Autologous Extracellular Vesicles Research Articles

Autologous blood extracellular vesicles and specific CD4+ T-cell co-activation.

Extracellular vesicles (EVs), which are generated by cell membrane budding in diverse cells, are present in variable numbers in the blood. An immunoregulatory role has been demonstrated principally for heterologous EVs, but the function of the EVs present naturally in blood remains unknown. We hypothesize that these autologous EVs might also modulate the phenotype and function of immune system cells, especially CD4+ T lymphocytes (TLs), as previously described for heterologous EVs. Several membranes and soluble immunoregulatory molecules were studied after the treatment of CD4+ TLs with autologous EVs. No direct activation was detected with autologous EVs, contrasting with the findings for heterologous EVs. However, following treatment with autologous EVs, a soluble form of CD27 (sCD27) was detected. sCD27 is strongly associated with lymphoproliferation. Autologous EVs have been shown to increase TL proliferation only after T-cell receptor (TcR) engagement due to polyclonal or specific-antigen stimulation. Our results therefore suggest that the EVs present in the blood have an immunomodulatory role different from that of heterologous EVs. These findings should be taken into account in future studies, particularly those focusing on infectious diseases, autotransfusion or doping practices.

Cloaked Viruses and Viral Factors in Cutting Edge Exosome-Based Therapies.

Extracellular vesicles (EVs) constitute a heterogeneous group of vesicles released by all types of cells that play a major role in intercellular communication. The field of EVs started gaining attention since it was realized that these vesicles are not waste bags, but they carry specific cargo and they communicate specific messages to recipient cells. EVs can deliver different types of RNAs, proteins, and lipids from donor to recipient cells and they can influence recipient cell functions, despite their limited capacity for cargo. EVs have been compared to viruses because of their size, cell entry pathways, and biogenesis and to viral vectors because they can be loaded with desired cargo, modified, and re-targeted. These properties along with the fact that EVs are stable in body fluids, they can be produced and purified in large quantities, they can cross the blood–brain barrier, and autologous EVs do not appear to cause major adverse effects, have rendered them attractive for therapeutic use. Here, we discuss the potential for therapeutic use of EVs derived from virus infected cells or EVs carrying viral factors. We have focused on six major concepts: (i) the role of EVs in virus-based oncolytic therapy or virus-based gene delivery approaches; (ii) the potential use of EVs for developing viral vaccines or optimizing already existing vaccines; (iii) the role of EVs in delivering RNAs and proteins in the context of viral infections and modulating the microenvironment of infection; (iv) how to take advantage of viral features to design effective means of EV targeting, uptake, and cargo packaging; (v) the potential of EVs in antiviral drug delivery; and (vi) identification of novel antiviral targets based on EV biogenesis factors hijacked by viruses for assembly and egress. It has been less than a decade since more attention was given to EV research and some interesting concepts have already been developed. In the coming years, additional information on EV biogenesis, how they are hijacked and utilized by pathogens, and their impact on the microenvironment of infection is expected to indicate avenues to optimize existing therapeutic tools and develop novel approaches.

Circulating LL37 targets plasma extracellular vesicles to immune cells and intensifies Behçet’s disease severity

ABSTRACTBehçet’s disease (BD) activity is characterised by sustained, over-exuberant immune activation, yet the underlying mechanisms leading to active BD state are poorly defined. Herein, we show that the human cathelicidin derived antimicrobial peptide LL37 associates with and directs plasma extracellular vesicles (EV) to immune cells, thereby leading to enhanced immune activation aggravating BD pathology. Notably, disease activity was correlated with elevated levels of circulating LL37 and EV plasma concentration. Stimulation of healthy PBMC with active BD patient EVs induced heightened IL1β, IFNα, IL6 and IP10 secretion compared to healthy and inactive BD EVs. Remarkably, when mixed with LL37, healthy plasma-EVs triggered a robust immune activation replicating the pathology inducing properties of BD EVs. The findings of this study could be of clinical interest in the management of BD, implicating LL37/EV association as one of the major contributors of BD pathogenesis.Abbreviations: BD: Behçet’s disease; EV: extracellular vesicle; BB: binding buffer; AnV: annexin V; autologEV: autologous extracellular vesicles; alloEV: allogeneic extracellular vesicles