Recent studies have demonstrated that TLR3 forms dimeric complexes with 45-bp segments of dsRNA, and that single TLR3 dimers formed with a 48-bp dsRNA ON are capable of activating transfected cells expressing high amounts of TLR3 (27). A goal of this study was to determine how TLR3/dsRNA complexes, formed with dsRNA ONs of varying lengths, function in primary cells, and to translate these findings into the development of well-defined, TLR3-dependent adjuvants. In this study, we examined the activation of DC by dsRNA ONs because this response is key for inducing acquired antiviral immunity. We have previously shown that the interaction of TLR3-ECD protein with dsRNA is highly dependent on dsRNA length and TLR3-ECD concentration (27), which implies that the ability of a specifically sized dsRNA ON to bind TLR3 and activate a cell is governed, in part, by the membrane density of TLR3 in the endosomes. Thus, the large differences in TLR3 expression levels that we observed between DC subsets are ...
Conjugating Ag to the modified SMEZ-2 superantigen construct M1 enables specific targeting to MHC class II+ APC in vivo without the toxic polyclonal T cell response associated with direct TCR engagement. Our results show that conjugated Ag is efficiently processed and presented to CD4+, and cross-presented to CD8+ T cells. Of particular significance, this form of Ag delivery provides access to pathway of cross-presentation operating in all DC populations assessed, including the three major DC subtypes in murine spleen. This finding contrasts with many other studies in which splenic CD4−CD8+ DC have been shown to be superior at cross-presentation than both of the CD8− DC subtypes (8, 9, 29). The knowledge that Ag can be efficiently targeted to promote cross-presentation in a variety of DC subtypes should be particularly useful in the design of vaccines against intracellular pathogens and tumors in which CD8+ T cell responses are desirable.. It has previously been reported that Ag incorporated ...
Cross-presentation is an important mechanism to elicit both immune defenses and tolerance. Although only a few DC subsets possess the machinery required for cross-presentation, little is known about differences in cross-presenting capabilities of DCs belonging to the same subpopulation but localized in different lymphoid organs. In this study, we demonstrate that steady-state thymic CD8(+) DCs can efficiently cross-prime naïve CD8(+) T cells in the absence of costimulation. Surprisingly, cross-priming by splenic CD8(+) DCs was dependent on licensing factors such as GM-CSF. In the absence of GM-CSF, antigen-MHC-class-I complexes were detected on thymic but not on splenic CD8(+) DCs, indicating that the cross-presentation capacity of the thymic subpopulation was higher. The observed cross-priming differences between thymic and splenic CD8(+) DCs did not correlate with differential antigen capture or costimulatory molecules found on the surface of DCs. Moreover, we did not detect overall ...
Cross-priming is a critical component of T cell responses to cancers and viruses, and involves transfer of antigen from antigen donor cells to the antigen presenting cells. In spite of the centrality of antigen in this process, the influence of the quantity of antigen expressed by the antigen donor cell on the efficiency of cross-priming remains unexamined. Here, I describe the creation of a novel system where the model antigen ovalbumin is expressed in P815 (d haplotype) cells under the control of an inducible promoter, producing a large amount of antigen synthesis upon induction. However, even in the un-induced condition, a very low level of ovalbumin can be detected using sensitive methods to amplify the weak signal. I have used titrated quantities of uninduced and induced cells, expressing vastly different quantities of ovalbumin, and have monitored cross-priming of the endogenous anti-OVA CD8+ T cell response quantitatively in C57BL/6 mice (b haplotype), using in vivo cytolytic T lymphocyte assays.
ABSTRACT: Cytotoxic T lymphocytes (CTL) responses are required to fight many diseases such as viral infections and tumors. At the same time, they can cause disease when induced inappropriately. Which factors regulate CTL and decide whether they should remain silent or react is open to debate. The phenomenon called cross-priming has received attention in this respect. That is, CTL expansion occurs if antigen is recognized on the surface of professional antigen presenting cells (APCs). This is in contrast to direct presentation where antigen is seen on the surface of the target cells (e.g. infected cells or tumor cells). Here we introduce a mathematical model, which takes the phenomenon of cross-priming into account. We propose a new mechanism of regulation which is implicit in the dynamics of the CTL: According to the model, the ability of a CTL response to become established depends on the ratio of cross-presentation to direct presentation of the antigen. If this ratio is relatively high, CTL ...
DCs are a critical component of immune responses in cancer primarily due to their ability to cross-present tumor-associated antigens. Cross-presentation by DCs in cancer is impaired, which may represent one of the obstacles for the success of cancer immunotherapies. Here, we report that polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) blocked cross-presentation by DCs without affecting direct presentation of antigens by these cells. This effect did not require direct cell-cell contact and was associated with transfer of lipids. Neutrophils (PMN) and PMN-MDSC transferred lipid to DCs equally well; however, PMN did not affect DC cross-presentation. PMN-MDSC generate oxidatively truncated lipids previously shown to be involved in impaired cross-presentation by DCs. Accumulation of oxidized lipids in PMN-MDSC was dependent on myeloperoxidase (MPO). MPO-deficient PMN-MDSC did not affect cross-presentation by DCs. Cross-presentation of tumor-associated antigens in vivo by DCs was improved ...
Antigen uptake by dendritic cells and intracellular routing of antigens to specific compartments is regulated by C-type lectin receptors that recognize glycan structures. The OVA-LeX-induced enhancement of T cell cross-priming is MGL1-dependent as shown by reduced CD8+ effector T cell frequencies in MGL1-deficient mice. Moreover MGL1-mediated cross-presentation of OVA-LeX neither required TAP-transporters nor Cathepsin-S and […]. Read More ». ...
DCs are fundamental players in antitumor immunity through a process known as antigen cross-presentation, in which they process tumor-derived antigens into the MHC class I pathway for presentation to T cells that have the ability to kill cancer cells. This DC function is also required for the success of cancer vaccines and immunotherapy, but it is well established that tumor-associated DCs are defective in their ability to perform antigen cross-presentation. DCs from cancer patients and tumor-bearing animal models also accumulate higher amounts of lipids compared with DCs from healthy individuals, a process that has been implicated in defective cross-presentation by DCs. The mechanism underlying this association was unknown.. In collaboration with the group of Valerian Kagan, Ph.D., D.Sc., at the University of Pittsburgh, Gabrilovich and colleagues analyzed in great detail the events that take place in the DCs from tumor-bearing mice models and found that impaired cross-presentation, which ...
First described in 1973 by Ralf Steinman, dendritic cells have since attracted considerable attention. Their properties of antigen capture, presentation and T cell activation, place them both as a key bridge between the innate and adaptive immunity, as well as a switch between tolerance and immunity. Although, the human and mouse DC network share many similarities, one subset was discovered in mouse that had not yet found its equivalent in human: the CD8+ DC characterised by their ability produce IL-12, but most particularly to uptake dead cells and "cross-present" these exogenous antigens on MHC class I molecules. This function has been shown to be essential in the immune defense against many viruses, intracellular bacteria and tumors as well as for the maintenance of self tolerance. Four studies in J. Exp. Med provide insight into a potential human homologue to the mouse cross-presentation specialist CD8+ DC. A nice minireview from two DC experts: Villadangos and Shortman. ...
Researchers in Gommermans lab are aiming to shed light on the pathological processes associated with multiple sclerosis disease progression. To do this they need to look at many markers within intact tissues to understand what the immune cells are doing and how they correlate with tissue damage in the brain. Using IMC allows them to take a comprehensive approach to viewing the tissue ecosystem, with a goal of understanding the relevance of the different immune cell subsets and their location and how this relates to mechanisms in multiple sclerosis disease process. Gommerman is Professor and Graduate Coordinator at the University of Toronto in the Department of Immunology, where she spearheaded a new Applied MSc. In addition to examining the role of B lymphocytes in multiple sclerosis patients, her group focuses on how members of the TNF superfamily of molecules regulate immunity and autoimmunity. Gommerman also is the lead PI on a study to examine the effect of global migration on ...
The Journal of Immunology Targeting the Effector Site with IFN- -Inducing TLR Ligands Reactivates Tumor-Resident CD8 T Cell Responses to Eradicate Established Solid Tumors 1 Andrew J. Currie, 2,3 * Robbert
IRVINE, Calif. - August 14, 2019 - AIVITA Biomedical, Inc., a biotech company specializing in innovative stem cell applications, announced today updated clinical data from its ongoing glioblastoma Phase 2 clinical trial, investigating AIVITAs platform immunotherapy targeting tumor-initiating cells. Blood plasma biomarker analyses have identified a robust immune response and a decrease of tumor biomarkers in 65% of treated patients, in a sample that represents 29% of the total Phase 2 clinical trial size.. Blood was collected from subjects at multiple time points, one week after each dose administration, and assayed for 450 different immune and tumor biomarkers. Treatment elicited a robust immune response, with biomarkers suggesting progressive activation of dendritic cell cross-presentation and progressive activation of a type II hypersensitivity antibody-mediated cytotoxic response. Most notably, 65% of the treated glioblastoma patients also showed a robust decrease of 27 different biomarkers ...
Link to Pubmed [PMID] - 22153078. Cell 2011 Dec;147(6):1355-68. Antigen (Ag) crosspresentation by dendritic cells (DCs) involves the presentation of internalized Ags on MHC class I molecules to initiate CD8+ T cell-mediated immunity in response to certain pathogens and tumor cells. Here, we identify the SNARE Sec22b as a specific regulator of Ag crosspresentation. Sec22b localizes to the ER-Golgi intermediate compartment (ERGIC) and pairs to the plasma membrane SNARE syntaxin 4, which is present in phagosomes (Phgs). Depletion of Sec22b inhibits the recruitment of ER-resident proteins to Phgs and to the vacuole containing the Toxoplasma gondii parasite. In Sec22b-deficient DCs, crosspresentation is compromised after Ag phagocytosis or endocytosis and after invasion by T. gondii. Sec22b silencing inhibited Ag export to the cytosol and increased phagosomal degradation by accelerating lysosomal recruitment. Our findings provide insight into an intracellular traffic pathway required for ...
The induction of cytotoxic CD8+ T cell responses requires the presentation of antigenic peptides by MHC class I molecules (MHC I). MHC I usually present peptides derived from endogenous proteins. However, some subtypes of dendritic cells (DCs) have developed the ability to efficiently present peptides derived from exogenous antigens on MHC I via a process called cross-presentation. Cross-presentation is intimately linked to the induction of anti-viral, -bacterial and -tumor cytotoxic T cell (CTL) responses, as well as a wide variety of CTL-mediated diseases and transplant rejections. The molecular and cellular mechanisms underlying cross-presentation have been studied intensively since its original description, yet understanding of this process is incomplete and on the forefront of immunological research. Numerous pathways and models, some of them conflicting, have been described so far. Here, we review the various pathways reported as involved in cross-presentation, highlighting the complexity of this
Purpose: We previously reported that autophagy in tumor cells plays a critical role in cross-presentation of tumor antigens and that autophagosomes are efficient antigen carriers for cross-priming of tumor-reactive CD8+ T cells. Here, we sought to characterize further the autophagosome-enriched vaccine named DRibble (DRiPs-containing blebs), which is derived from tumor cells after inhibition of protein degradation, and to provide insights into the mechanisms responsible for their efficacy as a novel cancer immunotherapy.. Experimental Design: DRibbles were characterized by Western blot and light or transmission electron microscopy. The efficiency of cross-presentation mediated by DRibbles was first compared with that of whole-tumor cells and pure proteins. The mechanisms of antigen cross-presentation by DRibbles were analyzed, and the antitumor efficacy of the DRibble vaccine was tested in 3LL Lewis lung tumors and B16F10 melanoma.. Results: The DRibbles sequester both long-lived and short-lived ...
The development of effective cancer vaccines remains an urgent, but as yet unmet, clinical need. cell responses associated with therapeutic benefit. Anti-tumor protection was dependent on cross-presenting Batf3+DC, pDC and CD8+T cells. CD103+DC from the skin/tumor dLN of the immunized mice appeared responsible for activation of Ag-specific na?ve CD8+T cells, but were dependent on pDC for optimal effectiveness. Similarly, human XBP1 improved the capacity of human blood- and skin-derived DC to activate human T cells. These data support an important intrinsic role for XBP1 in DC for effective cross-priming and orchestration of Batf3+DCCpDC interactions, thereby enabling Gap 27 effective vaccine induction of protective anti-tumor immunity. Keywords: XBP1, DC, Cancer Vaccines, Cross-priming, CD8+T cells Introduction Immunotherapies utilizing vaccines, antibodies, and T Gap 27 cells have the potential to (re)activate and optimize the bodys immune system to fight off cancer (1). Although vaccines are ...
The development of effective cancer vaccines remains an urgent, but as yet unmet, clinical need. cell responses associated with therapeutic benefit. Anti-tumor protection was dependent on cross-presenting Batf3+DC, pDC and CD8+T cells. CD103+DC from the skin/tumor dLN of the immunized mice appeared responsible for activation of Ag-specific na?ve CD8+T cells, but were dependent on pDC for optimal effectiveness. Similarly, human XBP1 improved the capacity of human blood- and skin-derived DC to activate human T cells. These data support an important intrinsic role for XBP1 in DC for effective cross-priming and orchestration of Batf3+DCCpDC interactions, thereby enabling Gap 27 effective vaccine induction of protective anti-tumor immunity. Keywords: XBP1, DC, Cancer Vaccines, Cross-priming, CD8+T cells Introduction Immunotherapies utilizing vaccines, antibodies, and T Gap 27 cells have the potential to (re)activate and optimize the bodys immune system to fight off cancer (1). Although vaccines are ...
Background: Treatments that generate T cell-mediated immunity to a patients unique neoantigens are the current holy grail of cancer immunotherapy. In particular, treatments that do not require cumbersome and individualized ex vivo processing or manufacturing processes are especially sought after. Here we report that AGI-134, a glycolipid-like small molecule, can be used for coating tumor cells with the xenoantigen Galalpha1-3Galbeta1-4GlcNAc (alpha-Gal) in situ leading to opsonization with pre-existing natural anti-alpha-Gal antibodies (in short anti-Gal), which triggers immune cascades resulting in T cell mediated anti-tumor immunity. Methods: Various immunological effects of coating tumor cells with alpha-Gal via AGI-134 in vitro were measured by flow cytometry: (1) opsonization with anti-Gal and complement, (2) antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells, and (3) phagocytosis and antigen cross-presentation by antigen presenting cells (APCs). A viability kit was used to test AGI
TY - JOUR. T1 - Differential capacity of human interleukin-4 and interferon-alpha monocyte-derived dendritic cells for cross-presentation of free versus cell-associated antigen. AU - Ruben, J.M.. AU - Bontkes, H.J.. AU - Westers, T.M.. AU - Hooijberg, E.. AU - Ossenkoppele, G.J.. AU - de Gruijl, T.D.. AU - van de Loosdrecht, A.A.. PY - 2015. Y1 - 2015. U2 - 10.1007/s00262-015-1741-1. DO - 10.1007/s00262-015-1741-1. M3 - Article. C2 - 26216454. VL - 64. SP - 1419. EP - 1427. JO - Cancer Immunology and Immunotherapy. JF - Cancer Immunology and Immunotherapy. SN - 0340-7004. IS - 11. ER - ...
S. cerevisiae, a nonpathogenic yeast, has recently gained interest as a vaccine vehicle for the treatment of cancer and infectious diseases. The construct is safe, as the yeast is heat killed before administration. It can be easily engineered to express antigens in large quantities and can be cultured rapidly. In addition, S. cerevisiae can induce a robust host immune response, delivering antigen to both MHC class I and II pathways by cross-priming (1, 4-6, 26). All of these qualities make S. cerevisiae an attractive vehicle for cancer immunotherapy. In this study, we sought to determine for the first time whether vaccination with a yeast construct expressing a TAA could break tolerance and induce antigen-specific T-cell and antitumor responses. The data presented here show that vaccination with yeast-CEA not only elicits CEA-specific CD4+ and CD8+ T-cell responses but also decreases tumor volume and increases overall survival in tumor-bearing mice. For comparison, CEA-Tg mice were also ...
The Dutch Cancer Society (KWF) has awarded 25.5 million euros to 50 new research projects in 16 different institutes.. 8 grants are awarded to Radboudumc researchers, 2 for our department:. Research project: Induction of neo-antigen specific T cells by specialised cross-presenting dendritic cells in epithelial ovarian cancer ...
Singh SK, Streng-Ouwehand I, Litjens M, Burgdorf S, Kurts C, Kalay H. Saeland E, Unger WWJ, and VAN KOOYK Y. Design of neo-glycoconjugates that target the Mannose Receptor and enhance TLR independent cross-presentation and Th1 polarization. Eur. J. Immunol, 41(4):916-25, 2011 ...
TY - JOUR. T1 - A subset of toll-like receptor ligands induces cross-presentation by bone marrow-derived dendritic cells. AU - Datta, Sandip K.. AU - Redecke, Vanessa. AU - Prilliman, Kiley R.. AU - Takabayashi, Kenji. AU - Corr, Maripat. AU - Tallant, Thomas. AU - DiDonato, Joseph. AU - Dziarski, Roman. AU - Akira, Shizuo. AU - Schoenberger, Stephen P.. AU - Raz, Eyal. PY - 2003/4/15. Y1 - 2003/4/15. N2 - Dendritic cells (DCs) are capable of cross-presenting exogenous Ag to CD8+ CTLs. Detection of microbial products by Toll-like receptors (TLRs) leads to activation of DCs and subsequent orchestration of an adaptive immune response. We hypothesized that microbial TLR ligands could activate DCs to cross-present Ag to CTLs. Using DCs and CTLs in an in vitro cross- presentation system, we show that a subset of microbial TLR ligands, namely ligands of TLR3 (poly(inosinic-cytidylic) acid) and TLR9 (immunostimulatory CpG DNA), induces cross-presentation. In contrast to presentation of Ag to CD4+ T ...
Absence of Cross-Presenting Cells in the Salivary Gland and Viral Immune Evasion Confine Cytomegalovirus Immune Control to Effector CD4 T ...
In this work, we have shown that overexpression of Bcl-2 protects peripheral CD8 T cells from deletion in response to cross-presented self antigen. The OT-I.Eμ-Bcl-2 and OT-I.vav.Bcl-2 cells appeared similar to wild-type OT-I cells in their ability to be activated and proliferate in response to cross-presented self-antigen. If sufficiently high numbers of OT-I.Eμ-Bcl-2 T cells were transferred, they induced autoimmune diabetes (Table I). As a pro-survival molecule Bcl-2 protects lymphocytes in vitro and in vivo against apoptosis induced by growth factor deprivation, DNA damage or treatment with corticosteroids or calcium ionophores (16). For activated T cells in vivo, bcl-2 transgene expression prolongs T cell survival following injection of mice with the superantigen staphylococcus enterotoxin B (SEB; reference 16), the transfer of HY-TCR CD8 T cells into male recipients (18), the immunization of mice expressing a transgenic LCMV-TCR in CD8 T cells with LCMV peptide (19) and the immunization ...
To determine if mesothelin is recognized by CD8+ T cells, we screened antigen-pulsed T2 cells in a quantitative ELISPOT-based assay using pre- and postvaccination CD8+ T cell-enriched PBLs from the 14 patients treated previously with the allogeneic, GM-CSF-secreting pancreatic tumor vaccine. Previously, we reported the association of in vivo postvaccination DTH responses to autologous tumor in three out of eight patients receiving the highest two doses of vaccine. PBLs obtained before vaccination and 28 d after the first vaccination were initially analyzed. T2-A3 cells pulsed with the two A3 binding epitopes were incubated overnight with CD8+ T cell-enriched lymphocytes isolated from the peripheral blood of patients 11 (an A3 non-DTH responder) and 13 (an A3 DTH responder), and analyzed using an IFN-γ ELISPOT assay. The ELISPOT assay was chosen because it requires relatively few lymphocytes, is among the most sensitive in vitro assays for quantitating antigen-specific T cells, and correlates ...
Topical antigen (Ag) application mimics natural Ag exposure across the skin. Soluble Ag introduced through this route requires cross-presentation by dendritic cells (DCs) to generate CD8 T cell responses, including skin-homing ...
Non-antigen-specific stimulatory cancer immunotherapies are commonly complicated by off-target effects. Antigen-specific immunotherapy, combining viral tumor antigen or personalized neoepitopes with immune targeting, offers a solution. However, the lack of flexible systems targeting tumor antigens to cross-presenting dendritic cells (DCs) limits clinical development. Although antigen-anti-Clec9A mAb conjugates target cross-presenting DCs, adjuvant must be codelivered for cytotoxic T lymphocyte (CTL) induction. We functionalized tailored nanoemulsions encapsulating tumor antigens to target Clec9A (Clec9A-TNE). Clec9A-TNE encapsulating OVA antigen targeted and activated cross-presenting DCs without additional adjuvant, promoting antigen-specific CD4+ and CD8+ T cell proliferation and CTL and antibody responses. OVA-Clec9A-TNE-induced DC activation required CD4 and CD8 epitopes, CD40, and IFN-α. Clec9A-TNE encapsulating HPV E6/E7 significantly suppressed HPV-associated tumor growth, while ...
Immunostimulatory cytidyl guanosyl (CpG) motifs are of great interest as cancer vaccine adjuvants. They act as potent inducers of Th1 responses, including the activation of cytotoxic CD8(+) T lymphocytes (CTL). Whereas animal models have provided clear evidence that CpG enhances antitumor immunity, clinical trials in humans have thus far been less successful. Applying cryosurgery as an instant in situ tumor destruction technique, we now show that timing of CpG administration crucially affects colocalization of antigen and CpG within EEA-1(+) and LAMP-1(+) compartments within dendritic cells in vivo. Moreover, antigen/CpG colocalization is directly correlated with antigen cross-presentation, the presence of CTL, and protective antitumor immunity. Thus, failure or success of CpG as a vaccine adjuvant may depend on colocalization of antigen/CpG inside DCs and hence on the timing of CpG administration. These data might aid in the design of future immunotherapeutic strategies for cancer patients ...
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The vertebrate immune system uses multiple, sometimes redundant, mechanisms to contain pathogenic microorganisms that are always evolving to evade host defenses. Thus, the cowpox virus (CPXV) uses genes encoding CPXV12 and CPXV203 to prevent direct MHC class I presentation of viral peptides by infected cells. However, CD8 T cells are effectively primed against CPXV by cross-presentation of viral Ags in young mice. Old mice accumulate defects in both CD8 T cell activation and cross-presentation. Using a double-deletion mutant (∆12∆203) of CPXV, we show that direct priming of CD8 T cells in old mice yields superior recall responses, establishing a key contribution of this mechanism to host antipoxvirus responses and enhancing our fundamental understanding of how viral manipulation of direct presentation impacts pathogenesis ...
The presence of TILs has been shown to be a favorable prognostic indicator in a number of cancers, and gene expression profiling demonstrated that patients with high baseline tumor expression of genes related to both innate and adaptive immune response were more likely to favorably respond to immunotherapy (7, 23, 24). The presence of TILs in tumors has been shown to be associated with type I IFN transcriptional profile, and additional studies demonstrated the critical role for type I IFN in CD8a+ DC-mediated antigen cross-presentation and priming of tumor-specific CD8+ T cells (8, 9). These findings provide a strong rationale to explore tumor therapeutic strategies that activate the type I IFN pathway. Indeed, combination therapy using intratumoral CpG oligonucleotides with antibodies targeting immune checkpoints has been shown to be an effective therapeutic strategy resulting in depletion of Tregs at the injected tumor site and in regression of distant tumors (25).. Here, to trigger ...
Ectopic expression of transcription factors has been used to reprogram differentiated somatic cells toward pluripotency or to directly reprogram them to other somatic cell lineages. This concept has been explored in the context of regenerative medicine. Here, we set out to generate dendritic cells (DCs) capable of presenting antigens from mouse and human fibroblasts. By screening combinations of 18 transcription factors that are expressed in DCs, we have identified PU.1, IRF8, and BATF3 transcription factors as being sufficient to reprogram both mouse and human fibroblasts to induced DCs (iDCs). iDCs acquire a conventional DC type 1-like transcriptional program, with features of interferon-induced maturation. iDCs secrete inflammatory cytokines and have the ability to engulf, process, and present antigens to T cells. Furthermore, we demonstrate that murine iDCs generated here were able to cross-present antigens to CD8+ T cells. Our reprogramming system should facilitate better understanding of ...
Superparamagnetic iron oxide nanoparticles (SPIO) have been synthesized and explored for use as carriers of various nanoadjuvants via loading into dendritic cells (DCs). In our study, homogeneous and superparamagnetic nanoparticles are susceptible to internalization by DCs and SPIO-pulsed DCs showed excellent biocompatibility and capacity for ovalbumin (OVA) cross-presentation. Herein, we found that SPIO-loaded DCs can promote the maturation and migration of DCs in vitro. SPIO coated with 3-aminopropyltrimethoxysilane (APTS) and meso-2,3-dimercaptosuccinic acid (DMSA), which present positive and negative charges, respectively, were prepared. We aimed to investigate whether the surface charge of SPIO can affect the antigen cross-presentation of the DCs. Additionally, the formation of interleukin-1β (IL-1β) was examined after treatment with oppositely charged SPIO to identify the nanoadjuvants mechanism. In conclusion, our results suggest that SPIO are biocompatible and can induce the migration of DCs
Enhanced apoptosis of BCG-infected macrophages has been shown to induce stronger dendritic cell-mediated cross-priming of T cells, leading to higher protection against tuberculosis (TB). Uncovering host effectors underlying BCG-induced apoptosis may then prove useful to improve BCG efficacy through …
Protein antigen (Ag)-based immunotherapies have the advantage to induce T cells with a potentially broad repertoire of specificities. However, soluble protein Ag is generally poorly cross-presented in
Alterations in gut microbiota impact the pathophysiology of several diseases, including cancer. Radiotherapy (RT), an established curative and palliative cancer treatment, exerts potent immune modulatory effects, inducing tumor-associated antigen (TAA) cross-priming with antitumor CD8+ T cell elicitation and abscopal effects. We tested whether the gut microbiota modulates antitumor immune response following RT distal to the gut. Vancomycin, an antibiotic that acts mainly on gram-positive bacteria and is restricted to the gut, potentiated the RT-induced antitumor immune response and tumor growth inhibition. This synergy was dependent on TAA cross presentation to cytolytic CD8+ T cells and on IFN-γ. Notably, butyrate, a metabolite produced by the vancomycin-depleted gut bacteria, abrogated the vancomycin effect. In conclusion, depletion of vancomycin-sensitive bacteria enhances the antitumor activity of RT, which has important clinical ramifications.. ...
BACKGROUND: Recent studies have shown that the thromboxaneA 2 -dependent pathway is dependent upon the adenosine diphosphate (ADP)-P2Y 12 pathway and that strong P2Y 12 receptor blockade alone causes inhibition of platelet aggregation that is minimally enhanced by aspirin. Data from the PLATO trial suggested that among ticagrelor-treated patients, high compared with low dose (,100mg\day) aspirin is associated with increased risk for ischemic events. OBJECTIVES: In the current prospective, randomized, placebo-controlled, double-blind, cross-over study, we sought to evaluate the impact of aspirin withdrawal on platelet reactivity in acute coronary syndrome (ACS) patients treated with a potent P2Y 12 blocker ...
Cancer, Bladder, Bladder Cancer, Mannose, Patients, Tumor, Patient, Risk, Risk Factors, Antigen, Antigen-presenting Cells, Antigens, Cancer Vaccines, Cancers, Cells, Chorionic Gonadotropin, Cross-presentation, Early Intervention, Gm-csf, Gonadotropin
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Peripheral blood lymphocytes from 9 monoclonal gammopathies of undetermined significance (MGUS) and 27 multiple myelomas (MM) were studied with a panel of monoclonal antibodies (MoAb) that recognize B and T lymphocytes and plasma cells. No difference in the percentage of B lymphocytes, identified by B1 and B4 MoAb, was observed in MGUS and MM patients versus normal controls. However, high percentages of circulating lymphocytes expressing plasma cell-associated antigens were detected in MM (HAN-PC1+ = 29.4 +/- 20.4%; TEC-T10+ = 27.8 +/- 19.2%) whereas they were in the normal range in MGUS (HAN-PC1+ = 8.8 +/- 5.8% p = 0.006; TEC-T10+ = 5.7 +/- 4.7% p less than 0.001). Almost identical results were obtained using PCA-1 MoAb in 17 of these patients. TEC-T10+ and PCA-1+ lymphocytes were sorted and re-analyzed with phycoerythrin conjugated MoAb in 3 healthy subjects, 2 MGUS, and 4 MM patients. In normal subjects and in MGUS the majority of PCA-1+ cells belonged to the B lineage (Leu 2-, Leu3-, Leu ...
Our team studies antigen presentation by DC. It has demonstrated cross-presentation ability of human plasmacytoid DC (pDC) and conventional DC1 bearing the chemokine receptor XCR1. We showed that DC perform cross-presentation of HIV antigens to specific CD8+ T lymphocytes specific for HIV very efficiently not only from apoptotic infected cells, but also from live cells. We are seeking to exploit this antigen presentation from live cells to kill cells which are HIV reservoirs or, with Armelle Prévost-Blondel, metastatic melanoma cells. (Immune activation and suppression during HIV infecton). We study the roles of different DC and monocyte/macrophage populations in T cell response polarization et in type I or III IFN production during HIV infection. We were the first to show during this infection the depletion of circulating DC et the accumulation of pro-inflammatory slan+ monocytes. Our aim is to reduce the reservoirs and the immune hyper activation and immune suppression which are linked to ...
The new Echo1USA Polymer XCR is in stock and ready for any sort of CQB gaming!. XCR Pistol in Black. XCR Pistol in Tan. 350 fps out of the box with an 8mm bearing gearbox for 20~ bps with a lipo and it is lipo ready!. ...
The ability of dendritic cells (DCs) to take up whole tumor cells and process their antigens for presentation to T cells (cross-priming) is an important mechanism for induction of tumor specific immunity. In vitro generated DCs were loaded with killed allogeneic breast cancer cells and offered to autologous naïve CD8+ T cells in 2-week and/or 3-week cultures. CD8+ T cell differentiation was measured by their capacity to secrete effector cytokines (interferon-γ) and kill breast cancer cells. Specificity was measured using peptides derived from defined breast cancer antigens. We found that DCs loaded with killed breast cancer cells can prime naïve CD8+ T cells to differentiate into effector cytotoxic T lymphocytes (CTLs). Importantly, these CTLs primed by DCs loaded with killed HLA-A*0201- breast cancer cells can kill HLA-A*0201+ breast cancer cells. Among the tumor specific CTLs, we found that CTLs specific for HLA-A2 restricted peptides derived from three well known shared breast tumor antigens,
... My laboratory is investigating various aspects of how the immune system carries out surveillance to detect viral infections, cancers and cell death. Among the areas of research are: (1) The alarm signals and the receptors that alert the immune system to potential danger; (2) The mechanisms by which sentinel cells (dendritic cells) acquire and display antigens to CD8 T cells (cross presentation), a process that is essential for immune surveillance of tissues; and, (3) The antigen presentation pathway by which virally infected or cancer cells display their antigens to effector CD8 T cells (MHC class I antigen presentation), a process that is essential for the immune system to detect and eliminate these pathological cells. The laboratory is in a new state of the art research building and part of a very strong and interactive immunology community at UMass Medical School. UMass Medical School is located in Worcester Massachusetts, just outside of Boston. Interested ...
June 1, 2018 - Socium Therapeutics, Inc. ("Socium") announced that it had finalized the acquisition of Aeterna Zentaris live recombinant oral allogenic immunotherapy platform ("Platform"), including AEZS-120, the most advanced product candidate for prostate cancer which is ready to enter a Phase I clinical trial. As part of the acquisition, Socium owns all intellectual property, regulatory dossiers, pre-clinical data and cellular material related to the Platform.. Tim Salmon, Co-founder, President and CEO of Socium, commented, "The Platform, which we refer to as the CReST Platform (Cross-presenting Recombinant Salmonella typhi Ty21a), represents a major step forward in immuno-oncology. The CReST Platform provides for oral delivery; leverages the long, safe human use of S. typhi Ty21a to treat typhoid fever; activates the largest concentration of immune cells in the gut; and induces tumor-antigen-specific killer T-cell activation in vivo. Candidates from the CReST Platform will be tested in ...
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Antigen uptake (FITC-OVA and FITC-DX) by D1 bulk population in the presence or absence of TNFα was analyzed by doublecolor FACS® analysis. The D1 cells that
Входит в надсемейство белков лектины C-типа/лектино-подобный домен C-типа (CTL/CTLD). Белки этого надсемейства имеют похожую конформацию и обладают различными функциями, включая клеточную адгезию, межклеточную передачу сигнала, обмен гликопротеинов, участие в воспалении и иммунном ответе. CLL-1 является отрицательным регулятором гранулоцитарных и моноцитарных функций. ...