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

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

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

Transport of binary water–ethanol mixtures through a multilayer hydrophobic zeolite membrane

Transport of water–ethanol mixtures through a hydrophobic tubular ZSM-5 (Si/Al = 300) zeolite membrane during pervaporation was studied experimentally and theoretically. The zeolite membrane was deposited on a support made of pure titania coated with three intermediate ceramic titania layers. The influence of feed concentration, feed temperature and permeate pressure on permeate fluxes and permeate concentrations was investigated in a wide range. Dusty gas model parameters of the support and all ceramic intermediate layers were calculated on the basis of gas permeation data. Mass transfer resistances and pressure drops in the different membrane layers during pervaporation were calculated for several process conditions. In particular the influence of the undesired but unavoidable pressure drop in the support and the intermediate layers on the effective driving force for pervaporation was evaluated and found to be relevant for predicting the overall process performance. The membrane prepared was found to be suitable for the recovery of highly concentrated ethanol from feed mixtures of relatively low ethanol concentrations at relatively low feed temperatures. Copyright © 2007 Elsevier B.V. All rights reserved

Using of zeolite NaA membranes for improved glycol dewatering in a pilot plant for natural gas drying

The dehydration of natural gas in production and storage facilities all over the world is dominated by Methylene glycol (TEG) dehydration plants. The regeneration of TEG is done by distillation at a temperature range of 190 to 205°C. To investigate an alternative to the conventional regeneration of Methylene glycol (TEG) from the gas drying process by distillation a first pilot plant was built using hydrophilic zeolite membranes for dewatering TEG. Laboratory studies and investigations at a dehydration plant showed that TEG can be regenerated by molecular sieve membranes. The regeneration temperature and the TEG recirculated quantity can be reduced. The pilot plant is completely integrated into a gas drying plant on an underground gas storage. Before installing 20 m2 of membrane area in the pilot plant extensive investigations were done on lab scale leading to further improvements of the membrane permeation abilities. Water contents in TEG of about 0.5 wt.% were achieved. First results gaining from the pilot plant showed that a high permeance (> 0.30 kg/(m2h),) was reached and could kept constant. The permeance increase strong with the water content of the TEG. The stringent requirements for the separation factor, i.e. the selectivity, has been solved with a TEG-content in the separated water < 2 g/l. The next step is to use a 19-channel tube instead of 4- channel tubes

Annexin A1 on the surface of early apoptotic cells suppresses CD8+ T cell immunity.

Prevention of an immune response against self-antigens derived from apoptotic cells is essential to preclude autoimmune and chronic inflammatory diseases. Here, we describe apoptosis induced externalization of endogenous cytosolic annexin 1 initiating an anti-inflammatory effector mechanism that suppresses the immune response against antigens of apoptotic cells. Cytosolic annexin 1 rapidly translocated to the apoptotic cell surface and inhibited dendritic cell (DC) activation induced by Toll like receptors (TLR). Annexin 1-inhibited DC showed strongly reduced secretion of pro-inflammatory cytokines (e.g. TNF and IL-12) and costimulatory surface molecules (e.g. CD40 and CD86), while anti-inflammatory mediators like PD-L1 remained unchanged. T cells stimulated by such DC lacked secretion of interferon-γ (IFN-γ) and TNF but retained IL-10 secretion. In mice, annexin 1 prevented the development of inflammatory DC and suppressed the cellular immune response against the model antigen ovalbumin (OVA) expressed in apoptotic cells. Furthermore, annexin 1 on apoptotic cells compromised OVA-specific tumor vaccination and impaired rejection of an OVA-expressing tumor. Thus, our results provide a molecular mechanism for the suppressive activity of apoptotic cells on the immune response towards apoptotic cell-derived self-antigens. This process may play an important role in prevention of autoimmune diseases and of the immune response against cancer