Central tolerance can be mediated by peripheral dendritic cells (DCs) that transport innocuous antigens (Ags) to the thymus for presentation to developing T cells, but the responsible DC subsets ...remained poorly defined. Immature plasmacytoid DCs (pDCs) express CCR9, a chemokine receptor involved in migration of T cell precursors to the thymus. We show here that CCR9 mediated efficient thymic entry of endogenous or i.v. transfused pDCs. pDCs activated by Toll-like receptor (TLR) ligands downregulated CCR9 and lost their ability to home to the thymus. Moreover, endogenous pDCs took up subcutaneously injected fluorescent Ag and, in the absence of TLR signals, transported Ag to the thymus in a CCR9-dependent fashion. Injected, Ag-loaded pDCs effectively deleted Ag-specific thymocytes, and this thymic clonal deletion required CCR9-mediated homing and was prevented by infectious signals. Thus, peripheral pDCs can contribute to immune tolerance through CCR9-dependent transport of peripheral Ags and subsequent deletion of Ag-reactive thymocytes.
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► CCR9 controls pDCs numbers in the thymus ► CCR9 is a marker and thymic homing receptor on immature pDCs ► TLR activation or lack of CCR9 prevents thymic clonal deletion by peripheral pDCs ► Peripheral Ag transport to the thymus by endogenous unactivated pDC is CCR9 dependent
Pluripotent stem cells (PSCs) are promising tools for modern regenerative medicine applications because of their stemness properties, which include unlimited self-renewal and the ability to ...differentiate into all cell types in the body. Evidence suggests that a rare population of cells within a tumor, termed cancer stem cells (CSCs), exhibit stemness and phenotypic plasticity properties that are primarily responsible for resistance to chemotherapy, radiotherapy, metastasis, cancer development, and tumor relapse. Different therapeutic approaches that target CSCs have been developed for tumor eradication.
In this review, we first provide an overview of different viewpoints about the origin of CSCs. Particular attention has been paid to views believe that CSCs are probably appeared through dysregulation of very small embryonic-like stem cells (VSELs) which reside in various tissues as the main candidate for tissue-specific stem cells. The expression of pluripotency markers in these two types of cells can strengthen the validity of this theory. In this regard, we discuss the common properties of CSCs and PSCs, and highlight the potential of PSCs in cancer studies, therapeutic applications, as well as educating the immune system against CSCs.
In conclusion, the resemblance of CSCs to PSCs can provide an appropriate source of CSC-specific antigens through cultivation of PSCs which brings to light promising ideas for prophylactic and therapeutic cancer vaccine development.
Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive lung disorder with an unknown etiology that causes irreversible lung scarring affecting the respiratory function. Nintedanib was ...approved in 2014 as an oral treatment for patients with IPF; however, the oral administration can induce unfavorable side effects such as gastrointestinal problems and liver enzyme increase. Inhalable therapeutics offer an attractive approach for lung disorders by providing a more localized delivery and circumventing oral off-target effects. Yet, Nintedanib has poor water solubility and a change in drug formulation is required to make Nintedanib suitable for inhalation.Exosomes are considered as a novel means of drug delivery. Previous studies have shown the therapeutic potential of Lung Spheroid Cell-derived exosomes (LSC Exo) when delivered through inhalation in pulmonary fibrosis. The objective of this study was to explore the potential of exosomes as Nintedanib carriers to enhance the drug anti-fibrotic responses while reducing Nintedanib oral side effects. For this purpose, Nintedanib was loaded into LSC Exo (Nin-LSCExo) via incubation and drug function was evaluated in vitro. Nin-LSC Exo was delivered tobleomycin-induced mouse model of pulmonary fibrosis through inhalation. Treatments were administered for seven consecutive days. The results revealed that LSC Exo can be utilized as an effective Nintedanib vehicle with no major manipulations. Moreover, it can provide additional benefits in reducing inflammation and fibrosis while preventing liver enzyme elevations. Overall,the present study is a proof-of-concept, demonstrating the potential of LSC Exo as drug carriers for future therapeutic applications.
Respiratory diseases are a global burden, with millions of deaths attributed to pulmonary illnesses and dysfunctions. Therapeutics have been developed, but they present major limitations regarding ...pulmonary bioavailability and product stability. To circumvent such limitations, we developed room-temperature-stable inhalable lung-derived extracellular vesicles or exosomes (Lung-Exos) as mRNA and protein drug carriers. Compared with standard synthetic nanoparticle liposomes (Lipos), Lung-Exos exhibited superior distribution to the bronchioles and parenchyma and are deliverable to the lungs of rodents and nonhuman primates (NHPs) by dry powder inhalation. In a vaccine application, severe acute respiratory coronavirus 2 (SARS-CoV-2) spike (S) protein encoding mRNA-loaded Lung-Exos (S-Exos) elicited greater immunoglobulin G (IgG) and secretory IgA (SIgA) responses than its loaded liposome (S-Lipo) counterpart. Importantly, S-Exos remained functional at room-temperature storage for one month. Our results suggest that extracellular vesicles can serve as an inhaled mRNA drug-delivery system that is superior to synthetic liposomes.
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•Lung extracellular vesicles (Lung-Exos) can package mRNA and protein drugs•Lung-Exos are deliverable through nebulization and dry powder inhalation•Dry powder Lung-Exos are room-temperature stable up to 28 days•Drug-loaded Lung-Exos can serve as an inhalable vaccine to illicit immune responses
Research in extracellular vesicles (EVs) is important to the field of translational medicine to develop therapeutics that are limited by poor cellular targeting and efficacy. The biological composition of EVs can be exploited as drug-delivery vehicles that may be engineered for cellular targeting or eliciting specific immune responses through their functions in membrane trafficking and cellular signaling. With the molecular composition of EVs varying depending on their parent-cell origin, the derivation of EVs can further refine nanomedicine by utilizing nanoparticles that are recognized by specific cellular microenvironments. EVs are found in almost all biological fluids, opening the application of EVs as tailored drug-delivery vesicles to a wide range of diseases.
Lipid nanoparticles have limitations in inhaled drug delivery, including low pulmonary bioavailability and unoptimized formulation. Lung-derived extracellular vesicles (Lung-Exos) may be naturally equipped for drug delivery to the lung. We determined the biodistribution of Lung-Exos following nebulization and dry powder inhalation, where Lung-Exos outperformed their biological and synthetic nanoparticle counterparts in drug distribution and retention. As an inhalable vaccine, Lung-Exos elicited greater protective antibody responses and pseudoviral clearance than their synthetic counterpart.
Acute myeloid leukemia (AML) is a hematologic malignancy that is not completely cured in patients even after heavy chemotherapy treatments, resulting in the relapses of disease. Inactivation of ...immune cells such as natural killer (NK) cells is probably one of the causes of relapse. In this review, we described the role of NK cells in AML patients and outlined the current approaches to use of these cells in treatment of AML disease. Relevant articles from 1997 up to date, published in PubMed, were studied and compiled. The articles all contained the keywords: natural killer cell, acute myeloid leukemia, and treatment. Recognition of AML blast cells by NK inhibitory receptors and their interaction reduces NK cell cytotoxicity. On the other hand, NK cell immunotherapy along with administration of cytokines such as IL-2 and IL-15 can enhance the expression of activating receptors such as NKG2D and reduce the incidence of relapse in AML patients. Targeting NK inhibitory receptors and the use of IL-2 and IL-15 cytokine therapy can upregulate NK-activating receptors which decrease the relapse rate and improve the survival of patients with AML.
Celiac disease (CD) is an immune-mediated enteropathy that occurs in genetically predisposed individuals associated with gluten intake. Currently, the only effective treatment for CD is life-lasting ...elimination of gluten from the diet, but adhering to it throughout life is burdensome. In addition, strict compliance with a gluten-free diet (GFD) does not lead to a complete restoration of intestinal microbiota. Although gluten is known to be a trigger in CD, various studies have demonstrated that the gut microbiota is involved in gluten metabolism, regulation of intestinal barrier permeability, and modulation of the immune response. Therefore, the gut microbiota has an important role in the pathogenesis, progression, and clinical manifestations of CD. This evidence supports the hypothesis that probiotics act as a strategy to modulate the intestinal microbiota into an anti-inflammatory state. Probiotics such as some bacterial species of the genera Bifidobacterium and Lactobacillus can protect the epithelial cells from gliadin-induced damage and improve symptoms and quality of life in GFD-treated patients, as an adjunctive treatment. This narrative review aims to discuss the recent scientific evidence of the relationship between the intestinal microbiota changes in CD and to understand the role of probiotics in CD treatment.
This paper describes an intelligent engine stop-start strategy for vehicles equipped with this system. This controller, at first stage, monitors the history of vehicle movement and quantifies the ...traffic condition. At the second stage, based on this traffic degree it adjusts one controller parameter named waiting time that is the time that has to pass for engine to shut down. This way, this strategy prevents engine from shutting down in very heavy traffic condition where too frequent stop start occur, when instead of improving fuel economy it results in increasing fuel consumption. In fact, this control strategy is addressing one problem of the conventional stop-start systems where regardless of traffic condition based on a simple if-then algorithm stops and starts the engine.
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