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Markus Granzin, Ana Stojanovic, Matthias Miller, Richard Childs, Volker Huppert, Adelheid Cerwenka
Natural killer (NK) cells are promising antitumor effector cells, but the generation of sufficient NK cell numbers for adoptive immunotherapy remains challenging. Therefore, we developed a method for highly efficient ex vivo expansion of human NK cells. Ex vivo expansion of NK cells in medium containing IL-2 and irradiated clinical-grade feeder cells (EBV-LCL) induced a 22-fold NK cell expansion after one week that was significantly increased to 53-fold by IL-21. Repeated stimulation with irradiated EBV-LCL and IL-2 and addition of IL-21 at the initiation of the culture allowed sustained NK cell proliferation with 10(11)-fold NK cell expansion after 6 weeks...
2016: Oncoimmunology
Hung C Tran, Zesheng Wan, Michael A Sheard, Jianping Sun, Jeremy R Jackson, Jemily Malvar, Yibing Xu, Larry Wang, Richard Sposto, Eugene S Kim, Shahab Asgharzadeh, Robert C Seeger
PURPOSE: Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. EXPERIMENTAL DESIGN: TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis...
October 10, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Benedetta Pignoloni, Cinzia Fionda, Valentina Dell'Oste, Anna Luganini, Marco Cippitelli, Alessandra Zingoni, Santo Landolfo, Giorgio Gribaudo, Angela Santoni, Cristina Cerboni
Elimination of virus-infected cells by cytotoxic lymphocytes is triggered by activating receptors, among which NKG2D and DNAM-1/CD226 play an important role. Their ligands, that is, MHC class I-related chain (MIC) A/B and UL16-binding proteins (ULBP)1-6 (NKG2D ligand), Nectin-2/CD112, and poliovirus receptor (PVR)/CD155 (DNAM-1 ligand), are often induced on virus-infected cells, although some viruses, including human CMV (HCMV), can block their expression. In this study, we report that infection of different cell types with laboratory or low-passage HCMV strains upregulated MICA, ULBP3, and PVR, with NKG2D and DNAM-1 playing a role in NK cell-mediated lysis of infected cells...
October 12, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Brennan Ashwood, Marvin Pollum, Carlos E Crespo-Hernández
In 2014, two unnatural nucleosides, d5SICS and dNaM, were shown to selectively base pair and replicate with high fidelity in a modified strain of E. coli, thus effectively expanding its genetic alphabet from four to six letters. More recently, a significant reduction in cell proliferation was reported in cells cultured with d5SICS, and putatively with dNaM, upon exposure to brief periods of near-visible radiation. The photosensitizing properties of the lowest-energy excited triplet state of both d5SICS and dNaM were implicated in their cytotoxicity...
October 10, 2016: Chemistry: a European Journal
Geok Choo Sim, Chengwen Liu, Ena Wang, Hui Liu, Caitlin Creasy, Zhimin Dai, Willem W Overwijk, Jason Roszik, Francesco M Marincola, Patrick Hwu, Elizabeth A Grimm, Laszlo G Radvanyi
Clinical responses to high-dose IL-2 therapy are limited due to selective expansion of CD4+CD25+oxp3+ T-regulatory cells (Tregs) especially ICOS+Tregs, rather than NK cells and effector T cells. These ICOS+Tregs are highly suppressive and constitutively express high levels of IL-2Ralpha (CD25) and CD39. Here, we characterized the effect of a mutant form of IL-2 (F42K), which preferentially binds to the lower affinity IL-2Rbetagamma with reduced binding to CD25, on Tregs, effector NK cells, and T-cell subsets...
October 3, 2016: Cancer Immunology Research
Brian H Chen, Riccardo E Marioni, Elena Colicino, Marjolein J Peters, Cavin K Ward-Caviness, Pei-Chien Tsai, Nicholas S Roetker, Allan C Just, Ellen W Demerath, Weihua Guan, Jan Bressler, Myriam Fornage, Stephanie Studenski, Amy R Vandiver, Ann Zenobia Moore, Toshiko Tanaka, Douglas P Kiel, Liming Liang, Pantel Vokonas, Joel Schwartz, Kathryn L Lunetta, Joanne M Murabito, Stefania Bandinelli, Dena G Hernandez, David Melzer, Michael Nalls, Luke C Pilling, Timothy R Price, Andrew B Singleton, Christian Gieger, Rolf Holle, Anja Kretschmer, Florian Kronenberg, Sonja Kunze, Jakob Linseisen, Christine Meisinger, Wolfgang Rathmann, Melanie Waldenberger, Peter M Visscher, Sonia Shah, Naomi R Wray, Allan F McRae, Oscar H Franco, Albert Hofman, André G Uitterlinden, Devin Absher, Themistocles Assimes, Morgan E Levine, Ake T Lu, Philip S Tsao, Lifang Hou, JoAnn E Manson, Cara L Carty, Andrea Z LaCroix, Alexander P Reiner, Tim D Spector, Andrew P Feinberg, Daniel Levy, Andrea Baccarelli, Joyce van Meurs, Jordana T Bell, Annette Peters, Ian J Deary, James S Pankow, Luigi Ferrucci, Steve Horvath
Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality...
September 28, 2016: Aging
Olivia M de Goede, Pascal M Lavoie, Wendy P Robinson
AIM: To provide insight into fetal nucleated red blood cell (nRBC) development using genome-wide DNA methylation (DNAm) profiling. MATERIALS & METHODS: The DNAm profile (Illumina 450K array) of cord blood (n = 7) derived nRBCs was compared with B cells, CD4 and CD8 T cells, natural killer cells, granulocytes, monocytes and placenta (n = 5). RESULTS: nRBCs and placenta had similarly low array-wide DNAm compared with white blood cells, but their patterns of hypomethylation differed at biologically relevant subsets of the array...
September 30, 2016: Epigenomics
Veronica Barcelona de Mendoza, Michelle L Wright, Comfort Agaba, Laura Prescott, Alexandra Desir, Cindy A Crusto, Yan V Sun, Jacquelyn Y Taylor
BACKGROUND: The causes of many cases of preterm birth (PTB) remain enigmatic. Increased understanding of how epigenetic factors are associated with health outcomes has resulted in studies examining DNA methylation (DNAm) as a contributing factor to PTB. However, few studies on PTB and DNAm have included African American women, the group with the highest rate of PTB. METHODS: The objective of this review was to systematically analyze the existing studies on DNAm and PTB among African American women...
September 19, 2016: Biological Research for Nursing
Marie Kalwa, Sonja Hänzelmann, Sabrina Otto, Chao-Chung Kuo, Julia Franzen, Sylvia Joussen, Eduardo Fernandez-Rebollo, Björn Rath, Carmen Koch, Andrea Hofmann, Shih-Han Lee, Andrew E Teschendorff, Bernd Denecke, Qiong Lin, Martin Widschwendter, Elmar Weinhold, Ivan G Costa, Wolfgang Wagner
There is a growing perception that long non-coding RNAs (lncRNAs) modulate cellular function. In this study, we analyzed the role of the lncRNA HOTAIR in mesenchymal stem cells (MSCs) with particular focus on senescence-associated changes in gene expression and DNA-methylation (DNAm). HOTAIR binding sites were enriched at genomic regions that become hypermethylated with increasing cell culture passage. Overexpression and knockdown of HOTAIR inhibited or stimulated adipogenic differentiation of MSCs, respectively...
September 14, 2016: Nucleic Acids Research
Katarina M Mirjačić Martinović, Nada Lj Babović, Radan R Džodić, Vladimir B Jurišić, Aleksandra Z Ninković, Gordana M Konjević
Considering tumor-mediated suppression of natural killer (NK) cells, the aim of this study was to investigate the in-vitro effects of interleukin (IL)-2 and IL-12, as immunostimulatory cytokines, on the functional and receptor characteristics of NK cells and their subsets in healthy control (HC) and metastatic melanoma (MM) patients. Peripheral blood mononuclear cells of 27 HC and 35 MM patients were stimulated in vitro with IL-2, IL-12, and their combination for functional and phenotypic analysis. IL-2, IL-12, and primarily their combination, significantly induced NK cell activity, CD107a degranulation marker, and perforin expression in NK cells and their subsets in HC and MM patients...
September 10, 2016: Melanoma Research
Conor J Kearney, Kelly M Ramsbottom, Ilia Voskoboinik, Phillip K Darcy, Jane Oliaro
Acute myeloid leukemia (AML) is associated with poor natural killer (NK) cell function through aberrant expression of NK-cell-activating receptors and their ligands on tumor cells. These alterations are thought to promote formation of inhibitory NK-target cell synapses, in which killer cell degranulation is attenuated. Allogeneic stem cell transplantation can be effective in treating AML, through restoration of NK cell lytic activity. Similarly, agents that augment NK-cell-activating signals within the immunological synapse may provide some therapeutic benefit...
August 2016: Oncoimmunology
Huaijian Guo, Stacey A Cranert, Yan Lu, Ming-Chao Zhong, Shaohua Zhang, Jun Chen, Rui Li, Sarah E Mahl, Ning Wu, Dominique Davidson, Stephen N Waggoner, André Veillette
Signaling lymphocytic activation molecule (SLAM) family receptors (SFRs) can mediate either activating or inhibitory effects during natural killer cell (NK cell) activation. In this study, we addressed the global role, regulation, and mechanism of action of the SLAM family in NK cells by analyzing a mouse lacking the entire ∼400-kilobase Slam locus, which encodes all six SFRs and CD48, the ligand of SFR 2B4. This mouse displayed enhanced NK cell activation responses toward hematopoietic target cells. Analyses of mice lacking individual SFRs showed that the inhibitory function of the Slam locus was due solely to 2B4 and was not influenced positively or negatively by other SFRs...
September 19, 2016: Journal of Experimental Medicine
Marvin Pollum, Brennan Ashwood, Steffen Jockusch, Minh Lam, Carlos E Crespo-Hernández
The base pair d5SICS·dNaM was recently reported to incorporate and replicate in the DNA of a modified strain of Escherichia coli, thus making the world's first stable semisynthetic organism. This newly expanded genetic alphabet may allow organisms to store considerably more information in order to translate proteins with unprecedented enzymatic activities. Importantly, however, there is currently no knowledge of the photochemical properties of d5SICS or dNaM-properties that are central to the chemical integrity of cellular DNA...
September 14, 2016: Journal of the American Chemical Society
Tihana Lenac Rovis, Paola Kucan Brlic, Noa Kaynan, Vanda Juranic Lisnic, Ilija Brizic, Stefan Jordan, Adriana Tomic, Daria Kvestak, Marina Babic, Pinchas Tsukerman, Marco Colonna, Ulrich Koszinowski, Martin Messerle, Ofer Mandelboim, Astrid Krmpotic, Stipan Jonjic
The poliovirus receptor (PVR) is a ubiquitously expressed glycoprotein involved in cellular adhesion and immune response. It engages the activating receptor DNAX accessory molecule (DNAM)-1, the inhibitory receptor TIGIT, and the CD96 receptor with both activating and inhibitory functions. Human cytomegalovirus (HCMV) down-regulates PVR expression, but the significance of this viral function in vivo remains unknown. Here, we demonstrate that mouse CMV (MCMV) also down-regulates the surface PVR. The m20.1 protein of MCMV retains PVR in the endoplasmic reticulum and promotes its degradation...
August 22, 2016: Journal of Experimental Medicine
Tomoko Inoue, Katsuyuki Adachi, Kei Kawana, Ayumi Taguchi, Takeshi Nagamatsu, Asaha Fujimoto, Kensuke Tomio, Aki Yamashita, Satoko Eguchi, Haruka Nishida, Hiroe Nakamura, Masakazu Sato, Mitsuyo Yoshida, Takahide Arimoto, Osamu Wada-Hiraike, Katsutoshi Oda, Yutaka Osuga, Tomoyuki Fujii
Cancer-associated fibroblasts (CAFs) play an important role in cancer expansion and progression in tumor microenvironment (TME), via both direct and indirect interactions. Natural killer (NK) cells play a crucial role in anticancer immunity. We investigated the inhibitory effects of CAFs on NK cell activity. CAFs were isolated from endometrial cancer tissue, while normal endometrial fibroblasts (NEFs) were obtained from normal endometrium with no pathological abnormality. NK cells were obtained from allogenic healthy volunteers...
October 2016: International Journal of Oncology
Joanna S Kritikou, Carin I M Dahlberg, Marisa A P Baptista, Arnika K Wagner, Pinaki P Banerjee, Lavesh Amar Gwalani, Cecilia Poli, Sudeepta K Panda, Klas Kärre, Susan M Kaech, Fredrik Wermeling, John Andersson, Jordan S Orange, Hanna Brauner, Lisa S Westerberg
To kill target cells, natural killer (NK) cells organize signaling from activating and inhibitory receptors to form a lytic synapse. Wiskott-Aldrich syndrome (WAS) patients have loss-of-function mutations in the actin regulator WASp and suffer from immunodeficiency with increased risk to develop lymphoreticular malignancies. NK cells from WAS patients fail to form lytic synapses, however, the functional outcome in vivo remains unknown. Here, we show that WASp KO NK cells had decreased capacity to degranulate and produce IFNγ upon NKp46 stimulation and this was associated with reduced capacity to kill MHC class I-deficient hematopoietic grafts...
2016: Scientific Reports
Angela C Bustamante, Allison E Aiello, Sandro Galea, Andrew Ratanatharathorn, Carol Noronha, Derek E Wildman, Monica Uddin
INTRODUCTION: Altered DNA methylation (DNAm) levels of hypothalamic-pituitary-adrenal (HPA) axis genes has been associated with exposure to childhood maltreatment (CM) and depression; however, it is unknown whether CM and depression have joint and potentially interacting effects on the glucocorticoid receptor (NR3C1) DNAm. We investigated the impact of CM and lifetime major depressive disorder (MDD) on NR3C1 DNAm and gene expression (GE) in 147 adult participants from the Detroit Neighborhood Health Study...
July 19, 2016: Journal of Affective Disorders
Konrad Rawlik, Amy Rowlatt, Albert Tenesa
Understanding how genetic variation affects intermediate phenotypes, like DNA methylation or gene expression, and how these in turn vary with complex human disease provides valuable insight into disease etiology. However, intermediate phenotypes are typically tissue and developmental stage specific, making relevant phenotypes difficult to assay. Assembling large case-control cohorts, necessary to achieve sufficient statistical power to assess associations between complex traits and relevant intermediate phenotypes, has therefore remained challenging...
October 2016: Genetics
Jamaji C Nwanaji-Enwerem, Elena Colicino, Letizia Trevisi, Itai Kloog, Allan C Just, Jincheng Shen, Kasey Brennan, Alexandra Dereix, Lifang Hou, Pantel Vokonas, Joel Schwartz, Andrea A Baccarelli
BACKGROUND: Ambient particles have been shown to exacerbate measures of biological aging; yet, no studies have examined their relationships with DNA methylation age (DNAm-age), an epigenome-wide DNA methylation based predictor of chronological age. OBJECTIVE: We examined the relationship of DNAm-age with fine particulate matter (PM2.5), a measure of total inhalable particle mass, and black carbon (BC), a measure of particles from vehicular traffic. METHODS: We used validated spatiotemporal models to generate 1-year PM2...
April 2016: Environmental Epigenetics
Salima Sadallah, Laurent Schmied, Ceylan Eken, Hojjatollah Nozad Charoudeh, Francesca Amicarella, Jürg A Schifferli
Platelet (PLT) transfusions are potentially life saving for individuals with low PLT numbers; however, previous work revealed that PLT transfusions are associated with increased infection risk. During storage, PLT intended for transfusion continuously shed ectosomes (Ecto) from their surface, which express immunomodulatory molecules like phosphatidylserine or TGF-β1. Recently, PLT-Ecto were shown to reduce proinflammatory cytokine release by macrophages and to favor the differentiation of naive T cells toward regulatory T cells...
September 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
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