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1.
Front Immunol ; 12: 636222, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33841418

RESUMEN

Dendritic cell (DC)-derived exosomes (DC EXO), natural nanoparticles of endosomal origin, are under intense scrutiny in clinical trials for various inflammatory diseases. DC EXO are eobiotic, meaning they are well-tolerated by the host; moreover, they can be custom-tailored for immune-regulatory or -stimulatory functions, thus presenting attractive opportunities for immune therapy. Previously we documented the efficacy of immunoregulatory DCs EXO (regDCs EXO) as immunotherapy for inflammatory bone disease, in an in-vivo model. We showed a key role for encapsulated TGFß1 in promoting a bone sparing immune response. However, the on- and off-target effects of these therapeutic regDC EXO and how target signaling in acceptor cells is activated is unclear. In the present report, therapeutic regDC EXO were analyzed by high throughput proteomics, with non-therapeutic EXO from immature DCs and mature DCs as controls, to identify shared and distinct proteins and potential off-target proteins, as corroborated by immunoblot. The predominant expression in regDC EXO of immunoregulatory proteins as well as proteins involved in trafficking from the circulation to peripheral tissues, cell surface binding, and transmigration, prompted us to investigate how these DC EXO are biodistributed to major organs after intravenous injection. Live animal imaging showed preferential accumulation of regDCs EXO in the lungs, followed by spleen and liver tissue. In addition, TGFß1 in regDCs EXO sustained downstream signaling in acceptor DCs. Blocking experiments suggested that sustaining TGFß1 signaling require initial interaction of regDCs EXO with TGFß1R followed by internalization of regDCs EXO with TGFß1-TGFß1R complex. Finally, these regDCs EXO that contain immunoregulatory cargo and showed biodistribution to lungs could downregulate the main severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) target receptor, ACE2 on recipient lung parenchymal cells via TGFß1 in-vitro. In conclusion, these results in mice may have important immunotherapeutic implications for lung inflammatory disorders.


Asunto(s)
/inmunología , Células Dendríticas/inmunología , Exosomas/inmunología , Proteoma/inmunología , /inmunología , Animales , Ratones , Proteómica , Receptor Tipo I de Factor de Crecimiento Transformador beta/inmunología , Factor de Crecimiento Transformador beta1/inmunología
2.
Front Immunol ; 12: 654587, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33841438

RESUMEN

Background: SARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD). Objective: With this study we aimed to shed new light on the pathogenesis of these two SARS-CoV-2-related clinical manifestations. Methods: We investigated lymphocyte and dendritic cells subsets, chemokine/cytokine profiles and evaluated the neutrophil activity mediators, myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with COVID-19 and 9 with MIS-C at the time of hospital admission. Results: Patients with MIS-C showed higher plasma levels of C reactive protein (CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than COVID-19 children. In addition, they displayed higher levels of the chemokines CXCL9 and CXCL10, mainly induced by IFN-γ. By contrast, we detected IFN-α in plasma of children with COVID-19, but not in patients with MIS-C. This observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at levels comparable to healthy controls. Moreover, quantification of the number of plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-α, showed profound depletion of this subset in MIS-C, but not in COVID-19. Conclusions: Our results show a pattern of immune response which is suggestive of type I interferon activation in COVID-19 children, probably related to a recent interaction with the virus, while in MIS-C the immune response is characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active Th1 type immune response. We believe that these immunological events, together with neutrophil activation, might be crucial in inducing the multisystem and cardiovascular damage observed in MIS-C.


Asunto(s)
/inmunología , Quimiocina CXCL10/inmunología , Quimiocina CXCL9/inmunología , Células Dendríticas/inmunología , Interferón gamma/inmunología , Células Plasmáticas/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios Retrospectivos
4.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33800150

RESUMEN

Celiac disease (CD) is a frequent intestinal inflammatory disease occurring in genetically susceptible individuals upon gluten ingestion. Recent studies point to a role in CD for genes involved in cell shape, adhesion and actin rearrangements, including a Rho family regulator, Rho GTPase-activating protein 31 (ARHGAP31). In this study, we investigated the morphology and actin cytoskeletons of peripheral monocyte-derived dendritic cells (DCs) from children with CD and controls when in contact with a physiological substrate, fibronectin. DCs were generated from peripheral blood monocytes of pediatric CD patients and controls. After adhesion on fibronectin, DCs showed a higher number of protrusions and a more elongated shape in CD patients compared with controls, as assessed by immunofluorescence actin staining, transmitted light staining and video time-lapse microscopy. These alterations did not depend on active intestinal inflammation associated with gluten consumption and were specific to CD, since they were not found in subjects affected by other intestinal inflammatory conditions. The elongated morphology was not a result of differences in DC activation or maturation status, and did not depend on the human leukocyte antigen (HLA)-DQ2 haplotype. Notably, we found that ARH-GAP31 mRNA levels were decreased while RhoA-GTP activity was increased in CD DCs, pointing to an impairment of the Rho pathway in CD cells. Accordingly, Rho inhibition was able to prevent the cytoskeleton rearrangements leading to the elongated morphology of celiac DCs upon adhesion on fibronectin, confirming the role of this pathway in the observed phenotype. In conclusion, adhesion on fibronectin discriminated CD from the controls' DCs, revealing a gluten-independent CD-specific cellular phenotype related to DC shape and regulated by RhoA activity.


Asunto(s)
Actinas/metabolismo , Enfermedad Celíaca/metabolismo , Forma de la Célula , Células Dendríticas/inmunología , Monocitos/metabolismo , Enfermedad Celíaca/patología , Adhesión Celular , Niño , Preescolar , Células Dendríticas/patología , Femenino , Fibronectinas/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Antígenos HLA-DQ/metabolismo , Humanos , Masculino , Monocitos/patología , Fosfoproteínas/metabolismo , Proteína de Unión al GTP rhoA/metabolismo
5.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33799879

RESUMEN

The development of nanocarriers (NC) for biomedical applications has gained large interest due to their potential to co-deliver drugs in a cell-type-targeting manner. However, depending on their surface characteristics, NC accumulate serum factors, termed protein corona, which may affect their cellular binding. We have previously shown that NC coated with carbohydrates to enable biocompatibility triggered the lectin-dependent complement pathway, resulting in enhanced binding to B cells via complement receptor (CR)1/2. Here we show that such NC also engaged all types of splenic leukocytes known to express CR3 at a high rate when NC were pre-incubated with native mouse serum resulting in complement opsonization. By focusing on dendritic cells (DC) as an important antigen-presenting cell type, we show that CR3 was essential for binding/uptake of complement-opsonized NC, whereas CR4, which in mouse is specifically expressed by DC, played no role. Further, a minor B cell subpopulation (B-1), which is important for first-line pathogen responses, and co-expressed CR1/2 and CR3, in general, engaged NC to a much higher extent than normal B cells. Here, we identified CR-1/2 as necessary for binding of complement-opsonized NC, whereas CR3 was dispensable. Interestingly, the binding of complement-opsonized NC to both DC and B-1 cells affected the expression of activation markers. Our findings may have important implications for the design of nano-vaccines against infectious diseases, which codeliver pathogen-specific protein antigen and adjuvant, aimed to induce a broad adaptive cellular and humoral immune response by inducing cytotoxic T lymphocytes that kill infected cells and pathogen-neutralizing antibodies, respectively. Decoration of nano-vaccines either with carbohydrates to trigger complement activation in vivo or with active complement may result in concomitant targeting of DC and B cells and thereby may strongly enhance the extent of dual cellular/humoral immune responses.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Antígeno CD11b/inmunología , Proteínas del Sistema Complemento/inmunología , Células Dendríticas/inmunología , Receptores de Complemento/inmunología , Animales , Subgrupos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Células Cultivadas , Activación de Complemento/inmunología , Proteínas del Sistema Complemento/metabolismo , Células Dendríticas/metabolismo , Dextranos/química , Portadores de Fármacos/química , Humanos , Activación de Linfocitos/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados , Nanopartículas/química , Proteínas Opsoninas/inmunología , Proteínas Opsoninas/metabolismo , Fagocitosis/inmunología , Receptores de Complemento/metabolismo
6.
Sci Signal ; 14(673)2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33688079

RESUMEN

IL-1ß is a key mediator of the cytokine storm linked to high morbidity and mortality from COVID-19, and IL-1ß blockade with anakinra and canakinumab during COVID-19 infection has entered clinical trials. Using mass cytometry of human peripheral blood mononuclear cells, we identified effector memory CD4+ T cells and CD4-CD8low/-CD161+ T cells, specifically those positive for the chemokine receptor CCR6, as the circulating immune subtypes with the greatest response to IL-1ß. This response manifested as increased phosphorylation and, thus, activation of the proinflammatory transcription factor NF-κB and was also seen in other subsets, including CD11c+ myeloid dendritic cells, classical monocytes, two subsets of natural killer cells (CD16-CD56brightCD161- and CD16-CD56dimCD161+), and lineage- (Lin-) cells expressing CD161 and CD25. IL-1ß also induced a rapid but less robust increase in the phosphorylation of the kinase p38 as compared to that of NF-κB in most of these immune cell subsets. Prolonged IL-1ß stimulation increased the phosphorylation of the transcription factor STAT3 and to a lesser extent that of STAT1 and STAT5 across various immune cell types. IL-1ß-induced production of IL-6 likely led to the activation of STAT1 and STAT3 at later time points. Interindividual heterogeneity and inhibition of STAT activation by anakinra raise the possibility that assays measuring NF-κB phosphorylation in response to IL-1ß in CCR6+ T cell subtypes could identify those patients at higher risk of cytokine storm and most likely to benefit from IL-1ß-neutralizing therapies.


Asunto(s)
/inmunología , Interleucina-1beta/sangre , Subgrupos de Linfocitos T/inmunología , /sangre , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Citometría de Flujo , Humanos , Interleucina-1beta/farmacología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Monocitos/clasificación , Monocitos/inmunología , Monocitos/metabolismo , FN-kappa B/sangre , Pandemias , Fosforilación , Receptores CCR6/sangre , Factores de Transcripción STAT/sangre , Factores de Transcripción STAT/inmunología , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/sangre
7.
Int J Nanomedicine ; 16: 1553-1564, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33658783

RESUMEN

Purpose: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Most current therapeutic strategies primarily include localized treatment, lacking effective systemic strategies. Meanwhile, recent studies have suggested that RNA vaccines can effectively activate antigen-presenting cells (APCs) and lymphocytes to produce a strong systemic immune response and inhibit tumor growth. However, tumor vaccines loaded with a single tumor antigen may induce immunosuppression and immune evasion, while identifying tumor-specific antigens can require expensive and laborious procedures. Therefore, the use of whole tumor cell antigens are currently considered to be promising, potentially effective, methods. Previously, we developed a targeted liposome-polycation-DNA (LPD) complex nanoparticle that possess a small size, high RNA encapsulation efficiency, and superior serum stability. These particles were found to successfully deliver RNA to tumor sites. In the current study, we encapsulated total tumor-derived RNA in lipid nanoparticles (LNPs) to target dendritic cells (DCs) to incite expeditious and robust anti-tumor immunity. Methods: Total tumor-derived RNA was extracted from liver cancer cells (Hepa1-6 cells). LNPs loaded with tumor RNA were then prepared thin-film hydration method. The ability of RNA LNPs to induce DC maturation, cytotoxicity, and anti-tumor activity, was investigated in vitro and in vivo. Results: The average particle size of LNPs and RNA LNPs was 102.22 ± 4.05 nm and 209.68 ± 6.14 nm, respectively, while the zeta potential was 29.97 ± 0.61 mV and 42.03 ± 0.42 mV, respectively. Both LNPs and RNA LNP vaccines exhibited good distribution and stability. In vitro, RNA LNP vaccines were capable of promoting DC maturation and inducing T lymphocytes to kill Hepa1-6 cells. In vivo, RNA LNP vaccines effectively prevent and inhibit HCC growth. Conclusion: RNA LNPs may serve as an effective antigen specific vaccine to induce anti-tumor immunity for HCC.


Asunto(s)
Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/terapia , Inmunoterapia , Lípidos/química , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/terapia , Nanopartículas/química , ARN Neoplásico/metabolismo , Animales , Vacunas contra el Cáncer/inmunología , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Humanos , Activación de Linfocitos/inmunología , Masculino , Ratones Endogámicos C57BL , Nanopartículas/administración & dosificación , Tamaño de la Partícula , Linfocitos T/inmunología
8.
J Immunother Cancer ; 9(3)2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33707314

RESUMEN

While vaccines directed against the SARS-CoV-2 spike protein will have varying degrees of effectiveness in preventing SARS-CoV-2 infections, the severity of infection will be determined by multiple host factors including the ability of immune cells to lyse virus-infected cells. This review will discuss the complexity of both adaptive and innate immunomes and how a flow-based assay can detect up to 158 distinct cell subsets in the periphery. This assay has been employed to show the effect of age on differences in specific immune cell subsets, and the differences in the immunome between healthy donors and age-matched cancer patients. Also reviewed are the numerous soluble factors, in addition to cytokines, that may vary in the pathogenesis of SARS-CoV-2 infections and may also be employed to help define the effectiveness of a given vaccine or other antiviral agents. Various steroids have been employed in the management of autoimmune adverse events in cancer patients receiving immunotherapeutics and may be employed in the management of SARS-CoV-2 infections. The influence of steroids on multiple immune cells subsets will also be discussed.


Asunto(s)
Inmunidad Adaptativa/inmunología , Linfocitos B/inmunología , Células Dendríticas/inmunología , Inmunidad Innata/inmunología , Células Asesinas Naturales/inmunología , Neoplasias/inmunología , Linfocitos T/inmunología , Factores de Edad , Antígeno B7-H1/inmunología , Ligando de CD40/inmunología , /uso terapéutico , Citocinas/inmunología , Susceptibilidad a Enfermedades , Glucocorticoides/uso terapéutico , Granzimas/inmunología , Humanos , Inmunosenescencia/inmunología , Células Supresoras de Origen Mieloide/inmunología , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/inmunología , Proteoma , Índice de Severidad de la Enfermedad , Subgrupos de Linfocitos T/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología
10.
Front Immunol ; 12: 627548, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33777012

RESUMEN

Background: Emerging evidence argues that monocytes, circulating innate immune cells, are principal players in COVID-19 pneumonia. The study aimed to investigate the role of soluble (s)CD163 and sCD14 plasmatic levels in predicting disease severity and characterize peripheral blood monocytes and dendritic cells (DCs), in patients with COVID-19 pneumonia (COVID-19 subjects). Methods: On admission, in COVID-19 subjects sCD163 and sCD14 plasmatic levels, and peripheral blood monocyte and DC subsets were compared to healthy donors (HDs). According to clinical outcome, COVID-19 subjects were divided into ARDS and non-ARDS groups. Results: Compared to HDs, COVID-19 subjects showed higher sCD163 (p<0.0001) and sCD14 (p<0.0001) plasmatic levels. We observed higher sCD163 plasmatic levels in the ARDS group compared to the non-ARDS one (p=0.002). The cut-off for sCD163 plasmatic level greater than 2032 ng/ml was predictive of disease severity (AUC: 0.6786, p=0.0022; sensitivity 56.7% [CI: 44.1-68.4] specificity 73.8% [CI: 58.9-84.7]). Positive correlation between plasmatic levels of sCD163, LDH and IL-6 and between plasmatic levels of sCD14, D-dimer and ferritin were found. Compared to HDs, COVID-19 subjects showed lower percentages of non-classical (p=0.0012) and intermediate monocytes (p=0.0447), slanDCs (p<0.0001), myeloid DCs (mDCs, p<0.0001), and plasmacytoid DCs (pDCs, p=0.0014). Compared to the non-ARDS group, the ARDS group showed lower percentages of non-classical monocytes (p=0.0006), mDCs (p=0.0346), and pDCs (p=0.0492). Conclusions: The increase in sCD163 and sCD14 plasmatic levels, observed on hospital admission in COVID-19 subjects, especially in those who developed ARDS, and the correlations of these monocyte/macrophage activation markers with typical inflammatory markers of COVID-19 pneumonia, underline their potential use to assess the risk of progression of the disease. In an early stage of the disease, the assessment of sCD163 plasmatic levels could have clinical utility in predicting the severity of COVID-19 pneumonia.


Asunto(s)
Antígenos CD/sangre , Antígenos de Diferenciación Mielomonocítica/sangre , Células Dendríticas/inmunología , Receptores de Lipopolisacáridos/sangre , Monocitos/inmunología , Células Mieloides/inmunología , Receptores de Superficie Celular/sangre , /inmunología , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , /diagnóstico , Estudios de Casos y Controles , Células Dendríticas/metabolismo , Células Dendríticas/virología , Progresión de la Enfermedad , Femenino , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Monocitos/virología , Células Mieloides/metabolismo , Células Mieloides/virología , Admisión del Paciente , Fenotipo , Índice de Severidad de la Enfermedad , Regulación hacia Arriba
11.
Nat Cell Biol ; 23(3): 219-231, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33649477

RESUMEN

Regulation of haematopoietic stem and progenitor cell (HSPC) fate is crucial during homeostasis and under stress conditions. Here we examine the aetiology of the Flt3 ligand (Flt3L)-mediated increase of type 1 conventional dendritic cells (cDC1s). Using cellular barcoding we demonstrate this occurs through selective clonal expansion of HSPCs that are primed to produce cDC1s and not through activation of cDC1 fate by other HSPCs. In particular, multi/oligo-potent clones selectively amplify their cDC1 output, without compromising the production of other lineages, via a process we term tuning. We then develop Divi-Seq to simultaneously profile the division history, surface phenotype and transcriptome of individual HSPCs. We discover that Flt3L-responsive HSPCs maintain a proliferative 'early progenitor'-like state, leading to the selective expansion of multiple transitional cDC1-primed progenitor stages that are marked by Irf8 expression. These findings define the mechanistic action of Flt3L through clonal tuning, which has important implications for other models of 'emergency' haematopoiesis.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Hematopoyesis/efectos de los fármacos , Células Madre Hematopoyéticas/efectos de los fármacos , Proteínas de la Membrana/farmacología , RNA-Seq , Análisis de la Célula Individual , Transcriptoma/efectos de los fármacos , Animales , Linaje de la Célula , Células Cultivadas , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/metabolismo , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo
12.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-33669410

RESUMEN

Melanoma is a severe and life-threatening malignancy derived from melanocytes. The traditional treatment for melanoma could not sustain satisfactory outcomes long term; however, the recent immune checkpoint treatment has made a breakthrough in these problems. Nivolumab is a representative immune checkpoint treatment, and this PD-1-targeted therapy has evolutionally developed and improved the clinical outcome in a recent decade. On the other hand, the clinical application of immune checkpoint treatment presents clinicians with novel questions, especially how to obtain additional efficacy and overcome the disadvantage by using this treatment. To answer these problems, we first investigated the distribution of PD-L1 in various organs to clarify the organs most affected by anti-PD-1 antibody treatment. Among various organs, lung, placenta, spleen, heart, and thyroid highly expressed PD-L1, while skin, thalamus, hippocampus, ovary, stomach, testis, and prostate showed lower expressions of PD-L1. Furthermore, the immune profiles were also examined in tumors and peripheral blood in patients with melanoma. PD-1 was highly expressed in CD8 and CD4 cells, and B cells also highly expressed PD-1 compared with NK cells. However, there was no significant difference in Th1/Th2/Th17 cytokines and inhibitory cytokine IL-10. Although nevus showed a low expression of PD-L1 compared with healthy skin, PD-L1 expression was increased in growth-phase melanoma. Finally, we analyzed the peripheral blood profiles in patients treated with nivolumab. PD-1-bearing dendritic cells (DCs) were increased during nivolumab treatment and Lin-CD11c+HLA-DR+ cells were highly increased during nivolumab treatment. These findings indicate a clue to answering the problems during nivolumab treatment and suggest to us the importance of multiple aspect observation during immune checkpoint treatment.


Asunto(s)
Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Melanoma/sangre , Melanoma/inmunología , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/inmunología , Antígeno B7-H1/metabolismo , Citocinas/metabolismo , Antígenos HLA-DR/metabolismo , Humanos , /uso terapéutico , Inmunoterapia/métodos , Melanoma/terapia , Nivolumab/farmacología , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias Cutáneas/terapia
13.
Int J Mol Sci ; 22(4)2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33671896

RESUMEN

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). MS and its animal model called experimental autoimmune encephalomyelitis (EAE) immunopathogenesis involve a plethora of immune cells whose activation releases a variety of proinflammatory mediators and free radicals. Vitamin D3 (VitD) is endowed with immunomodulatory and antioxidant properties that we demonstrated to control EAE development. However, this protective effect triggered hypercalcemia. As such, we compared the therapeutic potential of VitD and paricalcitol (Pari), which is a non-hypercalcemic vitamin D analog, to control EAE. From the seventh day on after EAE induction, mice were injected with VitD or Pari every other day. VitD, but not Pari, displayed downmodulatory ability being able to reduce the recruitment of inflammatory cells, the mRNA expression of inflammatory parameters, and demyelination at the CNS. Lower production of proinflammatory cytokines by lymph node-derived cells and IL-17 by gut explants, and reduced intestinal inflammation were detected in the EAE/VitD group compared to the EAE untreated or Pari groups. Dendritic cells (DCs) differentiated in the presence of VitD developed a more tolerogenic phenotype than in the presence of Pari. These findings suggest that VitD, but not Pari, has the potential to be used as a preventive therapy to control MS severity.


Asunto(s)
Antioxidantes/administración & dosificación , Colecalciferol/administración & dosificación , Encefalomielitis Autoinmune Experimental/prevención & control , Ergocalciferoles/administración & dosificación , Factores Inmunológicos/administración & dosificación , Profilaxis Posexposición/métodos , Animales , Antioxidantes/farmacología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Colecalciferol/farmacología , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/sangre , Encefalomielitis Autoinmune Experimental/inmunología , Ergocalciferoles/farmacología , Femenino , Factores Inmunológicos/farmacología , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/prevención & control , Índice de Severidad de la Enfermedad , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento
14.
Medicine (Baltimore) ; 100(13): e24519, 2021 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-33787569

RESUMEN

OBJECTIVES: This meta-analysis was designed to systematically evaluate whether autologous cytokine-induced killer cells (CIK) or dendritic cells and cytokine-induced killer cells (DC-CIK) immunotherapy combined with chemotherapy can improve the therapeutic effect and safety of chemotherapy in esophageal cancer (EC). MATERIALS AND METHODS: Randomized controlled trials (RCTs) were electronically searched databases including CNKI, WanFang, WeiPu, CBMDisc, PubMed, Web of Science, EMbase, the Cochrane Library, and Clinical Trials. The databases were searched for articles published until June 2019. Two researchers independently screened the literature, extracted data, and evaluated the quality of the included literature. Meta-analysis was performed using RevMan5.3. RESULTS: Seventeen studies (1416 participants) were included. The differences between CIK/DC-CIK combination chemotherapy and chemotherapy alone were significant. The results displayed that the number of CD3+, CD4+, CD4+/CD8+, and NK cells was significantly increased after 1 to 2 weeks of treatment with CIK/DC-CIK cells in the treatment group (all P < .05). In addition, the results shown that 1-year overall survival was significantly prolonged (P < .0001) and quality of life was improved (P = .001) in EC chemotherapy combined with immunotherapy groups compared with conventional treatment. Furthermore, cytokine expression levels of interleukin 2 (IL-2), tumor necrosis factor α (TNF-α), and interleukin 12 (IL-12) were significantly increased (P = .0003) as well as the levels of immunoglobulins were elevated (P < .00001). Serum levels of tumor marker molecules, carcinoembryonic antigen (CEA), carbohydrate antigen (CA)-199, and CA-125 were lower in treatment groups than that of control groups (P < .00001). No fatal adverse reactions were noted (P = .04). CONCLUSIONS: It is safe and effective for patients to use chemotherapy combined with CIK/DC-CIK immunotherapy. Immunotherapy can simultaneously improve the antitumor immune response. Specifically, DC-CIK cells can increase T lymphocyte subsets, CIK cells, NK cells, and immunoglobulins in peripheral blood to enhance antitumor immunity. Therefore, combination therapy enhances the immune function and improves the therapeutic efficacy of patients with EC.


Asunto(s)
Inmunidad Adaptativa/inmunología , Antineoplásicos/inmunología , Células Asesinas Inducidas por Citocinas/inmunología , Células Dendríticas/inmunología , Neoplasias Esofágicas/terapia , Anciano , Terapia Combinada , Neoplasias Esofágicas/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento
15.
Life Sci ; 271: 119152, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33548285

RESUMEN

Long non-coding RNAs (lncRNAs) were considered as accumulated genetic waste until they were found to be gene expression regulators by highly sensitive modern genomics platforms. It is a huge class of non-coding transcripts with an arbitrary length of >200 nucleotides, which has gained much attention in the past few years. Increasing evidence from several experimental studies unraveled the expression of lncRNA linked to immune response and disease progression. However, only a small number of lncRNAs have robust evidence of their function. Differential expression of lncRNAs in different immune cells is also evident. In this review, we focused on how lncRNAs expression assist in shaping immune cells (Macrophages, Dendritic cells, NK cells, T cells, B cells, eosinophils, neutrophils, and microglial cells) function and their response to the diseased conditions. Emerging evidence revealed lncRNAs may serve as key regulators in the innate and adaptive immune response system. So, the molecular mechanism insight into the function of lncRNAs in immune response may contribute to the development of potential therapeutic targets for various disease treatments. Therefore, it is imperative to explore the expression of lncRNAs and understand its relevance associated with the immune system.


Asunto(s)
Inmunidad Celular/genética , Inmunidad Celular/inmunología , Mediadores de Inflamación/inmunología , ARN Largo no Codificante/genética , ARN Largo no Codificante/inmunología , Inmunidad Adaptativa/genética , Inmunidad Adaptativa/inmunología , Animales , Células Dendríticas/inmunología , Humanos , Macrófagos/inmunología , Linfocitos T/inmunología
16.
Int J Mol Sci ; 22(4)2021 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-33557054

RESUMEN

The SWItch (SWI)3-related gene (SRG3) product, a SWI/Sucrose Non-Fermenting (SNF) chromatin remodeling subunit, plays a critical role in regulating immune responses. We have previously shown that ubiquitous SRG3 overexpression attenuates the progression of Th1/Th17-mediated experimental autoimmune encephalomyelitis. However, it is unclear whether SRG3 overexpression can affect the pathogenesis of inflammatory skin diseases such as atopic dermatitis (AD), a Th2-type immune disorder. Thus, to elucidate the effects of SRG3 overexpression in AD development, we bred NC/Nga (NC) mice with transgenic mice where SRG3 expression is driven by the ß-actin promoter (SRG3ß-actin mice). We found that SRG3ß-actin NC mice exhibit increased AD development (e.g., a higher clinical score, immunoglobulin E (IgE) hyperproduction, and an increased number of infiltrated mast cells and basophils in skin lesions) compared with wild-type NC mice. Moreover, the severity of AD pathogenesis in SRG3ß-actin NC mice correlated with expansion of interleukin 4 (IL4)-producing basophils and mast cells, and M2 macrophages. Furthermore, this accelerated AD development is strongly associated with Treg cell suppression. Collectively, our results have identified that modulation of SRG3 function can be applied as one of the options to control AD pathogenesis.


Asunto(s)
Ensamble y Desensamble de Cromatina , Dermatitis Atópica/etiología , Expresión Génica , Células Th2/inmunología , Células Th2/metabolismo , Factores de Transcripción/genética , Actinas/metabolismo , Animales , Biopsia , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Inmunidad Celular , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Transgénicos , Índice de Severidad de la Enfermedad
17.
Int J Mol Sci ; 22(4)2021 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-33578743

RESUMEN

The pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) is not fully understood, but evidence is accumulating that immune dysfunction plays a significant role. We previously reported that 31-week-old Tnfaip3DNGR1-KO mice develop pulmonary hypertension (PH) symptoms. These mice harbor a targeted deletion of the TNFα-induced protein-3 (Tnfaip3) gene, encoding the NF-κB regulatory protein A20, specifically in type I conventional dendritic cells (cDC1s). Here, we studied the involvement of dendritic cells (DCs) in PH in more detail. We found various immune cells, including DCs, in the hearts of Tnfaip3DNGR1-KO mice, particularly in the right ventricle (RV). Secondly, in young Tnfaip3DNGR1-KO mice, innate immune activation through airway exposure to toll-like receptor ligands essentially did not result in elevated RV pressures, although we did observe significant RV hypertrophy. Thirdly, PH symptoms in Tnfaip3DNGR1-KO mice were not enhanced by concomitant mutation of bone morphogenetic protein receptor type 2 (Bmpr2), which is the most affected gene in PAH patients. Finally, in human IPAH lung tissue we found co-localization of DCs and CD8+ T cells, representing the main cell type activated by cDC1s. Taken together, these findings support a unique role of cDC1s in PAH pathogenesis, independent of general immune activation or a mutation in the Bmpr2 gene.


Asunto(s)
Células Dendríticas/inmunología , Hipertensión Pulmonar Primaria Familiar/inmunología , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Células Dendríticas/patología , Hipertensión Pulmonar Primaria Familiar/genética , Hipertensión Pulmonar Primaria Familiar/patología , Eliminación de Gen , Ventrículos Cardíacos/inmunología , Ventrículos Cardíacos/patología , Humanos , Inmunidad Innata , Ratones , Mutación , Receptor Toll-Like 4/inmunología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética
18.
Exp Parasitol ; 223: 108082, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33581108

RESUMEN

Leishmaniasis is a complex vector-borne disease mediated by Leishmania parasite and a strong and long-lasting CD4+ Th1 and CD8+-T cell immunity is required to control the infection. Thus far multivalent subunit vaccines have met this requirement more promisingly. However several full protein sequences cannot be easily arranged in one construct. Instead, new emerging immune-informatics based epitope formulations surpass this restriction. Herein, we aimed to examine the protective potential of a dendritic cell based vaccine presenting epitopes to CD8+ and CD4+-T cells in combination with DNA vaccine encoding the same epitopes against murine cutaneous leishmaniasis. Immature DCs were loaded with epitopes (selected from parasite proteome) in vitro with or without CpG oligonucleotides and were used to immunize BALB/c mice. Peptide coding DNA was used to boost the system and immunological responses were evaluated after Leishmania (L.) major infectious challenge. The pre-challenge response to included epitopes was Th1 polarized which potentially lowered the infection at early time points post-challenge but not at later weeks. Collectively, DC prime-DNA boost was found to be a promising approach for Th1 polarization however the constituent epitopes undoubtedly make a significant contribution in the protection outcome of the vaccine.


Asunto(s)
Células de la Médula Ósea/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Leishmania major/inmunología , Leishmaniasis Cutánea/prevención & control , Vacunas Antiprotozoos , Secuencia de Aminoácidos , Animales , Linfocitos T CD4-Positivos/inmunología , Citocinas/metabolismo , Epítopos/química , Epítopos/inmunología , Femenino , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico/metabolismo , Proteoma/química , Vacunas de ADN
19.
J Exp Med ; 218(4)2021 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-33533916

RESUMEN

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.


Asunto(s)
/inmunología , Plasticidad de la Célula/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Proteínas de Transporte de Membrana/metabolismo , /inmunología , Biomarcadores , /virología , Citocinas/metabolismo , Células Dendríticas/virología , Interacciones Huésped-Patógeno/inmunología , Humanos , Hidroxicloroquina/farmacología , Hidroxicloroquina/uso terapéutico , Inmunomodulación , Inmunofenotipificación , Mediadores de Inflamación/metabolismo , Interferón Tipo I/metabolismo , Interferones/metabolismo
20.
J Vis Exp ; (168)2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33616089

RESUMEN

Targeted antigen delivery to cross-presenting dendritic cells (DC) in vivo efficiently induces T effector cell responses and displays a valuable approach in vaccine design. Antigen is delivered to DC via antibodies specific for endocytosis receptors such as DEC-205 that induce uptake, processing, and MHC class I- and II-presentation. Efficient and reliable conjugation of the desired antigen to a suitable antibody is a critical step in DC targeting and among other factors depends on the format of the antigen. Chemical conjugation of full-length protein to purified antibodies is one possible strategy. In the past, we have successfully established cross-linking of the model antigen ovalbumin (OVA) and a DEC-205-specific IgG2a antibody (αDEC-205) for in vivo DC targeting studies in mice. The first step of the protocol is the purification of the antibody from the supernatant of the NLDC (non-lymphoid dendritic cells)-145 hybridoma by affinity chromatography. The purified antibody is activated for chemical conjugation by sulfo-SMCC (sulfosuccinimidyl 4-[N-maleimidomethyl] cyclohexane-1-carboxylate) while at the same time the sulfhydryl-groups of the OVA protein are exposed through incubation with TCEP-HCl (tris (2-carboxyethyl) phosphine hydrochloride). Excess TCEP-HCl and sulfo-SMCC are removed and the antigen is mixed with the activated antibody for overnight coupling. The resulting αDEC-205/OVA conjugate is concentrated and freed from unbound OVA. Successful conjugation of OVA to αDEC-205 is verified by western blot analysis and enzyme-linked immunosorbent assay (ELISA). We have successfully used chemically crosslinked αDEC-205/OVA to induce cytotoxic T cell responses in the liver and to compare different adjuvants for their potential in inducing humoral and cellular immunity following in vivo targeting of DEC-205+ DC. Beyond that, such chemically coupled antibody/antigen conjugates offer valuable tools for the efficient induction of vaccine responses to tumor antigens and have been proven to be superior to classical immunization approaches regarding the prevention and therapy of various types of tumors.


Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Antígenos CD/inmunología , Células Dendríticas/inmunología , Inmunidad Celular/inmunología , Lectinas Tipo C/inmunología , Antígenos de Histocompatibilidad Menor/inmunología , Receptores de Superficie Celular/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Antígenos CD/metabolismo , Reactividad Cruzada , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Femenino , Técnicas In Vitro , Lectinas Tipo C/metabolismo , Ratones , Ratones Endogámicos C57BL , Antígenos de Histocompatibilidad Menor/metabolismo , Ovalbúmina/inmunología , Receptores de Superficie Celular/metabolismo
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