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Stefan Ryser, Angeles Estellés, Edgar Tenorio, Lawrence M Kauvar, Mikhail L Gishizky
We report here the cloning of native high affinity anti-TIM-3 and anti-KIR IgG monoclonal antibodies (mAbs) from peripheral blood mononuclear cells (PBMC) of healthy human donors. The cells that express these mAbs are rare, present at a frequency of less than one per 105 memory B-cells. Using our proprietary multiplexed screening and cloning technology CellSpot™ we assessed the presence of memory B-cells reactive to foreign and endogenous disease-associated antigens within the same individual. When comparing the frequencies of antigen-specific memory B-cells analyzed in over 20 screening campaigns, we found a strong correlation of the presence of anti-TIM-3 memory B-cells with memory B-cells expressing mAbs against three disease-associated antigens: (i) bacterial DNABII proteins that are a marker for Gram negative and Gram positive bacterial infections, (ii) hemagglutinin (HA) of influenza virus and (iii) the extracellular domain of anaplastic lymphoma kinase (ALK)...
2017: PloS One
Maria Carmen Ochoa, Luna Minute, Inmaculada Rodriguez, Saray Garasa, Elisabeth Perez-Ruiz, Susana Inogés, Ignacio Melero, Pedro Berraondo
Antibody-dependent cellular cytotoxicity (ADCC) is a set of mechanisms that target cells coated with IgG antibodies of the proper subclasses (IgG1 in the human) to be the prey of cell-to-cell cytolysis executed by immune cells expressing FcRIIIA (CD16A). These effectors include not only natural killer (NK) cells but also other CD16+ subsets such as monocyte/macrophages, NKT cells or γδ T cells. In cancer therapy, ADCC is exploited by antibodies that selectively recognize proteins on the surface of malignant cells...
April 2017: Immunology and Cell Biology
Lorenzo Moretta, Gabriella Pietra, Paola Vacca, Daniela Pende, Francesca Moretta, Alice Bertaina, Maria Cristina Mingari, Franco Locatelli, Alessandro Moretta
Natural killer (NK) cells play a major role in innate defenses against pathogens, primarily viruses, and are also thought to be part of the immunosurveillance against tumors. They express an array of surface receptors that mediate NK cell function. The human leukocytes antigen (HLA) class I-specific inhibitory receptors allow NK cells to detect and kill cells that have lost or under-express HLA class I antigens, a typical feature of tumor or virally infected cells. However, NK cell activation and induction of cytolytic activity and cytokine production depends on another important checkpoint, namely the expression on target cells of ligands recognized by activating NK receptors...
October 2016: Immunology Letters
Wei Wang, Amy K Erbe, Jacquelyn A Hank, Zachary S Morris, Paul M Sondel
Natural killer (NK) cells play a major role in cancer immunotherapies that involve tumor-antigen targeting by monoclonal antibodies (mAbs). NK cells express a variety of activating and inhibitory receptors that serve to regulate the function and activity of the cells. In the context of targeting cells, NK cells can be "specifically activated" through certain Fc receptors that are expressed on their cell surface. NK cells can express FcγRIIIA and/or FcγRIIC, which can bind to the Fc portion of immunoglobulins, transmitting activating signals within NK cells...
2015: Frontiers in Immunology
Tonguc Utku Yilmaz, Nuray Yazihan, Aydın Dalgic, Ezgi Ermis Kaya, Bulent Salman, Mehtap Kocak, Ethem Akcil
BACKGROUND & OBJECTIVES: Erythropoietin (EPO) has cytoprotective and anti-apoptotic effects in pathological conditions, including hypoxia and ischaemia-reperfusion injury. One of the targets to protect against injury is ATP-dependent potassium (KATP ) channels. These channels could be involved in EPO induced ischaemic preconditoning like a protective effect. We evaluated the cell cytoprotective effects of EPO in relation to KATP channel activation in the renal tubular cell culture model under hypoxic/normoxic conditions...
June 2015: Indian Journal of Medical Research
Kemal Beksac, Meral Beksac, Klara Dalva, Ergun Karaagaoglu, M Bulent Tirnaksiz
Approximately 30% of patients with stage II/III colorectal cancer develop recurrence following surgery. How individual regulation of host mediated anti-tumor cytotoxicity is modified by the killer-cell immunoglobulin-like receptor (KIRs) genotype is essential for prediction of outcome. We analyzed the frequency of KIR and KIR ligand Human Leukocyte Antigen Class I genotypes, and their effects on recurrence and disease-free survival (DFS). Out of randomly selected 87 colorectal cancer patients who underwent R0 resection operations between 2005 and 2008, 29 patients whose cancers progressed within a median five-year follow-up period were compared with 58 patients with no recurrence within the same time period...
2015: PloS One
Mariella Della Chiesa, Lorenzo Moretta, Letizia Muccio, Alice Bertaina, Francesca Moretta, Franco Locatelli, Alessandro Moretta
Natural killer cells play an important role in the immune responses against cancer and viral infections. In addition, NK cells have been shown to exert a key role in haploidentical hematopoietic stem cell (HSC) transplantation for the therapy of high-risk leukemias. The anti-leukemia effect is mostly related to the presence of "alloreactive" NK cells, i.e., mature KIR(+) NK cells that express inhibitory KIR mismatched with HLA class I (KIR-L) of the patient. In addition, an important role is played by certain activating KIR (primarily, but not only, KIR2DS1) upon interaction with their HLA class I ligand (C2 alleles)...
2016: Current Topics in Microbiology and Immunology
Flavio F Marsiglia, Stephanie L Ayers, Adrienne Baldwin-White, Jaime Booth
While parent and youth substance use prevention interventions have shown beneficial effects on preadolescents, many programs have typically targeted US born European American and African American families while overlooking the unique factors that characterize recent immigrant Latino families. This article presents the results on youth substance use when adding a culturally grounded parenting component, Familias Preparando la Nueva Generación (FPNG), to the existing and already proven efficacious classroom-based drug abuse prevention intervention, keepin'it REAL (kiR)...
January 2016: Prevention Science: the Official Journal of the Society for Prevention Research
Daniel Hernández-Ramírez, Mario A Esparza-Pérez, José L Ramirez-Garcialuna, J Rafael Arguello, Peter B Mandeville, Daniel E Noyola, Christian A García-Sepúlveda
Certain genotypic combinations of killer-cell immunoglobulin-like receptors (KIR) and human leukocyte antigens (HLA) have been associated with favourable outcomes after exposure to human immunodeficiency virus in Caucasoid and African populations. Human immunodeficiency virus (HIV) infection is characterized by a rapid exhaustion of CD4 cells, which results in impaired cellular immunity. During this early phase of infection, it is thought that the natural killer (NK) cells represent the main effector arm of the host immune response to HIV...
August 2015: Immunogenetics
Don M Benson, Adam D Cohen, Sundar Jagannath, Nikhil C Munshi, Gary Spitzer, Craig C Hofmeister, Yvonne A Efebera, Pascale Andre, Robert Zerbib, Michael A Caligiuri
PURPOSE: Natural killer (NK) cells may play an important role in the immune response to multiple myeloma; however, multiple myeloma cells express killer immunoglobulin-like receptor (KIR) ligands to prevent NK cell cytotoxicity. Lenalidomide can expand and activate NK cells in parallel with its direct effects against multiple myeloma; however, dexamethasone may impair these favorable immunomodulatory properties. IPH2101, a first-in-class antiinhibitory KIR antibody, has acceptable safety and tolerability in multiple myeloma as a single agent...
September 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Xiang-Yu Zhao, Ying-Jun Chang, Xiao-Su Zhao, Lan-Ping Xu, Xiao-Hui Zhang, Kai-Yan Liu, Dan Li, Xiao-Jun Huang
Natural killer (NK) cells that express self-HLA-specific receptors (where HLA is human leukocyte antigen) are "licensed" and more readily activated than unlicensed cells; therefore, NK-cell licensing could influence the antileukemia effects of NK cells following haploidentical stem cell transplantation (haplo-SCT). In this study, we compared the functionality of reconstituting NK cells, based on CD107α expression and interferon-γsecretion, in a cohort of 29 patients that expressed (n = 8) or lacked (n = 21) class I human leukocyte antigens for donor inhibitory killer cell immunoglobulin-like receptors (KIRs) following T-cell-replete haplo-SCT...
August 2015: European Journal of Immunology
Enxiu Wang, Liang-Chuan Wang, Ching-Yi Tsai, Vijay Bhoj, Zack Gershenson, Edmund Moon, Kheng Newick, Jing Sun, Albert Lo, Timothy Baradet, Michael D Feldman, David Barrett, Ellen Puré, Steven Albelda, Michael C Milone
Chimeric antigen receptors (CAR) bearing an antigen-binding domain linked in cis to the cytoplasmic domains of CD3ζ and costimulatory receptors have provided a potent method for engineering T-cell cytotoxicity toward B-cell leukemia and lymphoma. However, resistance to immunotherapy due to loss of T-cell effector function remains a significant barrier, especially in solid malignancies. We describe an alternative chimeric immunoreceptor design in which we have fused a single-chain variable fragment for antigen recognition to the transmembrane and cytoplasmic domains of KIR2DS2, a stimulatory killer immunoglobulin-like receptor (KIR)...
July 2015: Cancer Immunology Research
Subhashis Sarkar, Michel van Gelder, Willy Noort, Yunping Xu, Kasper M A Rouschop, Richard Groen, Harry C Schouten, Marcel G J Tilanus, Wilfred T V Germeraad, Anton C M Martens, Gerard M J Bos, Lotte Wieten
Immunotherapy with allogeneic natural killer (NK) cells offers therapeutic perspectives for multiple myeloma patients. Here, we aimed to refine NK cell therapy by evaluation of the relevance of HLA-class I and HLA-E for NK anti-myeloma reactivity. We show that HLA-class I was strongly expressed on the surface of patient-derived myeloma cells and on myeloma cell lines. HLA-E was highly expressed by primary myeloma cells but only marginally by cell lines. HLA-E(low) expression on U266 cells observed in vitro was strongly upregulated after in vivo (bone marrow) growth in RAG-2(-/-) γc(-/-) mice, suggesting that in vitro HLA-E levels poorly predict the in vivo situation...
August 2015: Cancer Immunology, Immunotherapy: CII
Katrin Töpfer, Marc Cartellieri, Susanne Michen, Ralf Wiedemuth, Nadja Müller, Dirk Lindemann, Michael Bachmann, Monika Füssel, Gabriele Schackert, Achim Temme
NK cells are emerging as new effectors for immunotherapy of cancer. In particular, the genetic engraftment of chimeric Ag receptors (CARs) in NK cells is a promising strategy to redirect NK cells to otherwise NK cell-resistant tumor cells. On the basis of DNAX-activation protein 12 (DAP12), a signaling adaptor molecule involved in signal transduction of activating NK cell receptors, we generated a new type of CAR targeting the prostate stem cell Ag (PSCA). We demonstrate in this article that this CAR, designated anti-PSCA-DAP12, consisting of DAP12 fused to the anti-PSCA single-chain Ab fragment scFv(AM1) confers improved cytotoxicity to the NK cell line YTS against PSCA-positive tumor cells when compared with a CAR containing the CD3ζ signaling chain...
April 1, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Maryam Hejazi, Angela R Manser, Julia Fröbel, Andrea Kündgen, Xiaoyi Zhao, Kathrin Schönberg, Ulrich Germing, Rainer Haas, Norbert Gattermann, Markus Uhrberg
Natural killer cells are well known to mediate anti-leukemic responses in myeloid leukemia but their role in myelodysplastic syndromes is not well understood. Here, in a cohort of newly diagnosed patients (n=75), widespread structural and functional natural killer cell defects were identified. One subgroup of patients (13%) had a selective deficiency of peripheral natural killer cells (count <10/mm(3) blood) with normal frequencies of T and natural killer-like T cells. Natural killer cell-deficient patients were predominantly found in high-risk subgroups and deficiency of these cells was significantly associated with poor prognosis...
May 2015: Haematologica
Martapolyana T M Silva, Fernanda P R A Ribeiro, Maria Alice M B Medeiros, Pedrita A Sampaio, Yonara M S Silva, Morganna T A Silva, Jullyana S S Quintans, Lucindo J Quintans-Júnior, Luciano A A Ribeiro
The monoterpenes are the main constituents of most essential oils and p-cymene is a monoterpene commonly found in various species of aromatic herbs, which has been reported for anti-inflammatory, antinociceptive, and antimicrobial activities. However, there is no report concerning its pharmacological activity on the vascular smooth muscle. The aim of current work was to investigate the effects of p-cymene in isolated rat aorta and also study its mechanism of action. In this work, we show that p-cymene has a relaxant effect, in a dose-dependent way, on the vascular smooth muscle, regardless of the presence of the endothelium...
2015: TheScientificWorldJournal
Inger S Nijhof, Jeroen J Lammerts van Bueren, Berris van Kessel, Pascale Andre, Yannis Morel, Henk M Lokhorst, Niels W C J van de Donk, Paul W H I Parren, Tuna Mutis
Despite recent treatment improvements, multiple myeloma remains an incurable disease. Since antibody-dependent cell-mediated cytotoxicity is an important effector mechanism of daratumumab, we explored the possibility of improving daratumumab-mediated cell-mediated cytotoxicity by blocking natural killer cell inhibitory receptors with the human monoclonal anti-KIR antibody IPH2102, next to activation of natural killer cells with the immune modulatory drug lenalidomide. In 4-hour antibody-dependent cell-mediated cytotoxicity assays, IPH2102 did not induce lysis of multiple myeloma cell lines, but it did significantly augment daratumumab-induced myeloma cell lysis...
February 2015: Haematologica
Matthew S Parsons, Liyen Loh, Shayarana Gooneratne, Rob J Center, Stephen J Kent
Antibody-dependent activation of natural killer (NK) cells might facilitate protective outcomes in the context of HIV exposure or infection. Antibody-dependent activation is heightened in NK cells educated by interactions between killer immunoglobulin-like receptors (KIRs) and their major histocompatibility complex class I ligands during ontogeny. Differentiated NK cells, defined as CD57, also exhibit enhanced antibody-dependent responsiveness. Although KIRs are more frequently expressed on CD57 NK cells, the presented data suggest education and differentiation make independent contributions to NK cell anti-HIV envelope antibody-dependent activation...
November 28, 2014: AIDS
Ayline Kübler, Jeanette Woiterski, Kai-Erik Witte, Hans-Jörg Bühring, Udo F Hartwig, Martin Ebinger, Lena Oevermann, Markus Mezger, Wolfgang Herr, Peter Lang, Rupert Handgretinger, Christian Münz, Maya C André
Therapeutic natural killer (NK)-cell-mediated alloreactivity toward acute myeloid leukemia has largely been attributed to mismatches between killer immunoglobulin-like receptors (KIRs) on NK cells and their ligands, HLA class I molecules, on target cells. While adult acute B-cell precursor leukemia (BCP-ALL) appears to be resistant to NK-cell-mediated lysis, recent data indicate that pediatric BCP-ALL might yet be a target of NK cells. In this study, we demonstrate in a donor-patient-specific NOD.Cg-Prkdc(scid) IL2rg(tmWjl)/Sz (NSG) xenotransplantation model that NK cells mediate considerable alloreactivity toward pediatric BCP-ALL in vivo...
December 18, 2014: Blood
Lorenzo Moretta, Elisa Montaldo, Paola Vacca, Genny Del Zotto, Francesca Moretta, Pietro Merli, Franco Locatelli, Maria Cristina Mingari
Natural killer (NK) cells are important effectors playing a relevant role in innate immunity, primarily in tumor surveillance and in defenses against viruses. Human NK cells recognize HLA class I molecules through surface receptors (KIR and NKG2A) that inhibit NK cell function and kill target cells that have lost (or underexpress) HLA class I molecules as it occurs in tumors or virus-infected cells. NK cell activation is mediated by an array of activating receptors and co-receptors that recognize ligands expressed primarily on tumors or virus-infected cells...
2014: International Archives of Allergy and Immunology
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