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Cross-presentation

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https://www.readbyqxmd.com/read/27926855/temporally-programmed-cd8%C3%AE-dc-activation-enhances-combination-cancer-immunotherapy
#1
Alice Tzeng, Monique J Kauke, Eric F Zhu, Kelly D Moynihan, Cary F Opel, Nicole J Yang, Naveen Mehta, Ryan L Kelly, Gregory L Szeto, Willem W Overwijk, Darrell J Irvine, K Dane Wittrup
Numerous synergistic cancer immunotherapy combinations have been identified, but the effects of relative dose timing are rarely considered. In established syngeneic mouse tumor models, we found that staggering interferon-α (IFNα) administration after, rather than before or simultaneously with, serum-persistent interleukin-2 (IL-2) and tumor-specific antibody significantly increased long-term survival. Successful combination therapy required IFNα-induced activation of cross-presenting CD8α(+) dendritic cells (DCs) following the release of antigenic tumor debris by the IL-2- and antibody-mediated immune response...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27899443/rab43-facilitates-cross-presentation-of-cell-associated-antigens-by-cd8%C3%AE-dendritic-cells
#2
Nicole M Kretzer, Derek J Theisen, Roxane Tussiwand, Carlos G Briseño, Gary E Grajales-Reyes, Xiaodi Wu, Vivek Durai, Jörn Albring, Prachi Bagadia, Theresa L Murphy, Kenneth M Murphy
In this study, to examine cross-presentation by classical dendritic cells (DCs; cDCs), we evaluated the role of RAB43, a protein found to be selectively expressed by Batf3-dependent CD8α(+) and CD103(+) compared with other DC subsets and immune lineages. Using a specific monoclonal antibody, we localized RAB43 expression to the Golgi apparatus and LAMP1(-) cytoplasmic vesicles. Mice with germline or conditional deletion of Rab43 are viable and fertile and have normal development of cDCs but show a defect for in vivo and in vitro cross-presentation of cell-associated antigen...
November 29, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27872208/blocking-virus-replication-during-acute-murine-cytomegalovirus-infection-paradoxically-prolongs-antigen-presentation-and-increases-the-cd8-t-cell-response-by-preventing-type-i-ifn-dependent-depletion-of-dendritic-cells
#3
Christopher P Loo, Christopher M Snyder, Ann B Hill
Increasing amounts of pathogen replication usually lead to a proportionate increase in size and effector differentiation of the CD8(+) T cell response, which is attributed to increased Ag and inflammation. Using a murine CMV that is highly sensitive to the antiviral drug famciclovir to modulate virus replication, we found that increased virus replication drove increased effector CD8(+) T cell differentiation, as expected. Paradoxically, however, increased virus replication dramatically decreased the size of the CD8(+) T cell response to two immunodominant epitopes...
November 21, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27871362/actin-is-an-evolutionarily-conserved-damage-associated-molecular-pattern-that-signals-tissue-injury-in-drosophila-melanogaster
#4
Naren Srinivasan, Oliver Gordon, Susan Ahrens, Anna Franz, Safia Deddouche, Probir Chakravarty, David Phillips, Ali A Yunus, Michael K Rosen, Rita S Valente, Luis Teixeira, Barry Thompson, Marc S Dionne, Will Wood, Caetano Reis E Sousa
Damage-associated molecular patterns (DAMPs) are molecules released by dead cells that trigger sterile inflammation and, in vertebrates, adaptive immunity. Actin is a DAMP detected in mammals by the receptor, DNGR-1, expressed by dendritic cells (DCs). DNGR-1 is phosphorylated by Src-family kinases and recruits the tyrosine kinase Syk to promote DC cross-presentation of dead cell-associated antigens. Here we report that actin is also a DAMP in invertebrates that lack DCs and adaptive immunity. Administration of actin to Drosophila melanogaster triggers a response characterised by selective induction of STAT target genes in the fat body through the cytokine Upd3 and its JAK/STAT-coupled receptor, Domeless...
November 22, 2016: ELife
https://www.readbyqxmd.com/read/27867197/p38%C3%AE-has-an-important-role-in-antigen-cross-presentation-by-dendritic-cells
#5
Yifan Zhou, Jianfeng Wu, Chunxiao Liu, Xueheng Guo, Xinyi Zhu, Yuan Yao, Yuhao Jiao, Peng He, Jiahuai Han, Li Wu
The role of the p38 signaling pathway in the innate and adaptive immune responses has been well documented, especially in inflammatory cytokine production by dendritic cells (DCs). However, whether the p38 signaling pathway affects the important antigen (Ag) presentation function of DCs remains largely unknown. In this study, we reported that the deletion of p38α resulted in an impaired cross-presentation ability of CD8(+) conventional DCs (cDCs) and a reduction in the direct presentation ability of CD8(-) cDCs ex vivo...
November 21, 2016: Cellular & Molecular Immunology
https://www.readbyqxmd.com/read/27861804/cd103-cd11b-salivary-gland-dendritic-cells-have-antigen-cross-presenting-capacity
#6
Lu Lu, Yukinori Tanaka, Naoto Ishii, Takashi Sasano, Shunji Sugawara
Dendritic cells (DCs) in lymphoid and non-lymphoid tissues are professional antigen-presenting cells that are essential for effective immunity and tolerance. However, the presence and characteristics of DCs in steady-state salivary glands (SGs) currently remain unknown. We herein identified CD64(-) CD11c(+) classical DCs (cDCs) as well as CD64(+) macrophages among CD45(+) MHC class II(+) antigen-presenting cells in steady-state murine SGs. SG cDCs were divided into CD103(+) CD11b(-) and CD103(-) CD11b(+) cDCs...
November 11, 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27861124/rab22a-controls-mhc-i-intracellular-trafficking-and-antigen-cross-presentation-by-dendritic-cells
#7
Ignacio Cebrian, Cristina Croce, Néstor A Guerrero, Nicolas Blanchard, Luis S Mayorga
Cross-presentation by MHC class I molecules allows the detection of exogenous antigens by CD8(+) T lymphocytes. This process is crucial to initiate cytotoxic immune responses against many pathogens (i.e., Toxoplasma gondii) and tumors. To achieve efficient cross-presentation, dendritic cells (DCs) have specialized endocytic pathways; however, the molecular effectors involved are poorly understood. In this work, we identify the small GTPase Rab22a as a key regulator of MHC-I trafficking and antigen cross-presentation by DCs...
December 2016: EMBO Reports
https://www.readbyqxmd.com/read/27836419/ebv-infection-and-multiple-sclerosis-lessons-from-a-marmoset-model
#8
REVIEW
Bert A 'tHart, Yolanda S Kap, Elena Morandi, Jon D Laman, Bruno Gran
Multiple sclerosis (MS) is thought to be initiated by the interaction of genetic and environmental factors, eliciting an autoimmune attack on the central nervous system. Epstein-Barr virus (EBV) is the strongest infectious risk factor, but an explanation for the paradox between high infection prevalence and low MS incidence remains elusive. We discuss new data using marmosets with experimental autoimmune encephalomyelitis (EAE) - a valid primate model of MS. The findings may help to explain how a common infection can contribute to the pathogenesis of MS...
December 2016: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/27836246/emerging-role-of-immunotherapy-in-urothelial-carcinoma-immunobiology-biomarkers
#9
REVIEW
Randy F Sweis, Matthew D Galsky
Urothelial bladder cancer is one of the first cancers recognized to be immunogenic since 40 years ago when the use of bacillus Calmette-Guerin was shown to prevent recurrence. Since that time, our knowledge of immune biology of cancer has expanded tremendously, and patients with bladder cancer finally have new active immunotherapeutic drugs on the horizon. Anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) therapy has shown impressively durable responses in urothelial bladder cancer (UBC), but the reported response rates warrant improvement...
December 2016: Urologic Oncology
https://www.readbyqxmd.com/read/27834857/the-cd8%C3%A2-%C2%BA-t-cell-mediated-immunity-induced-by-hpv-e6-uploaded-in-engineered-exosomes-is-improved-by-iscomatrix-tm-adjuvant
#10
Francesco Manfredi, Paola di Bonito, Barbara Ridolfi, Simona Anticoli, Claudia Arenaccio, Chiara Chiozzini, Adriana Baz Morelli, Maurizio Federico
We recently described the induction of an efficient CD8⁺ T cell-mediated immune response against a tumor-associated antigen (TAA) uploaded in engineered exosomes used as an immunogen delivery tool. This immune response cleared tumor cells inoculated after immunization, and controlled the growth of tumors implanted before immunization. We looked for new protocols aimed at increasing the CD8⁺ T cell specific response to the antigen uploaded in engineered exosomes, assuming that an optimized CD8⁺ T cell immune response would correlate with a more effective depletion of tumor cells in the therapeutic setting...
November 9, 2016: Vaccines
https://www.readbyqxmd.com/read/27833451/heat-shock-proteins-hsps-in-the-homeostasis-of-regulatory-t-cells-tregs
#11
REVIEW
Tomasz Koliński, Natalia Marek-Trzonkowska, Piotr Trzonkowski, Janusz Siebert
Heat shock proteins (HSPs) belong to the family of conservative polypeptides with a high homology of the primary structure. The uniqueness of this family lies in their ability to interact with a large number of different proteins and provide protection from cellular and environmental stress factors as molecular chaperones to keep protein homeostasis. While intracellular HSPs play a mainly protective role, extracellular or membrane-bound HSPs mediate immunological functions and immunomodulatory activity. In immune system are subsets of cells including regulatory T cells (Tregs) with suppressive functions...
2016: Central-European Journal of Immunology
https://www.readbyqxmd.com/read/27819292/saponin-based-adjuvants-induce-cross-presentation-in-dendritic-cells-by-intracellular-lipid-body-formation
#12
Martijn H den Brok, Christian Büll, Melissa Wassink, Annemarie M de Graaf, Jori A Wagenaars, Marthe Minderman, Mayank Thakur, Sebastian Amigorena, Eric O Rijke, Carla C Schrier, Gosse J Adema
Saponin-based adjuvants (SBAs) are being used in animal and human (cancer) vaccines, as they induce protective cellular immunity. Their adjuvant potency is a factor of inflammasome activation and enhanced antigen cross-presentation by dendritic cells (DCs), but how antigen cross-presentation is induced is not clear. Here we show that SBAs uniquely induce intracellular lipid bodies (LBs) in the CD11b+ DC subset in vitro and in vivo. Using genetic and pharmacological interference in models for vaccination and in situ tumour ablation, we demonstrate that LB induction is causally related to the saponin-dependent increase in cross-presentation and T-cell activation...
November 7, 2016: Nature Communications
https://www.readbyqxmd.com/read/27814617/tumor-abolition-and-antitumor-immunostimulation-by-physico-chemical-tumor%C3%A2-ablation
#13
Yona Keisari
Tumor ablation by thermal, chemical and radiological sources has received substantial attention for the treatment of many localized malignancies. The primary goal of most ablation procedures is to eradicate all viable malignant cells within a designated target volume through the application of energy or chemicals. Methods such as radiotherapy, chemical and biological ablation, photodynamic therapy, cryoablation, high-temperature ablation (radiofrequency, microwave, laser, and ultrasound), and electric-based ablation have been developed for focal malignancies...
January 1, 2017: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/27795841/molecular-and-cellular-mechanisms-of-antitumor-immune-response-activation-by-dendritic-cells
#14
O V Markov, N L Mironova, V V Vlasov, M A Zenkova
Dendritic cells (DCs) play a crucial role in the initiation and regulation of the antitumor immune response. Already , DC-based antitumor vaccines have been thoroughly explored both in animal tumor models and in clinical trials. DC-based vaccines are commonly produced from DC progenitors isolated from peripheral blood or bone marrow by culturing in the presence of cytokines, followed by loading the DCs with tumor-specific antigens, such as DNA, RNA, viral vectors, or a tumor cell lysate. However, the efficacy of DC-based vaccines remains low...
July 2016: Acta Naturae
https://www.readbyqxmd.com/read/27793999/glucocorticoid-induced-leucine-zipper-protein-controls-macropinocytosis-in-dendritic-cells
#15
Joseph Calmette, Matthieu Bertrand, Mathias Vétillard, Mehdi Ellouze, Shaun Flint, Valérie Nicolas, Armelle Biola-Vidamment, Marc Pallardy, Eric Morand, Françoise Bachelerie, Véronique Godot, Géraldine Schlecht-Louf
Ag sampling is a key process in dendritic cell (DC) biology. DCs use constitutive macropinocytosis, receptor-mediated endocytosis, and phagocytosis to capture exogenous Ags for presentation to T cells. We investigated the mechanisms that regulate Ag uptake by DCs in the steady-state and after a short-term LPS exposure in vitro and in vivo. We show that the glucocorticoid-induced leucine zipper protein (GILZ), already known to regulate effector versus regulatory T cell activation by DCs, selectively limits macropinocytosis, but not receptor-mediated phagocytosis, in immature and recently activated DCs...
October 28, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27793569/dendritic-cells-and-cancer-immunity
#16
REVIEW
Alycia Gardner, Brian Ruffell
Dendritic cells (DCs) are central regulators of the adaptive immune response, and as such are necessary for T-cell-mediated cancer immunity. In particular, antitumoral responses depend on a specialized subset of conventional DCs that transport tumor antigens to draining lymph nodes and cross-present antigen to activate cytotoxic T lymphocytes. DC maturation is necessary to provide costimulatory signals to T cells, but while DC maturation occurs within tumors, it is often insufficient to induce potent immunity, particularly in light of suppressive mechanisms within tumors...
December 2016: Trends in Immunology
https://www.readbyqxmd.com/read/27793335/role-of-heterogeneous-cell-population-on-modulation-of-dendritic-cell-phenotype-and-activation-of-cd8-t-cells-for-use-in-cell-based-immunotherapies
#17
Hannah Frizzell, Jaehyung Park, Natacha Comandante Lou, Kim A Woodrow
Dendritic cell (DC)-based immunotherapies have much utility in their ability to prime antigen-specific adaptive immune responses. However, there does not yet exist a consensus standard to how DCs should be primed. In this study, we aimed to determine the role of heterogeneous co-cultures, composed of both CD11c+ (DCs) and CD11c- cells, in combination with monophosphoryl lipid A (MPLA) stimulation on DC phenotype and function. Upon DC priming in different co-culture ratios, we observed reduced expression of MHCII and CD86 and increased antigen uptake among CD11c+ cells in a CD11c- dependent manner...
October 13, 2016: Cellular Immunology
https://www.readbyqxmd.com/read/27775706/eradication-of-large-established-tumors-in-mice-by-combination-immunotherapy-that-engages-innate-and-adaptive-immune-responses
#18
Kelly D Moynihan, Cary F Opel, Gregory L Szeto, Alice Tzeng, Eric F Zhu, Jesse M Engreitz, Robert T Williams, Kavya Rakhra, Michael H Zhang, Adrienne M Rothschilds, Sudha Kumari, Ryan L Kelly, Byron H Kwan, Wuhbet Abraham, Kevin Hu, Naveen K Mehta, Monique J Kauke, Heikyung Suh, Jennifer R Cochran, Douglas A Lauffenburger, K Dane Wittrup, Darrell J Irvine
Checkpoint blockade with antibodies specific for cytotoxic T lymphocyte-associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD-1) elicits durable tumor regression in metastatic cancer, but these dramatic responses are confined to a minority of patients. This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint. Here we describe a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse model of melanoma; to our knowledge tumors of this size have not previously been curable by treatments relying on endogenous immunity...
December 2016: Nature Medicine
https://www.readbyqxmd.com/read/27757298/exosome-driven-transfer-of-tumor-associated-pioneer-translation-products-ta-ptps-for-the-mhc-class-i-cross-presentation-pathway
#19
Emilie Duvallet, Mathilde Boulpicante, Takahiro Yamazaki, Chrysoula Daskalogianni, Rodrigo Prado Martins, Sonia Baconnais, Bénédicte Manoury, Robin Fahraeus, Sébastien Apcher
Cellular immune reactions against non-self-epitopes require activation of cytotoxic CD8(+) T-cells via cross-presentation of MHC class I-restricted peptides by professional antigen presenting cells (pAPCs), with the consequent detection and elimination of cells expressing the same antigens via the endogenous (direct) pathway. The source of peptides for the endogenous pathway is constituted of alternative mRNA translation products; however, it is still unclear which source of peptides is used for cross-presentation...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27753620/a-ph-and-ionic-strength-dependent-conformational-change-in-the-neck-region-regulates-dngr-1-function-in-dendritic-cells
#20
Pavel Hanč, Oliver Schulz, Hanna Fischbach, Stephen R Martin, Svend Kjær, Caetano Reis E Sousa
DNGR-1 is receptor expressed by certain dendritic cell (DC) subsets and by DC precursors in mouse. It possesses a C-type lectin-like domain (CTLD) followed by a poorly characterized neck region coupled to a transmembrane region and short intracellular tail. The CTLD of DNGR-1 binds F-actin exposed by dead cell corpses and causes the receptor to signal and potentiate cross-presentation of dead cell-associated antigens by DCs. Here, we describe a conformational change that occurs in the neck region of DNGR-1 in a pH- and ionic strength-dependent manner and that controls cross-presentation of dead cell-associated antigens...
November 15, 2016: EMBO Journal
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