scholarly journals Specific recognition of human CD3-CD16+ natural killer cells requires the expression of an autosomic recessive gene on target cells.

1990 ◽  
Vol 172 (1) ◽  
pp. 47-52 ◽  
Author(s):  
E Ciccone ◽  
D Pende ◽  
O Viale ◽  
G Tambussi ◽  
S Ferrini ◽  
...  
Keyword(s):  
Natural Killer ◽  
Tumor Cells ◽  
Effector Cell ◽  
Recessive Gene ◽  
Dominant Mode ◽  
Target Cells ◽  
Chromosome 6 ◽  
Specific Lysis ◽  
Cell Ratio ◽  
The Relationship

We analyzed the recently defined ability of CD3-CD16+ cells to specifically recognize and lyse normal allogeneic target cells (PHA-induced blasts). The susceptibility to lysis by a given alloreactive natural killer (NK) clone ("1 anti-A") was expressed by PHA blasts derived from 9 of 38 random donors analyzed. In all instances, the specific lysis of "susceptible" target cells was greater than 35% while that of "nonsusceptible" targets was less than 6% at an E/T cell ratio of 5:1. In addition to 1 anti-A, A anti-1 specific CD3-CD16+ clones could also be isolated from the reverse MLC combination. The relationship existing between lysis of normal allogeneic cells or tumor cells by the same CD3-CD16+ effector cell has been investigated: 1 anti-A specific CD3-CD16+ clones lysed PHA blasts of three of six cancer patients, while they lysed fresh tumor cells (ovarian carcinoma) from all six patients. The type of inheritance of the character "susceptibility to lysis" was analyzed in representative families. This analysis revealed that the character is inherited in an autosomic recessive fashion, and it is therefore different from MHC. We further investigated the type of segregation of the opposite character "resistance to lysis" (which is inherited in a dominant mode). The finding that this character segregated in all donors expressing given MHC haplotypes indicated that the gene regulating the expression of the NK-defined alloantigen is present on chromosome 6.

scholarly journals Preclinical characterization of 1-7F9, a novel human anti–KIR receptor therapeutic antibody that augments natural killer–mediated killing of tumor cells

Blood ◽  
2009 ◽  
Vol 114 (13) ◽  
pp. 2667-2677 ◽  
Author(s):  
Francois Romagné ◽  
Pascale André ◽  
Pieter Spee ◽  
Stefan Zahn ◽  
Nicolas Anfossi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Natural Killer ◽  
Tumor Cells ◽  
Nk Cell ◽  
Hla Class I ◽  
Therapeutic Antibody ◽  
Class I ◽  
Therapeutic Window ◽  
Target Cells ◽  
Term Survival

Abstract Inhibitory-cell killer immunoglobulin-like receptors (KIR) negatively regulate natural killer (NK) cell–mediated killing of HLA class I–expressing tumors. Lack of KIR-HLA class I interactions has been associated with potent NK-mediated antitumor efficacy and increased survival in acute myeloid leukemia (AML) patients upon haploidentical stem cell transplantation from KIR-mismatched donors. To exploit this pathway pharmacologically, we generated a fully human monoclonal antibody, 1-7F9, which cross-reacts with KIR2DL1, -2, and -3 receptors, and prevents their inhibitory signaling. The 1-7F9 monoclonal antibody augmented NK cell–mediated lysis of HLA-C–expressing tumor cells, including autologous AML blasts, but did not induce killing of normal peripheral blood mononuclear cells, suggesting a therapeutic window for preferential enhancement of NK-cell cytotoxicity against malignant target cells. Administration of 1-7F9 to KIR2DL3-transgenic mice resulted in dose-dependent rejection of HLA-Cw3–positive target cells. In an immunodeficient mouse model in which inoculation of human NK cells alone was unable to protect against lethal, autologous AML, preadministration of 1-7F9 resulted in long-term survival. These data show that 1-7F9 confers specific, stable blockade of KIR, boosting NK-mediated killing of HLA-matched AML blasts in vitro and in vivo, providing a preclinical basis for initiating phase 1 clinical trials with this candidate therapeutic antibody.

scholarly journals Integration of a virus membrane protein intothe lipid bilayer of target cells as a prerequisite for immune cytolysis. Specific cytolysis after virosome- target cell fusion

1978 ◽  
Vol 150 (6) ◽  
pp. 1383-1398 ◽  
Author(s):  
B Morein ◽  
D Barz ◽  
U Koszinowski ◽  
V Schirrmacher
Keyword(s):  
Tumor Cells ◽  
Lipid Bilayer ◽  
Target Cell ◽  
Semliki Forest Virus ◽  
Sendai Virus ◽  
Lipid Vesicles ◽  
Target Cells ◽  
Specific Lysis ◽  
Major Histocompatibility Antigens ◽  
Immune Cytolysis

Structural requirements for membrane antigens on target cells to mediate immune cytolysis were studied in a model system with purified membrane proteins from Semliki Forest virus (SFV). These SFV spike proteins were isolated in the form of detergent- and lipid-free protein micelles (29S complexes) or, after reconstitution into lipid vesicles, in the form of virosomes. Both the 29S complexes and the virosomes were found to bind well to murine tumor cells (P815 or Eb). When these cells, however, were used as target cells in complement-dependent lysis or in antibody-dependent cell- mediated cytotoxicity assays in the presence of anti-SFV serum, they were not lysed, although they effectively bound the antibody and consumed complement. The same tumor cells infected with SFV served as positive controls in both assays. Different results were obtained when inactivated Sendai virus was added as a fusion reagent to the cells coated with either virosomes or 29S complexes. Under these conditions the virosome-coated cells became susceptible to SFV- specific lysis, whereas the 29S complex-coated cells remained resistant. Evidence that the susceptibility to lysis ofvirosome-coated cells was dependent on active fusion and, therefore, integration of the viral antigens into the lipid bilayer of the target cells was derived from control experiments with enzyme-treated Sendai virus preparations. The 29S complexes and the virosomes partially and selectively blocked the target cell lysis by anti-H-2 sera but not by anti-non-H-2 sera confirming our previous finding that major histocompatibility antigens serve as receptors for SFV. The general significance of these findings for mechanisms of immune cytolysis is dicussed.

MHC Class I–Related Chain A Conjugated to Antitumor Antibodies Can Sensitize Tumor Cells to Specific Lysis by Natural Killer Cells

2005 ◽  
Vol 11 (20) ◽  
pp. 7516-7522 ◽  
Author(s):  
Claire Germain ◽  
Christel Larbouret ◽  
Valérie Cesson ◽  
Alena Donda ◽  
Werner Held ◽  
...  
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Class I ◽  
Specific Lysis ◽  
Killer Cells ◽  
Antitumor Antibodies

scholarly journals Interleukin-12–Activated Natural Killer Cells Recognize B7 Costimulatory Molecules on Tumor Cells and Autologous Dendritic Cells

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 196-206 ◽  
Author(s):  
Anja B. Geldhof ◽  
Muriel Moser ◽  
Laurence Lespagnard ◽  
Kris Thielemans ◽  
Patrick De Baetselier
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Synergistic Effects ◽  
Antigen Presenting Cells ◽  
Interleukin 12 ◽  
Target Cells ◽  
Effector Cells ◽  
Antigen Presenting

Activation of natural killer (NK) cells in the presence of interleukin-12 (IL-12) augments the capacity of these effector cells to recognize B7-1– and B7-2–expressing target cells. These effector cells also efficiently lyse autologous B7-positive progenitor or organ-derived dendritic cells, suggesting a physiologic regulatory pathway between IL-12, NK cells, and B7-expressing antigen-presenting cells. Although IL-12–activated NK cells secreted higher levels of interferon-γ, this cytokine did not play a role in synergistic effects of IL-12 and B7 on NK activation. The B7-counterreceptor was found to be selectively upregulated on IL-2/IL-12 as compared with IL-2–activated NK cells. CD28 is functionally involved in the recognition of B7 on target cells since IL-2/IL-12–activated NK cells derived from CD28 knockout mice were strongly reduced in their capacity to lyse syngeneic B7-positive tumor cells as well as antigen-presenting cells. However, recognition of B7 on allogeneic targets did not require the expression of CD28 on the IL-2/IL-12–activated NK cells. Hence, IL-12 triggers the expression of both CD28-dependent and CD28-independent mechanisms that allow NK cells to eliminate B7-positive target cells including autologous dendritic cells.

Inhibition of platelet aggregation and stimulation of natural killer cells functionality by administration of flavonoids

2011 ◽  
Vol 1 (2) ◽  
pp. 94-100
Author(s):  
Vasilis Theoharis ◽  
Ioannis Toliopoulos ◽  
Yannis Simos ◽  
Apostolos Metsios ◽  
Ioannis Zelovitis ◽  
...  
Keyword(s):  
Immune System ◽  
Platelet Aggregation ◽  
Natural Killer Cells ◽  
Cancer Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Target Cells ◽  
Killer Cells ◽  
Inhibition Of Platelet Aggregation ◽  
Stimulation Of

Platelets play an important role in homeostasis, inflammation and regulation of immune response. Natural Killer cells (NKC) on the other hand are the first line of defense of the immune system against viruses, bacteria and cancer cells. Platelets directly protect tumor cells from NK lysis. Thus, platelet aggregation around migrating cancer cells as well as the response of the immune system constitutes important mechanisms, which influence the progression of malignant diseases. The present study was designed to evaluate the possible effects of flavonoids (genistein, apigenin and quercetin) on the stimulation of the immune system and the inhibition of platelet aggregation. Two experimental protocols were used: a) ex vivo aggregation of human platelets, production of thromboxane A2 (TXA2) and estimation of the expression of the platelet membranic receptor GpIIb/IIIa, and b) functional activity of human NK lymphocytes against K562 target cells in vitro. All substances were found to induce a dose dependent inhibition of platelet aggregation and to reduce production of TXA2 in platelets. There was a decrease in the number of the GpIIb/IIIa receptors on the platelets surface membrane. Flow cytometry analysis revealed that all substances powerfully reinforce cytotoxic activity of NKC against K562 cells. These results show that flavonoids increase the susceptibility of tumor cells to NK cells by decreasing platelet aggregation and stimulating the NK lymphocyte activity.

scholarly journals Identification of four subsets of human CD3-CD16+ natural killer (NK) cells by the expression of clonally distributed functional surface molecules: correlation between subset assignment of NK clones and ability to mediate specific alloantigen recognition.

1990 ◽  
Vol 172 (6) ◽  
pp. 1589-1598 ◽  
Author(s):  
A Moretta ◽  
C Bottino ◽  
D Pende ◽  
G Tripodi ◽  
G Tambussi ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Human Tumor ◽  
Cytolytic Activity ◽  
Antigenic Determinants ◽  
Target Cells ◽  
Functional Surface ◽  
Double Positive ◽  
Specific Lysis

In previous studies we identified a surface molecule (termed GL183) capable of mediating cell activation and selectively expressed by a subset of human CD3-CD16+ natural killer (NK) cells. In this study we analyzed whether other subset-specific functional molecules were expressed in GL183- NK cells. To this end, mice were immunized with the PE29 (CD3-CD16+GL183-) NK clone. Monoclonal antibodies (mAbs) were selected by screening the hybridoma supernatants for their ability to trigger the cytolytic activity of clone PE29 against the human myelomonocytic leukemia U937. The EB6 mAb (IgG1) triggered the PE29 clone, but not a GL183+ clone used as a control. EB6+ cells ranged between 1 and 13% of peripheral blood lymphocytes and were largely included in the CD3-CD16+CD56+ cell populations (only less than 2% of EB6+ cells were CD3+). Analysis of resting or activated CD3-CD16+ populations, or clones for the expression of EB6 or GL183 mAbs, allowed us to identify four distinct, phenotypically stable, NK subsets (EB6+GL183-; EB6+GL183+; EB6-GL183+; EB6-GL183-). Similar to GL183 mAb, the EB6 mAb selectively triggered the NK subset expressing the corresponding surface antigen to lyse human tumor cell lines including U937, IGROV-I, M14, and A549. In addition, EB6 mAb sharply inhibited the cytolytic activity of EB6+ clones against P815, M12, and P3U1 murine target cells. In EB6+GL183+ ("double-positive") clones both EB6 and GL183 mAb inhibited the redirected killing of P815 cells induced by anti-CD16, anti-CD2 mAbs and phytohemagglutinin (PHA). Similar to GL183 molecules, molecules precipitated by EB6 mAb were represented by either single 58-kD chain or double chains of 55 and 58 kD (with no detectable differences in EB6+GL183- or EB6+GL183+ clones). In sequential immunoprecipitation experiments using the double-positive clones CEG52 and CA25.50, preclearing of cell lysates with EB6 or GL183 mAb removed only EB6 or GL183 molecules, respectively, thus indicating that the two antigenic determinants are carried by two distinct molecules. Peptide map analysis indicated that EB6 (or GL183) molecules precipitated from double-positive clones were identical to the corresponding molecules isolated from single-positive ones. On the other hand, comparison of the EB6 and GL183 maps revealed peptides that were unique to each molecule, although most of the major peptides migrated to identical positions. We further investigated whether correlation existed between the phenotypic assignment of NK clones and their ability to mediate specific lysis of normal allogeneic cells.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Antibody from Patients with Acute Human Immunodeficiency Virus (HIV) Infection Inhibits Primary Strains of HIV Type 1 in the Presence of Natural-Killer Effector Cells

2001 ◽  
Vol 75 (15) ◽  
pp. 6953-6961 ◽  
Author(s):  
Donald N. Forthal ◽  
Gary Landucci ◽  
Eric S. Daar
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antibody Response ◽  
Natural Killer ◽  
Effector Cell ◽  
Target Cells ◽  
Effector Cells ◽  
Viremia Level ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The partial control of viremia during acute human immunodeficiency virus type 1 (HIV-1) infection is accompanied by an HIV-1-specific cytotoxic T-lymphocyte (CTL) response and an absent or infrequent neutralizing antibody response. The control of HIV-1 viremia has thus been attributed primarily, if not exclusively, to CTL activity. In this study, the role of antibody in controlling viremia was investigated by measuring the ability of plasma or immunoglobulin G from acutely infected patients to inhibit primary strains of HIV-1 in the presence of natural-killer (NK) effector cells. Antibody that inhibits virus when combined with effector cells was present in the majority of patients within days or weeks after onset of symptoms of acute infection. Furthermore, the magnitude of this effector cell-mediated antiviral antibody response was inversely associated with plasma viremia level, and both autologous and heterologous HIV-1 strains were inhibited. Finally, antibody from acutely infected patients likely reduced HIV-1 yield in vitro both by mediating effector cell lysis of target cells expressing HIV-1 glycoproteins and by augmenting the release of β-chemokines from NK cells. HIV-1-specific antibody may be an important contributor to the early control of HIV viremia.

scholarly journals Interleukin-12–Activated Natural Killer Cells Recognize B7 Costimulatory Molecules on Tumor Cells and Autologous Dendritic Cells

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 196-206 ◽  
Author(s):  
Anja B. Geldhof ◽  
Muriel Moser ◽  
Laurence Lespagnard ◽  
Kris Thielemans ◽  
Patrick De Baetselier
Keyword(s):  
Dendritic Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Synergistic Effects ◽  
Antigen Presenting Cells ◽  
Interleukin 12 ◽  
Target Cells ◽  
Effector Cells ◽  
Antigen Presenting

Abstract Activation of natural killer (NK) cells in the presence of interleukin-12 (IL-12) augments the capacity of these effector cells to recognize B7-1– and B7-2–expressing target cells. These effector cells also efficiently lyse autologous B7-positive progenitor or organ-derived dendritic cells, suggesting a physiologic regulatory pathway between IL-12, NK cells, and B7-expressing antigen-presenting cells. Although IL-12–activated NK cells secreted higher levels of interferon-γ, this cytokine did not play a role in synergistic effects of IL-12 and B7 on NK activation. The B7-counterreceptor was found to be selectively upregulated on IL-2/IL-12 as compared with IL-2–activated NK cells. CD28 is functionally involved in the recognition of B7 on target cells since IL-2/IL-12–activated NK cells derived from CD28 knockout mice were strongly reduced in their capacity to lyse syngeneic B7-positive tumor cells as well as antigen-presenting cells. However, recognition of B7 on allogeneic targets did not require the expression of CD28 on the IL-2/IL-12–activated NK cells. Hence, IL-12 triggers the expression of both CD28-dependent and CD28-independent mechanisms that allow NK cells to eliminate B7-positive target cells including autologous dendritic cells.

scholarly journals CD38 contributes to human natural killer cell responses through a role in immune synapse formation

2018 ◽  
Author(s):  
Mathieu Le Gars ◽  
Christof Seiler ◽  
Alexander W. Kay ◽  
Nicholas L. Bayless ◽  
Elsa Sola ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Synapse Formation ◽  
Cell Function ◽  
Nk Cell ◽  
Critical Role ◽  
Target Cells ◽  
Immune Synapse ◽  
Ifn Γ

AbstractNatural killer (NK) cells use a diverse array of activating and inhibitory surface receptors to detect threats and provide an early line of defense against viral infections and cancer. Here, we demonstrate that the cell surface protein CD38 is a key human NK cell functional receptor through a role in immune synapse formation. CD38 expression marks a mature subset of human NK cells with a high functional capacity. NK cells expressing high levels of CD38 display enhanced killing and IFN-γ secretion in response to influenza virus-infected and tumor cells. Inhibition of CD38 enzymatic activity does not influence NK cell function, but blockade of CD38 and its ligand CD31 abrogates killing and IFN-γ expression in response to influenza-infected cells. Blockade of CD38 on NK cells similarly inhibits killing of tumor cells. CD38 localizes and accumulates at the immune synapse between NK cells and their targets, and blocking CD38 severely abrogates the ability of NK cells to form conjugates and immune synapses with target cells. Thus, CD38 plays a critical role in NK cell immune synapse formation. These findings open new avenues in immunotherapeutic development for cancer and infection by revealing a critical role for CD38 in NK cell function.

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