scholarly journals A role for elevated H-2 antigen expression in resistance to neoplasia caused by radiation-induced leukemia virus. Enhancement of effective tumor surveillance by killer lymphocytes.

1979 ◽  
Vol 149 (4) ◽  
pp. 898-909 ◽  
Author(s):  
D Meruelo
Keyword(s):  
Virus Infection ◽  
Leukemia Virus ◽  
Antigen Expression ◽  
Cell Surface Expression ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Altered Expression ◽  
Radiation Induced ◽  
Low Levels

Resistance to neoplasia caused by radiation-induced leukemia virus (RadLV) is mediated by gene(s) in the H-2D region of the major histocompatibility complex. The previous observation that rapid increases in cellular synthesis and cell-surface expression of H-2 antigens are detectable immediately after virus inoculation has suggested that altered expression of H-2 antigens may play a significant role in the mechanism(s) of host defense to virus infection. This concept is supported by the following observations. First, cell-mediated immunity against RadLV transformed or infected cells can be detected with ease when H-2-positive target cells are used in the cell-mediated lympholysis (CML) assay. (Although RadLV transformed cells obtained from overtly leukemic animals and maintained in tissue culture are H-2 negative, these cells can regain their H-2 phenotype by in vivo passage in normal animals. The H-2-negative cells are poor targets in a CML assay.) Second, resistant mice develop greater numbers of effectors when infected with RadLV than do susceptible mice. Third, injection of normal (uninfected) thymocytes into syngeneic recipients of resistant or susceptible H-2 type does not stimulate a CML response. However, injection of RadLV infected thymocytes from resistant mice produces a vigorous CMI response, and such thymocytes elicit the strongest response at a time when both H-2 and viral antigen expression is elevated. By contrast, injection of infected thymocytes from susceptible mice, which express viral antigens, but low levels of H-2 antigens, does not stimulate a CML reaction. These findings may explain the easier induction of leukemia found by many investigators when virus is inoculated into neonatal mice and the preferential thymus tropism of some oncogenic type-C RNA virus. Cells expressing very low levels of H-2, such as thymocytes, may serve as permissive targets for virus infection because they lack an important component (H-2 antigens) of the dual or altered recognition signal required to trigger a defensive host immune response.

scholarly journals Preleukemic expression of TL antigens in x-irradiated C57BL/6 mice.

1977 ◽  
Vol 146 (1) ◽  
pp. 271-276 ◽  
Author(s):  
E Stockert ◽  
L J Old
Keyword(s):  
Characteristic Feature ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Antigen Expression ◽  
Comparative Tests ◽  
Radiation Induced ◽  
Low Levels ◽  
Murine Leukemia ◽  
Overt Leukemia

Anomalous appearance of TL (thymus-leukemia) antigens is a characteristic feature of radiation-induced leukemias of C57bl/6 mice. We now report that thymocytes of irradiated C57BL/6 mice express TL antigens long before the development of overt leukemia. Thus, TL is a marker for preleukemic changes occurring during radiation leukemogenesis. Low levels of murine leukemia virus (MuLV)-related antigens are also detected on preleukemic thymocytes. Comparative tests on individual mice show no direct correlation between TL and MuLV antigen expression.

scholarly journals Increased synthesis and expression of H-2 antigens on thymocytes as a result of radiation leukemia virus infection: a possible mechanism for H-2 linked control of virus-induced neoplasia.

1978 ◽  
Vol 147 (2) ◽  
pp. 470-487 ◽  
Author(s):  
D Meruelo ◽  
S H Nimelstein ◽  
P P Jones ◽  
M Lieberman ◽  
H O McDevitt
Keyword(s):  
Virus Infection ◽  
Cell Surface ◽  
Leukemia Virus ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Electrophoretic Analysis ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Altered Expression ◽  
Thymus Cells

Previous studies from this laboratory have mapped resistance and/or susceptibility to radiation-induced leukemia virus (RadLV)-induced neoplasia to the H-2D region. H-2 linked effects on virus replication can be detected subsequent to the initial virus infection, and clear-cut differences in numbers of virus infected thymus cells can be detected as early as 5 wk after RadLV inoculation. Rapid increases in cellular synthesis and cell surface expression of H-2 antigens are detectable immediately after virus inoculation. These changes have been studied by immunofluorescence, absorption, cell surface iodination followed by sodium dodecyl-sulfate-polyacrylamide gel electrophoresis, and two dimensional gel electrophoretic analysis of internally labeled lymphocyte proteins. Expression of H-2K molecules is significantly increased in cells of susceptible and resistant animals. However, significant increases in expression of H-2D antigens occurs only on thymus cells from resistant strains (H-2Dd). Transformed cells of resistant and susceptible H-2 haplotypes adapted to tissue culture lack detectable H-2 antigens as determined by serological absorption studies. It is argued that altered expression of H-2 antigens plays a very significant role in the mechanism of host defense to virus infection.

scholarly journals Efficient genome editing in primary cells and in vivo using viral-derived “Nanoblades” loaded with Cas9/sgRNA ribonucleoproteins

2017 ◽  
Author(s):  
Philippe E. Mangeot ◽  
Valérie Risson ◽  
Floriane Fusil ◽  
Aline Marnef ◽  
Emilie Laurent ◽  
...  
Keyword(s):  
Stem Cells ◽  
Genome Editing ◽  
Target Genes ◽  
Bone Marrow Cells ◽  
Leukemia Virus ◽  
Target Cells ◽  
Mouse Bone Marrow ◽  
Primary Cells ◽  
Hematopoietic Stem

AbstractProgrammable nucleases have enabled rapid and accessible genome engineering in eukaryotic cells and living organisms. However, their delivery into target cells can be technically challenging when working with primary cells or in vivo. Using engineered murine leukemia virus-like particles loaded with Cas9/sgRNA ribonucleoproteins (“Nanoblades”), we were able to induce efficient genome-editing in cell lines and primary cells including human induced pluripotent stem cells, human hematopoietic stem cells and mouse bone-marrow cells. Transgene-free Nanoblades were also capable of in vivo genome-editing in mouse embryos and in the liver of injected mice. Nanoblades can be complexed with donor DNA for “all-in-one” homology-directed repair or programmed with modified Cas9 variants to mediate transcriptional up-regulation of target genes. Nanoblades preparation process is simple, relatively inexpensive and can be easily implemented in any laboratory equipped for cellular biology.

scholarly journals Induction of Genotype Cross-Reactive, Hepatitis C Virus-Specific, Cell-Mediated Immunity in DNA-Vaccinated Mice

2018 ◽  
Vol 92 (8) ◽  
pp. e02133-17 ◽  
Author(s):  
Danushka K. Wijesundara ◽  
Jason Gummow ◽  
Yanrui Li ◽  
Wenbo Yu ◽  
Benjamin J. Quah ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Dna Vaccine ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Specific Cell ◽  
Universal Vaccine ◽  
Cell Responses ◽  
Single Genotype

ABSTRACTA universal hepatitis C virus (HCV) vaccine should elicit multiantigenic, multigenotypic responses, which are more likely to protect against challenge with the range of genotypes and subtypes circulating in the community. A vaccine cocktail and vaccines encoding consensus HCV sequences are attractive approaches to achieve this goal. Consequently, in a series of mouse vaccination studies, we compared the immunogenicity of a DNA vaccine encoding a consensus HCV nonstructural 5B (NS5B) protein to that of a cocktail of DNA plasmids encoding the genotype 1b (Gt1b) and Gt3a NS5B proteins. To complement this study, we assessed responses to a multiantigenic cocktail regimen by comparing a DNA vaccine cocktail encoding Gt1b and Gt3a NS3, NS4, and NS5B proteins to a single-genotype NS3/4/5B DNA vaccine. To thoroughly evaluatein vivocytotoxic T lymphocyte (CTL) and T helper (Th) cell responses against Gt1b and Gt3a HCV peptide-pulsed target cells, we exploited a novel fluorescent-target array (FTA). FTA and enzyme-linked immunosorbent spot (ELISpot) analyses collectively indicated that the cocktail regimens elicited higher responses to Gt1b and Gt3a NS5B proteins than those with the consensus vaccine, while the multiantigenic DNA cocktail significantly increased the responses to NS3 and NS5B compared to those elicited by the single-genotype vaccines. Thus, a DNA cocktail vaccination regimen is more effective than a consensus vaccine or a monovalent vaccine at increasing the breadth of multigenotypic T cell responses, which has implications for the development of vaccines for communities where multiple HCV genotypes circulate.IMPORTANCEDespite the development of highly effective direct-acting antivirals (DAA), infections with hepatitis C virus (HCV) continue, particularly in countries where the supply of DAA is limited. Furthermore, patients who eliminate the virus as a result of DAA therapy can still be reinfected. Thus, a vaccine for HCV is urgently required, but the heterogeneity of HCV strains makes the development of a universal vaccine difficult. To address this, we developed a novel cytolytic DNA vaccine which elicits robust cell-mediated immunity (CMI) to the nonstructural (NS) proteins in vaccinated animals. We compared the immune responses against genotypes 1 and 3 that were elicited by a consensus DNA vaccine or a DNA vaccine cocktail and showed that the cocktail induced higher levels of CMI to the NS proteins of both genotypes. This study suggests that a universal HCV vaccine can most readily be achieved by use of a DNA vaccine cocktail.

Strong selection for cells containing new ecotropic recombinant murine leukemia virus provirus after propagation of C57BL/6 radiation-induced thymoma cells in vitro or in vivo

1983 ◽  
Vol 3 (9) ◽  
pp. 1675-1679
Author(s):  
P Jolicoeur ◽  
E Rassart ◽  
P Sankar-Mistry
Keyword(s):  
Cell Lines ◽  
Murine Leukemia Virus ◽  
Leukemia Virus ◽  
Primary Radiation ◽  
Secondary Tumors ◽  
Radiation Induced ◽  
Viral Sequences ◽  
Murine Leukemia

Using the Southern procedure, we have studied the presence of ecotropic-specific murine leukemia viral sequences in genomic DNA isolated from primary X-ray-induced thymomas, from lymphoid cell lines established from them, or from secondary tumors passaged in vivo. We found that primary radiation-induced thymomas and infiltrated spleens do not harbor newly acquired ecotropic provirus. However, additional ecotropic proviruses (which appear recombinant in the gagpol region) could be detected in most of the tumorigenic cell lines established in vitro from them and in tumors arising from subcutaneous transplantation of the primary thymomas. These results suggest that primary radiation-induced thymomas may not be clonal. They also indicate a strong correlation between the presence of ecotropic recombinant proviruses in the genome and the growth ability, both in vitro and in vivo, of specific cells within these thymomas, suggesting a possible mitogenic function for murine leukemia virus.

scholarly journals PSGL-1 restricts HIV-1 infectivity by blocking virus particle attachment to target cells

2020 ◽  
Vol 117 (17) ◽  
pp. 9537-9545 ◽  
Author(s):  
Yajing Fu ◽  
Sijia He ◽  
Abdul A. Waheed ◽  
Deemah Dabbagh ◽  
Zheng Zhou ◽  
...  
Keyword(s):  
Virus Particle ◽  
Influenza A ◽  
Leukemia Virus ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Target Cells ◽  
Viral Glycoprotein ◽  
Selectin Binding ◽  
Anti Hiv ◽  
Hiv 1

P-selectin glycoprotein ligand-1 (PSGL-1) is a dimeric, mucin-like, 120-kDa glycoprotein that binds to P-, E-, and L-selectins. PSGL-1 is expressed primarily on the surface of lymphoid and myeloid cells and is up-regulated during inflammation to mediate leukocyte tethering and rolling on the surface of endothelium for migration into inflamed tissues. Although it has been reported that PSGL-1 expression inhibits HIV-1 replication, the mechanism of PSGL-1–mediated anti-HIV activity remains to be elucidated. Here we report that PSGL-1 in virions blocks the infectivity of HIV-1 particles by preventing the binding of particles to target cells. This inhibitory activity is independent of the viral glycoprotein present on the virus particle; the binding of particles bearing the HIV-1 envelope glycoprotein or vesicular stomatitis virus G glycoprotein or even lacking a viral glycoprotein is impaired by PSGL-1. Mapping studies show that the extracellular N-terminal domain of PSGL-1 is necessary for its anti–HIV-1 activity, and that the PSGL-1 cytoplasmic tail contributes to inhibition. In addition, we demonstrate that the PSGL-1–related monomeric E-selectin–binding glycoprotein CD43 also effectively blocks HIV-1 infectivity. HIV-1 infection, or expression of either Vpu or Nef, down-regulates PSGL-1 from the cell surface; expression of Vpu appears to be primarily responsible for enabling the virus to partially escape PSGL-1–mediated restriction. Finally, we show that PSGL-1 inhibits the infectivity of other viruses, such as murine leukemia virus and influenza A virus. These findings demonstrate that PSGL-1 is a broad-spectrum antiviral host factor with a unique mechanism of action.

Pritumumab binding to glioma cells induces ADCC and inhibits tumor growth.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14004-e14004
Author(s):  
Santosh Kesari ◽  
Ivan Babic ◽  
Rajesh Mukthavaram ◽  
Pengfei Jiang ◽  
Natsuko Nomura ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Tumor Growth ◽  
Blood Brain Barrier ◽  
Intact Cell ◽  
Glioma Cells ◽  
Brain Barrier ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Blood Brain

e14004 Background: Pritumumab is a natural human IgG1 kappa antibody originally isolated from a regional draining lymph node of a patient with cervical carcinoma. This antibody binds ectodomain vimentin on the surface of tumor cells and has demonstrated some benefit to glioblastoma patients in limited clinical trials. We wanted to determine if pritumumab inhibits glioma growth in vivo and if binding to glioma cells induces cell-mediated immunity. Methods: Pritumumab was used in flow cytometry experiments with several glioma cell lines and patient-derived neurosphere lines. Antibody-dependent cell-mediated cytotoxicity (ADCC) reporter assay was used with glioma target cells. Xenograft studies were performed in mice with and without intact B- and NK- cells. Results: We performed flow cytometry using pritumumab antibody and demonstrate binding of pritumumab to the surface of glioma cells and patient-derived glioma initiating cells. We observed significant induction of ADCC by pritumumab binding to glioma cells. Xenograft studies demonstrated pritumumab was effective in preventing tumor growth in nude mice but not in SCID mice. Intact cell-mediated immunity was necessary for pritumumab’s anti-tumor effect. Analysis of a blood brain barrier model showed significant binding of pritumumab in brain tumor areas and minimal distribution in normal brain tissues suggesting the antibody can cross the blood brain barrier. Conclusions: Our data demonstratepritumumab binds glioma cells in vitro and can induce ADCC. In addition, pritumumab can limit the growth of xenograft glioma tumors in vivo only in the presence of intact cell-mediated immunity. Together these data suggest pritumumab is suitable for development as an anti-tumor therapeutic.

The influence of oxygen on the radiosensitizing activity of Photofrin II and hypericin

2007 ◽  
Vol 11 (10) ◽  
pp. 736-741 ◽  
Author(s):  
Pamela Schaffer ◽  
Ulrike Kulka ◽  
Birgit Ertl-Wagner ◽  
Roswita Hell ◽  
Alina Balandin ◽  
...  
Keyword(s):  
Carcinoma Cell ◽  
Cell Damage ◽  
Human Bladder ◽  
Photofrin Ii ◽  
Carcinoma Cell Lines ◽  
Radiation Induced ◽  
Low Levels ◽  
Sufficient Oxygen

Several clinical studies, as well as investigations performed on tissue cultures and murine tumor models, have demonstrated the in vitro and in vivo efficacy of Photofrin II and hypericin as radiosensitizing agents. The mechanisms involved in the radiosensitizing action of Photofrin II and hypericin are partially understood; the recognition of the major role performed by oxygen regarding the modulation of cellular radiosensitivity has prompted the present investigations on the relevance of oxygenation for the success of Photofrin II or hypericin-based radiation therapy of tumors. RT4 human bladder carcinoma cell lines were seeded and incubated with various concentrations of Photofrin II or hypericin under ambient and 5% oxygen levels. The cells were irradiated with ionizing radiation between 1 and 6 Gy. The same experiments were repeated with Photofrin II and hypericin alone, without radiation. The cell survival was evaluated. The results demonstrated an increase of radiation-induced cell damage in the presence of Photofrin II and hypericin, respectively, when sufficient oxygen was available. Low levels of oxygen reduced the activity of Photofrin II as well as of hypericin as a radiosensitizer, with minimal tumor damage ( p < 0.05 in a Student t-test). The mechanism of action of Photofrin II and hypericin as radiosensitizers requires the presence of sufficiently high oxygen concentrations.

scholarly journals Migration ofAntigen-Specific T Cells Away from CXCR4-Binding Human ImmunodeficiencyVirus Type 1gp120

2004 ◽  
Vol 78 (10) ◽  
pp. 5184-5193 ◽  
Author(s):  
Diana M. Brainard ◽  
William G. Tharp ◽  
Elva Granado ◽  
Nicholas Miller ◽  
Alicja K. Trocha ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Active Movement ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Cell Trafficking ◽  
Hiv 1

ABSTRACT Cell-mediated immunity depends in part on appropriate migration and localization of cytotoxic T lymphocytes (CTL), a process regulated by chemokines and adhesion molecules. Many viruses, including human immunodeficiency virus type 1 (HIV-1), encode chemotactically active proteins, suggesting that dysregulation of immune cell trafficking may be a strategy for immune evasion. HIV-1 gp120, a retroviral envelope protein, has been shown to act as a T-cell chemoattractant via binding to the chemokine receptor and HIV-1 coreceptor CXCR4. We have previously shown that T cells move away from the chemokine stromal cell-derived factor 1 (SDF-1) in a concentration-dependent and CXCR4 receptor-mediated manner. Here, we demonstrate that CXCR4-binding HIV-1 X4 gp120 causes the movement of T cells, including HIV-specific CTL, away from high concentrations of the viral protein. This migratory response is CD4 independent and inhibited by anti-CXCR4 antibodies and pertussis toxin. Additionally, the expression of X4 gp120 by target cells reduces CTL efficacy in an in vitro system designed to account for the effect of cell migration on the ability of CTL to kill their target cells. Recombinant X4 gp120 also significantly reduced antigen-specific T-cell infiltration at a site of antigen challenge in vivo. The repellant activity of HIV-1 gp120 on immune cells in vitro and in vivo was shown to be dependent on the V2 and V3 loops of HIV-1 gp120. These data suggest that the active movement of T cells away from CXCR4-binding HIV-1 gp120, which we previously termed fugetaxis, may provide a novel mechanism by which HIV-1 evades challenge by immune effector cells in vivo.

scholarly journals Specificity in Receptor Usage by T-Cell-Tropic Feline Leukemia Viruses: Implications for the In Vivo Tropism of Immunodeficiency-Inducing Variants

2001 ◽  
Vol 75 (19) ◽  
pp. 8888-8898 ◽  
Author(s):  
Adam S. Lauring ◽  
Maria M. Anderson ◽  
Julie Overbaugh
Keyword(s):  
T Cell ◽  
Receptor Binding ◽  
Leukemia Virus ◽  
Phosphate Transport ◽  
Productive Infection ◽  
Target Cells ◽  
Envelope Gene ◽  
Leukemia Viruses ◽  
Feline Leukemia Viruses

ABSTRACT Cytopathic, T-cell-tropic feline leukemia viruses (FeLV-T) evolve from FeLV-A in infected animals and demonstrate host cell specificities that are distinct from those of their parent viruses. We recently identified two cellular proteins, FeLIX and Pit1, required for productive infection by these immunodeficiency-inducing FeLV-T variants (M. M. Anderson, A. S. Lauring, C. C. Burns, and J. Overbaugh, Science 287:1828–1830, 2000). FeLV-T is the first example of a naturally occurring type C retrovirus that requires two proteins to gain entry into target cells. FeLIX is an endogenous protein that is highly related to the N-terminal portion of the FeLV envelope protein, which includes the receptor-binding domain. Pit1 is a multiple-transmembrane phosphate transport protein that also functions as a receptor for FeLV-B. The FeLV-B envelope gene is derived by recombination with endogenous FeLV-like sequences, and its product can functionally substitute for FeLIX in facilitating entry through the Pit1 receptor. In the present study, we tested other retrovirus envelope surface units (SUs) with their cognate receptors to determine whether they also could mediate infection by FeLV-T. Cells were engineered to coexpress the transmembrane form of the envelope proteins and their cognate receptors, or SU protein was added as a soluble protein to cells expressing the receptor. Of the FeLV, murine leukemia virus, and gibbon ape leukemia virus envelopes tested, we found that only those with receptor-binding domains derived from endogenous FeLV could render cells permissive for FeLV-T. We also found that there is a strong preference for Pit1 as the transmembrane receptor. Specifically, FeLV-B SUs could efficiently mediate infection of cells expressing the Pit1 receptor but could only inefficiently mediate infection of cells expressing the Pit2 receptor, even though these SUs are able to bind to Pit2. Expression analysis of feline Pit1 and FeLIX suggests that FeLIX is likely the primary determinant of FeLV-T tropism. These results are discussed in terms of current models for retrovirus entry and the interrelationship among FeLV variants that evolve in vivo.

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