account for the hindered infiltration. Together, this data suggests that PXL-NPs may effectively direct the immunomodulatory action of PXL to LN-resident DCs to alter immune responses.

2011

New immunomodulatory roles of lymphatic endothelium and implications for immunotherapy

Efthymia Vokali

The lymphatic system serves a critical role in fluid homeostasis, lipid metabolism and immune surveillance. The growing appreciation of its implication in various diseases challenges the conventional view of lymphatics as a passive transport system. Traditionally, the lymphatic endothelium has been perceived as a structural scaffold with certain immunological functions but no active involvement in immunomodulation. In the lymph nodes (LNs), the main sites of immune regulation in the periphery, lymphatic endothelial cells (LECs) come to close contact with immune cells, suggesting potential interactions. Indeed, LECs have been recently shown to suppress dendritic cell maturation and present peripheral tissue and tumor antigen for CD8+ T cell deletion. While LECs have only begun to be acknowledged as active regulators of immunity, their function and relative contribution in shaping immune responses is as yet poorly understood. This thesis aimed to elucidate the direct role of LECs in the induction of CD8+ T cell immunity and tolerance. First, we demonstrated that murine LECs can actively scavenge and cross-present exogenous antigen to cognate CD8+ T cells under non-inflamed conditions. By utilizing an in vitro coculture system and the model antigen ovalbumin, we investigated the antigen-specific interactions between LECs and CD8+ T cells. LEC-educated CD8+ T cells proliferated, exhibiting an activated phenotype, however, they displayed early-generation apoptosis and failed to produce effector cytokines. Our findings establish LECs as antigen-presenting cells and suggest that they may assist in the maintenance of peripheral tolerance during homeostasis. The particular differentiation state of LEC-educated CD8+ T cells prompted us to investigate whether they are terminally tolerized or they could escape the dysfunctional state. We demonstrated that LEC-educated CD8+ T cells adopted a distinct phenotype with central memory-like characteristics and shared multiple functional properties with memory cells. Upon antigen re-encounter, LEC-educated CD8+ T cells mounted proliferative responses and generated cytotoxic effector cells. More importantly, they participated in anti-infectious immunity while preserving a secondary-memory persistent population. Our findings reveal a unique differentiation state of antigen-experienced CD8+ T cells, generated under steady-state conditions, which remain inactive but can be functionally reactivated upon antigenic inflammatory challenge. This previously unanticipated feature of LECs triggered questions for their antigen-presenting function in an inflammatory setting. We asked whether the previously observed extensive proliferation of LECs in the LN during inflammation might directly influence the induction of immunity. We employed an anti-VEGFR3 blocking antibody to inhibit LEC proliferation and thus, reduce the number of LECs following vaccine immunization. Alternatively, we generated the Prox1-Cre-DTR mouse model, allowing for specific ablation of LECs following administration of diphtheria toxin in vivo. Our findings advance our perception of the relative contribution of LECs in the establishment of adaptive immunity. This thesis elucidates the multifaceted immunological role of LECs and strongly suggests the importance of harnessing their immunomodulatory function to enhance current vaccines and immunotherapeutic strategies. Looking forward, our work will contribute to future advances in the clinic.

EPFL2016

Elucidating the mechanisms of paclitaxel-loaded-nanoparticle-induced immune response

Efthymia Vokali

2011

New immunomodulatory roles of lymphatic endothelium and implications for immunotherapy

Efthymia Vokali

EPFL2016