Dectin-1 binding to annexins on apoptotic cells induces peripheral immune tolerance via NADPH oxidase-2

Summary Uptake of apoptotic cells (ACs) by dendritic cells (DCs) and induction of a tolerogenic DC phenotype is an important mechanism for establishing peripheral tolerance to self-antigens. The receptors involved and underlying signaling pathways are not fully understood. Here, we identify Dectin-1 as a crucial tolerogenic receptor binding with nanomolar affinity to the core domain of several annexins (annexin A1, A5, and A13) exposed on ACs. Annexins bind to Dectin-1 on a site distinct from the interaction site of pathogen-derived β-glucans. Subsequent tolerogenic signaling induces selective phosphorylation of spleen tyrosine kinase (SYK), causing activation of NADPH oxidase-2 and moderate production of reactive oxygen species. Thus, mice deficient for Dectin-1 develop autoimmune pathologies (autoantibodies and splenomegaly) and generate stronger immune responses (cytotoxic T cells) against ACs. Our data describe an important immunological checkpoint system and provide a link between immunosuppressive signals of ACs and maintenance of peripheral immune tolerance

Comparative analysis of protocols to induce human CD4+Foxp3+ regulatory T cells by combinations of IL‐2, TGF‐beta, retinoic acid, rapamycin and butyrate

Regulatory T cells (Tregs) suppress other immune cells and are critical mediators of peripheral tolerance. Therapeutic manipulation of Tregs is subject to numerous clinical investigations including trials for adoptive Treg transfer. Since the number of naturally occurring Tregs (nTregs) is minute, it is highly desirable to develop a complementary approach of inducing Tregs (iTregs) from naïve T cells. Mouse studies exemplify the importance of peripherally induced Tregs as well as the applicability of iTreg transfer in different disease models. Yet, procedures to generate iTregs are currently controversial, particularly for human cells. Here we therefore comprehensively compare different established and define novel protocols of human iTreg generation using TGF-β in combination with other compounds. We found that human iTregs expressed several Treg signature molecules, such as Foxp3, CTLA-4 and EOS, while exhibiting low expression of the cytokines Interferon-γ, IL- 10 and IL-17. Importantly, we identified a novel combination of TGF-β, retinoic acid and rapamycin as a robust protocol to induce human iTregs with superior suppressive activity in vitro compared to currently established induction protocols. However, iTregs generated by these protocols did not stably retain Foxp3 expression and did not suppress in vivo in a humanized graft-versus-host-disease mouse model, highlighting the need for further research to attain stable, suppressive iTregs. These results advance our understanding of the conditions enabling human iTreg generation and may have important implications for the development of adoptive transfer strategies targeting autoimmune and inflammatory diseases.Marie Curie Intra European Fellowship within the 7th European Community Framework Programme, FP7-PEOPLE-IEFDr. Ake Olssons FoundationKI Research FoundationsSwedish Research CouncilCERIC Linne CenterAFA insuranceStockholm County CouncilTorsten Soderberg FoundationPublishe

Exosomes derived from mesenchymal stem cells enhance radiotherapy-induced cell death in tumor and metastatic tumor foci

We have recently shown that radiotherapy may not only be a successful local and regional treatment but, when combined with MSCs, may also be a novel systemic cancer therapy. This study aimed to investigate the role of exosomes derived from irradiated MSCs in the delay of tumor growth and metastasis after treatment with MSC + radiotherapy (RT). The tumor cell loss rates found after treatment with the combination of MSC and RT and for exclusive RT, were: 44.4% % and 12,1%, respectively. Concomitant and adjuvant use of RT and MSC, increased the mice surviving time 22,5% in this group, with regard to the group of mice treated with exclusive RT and in a 45,3% respect control group. Moreover, the number of metastatic foci found in the internal organs of the mice treated with MSC + RT was 60% less than the mice group treated with RT alone. We reasoned that the exosome secreted by the MSC, could be implicated in tumor growth delay and metastasis control after treatment. Our results show that exosomes derived form MSCs, combined with radiotherapy, are determinant in the enhancement of radiation effects observed in the control of metastatic spread of melanoma cells and suggest that exosome-derived factors could be involved in the bystander, and abscopal effects found after treatment of the tumors with RT plus MSC. Radiotherapy itself may not be systemic, although it might contribute to a systemic effect when used in combination with mesenchymal stem cells owing the ability of irradiated MSCs-derived exosomes to increase the control of tumor growth and metastasis.This work was supported by CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico – Brasil, Junta de Andalucía, project of Excellence from Junta de Andalucía P12-CTS-383 to FJO, Spanish Ministry of Economy and Competitiveness SAF2015-70520-R to FJO and JMRdA, RTICC RD12/0036/0026 and CIBER Cáncer ISCIII CB16/12/00421 to FJO

Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death

The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall mmunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other mmunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.Peer reviewe

Notation et gestion des entreprises

Rating and company management In evaluating a debtor's repayment ability, the purpose of rating is to help the lender assess the risk he is accepting and consequently help him fix the remuneration that he can expect. But, over and above this outside view, rating is also increasingly influencing the strategic choices which companies make, in their endeavours to strike a balance between the profitability demanded by their shareholders and the level of risk accepted by the lenders, not forgetting that they must at the same time insure their long long-term development, principally through takeover policies. By examining the behaviour of some large french and foreign companies, the authors show what place rating takes in a company's strategic management and raise various questions concerning the way in which profitability and risk interact in rating assessment.Appréciation de la capacité de remboursement de la dette d'un émetteur, la notation a pour objet d'assister le prêteur dans la détermination du risque qu'il accepte de prendre et de l'aider à fixer en conséquence la rémunération attendue. Mais, au-delà de cette observation externe, la notation exerce également une influence croissante sur la détermination des choix stratégiques des entreprises, qui doivent arbitrer entre les exigences de rentabilité demandées par leurs actionnaires et le niveau de risque accepté par les prêteurs, tout en assurant leur développement à long terme, notamment par le jeu des politiques d'acquisition. A travers l'examen du comportement d'un certain nombre des grandes entreprises françaises et étrangères, les auteurs présentent la place de la notation dans la gestion stratégique de la firme et s'interrogent sur l'interaction entre la rentabilité et le risque dans l'appréciation portée par le «rating».Veverka François, Weyd Emmanuel. Notation et gestion des entreprises. In: Revue d'économie financière, n°32, 1995. Les technologies bancaires et financières. pp. 183-207

Ceramic-supported thin film composite membrane for organic solvent nanofiltration

The commercial success of membrane-based separation processes related to water treatment has helped launch an emergent field of membrane-based organic solvent nanofiltration (OSN). Polyamide, a mainstay selective layer material found in reverse osmosis (RO) thin film composite (TFC) membranes, has demonstrated excellent performance in OSN. RO membranes, however, are built on solvent-intolerant support layers, thus necessitating the use of other types of supporting materials that can operate in solvents without dissolution or swelling. In this work, we demonstrated the formation of a polyamide selective barrier layer in-situ onto a ceramic ultrafiltration (UF) membrane and evaluated the TFC membrane for use in OSN. We selected ceramic tubular UF membranes provided by the Fraunhofer Institute for Ceramic Technologies and Systems (IKTS) as substrates for this work. Some of our best performing membranes demonstrated a pure methanol permeance of 22.9 Lm−2 h−1 bar−1 and dye rejection for methyl orange (327.3 g/mol), acid fuchsin (585.5 g/mol), chlorophyllin (724.2 g/mol) and brilliant blue FCF (792.9 g/mol) of 42.8%, 92.9%, 99.4%, and 94.1%, respectively. This work represents the first time that polyamide selective has been directly formed onto a tubular ceramic membrane and tested for OSN

Wirtschaftlicher Einsatz keramischer Membranen zur integrierten Prozesswasserbewirtschaftung - Fallbeispiele

Due to their physical properties ceramic membranes offer a wide range of applications. Compared to polymeric membranes, ceramic membr anes are significantly more resistant against temperature and pH values as well as against mechanical stress. Furthermore they normally show significantly higher permeate fluxes. Starting with the development of ceramic supports (flat and tubular) of high porosity, membranes for micro- and ultrafiltration were developed. In the year 2000 the first ceramic nanofiltration membrane with a cut-off of 450 Dalton was developed. In the meantime, this membrane was commercialized and still is outstanding regarding its low cut-off

Seconde Nature – Nature & renaturation, un aperçu sensible d’une histoire des cours d’eau en mutation.

International audienc

Annexin-coated particles induce antigen-specific immunosuppression

Apoptotic cells mediate the development of tolerogenic dendritic cells (DC) and thus facilitate induction and maintenance of peripheral tolerance. Following the identification of the evolutionary conserved annexin core domain (Anx) as a specific signal on apoptotic cells which antagonises Toll-like receptor (TLR) signalling, we examined whether the tolerogenic capacity of Anx can be exploited to downregulate antigen-specific immune responses. The treatment of bone marrow-derived dendritic cells (BMDC) with particles harbouring Anx as well as the model antigen ovalbumin (OVA) attenuated the response of OVA-specific OT-II T cells. The co-culture of Anx-particle-treated DC and T cells resulted in an anergy-like phenotype characterized by reduced proliferation and cytokine secretion. Here we demonstrate that the anti-inflammatory effects of Anx which are mediated through DC can be used as a tool to generate a particle-based antigen delivery system that promotes antigen-specific immunosuppression. Such Anx-particles may be a new therapeutic approach for the treatment of autoimmune diseases