Inflammation enhances consumption and presentation of transfused RBC antigens by dendritic cells

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2736-2743 ◽  
Author(s):  
Jeanne E. Hendrickson ◽  
Traci E. Chadwick ◽  
John D. Roback ◽  
Christopher D. Hillyer ◽  
James C. Zimring
Keyword(s):  
Dendritic Cells ◽  
Costimulatory Molecule ◽  
Poly I:C ◽  
Concomitant Increase ◽  
Additional Insight ◽  
Polycytidylic Acid ◽  
Splenic Macrophages ◽  
Antigen Presenting ◽  
Insight Into

Factors regulating which patients become alloimmunized to red blood cell (RBC) antigens are poorly understood. Using a murine model of transfusion, we recently reported that viral-like inflammation with polyinosinic polycytidylic acid [poly (I:C)] significantly enhances RBC alloimmunization. Herein, we tested the hypothesis that poly (I:C) exerts this effect, at least in part, at the level of antigen-presenting cells (APCs). Using a novel in vivo method, we report that in the noninflamed state, most transfused RBCs were consumed by splenic macrophages, with only trace consumption by splenic dendritic cells (DCs). To a lesser extent, RBCs were also consumed by APCs in the liver. However, unlike soluble antigens, no RBCs were consumed by APCs in the lymph nodes. Inflammation with poly (I:C) induced significant consumption of transfused RBCs by splenic DCs, with a concomitant increase in costimulatory molecule expression. Moreover, this resulted in increased proliferation of CD4+ T cells specific for the mHEL RBC alloantigen. Finally, splenectomy abrogated the enhancing effects of poly (I:C) on RBC alloimmunization. Together, these data provide additional insight into the nature of transfused RBCs as an immunogen and provide a mechanism by which viral-like inflammation enhances alloimmunization to transfused RBCs.

scholarly journals Single-stranded DNA oligonucleotides inhibit TLR3-mediated responses in human monocyte-derived dendritic cells and in vivo in cynomolgus macaques

Blood ◽  
2012 ◽  
Vol 120 (4) ◽  
pp. 768-777 ◽  
Author(s):  
Annette E. Sköld ◽  
Maroof Hasan ◽  
Leonardo Vargas ◽  
Hela Saidi ◽  
Nathalie Bosquet ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Proinflammatory Cytokines ◽  
Viral Infections ◽  
Human Monocyte ◽  
Poly I:C ◽  
Single Stranded Dna ◽  
Dna Oligonucleotides ◽  
Polycytidylic Acid ◽  
Cynomolgus Macaques

Abstract TLR3 is a key receptor for recognition of double-stranded RNA and initiation of immune responses against viral infections. However, hyperactive responses can have adverse effects, such as virus-induced asthma. Strategies to prevent TLR3-mediated pathology are therefore desired. We investigated the effect of single-stranded DNA oligonucleotides (ssDNA-ODNs) on TLR3 activation. Human monocyte-derived dendritic cells up-regulate maturation markers and secrete proinflammatory cytokines on treatment with the synthetic TLR3 ligand polyinosine-polycytidylic acid (poly I:C). These events were inhibited in cultures with ssDNA-ODNs. Poly I:C activation of nonhematopoietic cells was also inhibited by ssDNA-ODNs. The uptake of poly I:C into cells was reduced in the presence of ssDNA-ODNs, preventing TLR3 engagement from occurring. To confirm this inhibition in vivo, we administered ssDNA-ODNs and poly I:C, alone or in combination, via the intranasal route in cynomolgus macaques. Proinflammatory cytokines were detected in nasal secretions in the poly I:C group, while the levels were reduced in the groups receiving ssDNA-ODNs or both substances. Our results demonstrate that TLR3-triggered immune activation can be modulated by ssDNA-ODNs and provide evidence of dampening proinflammatory cytokine release in the airways of cynomolgus macaques. These findings may open novel perspectives for clinical strategies to prevent or treat inflammatory conditions exacerbated by TLR3 signaling.

Recipient Inflammation That Increases Alloimmunization Also Enhances Consumption of Transfused RBCs by Dendritic Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 23-23
Author(s):  
Jeanne E. Hendrickson ◽  
John D. Roback ◽  
Christopher D. Hillyer ◽  
James C. Zimring
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
B Cells ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Antigen Presenting Cells ◽  
Poly I:C ◽  
Splenic Macrophages ◽  
Antigen Presenting

Background: Although much is known about the structure and immunogenicity of red blood cell (RBC) antigens, little is known about their processing and presentation by antigen presenting cells (APC). Red blood cells are a unique immunogen, in that they are given intravenously, without inflammation, and typically don’t enter peripheral tissues and lymphatics. Unlike pathogens, which cause an immune response in the majority of patients, only a small minority of chronically transfused patients develop alloantibodies to RBC antigens. In a murine model of RBC transfusion, we have previously reported that recipient inflammation, induced by Poly (I:C) (a double-stranded RNA that mimics viral inflammation), significantly enhances alloimmunization to RBC antigens. In this report, we explore the role of antigen presenting cells in the immune response to antigens on transfused RBCs, in an uninflammed state as well as in the presence of Poly (I:C). Methods: 3, 3-dihexadecyloxacarbocyanine perchlorate (DiO) was used as a fluorescent RBC label. Labeled RBCs were transfused into C57BL/6 recipient mice, in the absence or presence of inflammation with poly (I:C). 24 hours post-transfusion, APCs were analyzed in the spleen, liver, and lymph nodes. Macrophages (F4/80+) and dendritic cells (DC) (CD11c+) were gated on by flow cytometry, as were T cells (CD3+), B cells (CD19+) and RBCs (Terr 119+). RBC consumption was assessed by measuring DiO fluorescence in these cell populations. Results: In the absence of inflammation, the majority of RBCs are consumed by macrophages in the spleen, with 3 fold less consumption by liver macrophages and no consumption by lymph node macrophages. Both splenic and liver DCs consume 3 fold fewer RBCs than splenic macrophages. Recipient inflammation with Poly (I:C) alters this pattern, with a significant increase in consumption by both splenic and liver DCs and a decrease in consumption by splenic macrophages. As a negative control, no RBC consumption was seen after gating on non-phagocytic T cells or B cells. Likewise, measures of RBC consumption were not an artifact of RBC sticking to the APC surface, as staining for TER119 was negative. Discussion: Red blood cells are a unique immunogen, in that they circulate for many days, don’t enter lymphatics, and often don’t cause a detectable alloantibody response. These studies demonstrate that recipient inflammation with Poly (I:C), which we have previously reported enhances alloimmunization to transfused RBCs, significantly increases DC consumption of transfused RBCs. As DCs are typically considered to be more potent APCs than macrophages, and as we have previously shown that Poly (I:C) signficantly induces co-stimulatory molecule expression on DCs, these findings provide one potential mechanism by which inflammation enhances RBC alloimmunization. Ongoing studies are directly assessing the relative potency of these different APCs in their ability to activate CD4+ T cells specific for RBC antigens.

Anti-β2 Glycoprotein I Antibodies Cause Inflammation and Recruit Dendritic Cells in Platelet Clearance

2001 ◽  
Vol 86 (11) ◽  
pp. 1257-1263 ◽  
Author(s):  
Attilio Bondanza ◽  
Angelo Manfredi ◽  
Valérie Zimmermann ◽  
Matteo Iannacone ◽  
Angela Tincani ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Inflammatory Responses ◽  
Glycoprotein I ◽  
Activated Platelets ◽  
Tnf Α ◽  
Per Se ◽  
Antigen Presenting ◽  
Antiinflammatory Cytokine

SummaryScavenger phagocytes are mostly responsible for the in vivo clearance of activated or senescent platelets. In contrast to other particulate substrates, the phagocytosis of platelets does not incite pro-inflammatory responses in vivo. This study assessed the contribution of macrophages and dendritic cells (DCs) to the clearance of activated platelets. Furthermore, we verified whether antibodies against the β2 Glycoprotein I (β2GPI), which bind to activated platelets, influence the phenomenon. DCs did not per se internalise activated platelets. In contrast, macrophages efficiently phagocytosed platelets. In agreement with the uneventful nature of the clearance of platelets in vivo, phagocytosing macrophages did not release IL-1β, TNF-α or IL-10. β2GPI bound to activated platelets and was required for their recognition by anti-ββ2GPI antibodies. DCs internalised platelets opsonised by anti-ββ2GPI antibodies. The phagocytosis of opsonised platelets determined the release of TNF-α and IL-1β by DCs and macrophages. Phagocytosing macrophages, but not DCs, secreted the antiinflammatory cytokine IL-1β0. We conclude that anti-ββ2GPI antibodies cause inflammation during platelet clearance and shuttle platelet antigens to antigen presenting DCs.

scholarly journals 714 Selective expansion of antigen-specific CD8 T cells with engineered antigen presenting exosome

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A743-A743
Author(s):  
Tomoyoshi Yamano ◽  
Xiabing Lyu ◽  
Rikinari Hanayama
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Costimulatory Molecule ◽  
Animal Experiments ◽  
Surface Proteins ◽  
Hek293 Cells ◽  
Target Cells ◽  
Single Chain ◽  
Antigen Presenting

BackgroundExosomes are vesicular granules of about 100 nm and are secreted by many types of cells. Exosomes contain various proteins, lipids, and RNAs that are transported to target cells which induce functional and physiological changes. Exosomes are promising nano-vesicles for clinical application, owing to their high biocompatibility, low immunogenicity, and high drug delivery efficacy. Recent studies have demonstrated that exosomes from tumor cells or antigen presenting cells (APCs) regulate immune responses. Tumor derived exosomes express PD-L1 on their surface and suppress tumor immunity systemically. On the other hand, mature dendritic cells derived exosomes exert immune activation, and tumor immunotherapy using DCs exosome has been developed. However, few studies have been found to exert a significant effect on cancer treatment, may be because of low expression of costimulatory molecules and lack of cytokines on DCs derived exosomes.MethodsIt has been demonstrated that GFP can be conveyed into exosomes by conjugating GFP with tetraspanins, exosome-specific surface proteins. First, we generated a tetraspanin fusion protein with a single-chain MHCI trimer (scMHCI). IL-2 is inserted on the second extracellular loop of CD81, allowing robust and functional expression of IL-2 on the exosome. We collected exosomes from HEK293 cells culture, which stably express scMHCI-CD81-IL2 and CD80-MFGE8, and used as Antigen-presenting exosome(AP-Exo).ResultsAP-Exo expresses high expression of MHCI-peptide complex, costimulatory molecule, and cytokine, activating cognate CD8 T cells as dendritic cells do. AP-Exo selectively delivered co-stimulation and IL-2 to antigen-specific CD8 T cells, resulting in a massive expansion of antigen-specific CD8 T cells without severe adverse effects in mice. AP-Exo can expand endogenous tumor-specific CD8 T cells and induce the potent anti-tumor effect.ConclusionsOur strategy for building engineered exosomes that work like APCs might develop novel methods for cancer immunotherapy.Ethics ApprovalAll mice were housed in a specific pathogen-free facility, and all animal experiments were performed according to a protocol approved by Kanazawa University, Kanazawa, Japan.

scholarly journals Between biology and medicine: perspectives on the use of dendritic cells in anticancer therapy

2017 ◽  
Vol 71 (0) ◽  
pp. 0-0
Author(s):  
Agnieszka Szczygieł ◽  
Elżbieta Pajtasz-Piasecka
Keyword(s):  
Dendritic Cells ◽  
Ex Vivo ◽  
Anticancer Therapy ◽  
Point Of View ◽  
Proper Function ◽  
Innate And Adaptive Immunity ◽  
Factors Affecting ◽  
Antigen Presenting

Dendritic cells (DCs), as a link between innate and adaptive immunity, play a pivotal role in maintaining homeostasis of the immune system. The DC population is characterized by heterogeneity; it consists of many subpopulations which, despite their phenotypic and localization differences, play an essential function – they are professional antigen presenting cells. Due to their role, DCs can be utilized in a new cancer treatment strategy. Their main purpose is to generate an anticancer response leading to the elimination of cancer cells. The tumor microenvironment, abundant in immunosuppressive factors (e.g. IL-10, TGF-β, Arg1, IDO), impairs the proper function of DCs. For this reason, various strategies are necessary for ex vivo preparation of DC-based vaccines and for the support of in vivo DCs to fight against tumors. DC-based vaccines are combined with other forms of immunotherapy (e.g. blockade of immune checkpoint molecules, e.g. PD-1 or CTLA-4) or conventional types of therapies (e.g. chemotherapy). Despite the enormous progress that has been made in anticancer therapy in the past two decades, there are still many unresolved issues regarding the effectiveness of the DCs usage. In this paper we described, in both a mouse and a human subject, a series of DC subpopulations, differentiating in normal conditions or under the influence of cancer microenvironment. We listed factors affecting the quality of the in vivo and ex vivo generations of antitumoral responses, significant from a therapeutic point of view. Moreover, the most important strategies for the use of DCs in anticancer therapies, as well as further developments on this field, have been discussed.

scholarly journals Polyinosinic: Polycytidylic Acid and Murine Cytomegalovirus Modulate Expression of Murine IL-10 and IL-21 in White Adipose Tissue

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 569
Author(s):  
Pablo Garcia-Valtanen ◽  
Ruth Marian Guzman-Genuino ◽  
John D. Hayball ◽  
Kerrilyn R. Diener
Keyword(s):  
Adipose Tissue ◽  
B Cells ◽  
White Adipose Tissue ◽  
Ex Vivo ◽  
Interleukin 10 ◽  
Poly I:C ◽  
Murine Cytomegalovirus ◽  
Polycytidylic Acid ◽  
Polyinosinic Polycytidylic Acid

White adipose tissue (WAT) produces interleukin-10 and other immune suppressors in response to pathogen-associated molecular patterns (PAMPs). It also homes a subset of B-cells specialized in the production of IL-10, referred to as regulatory B-cells. We investigated whether viral stimuli, polyinosinic: polycytidylic acid (poly(I:C)) or whole replicative murine cytomegalovirus (MCMV), could stimulate the expression of IL-10 in murine WAT using in vivo and ex vivo approaches. Our results showed that in vivo responses to systemic administration of poly(I:C) resulted in high levels of endogenously-produced IL-10 and IL-21 in WAT. In ex vivo WAT explants, a subset of B-cells increased their endogenous IL-10 expression in response to poly(I:C). Finally, MCMV replication in WAT explants resulted in decreased IL-10 levels, opposite to the effect seen with poly(I:C). Moreover, downregulation of IL-10 correlated with relatively lower number of Bregs. To our knowledge, this is the first report of IL-10 expression by WAT and WAT-associated B-cells in response to viral stimuli.

scholarly journals Poly(I:C) and Lipopolysaccharide Innate Sensing Functions of Circulating Human Myeloid Dendritic Cells Are Affected In Vivo in Hepatitis C Virus-Infected Patients

2007 ◽  
Vol 81 (11) ◽  
pp. 5537-5546 ◽  
Author(s):  
Ian Gaël Rodrigue-Gervais ◽  
Loubna Jouan ◽  
Geneviève Beaulé ◽  
Dominike Sauvé ◽  
Julie Bruneau ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Poly I:C ◽  
Hcv Rna ◽  
Genomic Rna ◽  
Tnf Α ◽  
Wide Range ◽  
Rna Levels

ABSTRACT The role of peripheral dendritic cells (DCs) in hepatitis C virus (HCV) infection is unclear. To determine if persistent infection exerts an inhibitory pressure on HCV-specific innate responses, we analyzed DC function in blood through quantification of cell-associated HCV RNA levels in conjunction with multiparametric flow cytometry analysis of pathogen recognition receptor-induced cytokine expression. Independently of the serum viral load, fluorescence-activated cell sorter-purified total DCs had a wide range of cell-associated HCV genomic RNA copy numbers (mean log10, 5.0 per 106 cells; range, 4.3 to 5.8). Here we report that for viremic patients with high viral loads in their total DCs, the myeloid DC (MDC) subset displayed impaired expression of interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α) but normal IL-6 or chemokine CCL3 expression in response to poly(I:C) and lipopolysaccharide (LPS). IL-6-expressing cells from this subgroup of viremic patients demonstrated a significant increase (sixfold more) in TNF-α− IL-12− cell frequency compared to healthy donors (mean, 38.8% versus 6.5%; P < 0.0001), indicating a functional defect in a subpopulation of cytokine-producing MDCs (∼6% of MDCs). Attenuation of poly(I:C) and LPS innate sensing was HCV RNA density dependent and did not correlate with viremia or deficits in circulating MDC frequencies in HCV-infected patients. Monocytes from these patients were functionally intact, responding normally on a per-cell basis following stimulation, independent of cell-associated HCV RNA levels. Taken together, these data indicate that detection of HCV genomic RNA in DCs and loss of function in the danger signal responsiveness of a small proportion of DCs in vivo are interrelated rather than independent phenomena.

scholarly journals Rotavirus VP6 Adjuvant Effect on Norovirus GII.4 Virus-Like Particle Uptake and Presentation by Bone Marrow-Derived Dendritic Cells In Vitro and In Vivo

2020 ◽  
Vol 2020 ◽  
pp. 1-14 ◽  
Author(s):  
Kirsi Tamminen ◽  
Suvi Heinimäki ◽  
Timo Vesikari ◽  
Vesna Blazevic
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
Adjuvant Effect ◽  
Particle Uptake ◽  
Virus Like Particle ◽  
Norovirus Gii ◽  
Immortalized Cell ◽  
Antigen Presenting

We have previously shown that rotavirus (RV) inner capsid protein VP6 has an adjuvant effect on norovirus (NoV) virus-like particle- (VLP-) induced immune responses and studied the adjuvant mechanism in immortalized cell lines used as antigen-presenting cells (APCs). Here, we investigated the uptake and presentation of RV VP6 and NoV GII.4 VLPs by primary bone marrow-derived dendritic cells (BMDCs). The adjuvant effect of VP6 on GII.4 VLP presentation and NoV-specific immune response induction by BMDC in vivo was also studied. Intracellular staining demonstrated that BMDCs internalized both antigens, but VP6 more efficiently than NoV VLPs. Both antigens were processed and presented to antigen-primed T cells, which responded by robust interferon γ secretion. When GII.4 VLPs and VP6 were mixed in the same pulsing reaction, a subpopulation of the cells had uptaken both antigens. Furthermore, VP6 copulsing increased GII.4 VLP uptake by 37% and activated BMDCs to secrete 2-5-fold increased levels of interleukin 6 and tumor necrosis factor α compared to VLP pulsing alone. When in vitro-pulsed BMDCs were transferred to syngeneic BALB/c mice, VP6 improved NoV-specific antibody responses. The results of this study support the earlier findings of VP6 adjuvant effect in vitro and in vivo.

scholarly journals Induction of Polyomavirus-Specific CD8+T Lymphocytes by Distinct Dendritic Cell Subpopulations

2001 ◽  
Vol 75 (1) ◽  
pp. 544-547 ◽  
Author(s):  
Donald R. Drake ◽  
Mandy L. Shawver ◽  
Annette Hadley ◽  
Eric Butz ◽  
Charles Maliszewski ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Cell Epitope ◽  
T Cell Responses ◽  
T Cell Epitope ◽  
Cell Responses ◽  
Cd8 T Lymphocytes ◽  
Cell Subpopulations ◽  
Antigen Presenting

ABSTRACT Dendritic cells are pivotal antigen-presenting cells for generating adaptive T-cell responses. Here, we show that dendritic cells belonging to either the myeloid-related or lymphoid-related subset are permissive for infection by mouse polyomavirus and, when loaded with a peptide corresponding to the immunodominant anti-polyomavirus CD8+T-cell epitope or infected by polyomavirus, are each capable of driving expansion of primary polyomavirus-specific CD8+ T-cell responses in vivo.

scholarly journals Dendritic cells are potent antigen-presenting cells for microbial superantigens.

1992 ◽  
Vol 175 (1) ◽  
pp. 267-273 ◽  
Author(s):  
N Bhardwaj ◽  
S M Friedman ◽  
B C Cole ◽  
A J Nisanian
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Antigen Presenting Cells ◽  
Small Subset ◽  
Cell Functions ◽  
Cell Responses ◽  
Antigen Presenting

Dendritic cells are a small subset of human blood mononuclear cells that are potent stimulators of several T cell functions. Here we show they are 10-50-fold more potent than monocytes or B cells in inducing T cell responses to a panel of superantigens. Furthermore, dendritic cells can present femtomolar concentrations of superantigen to T cells even at numbers where other antigen-presenting cells (APCs) are inactive. Although dendritic cells express very high levels of the major histocompatibility complex products that are required to present superantigens, it is only necessary to pulse these APCs for 1 hour with picomolar levels of one superantigen, staphylococcal enterotoxin B, to maximally activate T cells. Our results suggest that very small amounts of superantigen will be immunogenic in vivo if presented on dendritic cells.

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