scholarly journals Enhancing the antitumor efficacy of a cell-surface death ligand by covalent membrane display

2015 ◽  
Vol 112 (18) ◽  
pp. 5679-5684 ◽  
Author(s):  
Pradeep M. Nair ◽  
Heather Flores ◽  
Alvin Gogineni ◽  
Scot Marsters ◽  
David A. Lawrence ◽  
...  
Keyword(s):  
Cell Surface ◽  
Lipid Bilayers ◽  
Therapeutic Potential ◽  
Supported Lipid Bilayers ◽  
Surface Attachment ◽  
Tnf Superfamily ◽  
Membrane Attachment ◽  
A Cell ◽  
Surface Ligand

TNF superfamily death ligands are expressed on the surface of immune cells and can trigger apoptosis in susceptible cancer cells by engaging cognate death receptors. A recombinant soluble protein comprising the ectodomain of Apo2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) has shown remarkable preclinical anticancer activity but lacked broad efficacy in patients, possibly owing to insufficient exposure or potency. We observed that antibody cross-linking substantially enhanced cytotoxicity of soluble Apo2L/TRAIL against diverse cancer cell lines. Presentation of the ligand on glass-supported lipid bilayers enhanced its ability to drive receptor microclustering and apoptotic signaling. Furthermore, covalent surface attachment of Apo2L/TRAIL onto liposomes—synthetic lipid-bilayer nanospheres—similarly augmented activity. In vivo, liposome-displayed Apo2L/TRAIL achieved markedly better exposure and antitumor activity. Thus, covalent synthetic-membrane attachment of a cell-surface ligand enhances efficacy, increasing therapeutic potential. These findings have translational implications for liposomal approaches as well as for Apo2L/TRAIL and other clinically relevant TNF ligands.

Factors Controlling Electropermeabilisation of Cell Membranes

2002 ◽  
Vol 1 (5) ◽  
pp. 319-327 ◽  
Author(s):  
M. P. Rols ◽  
M. Golzio ◽  
B. Gabriel ◽  
J. Teissié
Keyword(s):  
Cell Surface ◽  
Electric Field ◽  
Pulse Duration ◽  
Cell Membranes ◽  
Physical Parameters ◽  
Local Exchange ◽  
Physical Mechanisms ◽  
A Cell

Electric field pulses are a new approach for drug and gene delivery for cancer therapy. They induce a localized structural alteration of cell membranes. The associated physical mechanisms are well explained and can be safely controlled. A position dependent modulation of the membrane potential difference is induced when an electric field is applied to a cell. Electric field pulses with an overcritical intensity evoke a local membrane alteration. A free exchange of hydrophilic low molecular weight molecules takes place across the membrane. A leakage of cytosolic metabolites and a loading of polar drugs into the cytoplasm are obtained. The fraction of the cell surface which is competent for exchange is a function of the field intensity. The level of local exchange is strongly controlled by the pulse duration and the number of successive pulses. The permeabilised state is long lived. Its lifetime is under the control of the cumulated pulse duration. Cell viability can be preserved. Gene transfer is obtained but its mechanism is not a free diffusion. Plasmids are electrophoretically accumulated against the permeabilised cell surface and form aggregates due to the field effect. After the pulses, several steps follow: translocation to the cytoplasm, traffic to the nucleus and expression. Molecular structural and metabolic changes in cells remain mostly poorly understood. Nevertheless, while most studies were established on cells in culture ( in vitro), recent experiments show that similar effects are obtained on tissue ( in vivo). Transfer remains controlled by the physical parameters of the electrical treatment.

scholarly journals A generic cell surface ligand system for studying cell-cell recognition

2019 ◽  
Author(s):  
Eleanor M Denham ◽  
Michael I Barton ◽  
Susannah M Black ◽  
Marcus J Bridge ◽  
Ben de Wet ◽  
...  
Keyword(s):  
Cell Surface ◽  
Surface Density ◽  
Cell Receptor ◽  
Surface Receptors ◽  
Ligand System ◽  
Ligand Interactions ◽  
A Cell ◽  
Surface Ligand ◽  
Receptor Biology ◽  
Cell Cell

AbstractDose-response experiments are a mainstay of receptor biology studies and can reveal valuable insights into receptor function. Such studies of receptors that bind cell surface ligands are currently limited by the difficulty in manipulating the surface density of ligands at a cell-cell interface. Here we describe a generic cell surface ligand system that allows precise manipulation of cell surface ligand densities over several orders of magnitude. We validate the system for a range of immunoreceptors, including the T cell receptor (TCR), and show that this generic ligand stimulates via the TCR at a similar surface density as its native ligand. This system allows the effect of surface density, valency, dimensions, and affinity of the ligand to be manipulated. It can be readily extended to other receptor-cell surface ligand interactions, and will facilitate investigation into the activation of, and signal integration between, cell surface receptors.

Gingipains Inactivate a Cell Surface Ligand onPorphyromonas gingivalisThat Induces TLR2- and TLR4-Independent Signaling

2006 ◽  
Vol 50 (4) ◽  
pp. 315-325 ◽  
Author(s):  
Mami Kishimoto ◽  
Atsutoshi Yoshimura ◽  
Mariko Naito ◽  
Kuniaki Okamoto ◽  
Kenji Yamamoto ◽  
...  
Keyword(s):  
Cell Surface ◽  
A Cell ◽  
Surface Ligand

scholarly journals Human Cancer Antigen Globo H Is a Cell-Surface Ligand for Human Ribonuclease 1

2015 ◽  
Vol 1 (4) ◽  
pp. 181-190 ◽  
Author(s):  
Chelcie H. Eller ◽  
Tzu-Yuan Chao ◽  
Kiran K. Singarapu ◽  
Ouathek Ouerfelli ◽  
Guangbin Yang ◽  
...  
Keyword(s):  
Cell Surface ◽  
Human Cancer ◽  
Cancer Antigen ◽  
A Cell ◽  
Surface Ligand

scholarly journals Cytotoxicity of a cell-reactive immunotoxin containing ricin A chain is potentiated by an anti-immunotoxin containing ricin B chain.

1984 ◽  
Vol 160 (1) ◽  
pp. 341-346 ◽  
Author(s):  
E S Vitetta ◽  
R J Fulton ◽  
J W Uhr
Keyword(s):  
Cell Surface ◽  
Cell Line ◽  
Ricin A Chain ◽  
Daudi Cell ◽  
A Cell ◽  
A Chain ◽  
Ricin A

In vitro killing of the human Daudi cell line by either univalent [F(ab')] or divalent (IgG) forms of rabbit anti-human Ig (RAHIg) coupled to ricin A chain can be specifically potentiated by a "piggyback" treatment with ricin B chain coupled to goat anti-rabbit Ig (GARIg). When cells are treated with univalent immunotoxin (IT) [F(ab') RAHIg-A] and then cultured, IT can be detected on the cell surface for at least 5 h, since GARIg-B can still enhance killing at this time. These results provide a strategy for in vivo use of A chain- and B chain-containing IT.

scholarly journals Cholangiocyte expression of α2β1-integrin confers susceptibility to rotavirus-induced experimental biliary atresia

2008 ◽  
Vol 295 (1) ◽  
pp. G16-G26 ◽  
Author(s):  
Mubeen Jafri ◽  
Bryan Donnelly ◽  
Steven Allen ◽  
Alex Bondoc ◽  
Monica McNeal ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Surface ◽  
Biliary Atresia ◽  
Cell Lines ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Newborn Mice ◽  
A Cell

Inoculation of BALB/c mice with rhesus rotavirus (RRV) in the newborn period results in biliary epithelial cell (cholangiocyte) infection and the murine model of biliary atresia. Rotavirus infection of a cell requires attachment, which is governed in part by cell-surface expression of integrins such as α2β1. We hypothesized that cholangiocytes were susceptible to RRV infection because they express α2β1. RRV attachment and replication was measured in cell lines derived from cholangiocytes and hepatocytes. Flow cytometry was performed on these cell lines to determine whether α2β1 was present. Cholangiocytes were blocked with natural ligands, a monoclonal antibody, or small interfering RNA against the α2-subunit and were infected with RRV. The extrahepatic biliary tract of newborn mice was screened for the expression of the α2β1-integrin. Newborn mice were pretreated with a monoclonal antibody against the α2-subunit and were inoculated with RRV. RRV attached and replicated significantly better in cholangiocytes than in hepatocytes. Cholangiocytes, but not hepatocytes, expressed α2β1 in vitro and in vivo. Blocking assays led to a significant reduction in attachment and yield of virus in RRV-infected cholangiocytes. Pretreatment of newborn pups with an anti-α2 monoclonal antibody reduced the ability of RRV to cause biliary atresia in mice. Cell-surface expression of the α2β1-integrin plays a role in the mechanism that confers cholangiocyte susceptibility to RRV infection.

scholarly journals Compartment-Restricted Biotinylation Reveals Novel Features of Prion Protein Metabolism in Vivo

2010 ◽  
Vol 21 (24) ◽  
pp. 4325-4337 ◽  
Author(s):  
Amy B. Emerman ◽  
Zai-Rong Zhang ◽  
Oishee Chakrabarti ◽  
Ramanujan S. Hegde
Keyword(s):  
Cell Surface ◽  
Prion Protein ◽  
Protein Metabolism ◽  
Selective Detection ◽  
Wild Type ◽  
Selective Labeling ◽  
A Cell ◽  
Cellular Compartments ◽  
Made In

Proteins are often made in more than one form, with alternate versions sometimes residing in different cellular compartments than the primary species. The mammalian prion protein (PrP), a cell surface GPI-anchored protein, is a particularly noteworthy example for which minor cytosolic and transmembrane forms have been implicated in disease pathogenesis. To study these minor species, we used a selective labeling strategy in which spatially restricted expression of a biotinylating enzyme was combined with asymmetric engineering of the cognate acceptor sequence into PrP. Using this method, we could show that even wild-type PrP generates small amounts of the CtmPrP transmembrane form. Selective detection of CtmPrP allowed us to reveal its N-terminal processing, long half-life, residence in both intracellular and cell surface locations, and eventual degradation in the lysosome. Surprisingly, some human disease-causing mutants in PrP selectively stabilized CtmPrP, revealing a previously unanticipated mechanism of CtmPrP up-regulation that may contribute to disease. Thus, spatiotemporal tagging has uncovered novel aspects of normal and mutant PrP metabolism and should be readily applicable to the analysis of minor topologic isoforms of other proteins.

scholarly journals Coexistence of long and short DNA constructs within adhesion plaques

2020 ◽  
Author(s):  
Long Li ◽  
Mohammad Arif Kamal ◽  
Henning Stumpf ◽  
Franck Thibaudau ◽  
Kheya Sengupta ◽  
...  
Keyword(s):  
Lipid Bilayers ◽  
Optical Resolution ◽  
Simultaneous Action ◽  
Supported Lipid Bilayers ◽  
Physical Mechanisms ◽  
Domain Structures ◽  
Membrane Interfaces ◽  
A Cell ◽  
Physical Effects ◽  
Relative Differences

Adhesion domains forming at the membrane interfaces between two cells or a cell and the ex-tracellular matrix commonly involve multiple proteins bridges. However, the physical mechanisms governing the domain structures are not yet fully resolved. Here we present a joint experimental and theoretical study of a mimetic model-system, based on giant unilammelar vesicles interacting with supported lipid bilayers, with which the underlying physical effects can be clearly identified. In our case, adhesion is induced by simultaneous action of DNA linkers with two different lengths. We study the organization of bridges into domains as a function of relative fraction of long and short DNA constructs. Irrespective of the composition, we systematically find adhesion domains with coexisting DNA bridge types, despite their relative differences in length of 9 nm. However, at short length scales, below the optical resolution of the microscope, simulations suggest the formation of nanodomains by the minority fraction. The nano-aggregation is more significant for long bridges, which are also more stable, even though the enthalpy of membrane insertion is the same for both species.

scholarly journals Ly6d-L, a Cell Surface Ligand for Mouse Ly6d

Immunity ◽  
2000 ◽  
Vol 12 (2) ◽  
pp. 223-232 ◽  
Author(s):  
Jim Apostolopoulos ◽  
Ian F.C McKenzie ◽  
Mauro S Sandrin
Keyword(s):  
Cell Surface ◽  
A Cell ◽  
Surface Ligand
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