Projecting Changes in the Distribution and Productivity of Living Marine Resources: A Critical Review of the Suite of Modeling Approaches used in the Large European Project VECTORS

We review and compare four broad categories of spatially-explicit modelling approaches currently used to understand and project changes in the distribution and productivity of living marine resources including: 1) statistical species distribution models, 2) physiology-based, biophysical models of single life stages or the whole life cycle of species, 3) food web models, and 4) end-to-end models. Single pressures are rare and, in the future, models must be able to examine multiple factors affecting living marine resources such as interactions between: i) climate-driven changes in temperature regimes and acidification, ii) reductions in water quality due to eutrophication, iii) the introduction of alien invasive species, and/or iv) (over-)exploitation by fisheries. Statistical (correlative) approaches can be used to detect historical patterns which may not be relevant in the future. Advancing predictive capacity of changes in distribution and productivity of living marine resources requires explicit modelling of biological and physical mechanisms. New formulations are needed which (depending on the question) will need to strive for more realism in ecophysiology and behaviour of individuals, life history strategies of species, as well as trophodynamic interactions occurring at different spatial scales. Coupling existing models (e.g. physical, biological, economic) is one avenue that has proven successful. However, fundamental advancements are needed to address key issues such as the adaptive capacity of species/groups and ecosystems. The continued development of end-to-end models (e.g., physics to fish to human sectors) will be critical if we hope to assess how multiple pressures may interact to cause changes in living marine resources including the ecological and economic costs and trade-offs of different spatial management strategies. Given the strengths and weaknesses of the various types of models reviewed here, confidence in projections of changes in the distribution and productivity of living marine resources will be increased by assessing model structural uncertainty through biological ensemble modelling.

Projecting Changes in the Distribution and Productivity of Living Marine Resources: A Critical Review of the Suite of Modeling Approaches used in the Large European Project VECTORS

We review and compare four broad categories of spatially-explicit modelling approaches currently used to understand and project changes in the distribution and productivity of living marine resources including: 1) statistical species distribution models, 2) physiology-based, biophysical models of single life stages or the whole life cycle of species, 3) food web models, and 4) end-to-end models. Single pressures are rare and, in the future, models must be able to examine multiple factors affecting living marine resources such as interactions between: i) climate-driven changes in temperature regimes and acidification, ii) reductions in water quality due to eutrophication, iii) the introduction of alien invasive species, and/or iv) (over-)exploitation by fisheries. Statistical (correlative) approaches can be used to detect historical patterns which may not be relevant in the future. Advancing predictive capacity of changes in distribution and productivity of living marine resources requires explicit modelling of biological and physical mechanisms. New formulations are needed which (depending on the question) will need to strive for more realism in ecophysiology and behaviour of individuals, life history strategies of species, as well as trophodynamic interactions occurring at different spatial scales. Coupling existing models (e.g. physical, biological, economic) is one avenue that has proven successful. However, fundamental advancements are needed to address key issues such as the adaptive capacity of species/groups and ecosystems. The continued development of end-to-end models (e.g., physics to fish to human sectors) will be critical if we hope to assess how multiple pressures may interact to cause changes in living marine resources including the ecological and economic costs and trade-offs of different spatial management strategies. Given the strengths and weaknesses of the various types of models reviewed here, confidence in projections of changes in the distribution and productivity of living marine resources will be increased by assessing model structural uncertainty through biological ensemble modelling.

Tropical cyclone perceptions, impacts and adaptation in the Southwest Pacific: an urban perspective from Fiji, Vanuatu and Tonga

The destruction caused by tropical cyclone (TC) Pam in March 2015 is considered one of the worst natural disasters in the history of Vanuatu. It has highlighted the need for a better understanding of TC impacts and adaptation in the Southwest Pacific (SWP) region. Therefore, the key aims of this study are to (i) understand local perceptions of TC activity, (ii) investigate impacts of TC activity and (iii) uncover adaptation strategies used to offset the impacts of TCs. To address these aims, a survey (with 130 participants from urban areas) was conducted across three SWP small island states (SISs): Fiji, Vanuatu and Tonga (FVT). It was found that respondents generally had a high level of risk perception and awareness of TCs and the associated physical impacts, but lacked an understanding of the underlying weather conditions. Responses highlighted that current methods of adaptation generally occur at the local level, immediately prior to a TC event (preparation of property, gathering of food, finding a safe place to shelter). However higher level adaptation measures (such as the modification to building structures) may reduce vulnerability further. Finally, we discuss the potential
of utilising weather-related traditional knowledge and nontraditional knowledge of empirical and climate-model-based weather forecasts to improve TC outlooks, which would ultimately reduce vulnerability and increase adaptive capacity. Importantly, lessons learned from this study may result in the modification and/or development of existing adaptation strategies.

Farmers' Resilience to Climate Change in the Welsh Marshes

Climate change will exacerbate challenges facing food security in the UK. Increasing frequency and intensity of extreme weather events will further impact upon farm systems. At the heart of the impending challenges to UK agricultural production, farmers’ resilience will be tested to new limits. Research into farmers’ resilience to climate change in the UK is distinctly underdeveloped when compared to research in developing and other developed nations. This research gap is addressed through exploration of farmers’ resilience in the Welsh Marches, establishing the role of risk perceptions, local knowledge and adaptive capacity in farmers’ decision-making to limit climate shocks. Further contributions to agricultural geography are made through experimentation of a ‘cultural-behavioural approach’, seeking to revisit the behavioural approach in view of the cultural-turn. The Welsh Marches, situated on the English-Welsh border, has been selected as a focal point due to its agricultural diversity, and known experiences of extreme weather events. A phased mixed methodological approach is adopted. Phase one explores recorded and reported experiences of past extreme weather events in local meteorological records and local newspaper articles. Phase two consists of 115 survey-questionnaires, 15 in-depth semi-structured interviews, and a scenario based focus group with selected farmers from the Welsh Marches. This allows farmers’ resilience to climate change in the past, present and future to be explored. Original contributions to knowledge are made through demonstrating the value of focusing upon the culture of a specific farm community, applying a ‘bottom-up’ approach. The priority given to the weather in farmers’ decision-making is identified to be determined by individual relationships that farmers’ develop with the weather. Yet, a consensus of farmers’ observations has established recognition of considerable changes in the weather over the last 30 years, acknowledging more extremes and seasonal variations. In contrast, perceptions of future climate change are largely varied. Farmers are found to be disengaged with the communication of climate change science, as the global impacts portrayed are distant in time and place from probable impacts that may be experienced locally. Current communication of climate change information has been identified to alienate farmers from the local reality of probable future impacts. Adaptation options and responses to extreme weather and climate change are identified from measures found to be already implemented and considered for the future. A greater need to explore local knowledge and risk perception in relation to farmers’ understanding of future climate challenges is clear. There is a need to conduct comparable research in different farm communities across the UK. Progression into establishing the role of farmers’ resilience in responding effectively to future climate challenges has only just begun.

The Welsh Marches: Resilient Farmers? Exploring Farmers' Resilience to Extreme Weather Events in the Recent Past

In the 21st century climate change will cause a significant increase in the frequency and intensity of extreme weather events across Europe. Investigating farmers’ resilience to extreme weather events in the past can be used to establish the inherent level of resilience farmers’ will have to respond to comparable events in the future. The Welsh Marches has experienced a range of extreme weather events including: heatwaves, flooding; prolonged rainfall; and heavy snowfall. To identify the resilience of farmers in the Marches farmers’ apparent vulnerabilities, coping capacity, social capital and adaptive capacity that have been exposed in past events are discussed. Rural isolation is identified as an exacerbating factor of farming vulnerability. Yet, this is also an apparent source of resilience as farmers are found to rely on high social capital to assist each other in emergency and challenging situations during extreme weather events. The paper concludes by indicating that more localised studies are required, situated within unique farming cultures. This will enable a more complete picture of farmers’ resilience across Europe to be established.

Assessment of change in psychoanalysis : Another way of using the change after psychotherapy scales

A systematic method is presented whereby material from a full course of psychoanalytic treatment is analyzed to assess changes and identify patterns of change. Through an analysis of session notes, changes were assessed using the CHange After Psychotherapy scales (CHAP; Sandell 1987a), which evaluate changes in five rating variables (symptoms, adaptive capacity, insight, basic conflicts, and extratherapeutic factors). Change incidents were identified in nearly every session. Early in the analysis, relatively more change incidents related to insight were found than were found for the other types of change. By contrast, in the third year and part of the fourth year, relatively more change incidents related to basic conflicts and adaptive capacity were found. While changes related to symptoms occurred throughout the course of treatment, such changes were never more frequent than other types of change. A content analysis of the change incidents allowed a determination of when in the treatment the patient's main conflicts (identified clinically) were overcome. A crossing of quantitative data with clinical and qualitative data allowed a better understanding of the patterns of change.

Assessing and reducing vulnerability to climate change: Moving from theory to practical decision-support

As climate change continues to impact socio-ecological systems, tools that assist conservation managers to understand vulnerability and target adaptations are essential. Quantitative assessments of vulnerability are rare because available frameworks are complex and lack guidance for dealing with data limitations and integrating across scales and disciplines. This paper describes a semi-quantitative method for assessing vulnerability to climate change that integrates socio-ecological factors to address management objectives and support decision-making. The method applies a framework first adopted by the Intergovernmental Panel on Climate Change and uses a structured 10-step process. The scores for each framework element are normalized and multiplied to produce a vulnerability score and then the assessed components are ranked from high to low vulnerability. Sensitivity analyses determine which indicators most influence the analysis and the resultant decision-making process so data quality for these indicators can be reviewed to increase robustness. Prioritisation of components for conservation considers other economic, social and cultural values with vulnerability rankings to target actions that reduce vulnerability to climate change by decreasing exposure or sensitivity and/or increasing adaptive capacity. This framework provides practical decision-support and has been applied to marine ecosystems and fisheries, with two case applications provided as examples: (1) food security in Pacific Island nations under climate-driven fish declines, and (2) fisheries in the Gulf of Carpentaria, northern Australia. The step-wise process outlined here is broadly applicable and can be undertaken with minimal resources using existing data, thereby having great potential to inform adaptive natural resource management in diverse locations.

Integrating Environmental Justice and Social-Ecological Resilience for Successful Adaptation to Climate Change: Lessons from African American Communities on the Eastern Shore of the Chesapeake Bay

This research concerns the conceptual and empirical relationship between environmental justice and social-ecological resilience as it relates to climate change vulnerability and adaptation. Two primary questions guided this work. First, what is the level of resilience and adaptive capacity for social-ecological systems that are characterized by environmental injustice in the face of climate change? And second, what is the role of an environmental justice approach in developing adaptation policies that will promote social-ecological resilience? These questions were investigated in three African American communities that are particularly vulnerable to flooding from sea-level rise on the Eastern Shore of the Chesapeake Bay. Using qualitative and quantitative methods, I found that in all three communities, religious faith and the church, rootedness in the landscape, and race relations were highly salient to community experience. The degree to which these common aspects of the communities have imparted adaptive capacity has changed over time. Importantly, a given social-ecological factor does not have the same effect on vulnerability in all communities; however, in all communities political isolation decreases adaptive capacity and increases vulnerability. This political isolation is at least partly due to procedural injustice, which occurs for a number of interrelated reasons. This research further revealed that while all stakeholders (policymakers, environmentalists, and African American community members) generally agree that justice needs to be increased on the Eastern Shore, stakeholder groups disagree about what a justice approach to adaptation would look like. When brought together at a workshop, however, these stakeholders were able to identify numerous challenges and opportunities for increasing justice. Resilience was assessed by the presence of four resilience factors: living with uncertainty, nurturing diversity, combining different types of knowledge, and creating opportunities for self-organization. Overall, these communities seem to have low resilience; however, there is potential for resilience to increase. Finally, I argue that the use of resilience theory for environmental justice communities is limited by the great breadth and depth of knowledge required to evaluate the state of the social-ecological system, the complexities of simultaneously promoting resilience at both the regional and local scale, and the lack of attention to issues of justice.

Climate change adaptation solutions for the green sectors of selected zones in the MENA region

In this paper, we propose climate adaptation solutions for the green sectors in three different zones of MENA: Egypt’s Delta (irrigated), Karak, in the highlands of Jordan (rainfed), and Lebanon’s Orontes basin (mixed: rainfed-irrigated). We analysed land use and crop intensification, and calculated the economic productivity of water – a critical scarce resource in MENA. By integrating the results with evidence from literature on the potential impacts of climate change and socio-economic factors, we could identify vulnerability levels of the three regions and propose adaptation measures relying of the concept of the “food-water-energy nexus.” While the vulnerability levels are found to be high in the Delta (Egypt) and Karak (Jordan), mainly due to water scarcity and poor adaptive capacity, the vulnerability level is moderate in the Orontes zone (Lebanon) due to a diversified agricultural sector and good market development, coupled with moderate water scarcity. Proposed adaptation solutions range from measures to improve technical efficiency, to measures that encourage economically efficient allocation by use of market forces. For both cases, the development of market opportunities is emphasized to make the proposed measures attractive to farmers.

Les méthodes d’adaptation du Centre des droits de l’homme "Memorial" aux mesures étatiques russes- Les principes d’action d’une ONG de défense des droits de l’homme russe

En raison du virage semi-autoritaire de l’État russe au début des années 2000, l’adaptation aux mesures contraignantes de l’État, qu’elle soit consciente ou inconsciente, constitue un aspect fondamental du quotidien des ONG de défense des droits de l’homme russes. Cependant, il s’agit d’une question jusqu’ici négligée dans la littérature scientifique. Ainsi, ce mémoire a pour objet d’examiner la démarche d’adaptation d’une ONG particulièrement active sur la scène russe, le Centre des droits de l’homme Memorial, entre 1999 et 2014. La recherche révèle que cette ONG emploie deux méthodes afin de s’adapter aux mesures étatiques et que celles-ci sont, en fait, des principes d’action adoptés par l’organisation au moment de sa création. Le premier principe d’action s’appuie sur la coopération et la solidarité développées par le Centre des droits de l’homme Memorial avec d’autres ONG russes, des ONG internationales et des organisations internationales. En partenariat avec ces organisations, le Centre des droits de l’homme Memorial élabore des activités de recherche et de plaidoyer et mène des missions de surveillance des droits de l’homme. Ce principe d’action renforce considérablement la capacité d’adaptation de l’ONG et favorise l’exercice de son rôle de contrepouvoir. Le second principe d’action se fonde sur la recherche de collaboration constructive avec l’État. Lors d’interactions ponctuelles avec les autorités, l’organisation exerce un rôle d’expert en matière de droits de l’homme et tente de réduire les entraves posées à la société civile. Outre sa propriété adaptative, cette méthode d’adaptation combine deux fonctions inhérentes à la société civile, soit la représentation des intérêts des citoyens auprès des instances étatiques et l’établissement d’un partenariat avec l’État dans le but d’amener ce dernier à adopter des pratiques démocratiques. Ce mémoire montre la capacité du Centre des droits de l’homme Memorial à se mouvoir d’une méthode d’adaptation à l’autre afin de maximiser son action.

Adaptive control of hybrid battery energy storage systems under capacity fade

There is an increasing call for applications which use a mixture of batteries. These hybrid battery solutions may contain different battery types for example; using second life ex-transportation batteries in grid support applications or a combination of high power, low energy and low power, high energy batteries to meet multiple energy requirements or even the same battery types but under different states of health for example, being able to hot swap out a battery when it has failed in an application without changing all the batteries and ending up with batteries with different performances, capacities and impedances. These types of applications typically use multi-modular converters to allow hot swapping to take place without affecting the overall performance of the system. A key element of the control is how the different battery performance characteristics may be taken into account and the how the power is then shared among the different batteries in line with their performance. This paper proposes a control strategy which allows the power in the batteries to be effectively distributed even under capacity fade conditions using adaptive power sharing strategy. This strategy is then validated against a system of three different battery types connected to a multi-modular converter both with and without capacity fade mechanisms in place.

Sialyl Tn-Expressing Bladder Cancer Cells Induce a Tolerogenic Phenotype in Innate and Adaptive Immune Cells

Despite the wide acceptance that glycans are centrally implicated in immunity, exactly how they contribute to the tilt immune response remains poorly defined. In this study, we sought to evaluate the impact of the malignant phenotype-associated glycan, sialyl-Tn (STn) in the function of the key orchestrators of the immune response, the dendritic cells (DCs). In high grade bladder cancer tissue, the STn antigen is significantly overexpressed and correlated with the increased expression of ST6GALNAC1 sialyltransferase. Bladder cancer tissue presenting elevated expression of ST6GALNAC1 showed a correlation with increased expression of CD1a, a marker for bladder immature DCs and showed concomitant low levels of Th1-inducing cytokines IL-12 and TNF-α. In vitro, human DCs co-incubated with STn+ bladder cancer cells, had an immature phenotype (MHC-IIlow, CD80low and CD86low) and were unresponsive to further maturation stimuli. When contacting with STn+ cancer cells, DCs expressed significantly less IL-12 and TNF-α. Consistent with a tolerogenic DC profile, T cells that were primed by DCs pulsed with antigens derived from STn+ cancer cells were not activated and showed a FoxP3high IFN-γlow phenotype. Blockade of STn antigens and of STn+ glycoprotein, CD44 and MUC1, in STn+ cancer cells was able to lower the induction of tolerance and DCs become more mature. Overall, our data suggest that STn-expressing cancer cells impair DC maturation and endow DCs with a tolerogenic function, limiting their capacity to trigger protective anti-tumour T cell responses. STn antigens and, in particular, STn+ glycoproteins are potential targets for circumventing tumour-induced tolerogenic mechanisms.

HARNESSING iNKT CELLS WITH RECOMBINANT CD1d FUSION PROTEINS TO REDIRECT INNATE AND ADAPTIVE IMMUNITY TO THE TUMOR

Les thérapies du cancer, comme la radiothérapie et la chimiothérapie, sont couramment utilisées mais ont de nombreux effets secondaires. Ces thérapies invasives pour le patient nécessitent d'être améliorées et de nombreuses avancées ont été faites afin d'adapter et de personnaliser le traitement du cancer. L'immunothérapie a pour but de renforcer le système immunitaire du patient et de le rediriger de manière spécifique contre la tumeur. Dans notre projet, nous activons les lymphocytes Invariant Natural Killer T (iNKT) afin de mettre en place une immunothérapie innovatrice contre le cancer. Les cellules iNKT sont une unique sous-population de lymphocytes T qui ont la particularité de réunir les propriétés de l'immunité innée ainsi qu'adaptative. En effet, les cellules iNKT expriment à leur surface des molécules présentes aussi sur les cellules tueuses NK, caractéristique de l'immunité innée, ainsi qu'un récepteur de cellules T (TCR) qui représente l'immunité adaptative. Les cellules iNKT reconnaissent avec leur TCR des antigènes présentés par la molécule CD1d. Les antigènes sont des protéines, des polysaccharides ou des lipides reconnus par les cellules du système immunitaire ou les anticorps pour engendrer une réponse immunitaire. Dans le cas des cellules iNKT, l'alpha-galactosylceramide (αGC) est un antigène lipidique fréquemment utilisé dans les études cliniques comme puissant activateur. Après l'activation des cellules iNKT avec l'αGC, celles-ci produisent abondamment et rapidement des cytokines. Ces cytokines sont des molécules agissant comme des signaux activateurs d'autres cellules du système immunitaire telles que les cellules NK et les lymphocytes T. Cependant, les cellules iNKT deviennent anergiques après un seul traitement avec l'αGC c'est à dire qu'elles ne peuvent plus être réactivées, ce qui limite leur utilisation dans l'immunothérapie du cancer. Dans notre groupe, Stirnemann et al ont publié une molécule recombinante innovante, composée de la molécule CD1d soluble et chargée avec le ligand αGC (αGC/sCD1d). Cette protéine est capable d'activer les cellules iNKT tout en évitant l'anergie. Dans le système immunitaire, les anticorps sont indispensables pour combattre une infection bactérienne ou virale. En effet, les anticorps ont la capacité de reconnaître et lier spécifiquement un antigène et permettent l'élimination de la cellule qui exprime cet antigène. Dans le domaine de l'immunothérapie, les anticorps sont utilisés afin de cibler des antigènes présentés seulement par la tumeur. Ce procédé permet de réduire efficacement les effets secondaires lors du traitement du cancer. Nous avons donc fusionné la protéine recombinante αGC/CD1d à un fragment d'anticorps qui reconnaît un antigène spécifique des cellules tumorales. Dans une étude préclinique, nous avons démontré que la protéine αGC/sCD1d avec un fragment d'anticorps dirigé contre la tumeur engendre une meilleure activation des cellules iNKT et entraîne un effet anti-tumeur prolongé. Cet effet anti-tumeur est augmenté comparé à une protéine αGC/CD1d qui ne cible pas la tumeur. Nous avons aussi montré que l'activation des cellules iNKT avec la protéine αGC/sCD1d-anti-tumeur améliore l'effet anti- tumoral d'un vaccin pour le cancer. Lors d'expériences in vitro, la protéine αGC/sCD1d-anti- tumeur permet aussi d'activer les cellules humaines iNKT et ainsi tuer spécifiquement les cellules tumorales humaines. La protéine αGC/sCD1d-anti-tumeur représente une alternative thérapeutique prometteuse dans l'immunothérapie du cancer. - Les cellules Invariant Natural Killer T (iNKT), dont les effets anti-tumoraux ont été démontrés, sont de puissants activateurs des cellules Natural Killer (NK), des cellules dendritiques (DC) et des lymphocytes T. Cependant, une seule injection du ligand de haute affinité alpha-galactosylceramide (αGC) n'induit une forte activation des cellules iNKT que durant une courte période. Celle-ci est alors suivie d'une longue phase d'anergie, limitant ainsi leur utilisation pour la thérapie. Comme alternative prometteuse, nous avons montré que des injections répétées d'αGC chargé sur une protéine recombinante de CD1d soluble (αGC/sCD1d) chez la souris entraînent une activation prolongée des cellules iNKT, associée à une production continue de cytokine. De plus, le maintien de la réactivité des cellules iNKT permet de prolonger l'activité anti-tumorale lorsque la protéine αGC/sCD1d est fusionnée à un fragment d'anticorps (scFv) dirigé contre la tumeur. L'inhibition de la croissance tumorale n'est optimale que lorsque les souris sont traitées avec la protéine αGC/sCD1d-scFv ciblant la tumeur, la protéine αGC/sCD1d-scFv non-appropriée étant moins efficace. Dans le système humain, les protéines recombinantes αGC/sCD1d-anti-HER2 et anti-CEA sont capables d'activer et de faire proliférer des cellules iNKT à partir de PBMCs issues de donneurs sains. De plus, la protéine αGC/sCD1d-scFv a la capacité d'activer directement des clones iNKT humains en l'absence de cellules présentatrices d'antigènes (CPA), contrairement au ligand αGC libre. Mais surtout, la lyse des cellules tumorales par les iNKT humaines n'est obtenue que lorsqu'elles sont incubées avec la protéine αGC/sCD1d-scFv anti- tumeur. En outre, la redirection de la cytotoxicité des cellules iNKT vers la tumeur est supérieure à celle obtenue avec une stimulation par des CPA chargées avec l'αGC. Afin d'augmenter les effets anti-tumoraux, nous avons exploité la capacité des cellules iNKT à activer l'immunité adaptive. Pour ce faire, nous avons combiné l'immunothérapie NKT/CD1d avec un vaccin anti-tumoral composé d'un peptide OVA. Des effets synergiques ont été obtenus lorsque les traitements avec la protéine αGC/sCD1d-anti-HER2 étaient associés avec le CpG ODN comme adjuvant pour la vaccination avec le peptide OVA. Ces effets ont été observés à travers l'activation de nombreux lymphocytes T CD8+ spécifique de la tumeur, ainsi que par la forte expansion des cellules NK. Les réponses, innée et adaptive, élevées après le traitement avec la protéine αGC/sCD1d-anti-HER2 combinée au vaccin OVA/CpG ODN étaient associées à un fort ralentissement de la croissance des tumeurs B16- OVA-HER2. Cet effet anti-tumoral corrèle avec l'enrichissement des lymphocytes T CD8+ spécifiques observé à la tumeur. Afin d'étendre l'application des protéines αGC/sCD1d et d'améliorer leur efficacité, nous avons développé des fusions CD1d alternatives. Premièrement, une protéine αGC/sCD1d dimérique, qui permet d'augmenter l'avidité de la molécule CD1d pour les cellules iNKT. Dans un deuxième temps, nous avons fusionné la protéine αGC/sCD1d avec un scFv dirigé contre le récepteur 3 du facteur de croissance pour l'endothélium vasculaire (VEGFR-3), afin de cibler l'environnement de la tumeur. Dans l'ensemble, ces résultats démontrent que la thérapie médiée par la protéine recombinante αGC/sCD1d-scFv est une approche prometteuse pour rediriger l'immunité innée et adaptive vers le site tumoral. - Invariant Natural Killer T cells (iNKT) are potent activators of Natural Killer (NK), dendritic cells (DC) and T lymphocytes, and their anti-tumor activities have been well demonstrated. However, a single injection of the high affinity CD1d ligand alpha-galactosylceramide (αGC) leads to a strong but short-lived iNKT cell activation followed by a phase of long-term anergy, limiting the therapeutic use of this ligand. As a promising alternative, we have demonstrated that when αGC is loaded on recombinant soluble CD1d molecules (αGC/sCD1d), repeated injections in mice led to the sustained iNKT cell activation associated with continued cytokine secretion. Importantly, the retained reactivity of iNKT cell led to prolonged antitumor activity when the αGC/sCD1d was fused to an anti-tumor scFv fragments. Optimal inhibition of tumor growth was obtained only when mice were treated with the tumor-targeted αGC/CD1d-scFv fusion, whereas the irrelevant αGC/CD1d-scFv fusion was less efficient. When tested in a human system, the recombinant αGC/sCD1d-anti-HER2 and -anti-CEA fusion proteins were able to expand iNKT cells from PBMCs of healthy donors. Furthermore, the αGC/sCD1d-scFv fusion had the capacity to directly activate human iNKT cells clones without the presence of antigen-presenting cells (APCs), in contrast to the free αGC ligand. Most importantly, tumor cell killing by human iNKT cells was obtained only when co- incubated with the tumor targeted sCD1d-antitumor scFv, and their direct tumor cytotoxicity was superior to the bystander killing obtained with αGC-loaded APCs stimulation. To further enhance the anti-tumor effects, we exploited the ability of iNKT cells to transactivate the adaptive immunity, by combining the NKT/CD1d immunotherapy with a peptide cancer vaccine. Interestingly, synergistic effects were obtained when the αGC/sCD1d- anti-HER2 fusion treatment was combined with CpG ODN as adjuvant for the OVA peptide vaccine, as seen by higher numbers of activated antigen-specific CD8 T cells and NK cells, as compared to each regimen alone. The increased innate and adaptive immune responses upon combined tumor targeted sCD1d-scFv treatment and OVA/CpG vaccine were associated with a strong delay in B16-OVA-HER2 melanoma tumor growth, which correlated with an enrichment of antigen-specific CD8 cells at the tumor site. In order to extend the application of the CD1d fusion, we designed alternative CD1d fusion proteins. First, a dimeric αGC/sCD1d-Fc fusion, which permits to augment the avidity of the CD1d for iNKT cells and second, an αGC/sCD1d fused to an anti vascular endothelial growth factor receptor-3 (VEGFR-3) scFv, in order to target tumor stroma environment. Altogether, these results demonstrate that the iNKT-mediated immunotherapy via recombinant αGC/sCD1d-scFv fusion is a promising approach to redirect the innate and adaptive antitumor immune response to the tumor site.

How the gut links innate and adaptive immunity.

Mucosal surfaces represent the main sites in which environmental microorganisms and antigens interact with the host. Sentinel cells, including epithelial cells, lumenal macrophages, and intraepithelial dendritic cells, continuously sense the environment and coordinate defenses for the protection of mucosal tissues. The mucosal epithelial cells are crucial actors in coordinating defenses. They sense the outside world and respond to environmental signals by releasing chemokines and cytokines that recruit inflammatory and immune cells to control potential infectious agents and to attract cells able to trigger immune responses. Among immune cells, dendritic cells (DC) play a key role in controlling adaptive immune responses, due to their capacity to internalize foreign materials and to present antigens to naive T and B lymphocytes, locally or in draining organized lymphoid tissues. Immune cells recruited in epithelial tissues can, in turn, act upon the epithelial cells and change their phenotype in a process referred to as epithelial metaplasia.

Control of the adaptive response of the heart to stress via the Notch1 receptor pathway.

In the damaged heart, cardiac adaptation relies primarily on cardiomyocyte hypertrophy. The recent discovery of cardiac stem cells in the postnatal heart, however, suggests that these cells could participate in the response to stress via their capacity to regenerate cardiac tissues. Using models of cardiac hypertrophy and failure, we demonstrate that components of the Notch pathway are up-regulated in the hypertrophic heart. The Notch pathway is an evolutionarily conserved cell-to-cell communication system, which is crucial in many developmental processes. Notch also plays key roles in the regenerative capacity of self-renewing organs. In the heart, Notch1 signaling takes place in cardiomyocytes and in mesenchymal cardiac precursors and is activated secondary to stimulated Jagged1 expression on the surface of cardiomyocytes. Using mice lacking Notch1 expression specifically in the heart, we show that the Notch1 pathway controls pathophysiological cardiac remodeling. In the absence of Notch1, cardiac hypertrophy is exacerbated, fibrosis develops, function is altered, and the mortality rate increases. Therefore, in cardiomyocytes, Notch controls maturation, limits the extent of the hypertrophic response, and may thereby contribute to cell survival. In cardiac precursors, Notch prevents cardiogenic differentiation, favors proliferation, and may facilitate the expansion of a transient amplifying cell compartment.