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https://www.readbyqxmd.com/read/29769837/the-role-of-extracellular-adenosine-generation-in-the-development-of-autoimmune-diseases
#1
REVIEW
F Morandi, A L Horenstein, R Rizzo, F Malavasi
Adenosine (ADO) is an immunosuppressive molecule, which suppresses the immune responses by interacting with specific receptors expressed by immune effector cells. ADO is produced from ATP through the enzymatic activities of CD39 and CD73. Alternatively, ADO can be generated starting from NAD+ , which is metabolized by the concerted action of CD38, CD203a/PC-1, and CD73. The role of ADO in immunity has been characterized in the last years in physiology and in pathological settings. This review examines a panel of reports focused on the functions of ADO in the context of human autoimmune/inflammatory diseases and the selected animal models...
2018: Mediators of Inflammation
https://www.readbyqxmd.com/read/29769722/bystander-cd8-t-cells-are-abundant-and-phenotypically-distinct-in-human-tumour-infiltrates
#2
Yannick Simoni, Etienne Becht, Michael Fehlings, Chiew Yee Loh, Si-Lin Koo, Karen Wei Weng Teng, Joe Poh Sheng Yeong, Rahul Nahar, Tong Zhang, Hassen Kared, Kaibo Duan, Nicholas Ang, Michael Poidinger, Yin Yeng Lee, Anis Larbi, Alexis J Khng, Emile Tan, Cherylin Fu, Ronnie Mathew, Melissa Teo, Wan Teck Lim, Chee Keong Toh, Boon-Hean Ong, Tina Koh, Axel M Hillmer, Angela Takano, Tony Kiat Hon Lim, Eng Huat Tan, Weiwei Zhai, Daniel S W Tan, Iain Beehuat Tan, Evan W Newell
Various forms of immunotherapy, such as checkpoint blockade immunotherapy, are proving to be effective at restoring T cell-mediated immune responses that can lead to marked and sustained clinical responses, but only in some patients and cancer types1-4 . Patients and tumours may respond unpredictably to immunotherapy partly owing to heterogeneity of the immune composition and phenotypic profiles of tumour-infiltrating lymphocytes (TILs) within individual tumours and between patients5,6 . Although there is evidence that tumour-mutation-derived neoantigen-specific T cells play a role in tumour control2,4,7-10 , in most cases the antigen specificities of phenotypically diverse tumour-infiltrating T cells are largely unknown...
May 16, 2018: Nature
https://www.readbyqxmd.com/read/29759563/targeting-the-tumor-promoting-effects-of-adenosine-in-chronic-lymphocytic-leukemia
#3
REVIEW
Yiqing Cai, Lili Feng, Xin Wang
Chronic lymphocytic leukemia (CLL) is a hematological malignancy which is characterized by progressive accumulation of functionally deficient B cells in blood, bone marrow, and lymphatic tissue. The tumor microenvironment (TME) appears to play a critical role in genesis and progression of CLL. High levels of extracellular adenosine (ADO) are detected in CLL as a consequence of expression of ecto-enzymes, such as CD39 and CD73. Extracellular ADO exhibits a broad range of effects on cell cycle control, immunoregulation, angiogenesis and cytokine regulation through both direct and indirect mechanisms...
June 2018: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29758241/targeting-the-cd73-adenosine-axis-in-immuno-oncology
#4
REVIEW
David Allard, Pavel Chrobak, Bertrand Allard, Nouredin Messaoudi, John Stagg
The ectonucleotidases CD39 and CD73 are cell surface enzymes that catabolize the breakdown of extracellular ATP into adenosine. As such, they constitute critical components of the extracellular purinergic pathway and play important roles in maintaining tissue and immune homeostasis. With the coming of age of cancer immunotherapy, ectonucleotidases and adenosine receptors have emerged as novel therapeutic targets to enhance antitumor immune responses. With early-phase clinical trials showing promising results, it is becoming increasingly important to decipher the distinct mechanisms-of-action of adenosine-targeting agents, identify patients that will benefit from these agents and rationally develop novel synergistic combinations...
May 11, 2018: Immunology Letters
https://www.readbyqxmd.com/read/29751114/very-low-numbers-of-cd4-foxp3-tregs-expanded-in-donors-via-tl1a-ig-and-low-dose-il-2-exhibit-a-distinct-activation-functional-profile-and-suppress-gvhd-in-a-pre-clinical-model
#5
Sabrina Copsel, Dietlinde Wolf, Brandon Kale, Henry Barreras, Casey O Lightbourn, Cameron S Bader, W Alperstein, Norman H Altman, Krishna V Komanduri, Robert B Levy
Regulatory T cells (Tregs) are essential for the maintenance of tolerance and immune homeostasis. In allogeneic hematopoietic stem cell transplantation (aHSCT), transfer of appropriate Treg numbers is a promising therapy for the prevention of graft-versus-host disease (GVHD). We have recently reported a novel approach which induces the marked expansion and selective activation of Tregs in vivo by targeting TNF receptor superfamily 25 (TNFRSF25) and CD25. A potential advance to promote clinical application of Treg cells to ameliorate GVHD and other disorders would be the generation of more potent Treg populations...
May 8, 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29745882/the-adenosinergic-system-a-potential-player-in-the-pathogenesis-of-anca-associated-vasculitis
#6
REVIEW
Lovis Kling, Bernhard K Krämer, Benito A Yard, Anna-Isabelle Kälsch
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially lethal autoimmune disease whose pathology comprises disturbed T cell differentiation and functionality accompanied by dysfunctional autoreactive immunoglobulin development, culminating in destructive innate immune response as well. Purines, adenine nucleotides and adenosine in particular, have been elucidated as potent extracellular mediators for fine adjustment of these pivotal processes establishing human immunity. Therefore, the extracellular purinergic microenvironment is under control of ectonucleotidases CD39 and CD73 degrading pro-inflammatory adenosine triphosphate (ATP) to anti-inflammatory adenosine as well as adenosine deaminase bound to CD26 deactivating adenosine...
May 3, 2018: Clinical and Experimental Rheumatology
https://www.readbyqxmd.com/read/29742141/cd39-is-upregulated-during-activation-of-mouse-and-human-t-cells-and-attenuates-the-immune-response-to-listeria-monocytogenes
#7
Friederike Raczkowski, Anne Rissiek, Isabell Ricklefs, Kirsten Heiss, Valéa Schumacher, Kira Wundenberg, Friedrich Haag, Friedrich Koch-Nolte, Eva Tolosa, Hans-Willi Mittrücker
The ectoenzymes CD39 and CD73 degrade extracellular ATP to adenosine. ATP is released by stressed or damaged cells and provides pro-inflammatory signals to immune cells through P2 receptors. Adenosine, on the other hand, suppresses immune cells by stimulating P1 receptors. Thus, CD39 and CD73 can shape the quality of immune responses. Here we demonstrate that upregulation of CD39 is a consistent feature of activated conventional CD4+ and CD8+ T cells. Following stimulation in vitro, CD4+ and CD8+ T cells from human blood gained surface expression of CD39 but displayed only low levels of CD73...
2018: PloS One
https://www.readbyqxmd.com/read/29731713/cytokine-induced-killer-cells-express-cd39-cd38-cd203a-cd73-ectoenzymes-and-p1-adenosinergic-receptors
#8
Alberto L Horenstein, Antonella Chillemi, Roberta Zini, Valeria Quarona, Nicoletta Bianchi, Rossella Manfredini, Roberto Gambari, Fabio Malavasi, Davide Ferrari
Cytokine-induced killer (CIK) cells, a heterogeneous T cell population obtained by in vitro differentiation of peripheral blood mononuclear cells (PBMC), represent a promising immunological approach in cancer. Numerous studies have explored the role of CD38, CD39, CD203a/PC-1, and CD73 in generating extracellular adenosine (ADO) and thus in shaping the tumor niche in favor of proliferation. The findings shown here reveal that CIK cells are able to produce extracellular ADO via traditional (CD39/CD73) and/or alternative (CD38/CD203a/CD73 or CD203a/CD73) pathways...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29731087/seven-years-of-experiences-of-preclinical-experiments-of-xeno-heart-transplantation-of-pig-to-non-human-primate-cynomolgus-monkey
#9
S J Lee, J S Kim, H K Chee, I J Yun, K S Park, H S Yang, J H Park
BACKGROUND: The absolute shortage of donors compared with patients requiring transplantation is currently an unsolved problem, and the only possible solution may be xenotransplantation. To establish a successful clinical trial, a preclinical study using nonhuman primates is essential. Starting in November 2011, our team initiated heterotopic abdominal heart xenotransplantation, the first in the Republic of Korea. We present here the initial 7-year results. METHODS: A total of 22 xenotransplantation procedures have been performed since 2011...
May 2018: Transplantation Proceedings
https://www.readbyqxmd.com/read/29725032/novel-evidence-that-extracellular-nucleotides-and-purinergic-signaling-induce-innate-immunity-mediated-mobilization-of-hematopoietic-stem-progenitor-cells
#10
Mateusz Adamiak, Kamila Bujko, Monika Cymer, Monika Plonka, Talita Glaser, Magda Kucia, Janina Ratajczak, Henning Ulrich, Ahmed Abdel-Latif, Mariusz Z Ratajczak
Pharmacological mobilization of hematopoietic stem progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood (PB) is a result of mobilizing agent-induced "sterile inflammation" in the BM microenvironment due to complement cascade (ComC) activation. Here we provide evidence that ATP, as an extracellular nucleotide secreted in a pannexin-1-dependent manner from BM cells, triggers activation of the ComC and initiates the mobilization process. This process is augmented in a P2X7 receptor-dependent manner, and P2X7-KO mice are poor mobilizers...
March 30, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29719048/serotonin-decreases-the-production-of-th1-th17-cytokines-and-elevates-the-frequency-of-regulatory-cd4-t-cell-subsets-in-multiple-sclerosis-patients
#11
Priscila M Sacramento, Clarice Monteiro, Aleida S O Dias, Taissa M Kasahara, Thaís B Ferreira, Joana Hygino, Ana Cristina Wing, Regis M Andrade, Fernanda Rueda, Marisa C Sales, Claudia Cristina Vasconcelos, Cleonice A M Bento
Excessive levels of pro-inflammatory cytokines in the central nervous system (CNS) are associated with reduced serotonin (5-HT) synthesis, a neurotransmitter with diverse immune effects. In this study, we evaluated the ability of exogenous 5-HT to modulate the T-cell behavior of patients with multiple sclerosis (MS), a demyelinating autoimmune disease mediated by Th1 and Th17 cytokines. Here, 5-HT attenuated, in vitro, T-cell proliferation and Th1 and Th17 cytokines production in cell cultures from MS patients...
May 2, 2018: European Journal of Immunology
https://www.readbyqxmd.com/read/29712685/novel-effector-phenotype-of-tim-3-regulatory-t-cells-leads-to-enhanced-suppressive-function-in-head-and-neck-cancer-patients
#12
Zhuqing Liu, Elizabeth L McMichael, Gulidanna Shayan, Jing Li, Kevin Chen, Raghvendra M Srivastava, Lawrence P Kane, Binfeng Lu, Robert L Ferris
PURPOSE: Regulatory T (Treg) cells are important suppressive cells among tumor infiltrating lymphocytes (TIL). Treg express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear. EXPERIMENTAL DESIGN: CD4+CTLA-4+CD25high Treg were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression...
April 30, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29698570/interleukin-2-promotes-hepatic-regulatory-t-cell-responses-and-protects-from-biliary-fibrosis-in-murine-sclerosing-cholangitis
#13
Amy E Taylor, Alexandra N Carey, Ramesh Kudira, Celine S Lages, Tiffany Shi, Simon Lam, Rebekah Karns, Julia Simmons, Kumar Shanmukhappa, Maha Almanan, Claire A Chougnet, Alexander G Miethke
In the Mdr2 -/- mouse model low phospholipid bile instigates biliary epithelial injury, sterile inflammation, and fibrosis, thereby recapitulating disease mechanisms implicated in biliary atresia (BA) and primary sclerosing cholangitis. We hypothesize that T-lymphocytes contribute to the biliary injury and fibrosis in murine sclerosing cholangitis (SC) and that they are susceptible to suppression by regulatory T cells (Tregs). In juvenile Mdr2 -/- mice, intrahepatic CD8 lymphocytes were expanded and contraction of intrahepatic Tregs coincided with rising serum alanine transferase (ALT) and alkaline phosphatase (ALP) levels between days 14-30 of life...
April 26, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29688896/nox2-in-regulatory-t-cells-promotes-angiotensin-ii-induced-cardiovascular-remodeling
#14
Amber Emmerson, Silvia Cellone Trevelin, Heloise Mongue-Din, Pablo D Becker, Carla Ortiz, Lesley A Smyth, Qi Peng, Raul Elgueta, Greta Sawyer, Aleksandar Ivetic, Robert I Lechler, Giovanna Lombardi, Ajay M Shah
The superoxide-generating enzyme Nox2 contributes to hypertension and cardiovascular remodeling triggered by activation of the renin-angiotensin system. Multiple Nox2-expressing cells are implicated in angiotensin II (AngII)-induced pathophysiology, but the importance of Nox2 in leukocyte subsets is poorly understood. Here, we investigated the role of Nox2 in T cells, particularly Tregs. Mice globally deficient in Nox2 displayed increased numbers of Tregs in the heart at baseline whereas AngII-induced T-effector cell (Teffs) infiltration was inhibited...
April 24, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29619420/changes-in-natural-killer-cells-and-exhausted-memory-regulatory-t-cells-with-corticosteroid-therapy-in-acute-autoimmune-hepatitis
#15
Hannah C Jeffery, Manjit K Braitch, Chris Bagnall, James Hodson, Louisa E Jeffery, Rebecca E Wawman, Lin Lee Wong, Jane Birtwistle, Helen Bartlett, Ansgar W Lohse, Gideon M Hirschfield, Jessica Dyson, David Jones, Stefan G Hubscher, Paul Klenerman, David H Adams, Ye H Oo
Autoimmune hepatitis (AIH) is an immune-mediated liver disease currently treated by immunosuppressive medications with significant side effects. Thus, novel mechanistic treatments are greatly needed. We performed prospective deep immunophenotyping of blood immune cells in patients with acute AIH before and after corticosteroid therapy. Blood samples from 26 patients with acute AIH (United Kingdom-AIH Consortium) were phenotyped by flow cytometry at baseline and 4 months after starting corticosteroids. Pretreatment liver tissues were stained for forkhead box P3-positive (FOXP3POS ) regulatory T cells (Tregs), clusters of differentiation (CD)56POS natural killer (NK) cells, and chemokine (C-X-C motif) ligand 10...
April 2018: Hepatology communications
https://www.readbyqxmd.com/read/29579623/chemokines-and-cancer-new-immune-checkpoints-for-cancer-therapy
#16
REVIEW
Nathan Karin
The current review focuses on two chemokine-chemokine receptor interactions: CXCL10-CXCR3 and CCL1-CCR8. We show that CXCL10 acts on CD4+ and CD8+ T cells to enhance anti-tumor immunity, and explore the translational perspectives of these findings. As for CCR8 very recently, we identified a novel subset of CCR8+CD4+FOXp3+ regulatory T cells (Treg ) that are major drivers of immune regulation. We observed that one of the four CCR8 ligands, CCL1, produced by these cells, potentiates their suppressive activity via induction of CCR8, FOXp3, CD39, Granzyme-B, and IL-10 in a positive feedback mechanism, making them master drivers of immune regulation...
March 23, 2018: Current Opinion in Immunology
https://www.readbyqxmd.com/read/29559470/autocrine-adenosine-regulates-tumor-polyfunctional-cd73-cd4-effector-t-cells-devoid-of-immune-checkpoints
#17
Nicolas Gourdin, Marion Bossennec, Céline Rodriguez, Selena Vigano, Christelle Machon, Camilla Jandus, David Bauché, Julien Faget, Isabelle Durand, Nicolas Chopin, Olivier Tredan, Julien C Marie, Bertrand Dubois, Jérôme Guitton, Pedro Romero, Christophe Caux, Christine Ménétrier-Caux
The production of CD73-derived Adenosine (Ado) by Tregs, has been proposed as a resistance mechanism to anti-PD1 therapy in murine tumor models. We reported that Human Tregs express the ecto-nucleotidase CD39, that generates AMP from ATP, but do not express the AMPase CD73. In contrast, CD73 defined a subset of effector CD4+ T cells (Teffs), enriched in polyfunctional Th1.17 cells characterized by expression of CXCR3, CCR6 and MDR1 and production of IL-17A/IFN-γ/IL-22/GM-CSF. CD39+ Tregs selectively targeted CD73+ Teffs through cooperative degradation of ATP into Ado inhibiting and restricting the ability of CD73+ Teffs to secrete IL-17A...
March 20, 2018: Cancer Research
https://www.readbyqxmd.com/read/29558203/enzymes-of-the-purinergic-signaling-system-exhibit-diverse-effects-on-the-degeneration-of-valvular-interstitial-cells-in-a-3-d-microenvironment
#18
Andreas Weber, Mareike Barth, Jessica Isabel Selig, Silja Raschke, Konstantinos Dakaras, Alexander Hof, Julia Hesse, Jürgen Schrader, Artur Lichtenberg, Payam Akhyari
Calcific aortic valve disease is an active disease process with lipoprotein deposition, chronic inflammation, and progressive leaflet degeneration. Expression of ectonucleotidases, a group of membrane-bound enzymes that regulate the metabolism of ATP and its metabolites, may coregulate the degeneration process of valvular interstitial cells (VICs). The aim of this study was to investigate the role of the enzymes of the purinergic system in the degeneration process of VICs. Ovine VICs were cultivated in vitro under different prodegenerative conditions and treated with inhibitors of ectonucleoside triphosphate diphosphohydrolase 1 (CD39)/ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and 5'-nucleotidase (CD73), as well as with adenosine and adenosine receptor agonists...
March 20, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29555909/differential-expression-pattern-of-co-inhibitory-molecules-on-cd4-t-cells-in-uncomplicated-versus-complicated-malaria
#19
Annemieke Abel, Christiane Steeg, Francis Aminkiah, Otchere Addai-Mensah, Marylyn Addo, Nicola Gagliani, Christian Casar, Denis Dekugmen Yar, Ellis Owusu-Dabo, Thomas Jacobs, Maria Sophia Mackroth
The immune response of malaria patients is a main factor influencing the clinical severity of malaria. A tight regulation of the CD4+ T cell response or the induction of tolerance have been proposed to contribute to protection from severe or clinical disease. We therefore compared the CD4+ T cell phenotypes of Ghanaian children with complicated malaria, uncomplicated malaria, asymptomatic Plasmodium falciparum (Pf) infection or no infection. Using flow cytometric analysis and automated multivariate clustering, we characterized the expression of the co-inhibitory molecules CTLA-4, PD-1, Tim-3, and LAG-3 and other molecules implicated in regulatory function on CD4+ T cells...
March 19, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29550257/canonical-and-non-canonical-adenosinergic-pathways
#20
REVIEW
E Ferretti, A L Horenstein, C Canzonetta, F Costa, F Morandi
Adenosine (ADO) is an immunosuppressive molecule with multiple functions in different human organs. ADO is released through the concerted action of surface molecules endowed with enzymatic functions, that belong to two different adenosinergic pathways. The canonical pathway is started by CD39, that converts ATP to AMP. On the other hand, the non-canonical pathway metabolizes NAD+ to ADPR, through the action of CD38. The latter byproduct is then converted to AMP by CD203a/PC-1. Both pathways converge to CD73, that fully degrades AMP to the final product ADO...
March 14, 2018: Immunology Letters
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