Leukocytes migrating in lymph from the oro-nasal mucosae : interest for vaccination and immune tolerance

We developed a novel sheep model of lymphatic catheterisation to collect, in real time, cells circulating in the afferent lymph draining mainly the mucosae in the head. With this model, we were able to collect migrating leukocytes, either in their baseline condition, or after the administration of a vaccine antigen, from the oro-nasal mucosa to the draining lymph nodes where the immune response takes place. We showed that particulate antigens, such as bacteria, are taken from the tissues to the lymph nodes mainly by two types of cells, the monocytes and the granulocytes, and only occasionally by dendritic cells (DC). This finding challenges the general view, common among immunologists, whereby dendritic cells capture the antigen in the tissues before taking it to the lymph node. In addition, our study identified the permanent migration of a subset of DC - expressing the CD26 molecule – which carries cell-derived apoptotic bodies of self. This DC subset could be responsible for self-tolerance, a mechanism involved in control of transplant rejection, autoimmune diseases and vaccination.Un modèle original de cathétérisme lymphatique chez l'ovin, développé dans notre laboratoire, permet d'accéder en temps réel aux cellules en migration dans la lymphe drainant principalement les muqueuses de la tête de l'animal. Ainsi, à l'état basal ou après administration d'un antigène vaccinal, il est possible de collecter des cellules leucocytaires migrant depuis les muqueuses oro-nasales vers les ganglions, sites décisionnels de la réponse immune. Grâce à ce modèle, nous avons montré que des antigènes particulaires, notamment des bactéries, étaient transportés dans la lymphe essentiellement par deux types de cellules, les monocytes et les granulocytes et plus marginalement par les cellules dendritiques (DC). Ces résultats modifient la vision linéaire communément admise selon laquelle les DC capturent, transportent et présentent les antigènes aux lymphocytes naïfs; ils suggèrent que d'autres populations phagocytaires, impliquées dans le transport antigénique, pourraient moduler la réponse immune. Par ailleurs, nous avons mis en évidence la migration permanente d'une sous-population de DC, identifiée par la molécule CD26, qui transporte des débris de cellules du soi. Ce phénomène pourrait être impliqué dans la tolérance périphérique, mécanisme d'importance dans le rejet des greffes, les maladies auto-immunes et la vaccination

An in vitro model to assess the immunosuppressive effect of tick saliva on the mobilization of inflammatory monocyte-derived cells

Tick-borne pathogens cause potent infections. These pathogens benefit from molecules contained in tick saliva that have evolved to modulate host innate and adaptive immune responses. This is called "saliva-activated transmission" and enables tick-borne pathogens to evade host immune responses. Ticks feed on their host for relatively long periods; thus, mechanisms counteracting the inflammation-driven recruitment and activation of innate effector cells at the bite site, are an effective strategy to escape the immune response. Here, we developed an original in vitro model to evaluate and to characterize the immunomodulatory effects of tick saliva that prevent the establishment of a local inflammatory immune response. This model mimics the tick bite and enables the assessment of the effect of saliva on the inflammatory-associated dynamic recruitment of cells from the mononuclear phagocyte system. Using this model, we were able to recapitulate the dual effect of tick saliva on the mobilization of inflammatory monocyte-derived cells, i.e. (i) impaired recruitment of monocytes from the blood to the bite wound; and (ii) poor mobilization of monocyte-derived cells from the skin to the draining lymph node. This simple tool reconstitutes the effect of tick saliva in vivo, which we characterized in the mouse, and should enable the identification of important factors facilitating pathogen infection. Furthermore, this model may be applied to the characterization of any pathogen-derived immunosuppressive molecule affecting the establishment of the inflammatory immune response

Engulfing tumors with synthetic extracellular matrices for cancer

available in PMC 2010 June 1.Local immunotherapies are under investigation for the treatment of unresectable tumors and sites of solid tumor resection to prevent local recurrence. Successful local therapy could also theoretically elicit systemic immune responses against cancer. Here we explored the delivery of therapeutic dendritic cells (DCs), cytokines, or other immunostimulatory factors to tumors via the use of ‘self-gelling’ hydrogels based on the polysaccharide alginate, injected peritumorally around established melanoma lesions. Peritumoral injection of alginate matrices loaded with DCs and/or an interleukin-15 superagonist (IL-15SA) around 14-day established ova-expressing B16F0 murine melanoma tumors promoted immune cell accumulation in the peritumoral matrix, and matrix infiltration correlated with tumor infiltration by leukocytes. Single injections of IL-15SA-carrying gels concentrated the cytokine in the tumor site ∼40-fold compared to systemic injection and enabled a majority of treated animals to suppress tumor growth for a week or more. Further, we found that single injections of alginate matrices loaded with IL-15SA and the Toll-like receptor ligand CpG or two injections of gels carrying IL-15SA alone could elicit comparable anti-tumor activity without the need for exogenous DCs. Thus, injectable alginate gels offer an attractive platform for local tumor immunotherapy, and facilitate combinatorial treatments designed to promote immune responses locally at a tumor site while limiting systemic exposure to potent immunomodulatory factors.United States. Defense Advanced Research Projects Agency ( (contract # W81XWH-04-C-0139)National Institutes of Health (U.S.) (NIH Grant EB007280)National Institutes of Health (U.S.) (NIH Grant U54-CA126515)National Institutes of Health (U.S.) (NIH Grant U54-CA112967)National Science Foundation (U.S.) (award 0348259

The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8α+ dendritic cells

Human BDCA3+ dendritic cells (DCs) were suggested to be homologous to mouse CD8α+ DCs. We demonstrate that human BDCA3+ DCs are more efficient than their BDCA1+ counterparts or plasmacytoid DCs (pDCs) in cross-presenting antigen and activating CD8+ T cells, which is similar to mouse CD8α+ DCs as compared with CD11b+ DCs or pDCs, although with more moderate differences between human DC subsets. Yet, no specific marker was known to be shared between homologous DC subsets across species. We found that XC chemokine receptor 1 (XCR1) is specifically expressed and active in mouse CD8α+, human BDCA3+, and sheep CD26+ DCs and is conserved across species. The mRNA encoding the XCR1 ligand chemokine (C motif) ligand 1 (XCL1) is selectively expressed in natural killer (NK) and CD8+ T lymphocytes at steady-state and is enhanced upon activation. Moreover, the Xcl1 mRNA is selectively expressed at high levels in central memory compared with naive CD8+ T lymphocytes. Finally, XCR1−/− mice have decreased early CD8+ T cell responses to Listeria monocytogenes infection, which is associated with higher bacterial loads early in infection. Therefore, XCR1 constitutes the first conserved specific marker for cell subsets homologous to mouse CD8α+ DCs in higher vertebrates and promotes their ability to activate early CD8+ T cell defenses against an intracellular pathogenic bacteria

Neonatal Colonisation Expands a Specific Intestinal Antigen-Presenting Cell Subset Prior to CD4 T-Cell Expansion, without Altering T-Cell Repertoire

Interactions between the early-life colonising intestinal microbiota and the developing immune system are critical in determining the nature of immune responses in later life. Studies in neonatal animals in which this interaction can be examined are central to understanding the mechanisms by which the microbiota impacts on immune development and to developing therapies based on manipulation of the microbiome. The inbred piglet model represents a system that is comparable to human neonates and allows for control of the impact of maternal factors. Here we show that colonisation with a defined microbiota produces expansion of mucosal plasma cells and of T-lymphocytes without altering the repertoire of alpha beta T-cells in the intestine. Importantly, this is preceded by microbially-induced expansion of a signal regulatory protein α-positive (SIRPα+) antigen-presenting cell subset, whilst SIRPα−CD11R1+ antigen-presenting cells (APCs) are unaffected by colonisation. The central role of intestinal APCs in the induction and maintenance of mucosal immunity implicates SIRPα+ antigen-presenting cells as orchestrators of early-life mucosal immune development

Challenges and Opportunities of a Mucosal Platform for Nasal Vaccination

International audienc

Mise en œuvre d'un langage à mobilité forte

In order to avoid the problems raised by the integration of a growing number of programmable home appliances, we propose a language with mobile agents. These mobile agents are capable of migrating from one appliance or computer to another in order to work on its local resources, which allows us to benefit from each appliance's capabilities from a single program. This language is called ULM: Un Langage pour la Mobilité. We present in this dissertation its features, its differences with other languages, as well as its implementation. ULM is based on the Scheme language, to which we have added functionality linked with mobility and the communication of mobile agents. ULM has a number of primitives allowing the creation of strongly mobile agents, with a cooperative deterministic scheduling, and control primitives such as suspension or weak preemption. We present in this dissertation the integration of these primitives in the Scheme language, as well as their interaction and the addition of new primitives such as strong preemption and safe migration. We then present the denotational semantics, and its implementation with a bytecode compiler and two virtual machines: one written in Bigloo Scheme for execution on traditional computers, the other in Java ME for mobile phones. We present then the possible use of ULM as a replacement for programs written for event loops, the interfacing of ULM and external languages, a few examples of ULM applications, and future work before we conclude.Afin de résoudre les problèmes liés à l'intégration d'un nombre croissant d'appareils programmables, nous proposons un langage d'agents mobiles. Ces agents mobiles sont capables de migrer d'un appareil ou ordinateur à l'autre afin d'exploiter au mieux ses ressources, ce qui permet de profiter au mieux des capacités de chaque appareil à partir d'un unique programme. Ce langage est ULM: Un Langage pour la Mobilité. Nous présentons dans cette thèse ses fonctionnalités, ses particularités, ainsi que sa mise en œuvre. ULM est un dérivé du langage Scheme, auquel nous avons ajouté les fonctionnalités liées à la mobilité ainsi qu'à l'interaction entre les agents mobiles. ULM possède un ensemble de primitives permettant la création d'agents à mobilité forte, avec un ordonnancement coopératif déterministe, et des primitives de contrôles telles que la suspension ou la préemption faible. Nous présentons dans cette thèse l'intégration de ces primitives dans le langage Scheme, ainsi que leur interaction et l'ajout de certaines nouvelles primitives telles que la préemption forte ou la migration sûre. Nous présentons ensuite la sémantique dénotationnelle du langage et sa mise en œuvre au moyen d'un compilateur vers code-octet, et de deux machines virtuelles: une écrite en Bigloo Scheme pour exécution sur des ordinateurs traditionnels, l'autre écrite en Java ME pour les téléphones portables. Nous présentons ensuite l'utilisation possible d'ULM comme remplacement de programmes écrits pour des boucles d'évènements, l'interface entre ULM et des langages externes, quelques exemples d'utilisation d'ULM, puis les travaux futurs avant de conclure

Des modes de legitimation des enfants naturels.

LEIDSSTELSELOPLADEN-RUG0

Caractérisation biochimique de la variabilité des populations du puceron pois : Acyrthosiphon pisum (Harris)

*INRA, Laboratoire de zoologie, 86600 Lusignan (FRA) Diffusion du document : INRA, Laboratoire de zoologie, 86600 Lusignan (FRA) Diplôme : Maîtris

Mobile Reactive Programming in ULM

We present the embedding of ULM [7] in Scheme and an implementation of a compiler and virtual machine for it. ULM is a core programming model that allows multi-threaded and distributed programming via strong mobility with a deterministic semantics. We present the multi-threading and distributed primitives of ULM step by step using examples. The introduction of mobility in a Scheme language raises questions about the semantics of variables with respect to migration. We expose the problems and offer two solutions alongside ULM's network references. We also present our implementation of the compiler, virtual machine and the concurrent threading library written in Scheme