Tacrolimus pretreatment attenuates preexisting xenospecific immunity and abrogates hyperacute rejection in a presensitized hamster to rat liver transplant model

In the hamster to rat liver transplant model, we determined the efficacy of tacrolimus in attenuating natural xenospecific humoral immunity and in abrogating the hyperacute liver rejection that is produced by presensitizing the Lewis rat recipient. Hamster livers, transplanted orthotopically into naive rats (controls), were rejected with animal death after 6.4±0.5 (SD) days. The infusion on (day -6) of 1.5 x 107 hamster hepatocytes, or of 1.5 x 108 nonparenchymal cells (NPC), resulted in hyperacute rejection and death in ≤1.9 days. However, when the rats were pretreated with 1 mg/kg/day tacrolimus from days -6 to -1, survival of non-presensitized animals was prolonged to 25±20 days and that of recipients presensitized with hamster hepatocytes to 36±16 days or with NPC to 32±1.7 days. The tacrolimus pretreatment significantly reduced the hamster-specific complement-dependent cytotoxic antibodies response directed to liver NPC but not to lymph node cell targets. These observations suggest that the prolongation of survival by appropriately timed treatment with this T cell directed drug model is caused by the inhibition of humoral as well as cellular xenograft rejection

Intravital Two-Photon Imaging of T-Cell Priming and Tolerance in the Lymph Node

International audienceTwo-photon microscopy makes it possible to image in real-time fluorescently labeled cells located in deep tissue environments. We describe a procedure to visualize the behavior of lymph node T cells during either priming or tolerance, in live, anesthetized mice. Intravital imaging of T lymphocytes is a powerful tool to study the cellular orchestration of adaptive immune responses in physiological settings. This method should provide new insights into the regulation of lymphocyte migration and cell-cell interactions in various immunological contexts

CD4 T cells integrate signals delivered during successive DC encounters in vivo

International audienceThe cellular mode of T cell priming in vivo remains to be characterized fully. We investigated the fate of T cell-dendritic cell (DC) interactions in the late phase of T cell activation in the lymph node. In general, CD4 T cells detach from DCs before undergoing cell division. Using a new approach to track the history of antigen (Ag)-recognition events, we demonstrated that activated/divided T cells reengage different DCs in an Ag-specific manner. Two-photon imaging of intact lymph nodes suggested that T cells could establish prolonged interactions with DCs at multiple stages during the activation process. Importantly, signals that are delivered during subsequent DC contacts are integrated by the T cell and promote sustained IL-2R ␣ expression and IFN-␥ production. Thus, repeated encounters with Ag-bearing DCs can occur in vivo and modulate CD4 T cell differentiation programs

Intravital Two-Photon Imaging of Natural Killer Cells and Dendritic Cells in Lymph Nodes

International audienceTwo-photon microscopy makes it possible to image in real-time fluorescently labeled cells located in deep tissue environments. We describe a procedure to visualize the behavior of natural killer (NK) cells and dendritic cells (DC) in the lymph nodes of live, anesthetized mice. Intravital two-photon imaging is a powerful tool to study the migration and cell interactions of immune cells such as NK and DC in physiological settings

Real-Time Manipulation of T Cell-Dendritic Cell Interactions In Vivo Reveals the Importance of Prolonged Contacts for CD4+ T Cell Activation

International audienceT cells interact with dendritic cells (DCs) for periods lasting from minutes to hours. However, a causal link between the duration of this interaction and the efficiency of T cell activation has not been established in vivo. Employing intravital two-photon imaging, we manipulated T cell-DC interactions in real time and found that the first T cell-DC encounter often resulted in a long-lived interaction. Moreover, the cessation of T cell receptor-major histocompatibility complex signals promoted cellular dissociation, suggesting that antigen availability on DCs regulates contact duration. Finally, at least 6 hr of in vivo T cell-DC interaction were required for naive CD4 + T cells to undergo clonal expansion. These results establish the importance of prolonged T cell-DC interactions for efficient CD4 + T cell activation in vivo

Decoding the dynamics of T cell-dendritic cell interactions in vivo

International audienceT lymphocytes receive activation signals during their encounters with antigen-bearing dendritic cells (DCs) in secondary lymphoid organs. With the recent application of two-photon imaging to visualize immune responses as they happen, the dynamics of T cell-DC interactions have been dissected in several mouse models. As we are integrating the results of these new studies, we are learning that the dynamics of T cell-DC interactions are regulated by multiple immunological parameters and, most importantly, that the spatiotemporal characteristics of these cell-cell contacts encode part of the T-cell fate

Improvement of reliability in active networks with intentional islanding

DERs are gaining more and more importance in distribution and they are predicted to drastically change the whole distribution system. Distribution network will be no longer a passive termination of transmission network and the concept of active network has been recently introduced to indicate a new kind of distribution with DERs actively involved in system management and operation. Intentional islanding, i.e. the use of DG to supply portions (cells, microgrids) of distribution network during upstream line faults and scheduled interruptions, can be a valuable option to reduce the number of service interruptions. In the paper, an algorithm for the optimal allocation of automatic sectionalizing switching devices has been improved for the maximum exploitation of intentional islanding. Line faults and overloads have been considered as causes of interruptions. Stochastic models have been adopted to assess the probability of overloads and of properly functioning intentional islands. The application to real world case studies has highlighted the benefits achievable with intentional islanding as well as the inability of common reliability indexes (e.g. SAIFI, SAIDI) to properly perceive advantages that are inherently local

Multi-MicroGrids for innovative distribution networks in rural areas

MicroGrids (MGs) are one of the most promising developments for the distribution system to increase the reliability with respect to disturbances of power delivery and the resiliency of some localised areas with reference to major external events capable to cause extended black-outs. With a distribution design that allows the decomposition into small, autonomous portions like MGs, customers that are not directly involved in the fault can be supplied. In this case, the distribution system acts as a backbone that provides connectivity to several MGs. The system can be regarded as a Multi-MicroGrid (MMG). It requires rethinking the operational/planning methodologies of distribution systems to exploit the opportunities from such a novel arrangement. In this paper, a planning methodology is presented that aims at defining expansion plans for MV distribution systems with MGs, using probabilistic approaches to taking into account the variability of loads and Distributed Generation. It allows the distribution planner to find the optimal development plan of a given distribution network, particularly in rural areas. The application to realistic case studies highlights the benefits from MMG intentional islanding, with reference to the postponement of network investments and improvement of Quality of Service