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Sample records for circulating natural killer

  1. The effects of phototherapy on the numbers of circulating natural killer cells and T lymphocytes in psoriasis.

    LENUS (Irish Health Repository)

    Tobin, A M

    2009-04-01

    The innate immune system is believed to be important in the pathogenesis of psoriasis and natural killer (NK) have been found in increased numbers in psoriatic plaques. Alterations in the numbers of NK cells in peripheral blood have been reported. We investigated the effect of phototherapy on levels of peripheral NK cells and lymphocytes in patients with psoriasis. In nine patients whom we followed before, during and after narrowband ultraviolet B (UVB) treatment there were no differences in the numbers of circulating lymphocytes, lymphocyte subsets or cells expressing NK markers and controls. Treatment with narrowband UVB did, however, significantly lower circulating CD4 counts which gradually recovered posttreatment.

  2. Natural killer cells in psoriasis.

    LENUS (Irish Health Repository)

    Tobin, A M

    2012-02-01

    Psoriasis is one of the most common immune-mediated disorders. There is evidence that it is mediated by Th1 and, more recently, Th17 cells. The cytokine pattern, particularly the dominance of TNF-alpha, implicates the innate immune system in psoriasis pathogenesis. Of the many components of the innate immune system known to be involved in psoriatic lesions, natural killer and natural killer T cells appear to have a unique role. We review the evidence supporting a role for natural killer cells in psoriasis.

  3. Natural killer cells in leukemogenesis

    International Nuclear Information System (INIS)

    In order to relate a reduced natural killer (NK) cell function to leukemogenesis, NK cells in the spleen and peritoneal exudate cells, with and without stimulation by Corynebacterium parvum, were tested in mice of various strains after split dose irradiation and after leukemogenic treatment with butyl- and methylnitrosourea. The investigations included also mice submitted to non-leukemogenic irradiation (1 x 1.5 and 1 x 4.5 Gy) and mice submitted to an additional treatment with hydrocortisone, which delays leukemia development after methylnitrosourea. There was, indeed, a NK-cell depression, but no major differences were seen between mice prone to leukemia development and those after cytotoxic, but nonleukemogenic, treatment. (author)

  4. Deficient natural killer cell function in preeclampsia

    International Nuclear Information System (INIS)

    Natural killer cell activity of peripheral blood lymphocytes was measured against K-562 target cells with a 4-hour 51Cr release assay in 15 primigravid women with preeclamptic symptoms. Nineteen primigravid women with an uncomplicated pregnancy and 18 nonpregnant women served as controls. The natural killer cell activity of preeclamptic women was observed to be significantly lower than that of both control groups. Natural killer cells in preeclamptic women responded normally to augmentation caused by interferon. These findings give further evidence for the participation of the maternal immune system in this pregnancy disorder

  5. Deficient natural killer cell function in preeclampsia

    Energy Technology Data Exchange (ETDEWEB)

    Alanen, A.; Lassila, O.

    1982-11-01

    Natural killer cell activity of peripheral blood lymphocytes was measured against K-562 target cells with a 4-hour /sup 51/Cr release assay in 15 primigravid women with preeclamptic symptoms. Nineteen primigravid women with an uncomplicated pregnancy and 18 nonpregnant women served as controls. The natural killer cell activity of preeclamptic women was observed to be significantly lower than that of both control groups. Natural killer cells in preeclamptic women responded normally to augmentation caused by interferon. These findings give further evidence for the participation of the maternal immune system in this pregnancy disorder.

  6. Natural killer cell activity during measles.

    Science.gov (United States)

    Griffin, D E; Ward, B J; Jauregui, E; Johnson, R T; Vaisberg, A

    1990-01-01

    Natural killer cells are postulated to play an important role in host anti-viral defences. We measured natural killer cell activity in 30 individuals with acute measles (73 +/- 21 lytic units (LU)/10(7) cells) and 16 individuals with other infectious diseases (149 +/- 95 LU) and found it reduced compared with values for adults (375 +/- 70 LU; P less than 0.001) or children (300 +/- 73 LU, P less than 0.01) without infection. Reduced natural killer cell activity was found in measles patients with (84 +/- 30 LU) and without (55 +/- 18 LU) complications and was present for at least 3 weeks after the onset of the rash. Activity was increased by in vitro exposure of cells to interleukin-2. Depressed natural killer cell activity parallels in time the suppression of other parameters of cell-mediated immunity that occurs during measles. PMID:1696863

  7. Influence of human cytomegalvirus on the expression of natural-killer group 2-members receptors on the natural killer cells

    Institute of Scientific and Technical Information of China (English)

    顾绍庆

    2014-01-01

    Objective To examine the effect of human cytomegalovirus(CMV)on the expressions of natural-killer group2-members(NKG2),including natural-killer group 2-member A(NKG2A),natural-killer group 2-member C(NKG2C)and natural-killer group 2-member D(NKG2D)receptors on the natural killer(NK)cells.Methods NK cells were isolated from the peripheral blood mononuclear cells of 20 healthy individuals using

  8. Viral Evasion of Natural Killer Cell Activation

    Science.gov (United States)

    Ma, Yi; Li, Xiaojuan; Kuang, Ersheng

    2016-01-01

    Natural killer (NK) cells play a key role in antiviral innate defenses because of their abilities to kill infected cells and secrete regulatory cytokines. Additionally, NK cells exhibit adaptive memory-like antigen-specific responses, which represent a novel antiviral NK cell defense mechanism. Viruses have evolved various strategies to evade the recognition and destruction by NK cells through the downregulation of the NK cell activating receptors. Here, we review the recent findings on viral evasion of NK cells via the impairment of NK cell-activating receptors and ligands, which provide new insights on the relationship between NK cells and viral actions during persistent viral infections. PMID:27077876

  9. Persistent changes in circulating and intestinal γδ T cell subsets, invariant natural killer T cells and mucosal-associated invariant T cells in children and adults with coeliac disease.

    Directory of Open Access Journals (Sweden)

    Margaret R Dunne

    Full Text Available Coeliac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals. The only current therapy is a lifelong gluten free diet. While much work has focused on the gliadin-specific adaptive immune response in coeliac disease, little is understood about the involvement of the innate immune system. Here we used multi-colour flow cytometry to determine the number and frequency of γδ T cells (Vδ1, Vδ2 and Vδ3 subsets, natural killer cells, CD56(+ T cells, invariant NKT cells, and mucosal associated invariant T cells, in blood and duodenum from adults and children with coeliac disease and healthy matched controls. All circulating innate lymphocyte populations were significantly decreased in adult, but not paediatric coeliac donors, when compared with healthy controls. Within the normal small intestine, we noted that Vδ3 cells were the most abundant γδ T cell type in the adult epithelium and lamina propria, and in the paediatric lamina propria. In contrast, patients with coeliac disease showed skewing toward a predominant Vδ1 profile, observed for both adult and paediatric coeliac disease cohorts, particularly within the gut epithelium. This was concurrent with decreases in all other gut lymphocyte subsets, suggesting a specific involvement of Vδ1 cells in coeliac disease pathogenesis. Further analysis showed that γδ T cells isolated from the coeliac gut display an activated, effector memory phenotype, and retain the ability to rapidly respond to in vitro stimulation. A profound loss of CD56 expression in all lymphocyte populations was noted in the coeliac gut. These findings demonstrate a sustained aberrant innate lymphocyte profile in coeliac disease patients of all ages, persisting even after elimination of gluten from the diet. This may lead to impaired immunity, and could potentially account for the increased incidence of autoimmune co-morbidity.

  10. Natural Killer cells and liver fibrosis

    Directory of Open Access Journals (Sweden)

    Frank eFasbender

    2016-01-01

    Full Text Available In the 40 years since the discovery of Natural Killer (NK cells it has been well established that these innate lymphocytes are important for early and effective immune responses against transformed cells and infections with different pathogens. In addition to these classical functions of NK cells, we now know that they are part of a larger family of innate lymphoid cells and that they can even mediate memory-like responses. Additionally, tissue resident NK cells with distinct phenotypical and functional characteristics have been identified. Here we focus on the phenotype of different NK cell subpopulations that can be found in the liver and summarize the current knowledge about the functional role of these cells with a special emphasis on liver fibrosis. NK cell cytotoxicity can contribute to liver damage in different forms of liver disease. However, NK cells can limit liver fibrosis by killing hepatic stellate cell-derived myofibroblasts, which play a key role in this pathogenic process. Therefore, liver NK cells need to be tightly regulated in order to balance these beneficial and pathological effects.

  11. Models for Natural Killer Cell Repertoire Formation

    Directory of Open Access Journals (Sweden)

    Ramit Mehr

    2003-01-01

    Full Text Available Natural killer (NK cells lyse only cells that do not express sufficient levels of self class I MHC molecules. Inhibition of lysis is mediated by inhibitory receptors expressed by NK cells, such as the murine Ly49 receptors, that bind to MHC class I molecules. Since inhibitory receptor genes and MHC class I genes are located on different chromosomes, and are hence not automatically co-inherited, NK cells apparently adapt to the MHC environment during their development. Two models have been proposed to account for this “education” process of NK cells. The two-step selection model postulates that developing NK cells initiate the stable expression of a random set of Ly49 genes, and then undergo two selection steps, one for cells that express a sufficient number of self-MHC receptors, and one against cells that express too many inhibitory receptors. The sequential model postulates that a cell keeps initiating the stable expression of additional inhibitory receptors until a sufficient expression level of self-MHC specific receptors is reached, and the cell matures. In this study we implement both models in computer simulations, and compare simulation results to experimental data, in order to evaluate the relative plausibility of the two models.

  12. Are natural killer cells protecting the metabolically healthy obese patient?

    LENUS (Irish Health Repository)

    Lynch, Lydia A

    2012-02-01

    With the emerging obesity pandemic, identifying those who appear to be protected from adverse consequences such as type 2 diabetes and certain malignancies will become important. We propose that the circulating immune system plays a role in the development of these comorbidities. Clinical data and blood samples were collected from 52 patients with severe obesity attending a hospital weight-management clinic and 11 lean healthy controls. Patients were classified into metabolically "healthy obese" (n = 26; mean age 42.6 years, mean BMI 46.8 kg\\/m(2)) or "unhealthy obese" (n = 26; mean age 45 years, mean BMI 47.5 kg\\/m(2)) groups, based upon standard cutoff points for blood pressure, lipid profile, and fasting glucose. Circulating lymphoid populations and phenotypes were assessed by flow cytometry. Obese patients had significantly less circulating natural killer (NK) and cytotoxic T lymphocytes (CTL) compared to lean controls. There were significantly higher levels of NK cells and CTLs in the healthy obese group compared to the unhealthy obese group (NK: 11.7% vs. 6.5%, P < 0.0001, CD8 13.4% vs. 9.3%, P = 0.04), independent of age and BMI and these NK cells were also less activated in the healthy compared to the unhealthy group (CD69, 4.1% vs. 11.8%, P = 0.03). This is the first time that quantitative differences in the circulating immune system of obese patients with similar BMI but different metabolic profiles have been described. The significantly higher levels of CTLs and NK cells, which express fewer inhibitory molecules, could protect against malignancy, infection, and metabolic disease seen in obesity.

  13. Changes in Natural Killer Cell Subsets in Pediatric Liver Transplant Recipients1

    OpenAIRE

    Pham, Betty; Piard-Ruster, Karine; Silva, Richard; Gallo, Amy; Esquivel, Carlos O.; Martinez, Olivia M.; Krams, Sheri M.

    2012-01-01

    Natural killer (NK) cells are important in the immune response against tumors and virally infected cells. A balance of inhibitory and activating receptors controls the effector functions of NK cells. We examined the fate of circulating NK cells and the expression of the NK cell activating receptors in pediatric liver transplant recipients. Blood specimens were collected from 38 pediatric liver transplant recipients before transplant, and at 1 week, 1, 3, 6, and 9 months, and 1 year post-trans...

  14. Natural Circulation with Boiling

    International Nuclear Information System (INIS)

    A number of parameters with dominant influence on the power level at hydrodynamic instability in natural circulation, two-phase flow, have been studied experimentally. The geometrical dependent quantities were: the system driving head, the boiling channel and riser dimensions, the single-phase as well as the two phase flow restrictions. The parameters influencing the liquid properties were the system pressure and the test section inlet subcooling. The threshold of instability was determined by plotting the noise characteristics in the mass flow records against power. The flow responses to artificially obtained power disturbances at instability conditions were also measured in order to study the nature of hydrodynamic instability. The results presented give a review over relatively wide ranges of the main parameters, mainly concerning the coolant performance in both single and parallel boiling channel flow. With regard to the power limits the experimental results verified that the single boiling channel performance was intimately related to that of the parallel channels. In the latter case the additional inter-channel factors with attenuating effects were studied. Some optimum values of the parameters were observed

  15. Evolution of male-killer suppression in a natural population.

    Directory of Open Access Journals (Sweden)

    Emily A Hornett

    2006-09-01

    Full Text Available Male-killing bacteria are widespread in arthropods, and can profoundly alter the reproductive biology of their host species. Here we detail the first case of complete suppression of a male killer. The nymphalid butterfly Hypolimnas bolina is infected with a strain of the bacterium Wolbachia, wBol1, which kills male host embryos in Polynesian populations, but does not do so in many areas of Southeast Asia, where both males and female adults are naturally infected, and wBol1-infected females produce a 1:1 sex ratio. We demonstrate that absence of male killing by wBol1 is associated with dominant zygotic suppression of the action of the male killer. Simulations demonstrate host suppressors of male-killer action can spread very rapidly, and historical data indicating the presence of male killing in Southeast Asia in the very recent past suggests suppressor spread has been a very recent occurrence. Thus, male killer/host interactions are much more dynamic than previously recognised, with rapid and dramatic loss of the phenotype. Our results also indicate that suppression can render male killers completely quiescent, leading to the conclusion that some species that do not currently express a male killer may have done so in the past, and thus that more species have had their biology affected by these parasites than previously believed.

  16. Transplantation and innate immunity: the lesson of natural killer cells

    Directory of Open Access Journals (Sweden)

    Moretta Lorenzo

    2009-12-01

    Full Text Available Abstract Natural killer cells have been demonstrated to play a major role in mediating an anti-leukemia effect in patients given a T-cell depleted allogeneic hematopoietic stem cell transplantation from an HLA-haploidentical family donor. In particular, donor-derived natural killer cells, which are alloreactive (i.e. KIR/HLA mismatched towards recipient cells, significantly contribute to the eradication of leukemia blasts escaping the preparative regimen to transplantation. A recent study on high-risk pediatric acute lymphoblastic leukemia refractory to chemotherapy further highlighted the importance of donors with alloreactive natural killer cells in haploidentical hematopoietic stem cell transplantation, as it demonstrated that these cells can emerge starting from the fourth-fifth month after the allograft and persist for many months. This study represents a major breakthrough in the cure of otherwise fatal leukemias, providing information on the best criteria for choosing the optimal donor.

  17. Natural killer cell activity during premedication, anaesthesia and surgery

    DEFF Research Database (Denmark)

    Tønnesen, E; Mickley, H; Grunnet, N

    1983-01-01

    Natural killer (NK) cell activity of peripheral blood mononuclear cells was measured against K-562 target cells in a 51Cr release assay in eight patients undergoing total hip replacement surgery. Eight consecutive blood samples were taken from each patient. A significant increase of NK cell...... days. The findings of this study indicate that premedication, anaesthesia and surgery cause a rapid and transient increase in NK cell activity, followed by a decline in activity postoperatively. The transient increase in activity may be explained by mobilization of natural killer cells from extravasal...

  18. File list: ALL.Bld.10.AllAg.Natural_Killer_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  19. File list: Oth.Bld.10.AllAg.Natural_Killer_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  20. File list: His.Bld.20.AllAg.Natural_Killer_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  1. File list: DNS.Bld.05.AllAg.Natural_Killer_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  9. File list: Pol.Bld.05.AllAg.Natural_Killer_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  10. File list: ALL.Bld.05.AllAg.Natural_Killer_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  11. File list: ALL.Bld.20.AllAg.Natural_Killer_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  13. File list: ALL.Bld.50.AllAg.Natural_Killer_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  20. Impaired cytotoxicity associated with defective natural killer cell differentiation in myelodysplastic syndromes

    OpenAIRE

    Hejazi, Maryam; Manser, Angela R.; Fröbel, Julia; Kündgen, Andrea; Zhao, Xiaoyi; Schönberg, Kathrin; Germing, Ulrich; Haas, Rainer; Gattermann, Norbert; Uhrberg, Markus

    2015-01-01

    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

  1. EFFECT OF NICKEL AND MANGANESE ON NATURAL KILLER CELL ACTIVITY

    Science.gov (United States)

    A single intramuscular injection of NiCl2 causes a suppression of natural killer (NK) cell activity, while a single injection of MnCl2 enhances NK activity. When injected together Mn preempts the suppressive effect of Ni on NK activity.

  2. Defective Natural Killer cell antiviral capacity in paediatric HBV infection

    DEFF Research Database (Denmark)

    Heiberg, Ida Louise; Laura J., Pallett; Winther, Thilde Nordmann;

    2015-01-01

    Natural Killer (NK) cells exhibit dysregulated effector function in adult chronic HBV infection (CHB), which may contribute to virus persistence. The role of NK cells in children infected perinatally with HBV is less studied. Access to a unique cohort enabled the cross-sectional evaluation of NK...

  3. Depressed natural killer cell activity in acute myocardial infarction

    DEFF Research Database (Denmark)

    Klarlund, K; Pedersen, B K; Theander, T G;

    1987-01-01

    Natural killer (NK) cell activity against K562 target cells was measured in patients within 24 h of acute myocardial infarction (AMI) and regularly thereafter for 6 weeks. NK cell activity was suppressed on days 1, 3, and 7 (P less than 0.01), day 14 (P less than 0.05) and at 6 weeks (P = 0...

  4. Proteomics of membrane microdomains from activated human natural killer cells

    Czech Academy of Sciences Publication Activity Database

    Man, Petr; Pompach, Petr; Vančurová, Markéta; Novák, Petr; Kavan, Daniel; Mrázek, Hynek; Bezouška, Karel

    Bremen : German Society for Mass Spectrometry, 2009. s. 128-128. [International Mass Spectrometry Conference /18./. 30.08.2009-04.09.2009, Bremen] R&D Projects: GA MŠk LC07017; GA AV ČR KJB500200612 Institutional research plan: CEZ:AV0Z50200510 Keywords : mass spectrometry * natural killer cells Subject RIV: EE - Microbiology, Virology

  5. Invariant natural killer T cells in hematopoietic stem cell transplantation: killer choice for natural suppression.

    Science.gov (United States)

    Guan, P; Bassiri, H; Patel, N P; Nichols, K E; Das, R

    2016-05-01

    Invariant natural killer T cells (iNKTs) are innate-like lipid-reactive T lymphocytes that express an invariant T-cell receptor (TCR). Following engagement of the iTCR, iNKTs rapidly secrete copious amounts of Th1 and Th2 cytokines and promote the functions of several immune cells including NK, T, B and dendritic cells. Accordingly, iNKTs bridge the innate and adaptive immune responses and modulate susceptibility to autoimmunity, infection, allergy and cancer. Allogeneic hematopoietic stem cell transplantation (HSCT) is one of the most effective treatments for patients with hematologic malignancies. However, the beneficial graft versus leukemia (GvL) effect mediated by the conventional T cells contained within the allograft is often hampered by the concurrent occurrence of graft versus host disease (GvHD). Thus, developing strategies that can dissociate GvHD from GvL remain clinically challenging. Several preclinical and clinical studies demonstrate that iNKTs significantly attenuate GvHD without abrogating the GvL effect. Besides preserving the GvL activity of the donor graft, iNKTs themselves exert antitumor immune responses via direct and indirect mechanisms. Herein, we review the various mechanisms by which iNKTs provide antitumor immunity and discuss their roles in GvHD suppression. We also highlight the opportunities and obstacles in manipulating iNKTs for use in the cellular therapy of hematologic malignancies. PMID:26878658

  6. Establishment and application of a highly sensitive coupled luminescent method (CLM) to study natural killer cell cytolytic activity

    OpenAIRE

    Ogbomo, Henry

    2008-01-01

    Natural killer (NK) cells are white blood lymphocytes of the innate immune system that have diverse biological functions, including recognition and destruction of certain microbial infections and neoplasms [1]. NK cells comprise ~ 10% of all circulating lymphocytes and are also found in peripheral tissues including the liver, peritoneal cavity and placenta. Resting NK cells circulate in the blood, but, following activation by cytokines, they are capable of extravasation and infiltration into ...

  7. Effects of ultraviolet irradiation on natural killer cell function in systemic lupus erythematosus

    International Nuclear Information System (INIS)

    In vitro irradiation with long wavelength ultraviolet light (UV-A), in clinically relevant dosages, of a natural killer cell line containing cell preparations from 17 control subjects reduced natural killer cell cytotoxicity with the cell line K562 as target. The spontaneous function of natural killer cells from 12 patients with systematic lupus erythematosus (SLE) correlated inversely with the one hour erythrocyte sedimentation rate, but not with glucocorticoid doses. After UV-A exposure, natural killer cells from patients with SLE exert either increased or decreased cytotoxicity, and the direction of change is inversely correlated with the spontaneous natural killer cell function. (Author)

  8. Impaired cytotoxicity associated with defective natural killer cell differentiation in myelodysplastic syndromes.

    Science.gov (United States)

    Hejazi, Maryam; Manser, Angela R; Fröbel, Julia; Kündgen, Andrea; Zhao, Xiaoyi; Schönberg, Kathrin; Germing, Ulrich; Haas, Rainer; Gattermann, Norbert; Uhrberg, Markus

    2015-05-01

    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. In the second subgroup, comprising the majority of patients (76%), natural killer cells were present but exhibited poor cytotoxicity. The defect was strongly associated with reduced levels of perforin and granzyme B. Notably, natural killer cell function and arming of cytotoxic granules could be fully reconstituted by in vitro stimulation. Further phenotypic analysis of these patients revealed an immature natural killer cell compartment that was biased towards CD56(bright) cells. The residual CD56(dim) cells exhibited a significant increase of the unlicensed NKG2A(-)KIR(-) subset and a striking reduction in complexity of the repertoire of killer cell immunoglobulin-like receptors. Taken together, these results suggest that the widespread defects in natural killer cell function occurring in patients with myelodysplastic syndromes are mostly due to either unsuccessful or inefficient generation of mature, functionally competent natural killer cells, which might contribute to disease progression through impaired immune surveillance. PMID:25682594

  9. Uterine Natural Killer Cells: Their Choices, Their Missions

    Institute of Scientific and Technical Information of China (English)

    Jianhong Zhang; B Anne Croy; Zhigang Tian

    2005-01-01

    Uterine natural killer (uNK) cells, sharing many characters with peripheral blood natural killer (pNK) cells, are a major uterine lymphocyte population at early gestational stages during normal pregnancy in placental mammals.The functions of uNK cells include cytokine production and cytotoxcity that are regulated by signals through activating and inhibitory receptors. UNK cells differ from pNK cells however and contribute to the structural changes that accompany the differentiation of the maternal-fetal interface. Immunological mechanisms must provide a balanced environment for uNK cell proliferation, differentiation and activation through intricate signaling pathways. An improved knowledge of mechanisms regulating uNK cells development and the cytokine network at the maternal-fetal interface of mice and humans might be useful to harness the power of these cells for maintenance of pregnancy. Cellular & Molecular Immunology. 2005;2(2):123-129.

  10. Role of inositol phospholipid signaling in natural killer cell biology

    OpenAIRE

    Gumbleton, Matthew; Kerr, William G.

    2013-01-01

    Natural killer (NK) cells are important for host defense against malignancy and infection. At a cellular level NK cells are activated when signals from activating receptors exceed signaling from inhibitory receptors. At a molecular level NK cells undergo an education process to both prevent autoimmunity and acquire lytic capacity. Mouse models have shown important roles for inositol phospholipid signaling in lymphocytes. NK cells from mice with deletion in different members of the inositol ph...

  11. STAT4-associated natural killer cell tolerance following liver transplantation

    OpenAIRE

    Jamil, K M; Hydes, T.J.; Cheent, K.S.; Cassidy, S A; Traherne, J. A.; Jayaraman, J.; Trowsdale, J.; Alexander, G J; Little, A M; McFarlane, H.; Heneghan, M. A.; Purbhoo, M.A.; Khakoo, S I

    2016-01-01

    Objective: Natural killer (NK) cells are important mediators of liver inflammation in chronic liver disease. The aim of this study was to investigate why liver transplants (LTs) are not rejected by NK cells in the absence of human leukocyte antigen (HLA) matching, and to identify a tolerogenic NK cell phenotype. Design: Phenotypic and functional analyses on NK cells from 54 LT recipients were performed, and comparisons made with healthy controls. Further investigation was performed using ...

  12. Polyfunctionality of natural killer cell in healthy donors

    OpenAIRE

    Yupanun WUTTI-IN; Preeyanat VONGCHAN; Thananchai, Hathairat

    2016-01-01

    Background: Natural killer (NK) cells are important guards of the innate immune system, which act by performing as primary effector cells in viral infections. NK cell function is regulated by the engagement of activating and/or inhibitory receptors on individual NK cell surfaces. Subsequent to activation, the release of preformed cytolytic granules or cytokines occurs. Recently, the polyfunctionality of NK cells has been described as a potent NK cell subset that mediates antiviral response in...

  13. Neutrophil depletion impairs natural killer cell maturation, function, and homeostasis

    OpenAIRE

    Jaeger, B. N.; Donadieu, J.; Cognet, C.; Bernat, C.; Ordonez-Rueda, D.; Barlogis, V.; Mahlaoui, N.; Fenis, A.; Narni-Mancinelli, E.; Beaupain, B.; Bellanne-Chantelot, C.; Bajenoff, M.; Malissen, B.; Malissen, M; Vivier, E.

    2012-01-01

    Natural killer (NK) cells are bone marrow (BM)–derived granular lymphocytes involved in immune defense against microbial infections and tumors. In an N-ethyl N-nitrosourea (ENU) mutagenesis strategy, we identified a mouse mutant with impaired NK cell reactivity both in vitro and in vivo. Dissection of this phenotype showed that mature neutrophils were required both in the BM and in the periphery for proper NK cell development. In mice lacking neutrophils, NK cells displayed hyperproliferation...

  14. Natural killer cells in non-hematopoietic malignancies

    OpenAIRE

    Desbois, Mélanie; Rusakiewicz, Sylvie; Locher, Clara; Zitvogel, Laurence; Chaput, Nathalie

    2012-01-01

    Natural killer (NK) cells belong to the innate immune system and were initially described functionallywise by their spontaneous cytotoxic potential against transformed or virus-infected cells. A delicate balance between activating and inhibiting receptors regulates NK cell tolerance. A better understanding of tissue resident NK cells, of NK cell maturation stages and migration patterns has evolved allowing a thoughtful evaluation of their modus operandi. While evidence has been brought up for...

  15. Revving up natural killer cells and cytokine-induced killer cells against hematological malignancies

    Directory of Open Access Journals (Sweden)

    Gianfranco ePittari

    2015-05-01

    Full Text Available Natural killer (NK cells belong to innate immunity and exhibit cytolytic activity against infectious pathogens and tumor cells. NK-cell function is finely tuned by receptors that transduce inhibitory or activating signals, such as killer immunoglobulin-like receptors (KIR, NK Group 2 member D (NKG2D, NKG2A/CD94, NKp46 and others, and recognize both foreign and self-antigens expressed by NK-susceptible targets. Recent insights into NK-cell developmental intermediates have translated into a more accurate definition of culture conditions for the in vitro generation and propagation of human NK cells. In this respect, interleukin (IL-15 and IL-21 are instrumental in driving NK-cell differentiation and maturation, and hold great promise for the design of optimal NK-cell culture protocols.Cytokine-induced killer (CIK cells possess phenotypic and functional hallmarks of both T cells and NK cells. Similar to T cells, they express CD3 and are expandable in culture, while not requiring functional priming for in vivo activity, like NK cells. CIK cells may offer some advantages over other cell therapy products, including ease of in vitro propagation and no need for exogenous administration of IL-2 for in vivo priming.NK cells and CIK cells can be expanded using a variety of clinical-grade approaches, before their infusion into patients with cancer. Herein, we discuss GMP-compliant strategies to isolate and expand human NK and CIK cells for immunotherapy purposes, focusing on clinical trials of adoptive transfer to patients with hematological malignancies.

  16. Monkeypox Virus Infection of Rhesus Macaques Induces Massive Expansion of Natural Killer Cells but Suppresses Natural Killer Cell Functions

    OpenAIRE

    Song, Haifeng; Josleyn, Nicole; Janosko, Krisztina; Skinner, Jeff; Reeves, R. Keith; Cohen, Melanie; Jett, Catherine; Johnson, Reed; Blaney, Joseph E.; Bollinger, Laura; Jennings, Gerald; Jahrling, Peter B

    2013-01-01

    Natural killer (NK) cells play critical roles in innate immunity and in bridging innate and adaptive immune responses against viral infection. However, the response of NK cells to monkeypox virus (MPXV) infection is not well characterized. In this intravenous challenge study of MPXV infection in rhesus macaques (Macaca mulatta), we analyzed blood and lymph node NK cell changes in absolute cell numbers, cell proliferation, chemokine receptor expression, and cellular functions. Our results show...

  17. Present and future of allogeneic natural killer cell therapy

    Directory of Open Access Journals (Sweden)

    Okjae eLim

    2015-06-01

    Full Text Available Natural killer (NK cells are innate lymphocytes that are capable of eliminating tumor cells and are therefore used for cancer therapy. Although many early investigators used autologous NK cells, including lymphokine-activated killer cells, the clinical efficacies were not satisfactory. Meanwhile, human leukocyte antigen (HLA-haploidentical hematopoietic stem cell transplantation revealed the anti-tumor effect of allogeneic NK cells, and HLA-haploidentical, killer cell immunoglobulin-like receptor (KIR ligand-mismatched allogeneic NK cells are currently used for many protocols requiring NK cells. Moreover, allogeneic NK cells from non-HLA-related healthy donors have been recently used in cancer therapy. The use of allogeneic NK cells from non-HLA-related healthy donors allows the selection of donor NK cells with higher flexibility and to prepare expanded, cryopreserved NK cells for instant administration without delay for ex vivo expansion. In cancer therapy with allogeneic NK cells, optimal matching of donors and recipients is important to maximize the efficacy of the therapy. In this review, we summarize the present state of allogeneic NK cell therapy and its future directions.

  18. Natural killer T-cell lymphoma originating from the orbit

    Institute of Scientific and Technical Information of China (English)

    DAI Wei; ZHONG Ming; SHEN Wei; ZOU Ke; BAI Chen-guang

    2012-01-01

    Natural killer T-cell lymphoma (NKTL) is a malignant neoplasm which usually involves the nasal cavity or paranasal sinuses,while an orbit origin is extremely rare.Here we report the clinical,radiological and histopathologic features of a patient with NKTL originating from the orbit.We analyzed the clinical and radiologic records in the whole course of the disease.We also reviewed the morphology and immunohistochemistry of the neoplasm biopsy,including the presence of CD56,CD3 and cytotoxic molecules.This case demonstrated that nasal-type NKTL with a poor prognosis can originate from the orbit.

  19. Invariant natural killer T cell–natural killer cell interactions dictate transplantation outcome after α-galactosylceramide administration

    OpenAIRE

    Kuns, Rachel D.; Morris, Edward S.; MacDonald, Kelli P.A.; Markey, Kate A.; Helen M. Morris; Raffelt, Neil C.; Banovic, Tatjana; Don, Alistair L. J.; Rowe, Vanessa; Burman, Angela C.; Clouston, Andrew D; Farah, Camile; Besra, Gurdyal S.; Illarionov, Petr A.; Smyth, Mark J

    2009-01-01

    Invariant natural killer T cells (iNKT cells) have pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. iNKT cells are activated through their T-cell receptors by glycolipid moieties (typically the α-galactosylceramide [α-GalCer] derivative KRN7000) presented within CD1d. We investigated the ability of modified α-GalCer molecules to differentially modulate alloreactivity and GVL. KRN7000 and the N-acyl variant, C20:2, were administered in multiple well-es...

  20. Examples of natural circulation in PHWR

    International Nuclear Information System (INIS)

    The main objective of this lecture is to provide deep insight into the complex natural circulation phenomena in the core of a Pressurised Heavy Water Reactor. A detailed account of natural circulation tests conducted in an Indian PHWR is given in this lecture. This will enable the participants to appreciate the importance of natural circulation in a nuclear reactor to a greater extent. (author)

  1. Natural circulation systems: advantages and challenges

    International Nuclear Information System (INIS)

    This lecture briefly explains the principle of working of a natural circulation system, its various advantages and applications in nuclear and other industries. The major challenges to be overcome before the wide acceptance of natural circulation as the normal mode of coolant circulation in nuclear power reactors are briefly described. Classification of NCSs and the terminologies commonly encountered in natural circulation literature are also briefly explained. (author)

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  10. Impact of polysialylated CD56 on natural killer cell cytotoxicity

    Directory of Open Access Journals (Sweden)

    Kaltschmidt Christian

    2007-08-01

    Full Text Available Abstract Background Siglec-7, a sialic acid binding inhibitory receptor expressed by NK cells is masked in vivo by a so far unknown ligand. It shows a strong binding prevalence for α-2,8-linked disialic acids in vitro. Results Here we describe the expression of PSA-NCAM (α-2,8-linked polysialic acid modified NCAM on functional adult peripheral blood natural killer cells and examine its possible role in masking Siglec-7. Unmasking of Siglec-7 using Clostridium perfringens neuraminidase massively reduces NK cell cytotoxicity. By contrast a specific removal of PSA using Endo-NF does not lead to a reduction of NK cell cytotoxicity. Conclusion The results presented here therefore indicate that PSA-NCAM is not involved in masking Siglec-7.

  11. Prolonged treatment response in aggressive natural killer cell leukemia.

    Science.gov (United States)

    Osuji, N; Matutes, E; Morilla, A; Del Giudice, I; Wotherspoon, A; Catovsky, D

    2005-05-01

    We describe a case of natural killer (NK) cell leukemia with acute presentation, systemic symptoms and hepatosplenomegaly. The uniform and aberrant phenotype of NK cells with infiltration of bone marrow and spleen was in keeping with a malignant diagnosis. Aggressive presentation was demonstrated by marked constitutional symptoms and significant tumor burden (liver, spleen, blood, bone marrow). The subsequent clinical course has been indolent, but this may have been influenced by treatment. Treatment consisted sequentially of splenectomy, intravenous pentostatin and the combination of cyclosporine A and recombinant human erythropoietin and has resulted in survival of over 48 months. We discuss the difficulties in the diagnosis of this condition, explore possible causes of cytopenia(s), and highlight the role of immunosuppression in controlling disease manifestations in large granular lymphocyte proliferative disorders. PMID:16019515

  12. Natural killer cells: walking three paths down memory lane.

    Science.gov (United States)

    Min-Oo, Gundula; Kamimura, Yosuke; Hendricks, Deborah W; Nabekura, Tsukasa; Lanier, Lewis L

    2013-06-01

    Immunological memory has traditionally been regarded as a unique feature of the adaptive immune response, mediated in an antigen-specific manner by T and B lymphocytes. All other hematopoietic cells, including natural killer (NK) cells, are classified as innate immune cells, which have been considered short-lived but can respond rapidly against pathogens in a manner not thought to be driven by antigen. Interestingly, NK cells have recently been shown to survive long term after antigen exposure and subsequently mediate antigen-specific recall responses. In this review, we address the similarities between, and the controversies surrounding, three major viewpoints of NK memory that have arisen from these recent studies: (i) mouse cytomegalovirus (MCMV)-induced memory; (ii) cytokine-induced memory; and (iii) liver-restricted memory cells. PMID:23499559

  13. Activation of Natural Killer cells during microbial infections

    Directory of Open Access Journals (Sweden)

    Amir eHorowitz

    2012-01-01

    Full Text Available Natural killer (NK cells are large granular lymphocytes that express a diverse array of germline encoded inhibitory and activating receptors for MHC Class I and Class I-like molecules, classical co-stimulatory ligands and cytokines. The ability of NK cells to be very rapidly activated by inflammatory cytokines, to secrete effector cytokines and to kill infected or stressed host cells, suggests that they may be among the very early responders during infection. Recent studies have also identified a small number of pathogen-derived ligands that can bind to NK cell surface receptors and directly induce their activation. Here we review recent studies that have begun to elucidate the various pathways by which viral, bacterial and parasite pathogens activate NK cells. We also consider two emerging themes of NK cell-pathogen interactions, namely their contribution to adaptive immune responses and their potential to take on regulatory and immunomodulatory functions.

  14. Distribution of natural killer cell receptors in HIV infected individuals

    Institute of Scientific and Technical Information of China (English)

    JIANG Yong-jun; SHANG Hong; ZHANG Zi-ning; DIAO Ying-ying; GENG Wen-qing; DAI Di; LIU Jing; WANG Ya-nan; ZHANG Min; HAN Xiao-xu

    2007-01-01

    @@ Natural killer (NK) cells are bone marrow derived,large granular lymphocytes, comprising approximately 10% to 20% of the mononuclear cell fraction in normal peripheral blood. They form a part of the first line defense mechanism against tumoural and viral spreading.1-4 Unlike T and B cells, NK cells do not require gene rearrangement for assembly of their receptor genes; rather, NK cells discriminate potential target cells based on the levels of self major histocompatibility complex (MHC) class Ⅰ expression on such cells.5,6 There are two kinds of NK cell receptors.2,7,8 Inhibitory receptors recognize MHC class Ⅰ molecules and deliver a downregulatory signal that inactivates the lyric machinery of NK cells. Stimulatory receptors expressed by NK cells deliver an activation signal.

  15. Regulation of Natural Killer Cell Function by STAT3

    Directory of Open Access Journals (Sweden)

    Nicholas eCacalano

    2016-04-01

    Full Text Available Natural killer (NK cells, key members of a distinct hempatopoietic lineage, innate lymphoid cells (ILCs, are critical effectors that mediate cytotoxicity toward tumor and virally-infected cells but also regulate inflammation, antigen presentation and the adaptive immune response. It has been shown that NK cells can regulate the development and activation of many other components of the immune response such as dendritic cells, which in turn, modulate the function of NK cells in multiple synergistic feed back loops driven by cell-cell contact and the secretion of cytokines and chemokines that control effector function and migration of cells to sites of immune activation. The Signal Transducer and Activator of Transcription (STAT-3 is involved in driving almost all of the pathways that control NK cytolytic activity as well as the reciprocal regulatory interactions between NK cells and other components of the immune system. In the context of tumor immunology, NK cells are a first line of defense that eliminates pre-cancerous and transformed cells early in the process of carcinogenesis, through a mechanism of immune surveillance. Even after tumors become established, NK cells are critical components of anti-cancer immunity: dysfunctional NK cells are often found in the peripheral blood of cancer patients and the lack of NK cells in the tumor microenvironment often correlates with poor prognosis. The pathways and soluble factors activated in tumor-associated NK cells, cancer cells, and regulatory myeloid cells which determine the outcome of cancer immunity are all critically regulated by STAT3. Using the tumor microenvironment as a paradigm, we present here an overview of the research that has revealed fundamental mechanisms through which STAT3 regulates all aspects of natural killer cell biology, including NK development, activation, target cell killing, and fine tuning of the innate and adaptive immune responses.

  16. Quantitation of natural killer cell precursors in man.

    Science.gov (United States)

    Gharehbaghian, Ahmad; Haque, K M Gausul; Truman, Carol; Newman, John; Bradley, Benjamin A

    2002-02-01

    A technique was developed to measure the frequency of natural killer cell precursors (NKpf) in human peripheral blood mononuclear cell (PBMC) samples. Functional maturity of NK cells was reflected in their ability to lyse target cells from the K562 cell line. During the development of the technique, venous blood was taken from one healthy adult and assayed at different times to avoid individual variation. The technique was based on the principle of limiting dilution analysis. The NKpf assay was set up with a range of cell dilutions from 40,000 to 625 per 100 microl/well in 96-well culture plates. At the end of the culture period, the K562 cell line labelled with europium (Eu-K562) was added and the Eu-release was measured in culture supernatants using time-resolved fluorometry. The NKpf value differed between individuals and was influenced by the length of time in culture, being maximal at day 5. Maturation of NKp required the continuous presence of recombinant interleukin 2 (rIL-2), or rIL-15, both being equally effective. In the absence of cytokines, the functional NK cells declined rapidly beyond 24 h in culture. Irradiated allogeneic cells appeared to substitute in part for cytokines, but the numbers of allo-activated NKpf were lower than those observed when allo-activated NKpf were cultured with rIL-2. This suggested selective activation by the allogeneic stimulus of subsets of NKp or rIL-2-rescue of NKp subsets destined for apoptotic cell death. Alternatively, the increased frequency could have been attributable to activation of precursors of natural killer-T cells (NK-Tp). This assay is suitable for estimating the total number of precursors of functional NK cells in the blood of patients. PMID:11792377

  17. Natural killer cells: Biology, functions and clinical relevance

    Directory of Open Access Journals (Sweden)

    Vojvodić Svetlana

    2010-01-01

    Full Text Available Introduction. Natural Killer cells (NK cells represent the subset of peripheral lymphocytes that play critical role in the innate immune response to virus-infected and tumor transformed cells. Lysis of NK sensitive target cells could be mediated independently of antigen stimulation and without requirement of peptide presentation by the major histocompatibility complex (MHC molecules. NK cell activity and functions are controlled by a considerable number of cell surface receptors, which exist in both inhibitory and activating isoforms. There are several groups of NK cell surface receptors: 1 killer immunoglobulin like receptors-KIR, 2 C-type lectin receptors,3natural citotoxicity receptors-NCR and 4 Toll-like receptors-TLR. Functions of NK receptors. Defining the biology of NK cell surface receptors has contributed to the concept of the manner how NK cells selectively recognize and lyse tumor and virally infected cells while sparing normal cells. Further, identification of NK receptor ligands and their expression on the normal and transformed cells has led to the development of clinical approaches to manipulating receptor/ligand interactions that showed clinical benefit. NK cells are the first lymphocyte subset that reconstitute the peripheral blood following allogeneic HSCT and multiple roles for alloreactive donor NK cells have been demonstrated, in diminishing Graft vs. Host Disease (GvHD through selective killing recipient dendritic cells, prevention of graft rejection by killing recipient T cells and participation in Graft vs. Leukaemia (GvL effect through destruction of residual host tumor cells. Conclusion. Besides their role in HSCT, NK cell receptors have an important clinical relevance that reflects from the fact that they play a crucial role in the development of some diseases as well as in possibilities of managing all NK receptors through selective expansion and usage of NK cells in cancer immunotherapy.

  18. HPV vaccine stimulates cytotoxic activity of killer dendritic cells and natural killer cells against HPV-positive tumour cells

    OpenAIRE

    Van den Bergh, Johan M J; Guerti, Khadija; Willemen, Yannick; Lion, Eva; Cools, Nathalie; Goossens, Herman; Vorsters, Alex; Van Tendeloo, Viggo F.I.; Anguille, Sébastien; Van Damme, Pierre; Smits, Evelien L. J. M.

    2014-01-01

    Cervarix™ is approved as a preventive vaccine against infection with the human papillomavirus (HPV) strains 16 and 18, which are causally related to the development of cervical cancer. We are the first to investigate in vitro the effects of this HPV vaccine on interleukin (IL)-15 dendritic cells (DC) as proxy of a naturally occurring subset of blood DC, and natural killer (NK) cells, two innate immune cell types that play an important role in antitumour immunity. Our results show that exposur...

  19. Tissue detection of natural killer cells in colorectal adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Patsouris Efstratios S

    2004-09-01

    Full Text Available Abstract Background Natural killer (NK cells represent a first line of defence against a developing cancer; however, their exact role in colorectal cancer remains undetermined. The aim of the present study was to evaluate the expression of CD16 and CD57 [immunohistochemical markers of natural NK cells] in colorectal adenocarcinoma. Methods Presence of NK cells was investigated in 82 colorectal adenocarcinomas. Immunohistochemical analysis was performed, using 2 monoclonal antibodies (anti-Fc Gamma Receptor II, CD16 and an equivalent to Leu-7, specific for CD-57. The number of immunopositive cells (% was evaluated by image analysis. The cases were characterized according to: patient gender and age, tumor location, size, grade, bowel wall invasion, lymph node metastases and Dukes' stage. Results NK cells were detected in 79/82 cases at the primary tumor site, 27/33 metastatic lymph nodes and 3/4 hepatic metastases; they were detected in levels similar to those reported in the literature, but their presence was not correlated to the clinical or pathological characteristics of the series, except for a negative association with the patients' age (p = 0.031. Conclusions Our data do not support an association of NK cell tissue presence with clinical or pathological variables of colorectal adenocarcinoma, except for a negative association with the patients' age; this might possibly be attributed to decreased adhesion molecule expression in older ages.

  20. Aggressive natural killer-cell leukemia: Classical presentation of a rare disease

    Directory of Open Access Journals (Sweden)

    Priya M Jacob

    2014-01-01

    Full Text Available Aggressive natural killer-cell leukaemia is a rare aggressive form of natural killer-cell neoplasm. We report a case of a 40-year-old male who presented with jaundice, raised blood counts,generalised lymphadenopathy and hepatosplenomegaly. The diagnosis was established by flow cytometric analysis of bone marrow aspirate. The patient, however, succumbed to his illness within 2 weeks of starting chemotherapy. To the best of our knowledge, this is the third reported case from India.

  1. The DNA methylation profile of activated human natural killer cells.

    Science.gov (United States)

    Wiencke, John K; Butler, Rondi; Hsuang, George; Eliot, Melissa; Kim, Stephanie; Sepulveda, Manuel A; Siegel, Derick; Houseman, E Andres; Kelsey, Karl T

    2016-05-01

    Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in naïve NK, T- and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states. PMID:26967308

  2. Advantages and Applications of CAR-Expressing Natural Killer Cells

    Directory of Open Access Journals (Sweden)

    Wolfgang eGlienke

    2015-02-01

    Full Text Available In contrast to donor T cells, natural killer (NK cells are known to mediate anti-cancer effects without the risk of inducing graft-versus-host disease (GvHD. In order to improve cytotoxicity against resistant cancer cells, auspicious efforts have been made with chimeric antigen receptor (CAR expressing T- and NK cells. These CAR-modified cells express antigen receptors against tumor-associated surface antigens, thus redirecting the effector cells and enhancing tumor-specific immunosurveillance. However, many cancer antigens are also expressed on healthy tissues, potentially leading to off tumor/ on target toxicity by CAR-engineered cells. In order to control such potentially severe side effects, the insertion of suicide genes into CAR-modified effectors can provide a means for efficient depletion of these cells. While CAR-expressing T cells have entered successfully clinical trials, experience with CAR-engineered NK cells is mainly restricted to pre-clinical investigations and predominantly to NK cell lines. In this review we summarize the data on CAR expressing NK cells focusing on the possible advantage using these short-lived effector cells and discuss the necessity of suicide switches. Furthermore, we address the compliance of such modified NK cells with regulatory requirements as a new field in cellular immunotherapy.

  3. Involvement of LSECtin in the hepatic natural killer cell response.

    Science.gov (United States)

    Yang, Juntao; Wang, He; Wang, Min; Liu, Biao; Xu, Hui; Xu, Feng; Zhao, Dianyuan; Hu, Bin; Zhao, Na; Wang, Junyi; Liu, Di; Tang, Li; He, Fuchu

    2016-07-15

    Accumulating evidence has indicated that natural killer cells (NK cells) play an important role in immune responses generated in the liver. However, the underlying molecular basis for local immune regulation is poorly understood. Mice were intraperitoneally injected with polyinosinic-polycytidylic acid (PolyI:C) at a dose of 20 mg/kg body wt. The percentage and absolute number of NK cells in the liver were analysed with flow cytometry. LSECtin knockout mice and LSECtin cDNA plasmids were used for analyze the role of LSECtin in hepatic NK cell regulation in vivo. Here, we show that the C-type lectin LSECtin, a member of the DC-SIGN family, is a novel liver regulator for NK cells. LSECtin could bind to NK cells in a carbohydrate-dependent manner and could regulate the number of hepatic NK cells. In the NK cell-mediated acute liver injury model induced with PolyI:C, the exogenous expression of LSECtin accelerated NK cell-induced liver injury, whereas the absence of LSECtin ameliorated this condition. Our results reveal that LSECtin is a novel, liver-specific NK cell regulator that may be a target for the treatment of inflammatory diseases in the liver. PMID:27184407

  4. Natural killer cell mediated cytotoxic responses in the Tasmanian devil.

    Science.gov (United States)

    Brown, Gabriella K; Kreiss, Alexandre; Lyons, A Bruce; Woods, Gregory M

    2011-01-01

    The Tasmanian devil (Sarcophilus harrisii), the world's largest marsupial carnivore, is under threat of extinction following the emergence of an infectious cancer. Devil facial tumour disease (DFTD) is spread between Tasmanian devils during biting. The disease is consistently fatal and devils succumb without developing a protective immune response. The aim of this study was to determine if Tasmanian devils were capable of forming cytotoxic antitumour responses and develop antibodies against DFTD cells and foreign tumour cells. The two Tasmanian devils immunised with irradiated DFTD cells did not form cytotoxic or humoral responses against DFTD cells, even after multiple immunisations. However, following immunisation with xenogenic K562 cells, devils did produce cytotoxic responses and antibodies against this foreign tumour cell line. The cytotoxicity appeared to occur through the activity of natural killer (NK) cells in an antibody dependent manner. Classical NK cell responses, such as innate killing of DFTD and foreign cancer cells, were not observed. Cells with an NK-like phenotype comprised approximately 4 percent of peripheral blood mononuclear cells. The results of this study suggest that Tasmanian devils have NK cells with functional cytotoxic pathways. Although devil NK cells do not directly recognise DFTD cancer cells, the development of antibody dependent cell-mediated cytotoxicity presents a potential pathway to induce cytotoxic responses against the disease. These findings have positive implications for future DFTD vaccine research. PMID:21957452

  5. Natural Killer Cells: Biology and Clinical Use in Cancer Therapy

    Institute of Scientific and Technical Information of China (English)

    William H. D. Hallett; William J. Murphy

    2004-01-01

    Natural killer (NK) cells have the ability to mediate both bone marrow rejection and promote engraftment, as well as the ability to elicit potent anti-tumor effects. However the clinical results for these processes are still elusive. Greater understanding of NK cell biology, from activating and inhibitory receptor functions to the role of NK cells in allogeneic transplantation, needs to be appreciated in order to draw out the clinical potential of NK cells. Mechanisms of bone marrow cell (BMC) rejection are known to be dependant on inhibitory receptors specific for major histocompatibility complex (MHC) molecules and on activating receptors that have many potential ligands. The modulation of activating and inhibitory receptors may hold the key to clinical success involving NK cells. Pre-clinical studies in mice have shown that different combinations of activating and inhibitory receptors on NK cells can reduce graft-versus-host disease (GVHD), promote engraftment, and provide superior graft-versus-tumor (GVT) responses. Recent clinical data have shown that the use of KIR-ligand incompatibility produces tremendous graft-versus-leukemia effect in patients with acute myeloid leukemia at high risk of relapse. This review will attempt to be a synthesis of current knowledge concerning NK cells, their involvement in BMT, and their use as an immunotherapy for cancer and other hematologic malignancies. Cellular & Molecular Immunology. 2004;1(1):12-21.

  6. Neoadjuvant immunotherapy enhances radiosensitivity through natural killer cell activation.

    Science.gov (United States)

    Chi, Chau-Hwa; Wang, Yu-Shan; Yang, Chieh-Han; Chi, Kwan-Hwa

    2010-02-01

    We investigated whether natural killer (NK) cells in the tumor microenvironment have a radiosensitization effect. The radiosensitization effect of combined CpG and Herceptin((R)) (Genentech, Inc., South San Francisco, CA) (CpG/Herceptin), given before or after radiation, was evaluated by using a murine colon cancer cell line overexpressing human HER2/neu, CT26HER2/neu. In vitro radiosensitization effects were investigated by coculture of CT26HER2/neu with splenocytes, CpG, and Herceptin before applying radiation. Tumor cells, cocultured with CpG-pretreated splenocytes and Herceptin, were more vulnerable to radiation damage. In BALB/c mice injected with CT26HER2/neu, CpG/Herceptin administered before radiotherapy was associated with a better retardation of tumor growth than when administered after radiotherapy. The radiosensitization effect was significantly abrogated by NK-cell depletion, indicating that NK cells play an essential role in it. Further, surviving mice treated with CpG or CpG/Herceptin and reverse transcriptase were resistant to renewed tumor challenge, suggesting the presence of an induced immune response to the tumor. Neoadjuvant immunotherapy with CpG/Herceptin may improve response to radiotherapy of HER2/neu-expressing tumors. PMID:20187795

  7. Natural killer cells in non-hematopoietic malignancies.

    Science.gov (United States)

    Desbois, Mélanie; Rusakiewicz, Sylvie; Locher, Clara; Zitvogel, Laurence; Chaput, Nathalie

    2012-01-01

    Natural killer (NK) cells belong to the innate immune system and were initially described functionallywise by their spontaneous cytotoxic potential against transformed or virus-infected cells. A delicate balance between activating and inhibiting receptors regulates NK cell tolerance. A better understanding of tissue resident NK cells, of NK cell maturation stages and migration patterns has evolved allowing a thoughtful evaluation of their modus operandi. While evidence has been brought up for their relevance as gate keepers in some hematopoietic malignancies, the role of NK cells against progression and dissemination of solid tumors remains questionable. Hence, many studies pointed out the functional defects of the rare NK cell infiltrates found in tumor beds and the lack of efficacy of adoptively transferred NK cells in patients. However, several preclinical evidences suggest their anti-metastatic role in a variety of mouse tumor models. In the present review, we discuss NK cell functions according to their maturation stage and environmental milieu, the receptor/ligand interactions dictating tumor cell recognition and recapitulate translational studies aimed at deciphering their prognostic or predictive role against human solid malignancies. PMID:23269924

  8. THE KINETICS OF CYTOPLASMIC GRANULE SECRETION IN NATURAL KILLER CYTOTOXICITY

    Institute of Scientific and Technical Information of China (English)

    龚伊红; R.R.Hcrberman; C.W.Reynolds

    1994-01-01

    Antisexum against purified cytoplasmic granules from rat LGL tumor cells, and protein A-gold inmmnoelec-tron microscopy were used to study the secretory events in lysis of YAC-1 tumor cells by rat LGL tumor cells or by isolated LGL from normal rats. After 30 min incubation of effector and target cells together, gold-labeled cyto-plasmic granules were often seen concentrated in the area of the LGL adjacent to the ~ YAC-1 Within 60min,the grantees were observed to move to the cell border near the conjugazed site. At this point, fine granules were fused with file cell membrane, and subsequently released file gold-labeled contents into the junction between the LGL and the target cell. Gold particles could be seen at the B-T interface, on the surface,or sometimes on the target cell surface.These data provide direct evidence for the hypothesis that under conditions of active cytotoxicity,natural killer cells secrete their cytoplasmic granule contents leading to the deposition of granule material on the target cell surface and the eventual lysis of the cell.

  9. Id2 regulates hyporesponsive invariant natural killer T cells

    Science.gov (United States)

    Stradner, Martin H; Cheung, Kitty P; Lasorella, Anna; Goldrath, Ananda W; D’Cruz, Louise M

    2016-01-01

    While the invariant natural killer T (iNKT)-cell response to primary stimulation with the glycolipid, α-galactosylceramide (αGalCer), is robust, the secondary response to this stimulus is muted resulting in a hyporesponsive state characterized by anti-inflammatory interleukin-10 (IL-10) production and high expression of programmed cell death 1 (PD1) and neuropilin 1 (NRP1). The E protein transcription factors and their negative regulators, the Id proteins, have previously been shown to regulate iNKT cell thymic development, subset differentiation and peripheral survival. Here, we provide evidence that the expression of the transcriptional regulator Id2 is downregulated upon stimulation of iNKT cells with their cognate antigen. Moreover, loss of Id2 expression by iNKT cells resulted in a hyporesponsive state, with splenic Id2-deficient iNKT cells expressing low levels of TBET, high levels of PD1 and NRP1 and production of IL-10 upon stimulation. We propose that downregulation of Id2 expression is an essential component of induction of the anti-inflammatory, hyporesponsive state in iNKT cells. PMID:26880074

  10. Introduction to instabilities in natural circulation systems

    International Nuclear Information System (INIS)

    This lecture reviews the various natural circulation instabilities and their classification instabilities observed during various stages of natural circulation such as single-phase, boiling inception and fully developed two-phase flow are described. The mechanisms causing the instabilities are also briefly described. (author)

  11. Deprivation of human natural killer cells and antitumor immune response

    Directory of Open Access Journals (Sweden)

    Vyacheslav Ogay

    2014-01-01

    Full Text Available Introduction: Cell-based immunotherapy has been given increased attention as a treatment for cancer. Human natural killer (NK cells are resident lymphocyte populations. They exhibit potent antitumor activity without human leukocyte antigen matching and without prior antigen exposure. They also are a promising tool for immunotherapy of solid and hematologic cancers. However, most cancer patients do not have enough NK cells to induce an effective antitumor immune response. This demonstrates a need for a source of NK cells that can supplement the endogenous cell population. Material and methods: In this study, we derived induced pluripotent stem cells (iPSCs from peripheral blood T-lymphocytes using Sendai virus vectors. Results: Generated iPSCs exhibited monoclonal T cell receptors (TCR rearrangement in their genome, a hallmark of mature terminally differentiated T cells. These iPSCs were differentiated into NK cells using a two-stage coculture system: iPSCs into hematopoietic CD34+ cells with feeder cells M210-B4 (ATCC, USA and CD34+ cells into mature NK cells with AFT024 cells (ATCC, USA. Our results showed that iPSC-derived NK cells expressed CD56, CD16, NKp 44 and NKp 46, possessed high cytotoxic activity  and produced high level of interferon-γ. Conclusion: Based on our data, derivation of NK cells from induced pluripotent stem cells should be considered in the treatment of oncologic diseases.This would allow for the development of cell therapy for cancer using immunologically compatible NK cells derived from iPSCs. This may contribute to a more efficient treatment of oncologic diseases in addition to traditional cancer treatment.

  12. Potassium channels mediate killing by human natural killer cells

    International Nuclear Information System (INIS)

    Human natural killer (NK) cells in peripheral blood spontaneously recognize and kill a wide variety of target cells. It has been suggested that ion channels are involved in the killing process because there is a Ca-dependent stage and because killing by presensitized cytotoxic T lymphocytes, which in many respects resembles NK killing, is associated with changes in K and Na transport in the target cell. Using the whole-cell variation of the patch-clamp technique, the authors found a voltage-dependent potassium (K+) current in NK cells. The K+ current was reduced in a dose-dependent manner by the K-channel blockers 4-aminopyridine and quinidine and by the traditional Ca-channel blockers verapamil and Cd2+. They tested the effects of ion-channel blockers on killing of two commonly used target cell lines: K562, which is derived from a human myeloid leukemia, and U937, which is derived from a human histiocytic leukemia. Killing of K562 target cells, determined in a standard 51Cr-release assay, was inhibited in a dose-dependent manner by verapamil, quinidine, Cd2+, and 4-aminopyridine at concentrations comparable to those that blocked the K+ current in NK cells. In K562 target cells only a voltage-dependent Na= current was found and it was blocked by concentrations of tetrodotoxin that had no effect on killing. Killing of U937 target cells was also inhibited by the two ion-channel blockers tested, quinidine and verapamil. In this cell line only a small K+ current was found that was similar to the one in NK cells. The findings show that there are K channels in NK cells and that these channels play a necessary role in the killing process

  13. Psychosocial resources, aging, and natural killer cell terminal maturity.

    Science.gov (United States)

    Segerstrom, Suzanne C; Al-Attar, Ahmad; Lutz, Charles T

    2012-12-01

    Psychosocial factors may influence aspects of immunological aging. The present study tested the hypothesis that psychosocial resources correlate with the expression of the cell surface maker CD57 on natural killer (NK) immune cells. CD57 is a marker of terminal maturation and senescence in this cell subset. The study further tested the relative contribution of specific resources in the social, psychological, financial, and status-skill domains, given the potential differential value of different resources for younger and older adults, and the contribution of relative versus absolute resources. Younger (n = 38) and older (n = 34) women completed measures of relative and absolute resources and had blood drawn. Examined both between groups and within the older women, older age and fewer total relative resources were associated with more CD57 expression on NK cells. One SD in resources was the equivalent of 5 years of aging among the older women. Among the specific resource types, a preponderance of financial resources, both relative and absolute, was associated with less CD57 expression on NK cells, and these relationships did not significantly vary between younger and older women. There was no evidence that depressive symptoms mediated the effects of resources on CD57 expression on NK cells. These findings provide support for the hypothesis that the sense that one has substantial resources, particularly with regard to finances and possessions, may retard age-associated aspects of the microenvironment in which NK cells develop and mature, independent of effects on distress, and this process may begin in younger adulthood. PMID:22708535

  14. Regulation of Natural Killer Cell Function by STAT3

    Science.gov (United States)

    Cacalano, Nicholas A.

    2016-01-01

    Natural killer (NK) cells, key members of a distinct hematopoietic lineage, innate lymphoid cells, are not only critical effectors that mediate cytotoxicity toward tumor and virally infected cells but also regulate inflammation, antigen presentation, and the adaptive immune response. It has been shown that NK cells can regulate the development and activation of many other components of the immune response, such as dendritic cells, which in turn, modulate the function of NK cells in multiple synergistic feed back loops driven by cell–cell contact, and the secretion of cytokines and chemokines that control effector function and migration of cells to sites of immune activation. The signal transducer and activator of transcription (STAT)-3 is involved in driving almost all of the pathways that control NK cytolytic activity as well as the reciprocal regulatory interactions between NK cells and other components of the immune system. In the context of tumor immunology, NK cells are a first line of defense that eliminates pre-cancerous and transformed cells early in the process of carcinogenesis, through a mechanism of “immune surveillance.” Even after tumors become established, NK cells are critical components of anticancer immunity: dysfunctional NK cells are often found in the peripheral blood of cancer patients, and the lack of NK cells in the tumor microenvironment often correlates to poor prognosis. The pathways and soluble factors activated in tumor-associated NK cells, cancer cells, and regulatory myeloid cells, which determine the outcome of cancer immunity, are all critically regulated by STAT3. Using the tumor microenvironment as a paradigm, we present here an overview of the research that has revealed fundamental mechanisms through which STAT3 regulates all aspects of NK cell biology, including NK development, activation, target cell killing, and fine tuning of the innate and adaptive immune responses.

  15. Natural Circulation Performance in Nuclear Power Plants

    International Nuclear Information System (INIS)

    The present paper deals with a study of natural circulation in PWR systems, The study consists of two parts: in the first one, natural circulation in experimental facilities simulating PWR plants was analyzed. This made it possible to gather a broad data base which was assumed as a reference for the subsequent part of the research. Seven Nuclear Power Plants nodalizations and additional experimental data from ''non-PWR'' facilities have been considered in the second part of the paper. Conclusions are drawn about natural circulation capabilities derived for the seven Nuclear Power Plants nodalizations and from data base pertinent to three ''non-PWR'' facilities. (author)

  16. Natural circulation performance in nuclear power plants

    International Nuclear Information System (INIS)

    The present paper deals with a study of natural circulation in PWR systems. The study consists of two parts: in the first one, natural circulation in experimental facilities simulating PWR plants was analysed. This made it possible to gather a broad data base which was assumed as a reference for the subsequent part of the research. Seven Nuclear Power Plants nodalization and additional experimental data from 'non-PWR' facilities have been considered in the second part of the paper. Conclusions are drawn about natural circulation capabilities derived for the seven Nuclear Power Plants nodalization and from data base pertinent to three 'non-PWR' facilities. (author)

  17. Local phenomena associated with natural circulation

    International Nuclear Information System (INIS)

    The objective of this lecture is to impart to the participants an adequate knowledge of various phenomena encountered in the natural circulation systems of a nuclear reactor. All the components of the primary system of a nuclear reactor are described and phenomena occurring in each of them are explained. A comprehensive coverage of related thermohydraulic relationships is provided which will enable the participants to carryout the process design of a natural circulation system. (author)

  18. Fractalkine expression induces endothelial progenitor cell lysis by natural killer cells.

    Directory of Open Access Journals (Sweden)

    Dilyana Todorova

    Full Text Available BACKGROUND: Circulating CD34(+ cells, a population that includes endothelial progenitors, participate in the maintenance of endothelial integrity. Better understanding of the mechanisms that regulate their survival is crucial to improve their regenerative activity in cardiovascular and renal diseases. Chemokine-receptor cross talk is critical in regulating cell homeostasis. We hypothesized that cell surface expression of the chemokine fractalkine (FKN could target progenitor cell injury by Natural Killer (NK cells, thereby limiting their availability for vascular repair. METHODOLOGY/PRINCIPAL FINDINGS: We show that CD34(+-derived Endothelial Colony Forming Cells (ECFC can express FKN in response to TNF-α and IFN-γ inflammatory cytokines and that FKN expression by ECFC stimulates NK cell adhesion, NK cell-mediated ECFC lysis and microparticles release in vitro. The specific involvement of membrane FKN in these processes was demonstrated using FKN-transfected ECFC and anti-FKN blocking antibody. FKN expression was also evidenced on circulating CD34(+ progenitor cells and was detected at higher frequency in kidney transplant recipients, when compared to healthy controls. The proportion of CD34(+ cells expressing FKN was identified as an independent variable inversely correlated to CD34(+ progenitor cell count. We further showed that treatment of CD34(+ circulating cells isolated from adult blood donors with transplant serum or TNF-α/IFN-γ can induce FKN expression. CONCLUSIONS: Our data highlights a novel mechanism by which FKN expression on CD34(+ progenitor cells may target their NK cell mediated killing and participate to their immune depletion in transplant recipients. Considering the numerous diseased contexts shown to promote FKN expression, our data identify FKN as a hallmark of altered progenitor cell homeostasis with potential implications in better evaluation of vascular repair in patients.

  19. Increased natural killer-cell mobilization and cytotoxicity during marital conflict.

    Science.gov (United States)

    Dopp, J M; Miller, G E; Myers, H F; Fahey, J L

    2000-03-01

    Natural killer (NK) cells are reproducibly mobilized into the circulation in response to intense physical exercise or acute psychological stress, and altered expression of adhesion molecules potentially contributes to NK-cell mobilization. Studies of leukocyte mobilization during acute stress have used psychological stressors which facilitate tight experimental control but have limited applicability to everyday life. We therefore used a laboratory model of marital conflict as an experientially meaningful acute stressor to elucidate relationships among conflict, cardiovascular reactivity, and altered leukocyte phenotype and function. Forty-one ethnically diverse, nondistressed, healthy married couples were asked to discuss a specific problem in their marriage for 15 min. Blood pressure and heart rate were measured before, during, and after the discussion, and blood was remotely drawn at the same time points to quantify numbers of specific leukocyte subsets, NK-cell adhesion molecule expression, and NK cytotoxicity. Couples responded to the conflict task with cardiovascular reactivity; increases in the percentages of circulating NK cells and CD8(+) T cells and decreases in the percentage of circulating CD4(+) T cells; decreases in the percentage of NK cells that express L-selectin; and increases in NK-cell cytotoxicity without a commensurate increase in per-cell cytotoxicity. Rapid downregulation or shedding of L-selectin (CD62L) from NK cells did not contribute to their mobilization during conflict. Instead, CD62L(-) NK cells were mobilized while CD62L(+) NK cells were selectively retained in the vascular marginating pool and/or in extravascular tissue. From a broader perspective, the data support the hypothesis that altered trafficking of specific leukocyte subsets is an integral component of the fight-or-flight response to an acute stressor. PMID:10729214

  20. Postoperative Regulatory T-Cells and Natural Killer Cells in Stage I Nonsmall Cell Lung Cancer Underwent Video-assisted Thoracoscopic Lobectomy or Thoracotomy

    OpenAIRE

    Sai Zhang; Sai-Bo Pan; Qing-Hua Lyu; Pin Wu; Guang-Ming Qin; Qi Wang; Zhong-Liang He; Xue-Ming He; Ming Wu; Gang Chen

    2015-01-01

    Background: Regulatory T-cells (Treg) play key roles in suppressing cell-mediated immunity in cancer patients. Little is known about perioperative Treg fluctuations in nonsmall cell lung cancer (NSCLC). Video-assisted thoracoscopic (VATS) lobectomy, as a minimal invasive procedure for treating NSCLC, may have relatively less impact on the patient′s immune system. This study aimed to observe perioperative dynamics of circulating Treg and natural killer (NK) cell levels in NSCLC patients who un...

  1. Recognition of microbial glycolipids by Natural Killer T cells

    Directory of Open Access Journals (Sweden)

    Dirk Michael Zajonc

    2015-08-01

    Full Text Available T cells can recognize microbial antigens when presented by dedicated antigen-presenting molecules. While peptides are presented by classical members of the Major Histocompatibility (MHC family (MHC I and II, lipids, glycolipids and lipopeptides can be presented by the non-classical MHC member CD1. The best studied subset of lipid-reactive T cells are Type I Natural killer T (iNKT cells that recognize a variety of different antigens when presented by the non-classical MHCI homolog CD1d. iNKT cells have been shown to be important for the protection against various microbial pathogens, including B. burgdorferi the causative agents of Lyme disease and S. pneumoniae, which causes pneumococcal meningitis and community-acquired pneumonia. Both pathogens carry microbial glycolipids that can trigger the T cell antigen receptor (TCR, leading to iNKT cell activation. iNKT cells have an evolutionary conserved TCR alpha chain, yet retain the ability to recognize structurally diverse glycolipids. They do so using a conserved recognition mode, in which the TCR enforces a conserved binding orientation on CD1d. TCR binding is accompanied by structural changes within the TCR binding site of CD1d, as well as the glycolipid antigen itself. In addition to direct recognition of microbial antigens, iNKT cells can also be activated by a combination of cytokines (IL-12/IL-18 and TCR stimulation. Many microbes carry TLR antigens and microbial infections can lead to TLR activation. The subsequent cytokine response in turn lower the threshold of TCR mediated iNKT cell activation, especially when weak microbial or even self-antigens are presented during the cause of the infection. In summary, iNKT cells can be directly activated through TCR triggering of strong antigens, while cytokines produced by the innate immune response may be necessary for TCR triggering and iNKT cell activation in the presence of weak antigens. Here we will review the molecular basis of iNKT cell

  2. Experimental and numerical investigation of natural circulation phenomena in a rectangular natural circulation loop

    International Nuclear Information System (INIS)

    Natural circulation is the key phenomena in the passive cooling systems. Thus, it is important to study the flow characteristics and heat transfer behavior in natural circulation. The natural circulation phenomena in steady state and transient form is investigated using 3D CFD simulations, carried out using OpenFoam 2.2.0. The first part consists of a steady-state study, in which the results are validated by data available from a set of experiments conducted over a range of heater power (130W-360W). The second part consists of a transient study of flow development and establishment of natural circulation within this loop. (author)

  3. Postoperative infection and natural killer cell function following blood transfusion in patients undergoing elective colorectal surgery

    DEFF Research Database (Denmark)

    Jensen, L S; Andersen, A J; Christiansen, P M;

    1992-01-01

    The frequency of infection in 197 patients undergoing elective colorectal surgery and having either no blood transfusion, transfusion with whole blood, or filtered blood free from leucocytes and platelets was investigated in a prospective randomized trial. Natural killer cell function was measured...... confidence interval 13-32 per cent), in one patient transfused with blood free from leucocytes and platelets (2 per cent, 95 per cent confidence interval 0.05-11 per cent) and in two non-transfused patients (2 per cent, 95 per cent confidence interval 0.3-8 per cent) (P less than 0.01). Natural killer cell...

  4. Linking CD11b+ Dendritic Cells and Natural Killer T Cells to Plaque Inflammation in Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Miche Rombouts

    2016-01-01

    Full Text Available Atherosclerosis remains the leading cause of death and disability in our Western society. To investigate whether the dynamics of leukocyte (subpopulations could be predictive for plaque inflammation during atherosclerosis, we analyzed innate and adaptive immune cell distributions in blood, plaques, and lymphoid tissue reservoirs in apolipoprotein E-deficient (ApoE−/− mice and in blood and plaques from patients undergoing endarterectomy. Firstly, there was predominance of the CD11b+ conventional dendritic cell (cDC subset in the plaque. Secondly, a strong inverse correlation was observed between CD11b+ cDC or natural killer T (NKT cells in blood and markers of inflammation in the plaque (including CD3, T-bet, CCR5, and CCR7. This indicates that circulating CD11b+ cDC and NKT cells show great potential to reflect the inflammatory status in the atherosclerotic plaque. Our results suggest that distinct changes in inflammatory cell dynamics may carry biomarker potential reflecting atherosclerotic lesion progression. This not only is crucial for a better understanding of the immunopathogenesis but also bares therapeutic potential, since immune cell-based therapies are emerging as a promising novel strategy in the battle against atherosclerosis and its associated comorbidities. The cDC-NKT cell interaction in atherosclerosis serves as a good candidate for future investigations.

  5. Self-association of an activating natural killer cell receptor, KIR2DS1.

    Science.gov (United States)

    Hayley, Michael; Bourbigot, Sarah; Booth, Valerie

    2011-01-01

    As a major component of the innate immune system, natural killer cells are responsible for activating the cytolytic killing of certain pathogen-infected or tumor cells. The self-recognition of natural killer cells is achieved in part by the killer cell immunoglobulin-like receptors (KIRs) protein family. In the current study, using a suite of biophysical methods, we investigate the self-association of an activating KIR, KIR2DS1. This KIR is of particular interest because when in the presence of the HLA-Cw6 protein, KIR2DS1 becomes a major risk factor for psoriasis, an autoimmune chronic skin disease. Using circular dichroism spectroscopy, dynamic light scattering, and atomic force microscopy, we reveal that KIR2DS1 self-associates in a well-defined fashion. Our novel results on an activating KIR allow us to suggest a working model for the KIR2DS1- HLA class I molecular mechanism. PMID:21912587

  6. Experimental study of the natural circulation phenomena

    International Nuclear Information System (INIS)

    The objective of this paper is to study the natural circulation in experimental loops and extend the results to nuclear facilities. New generation of compact nuclear power plants use the natural circulation as cooling and residual heat removal systems in case of accidents or shutdown. Lately the interest in this phenomenon, by scientific community, has increased. The experimental loop, described in this paper, was assembled at Escola Politecnica - USP at the Chemical Engineering Department. It is the goal to generate information to help with the understanding of the one and two phase natural circulation phenomena. Some experiments were performed with different levels of heat power and different flow of the cooling water at the secondary circuit. The data generated from these experiments are going to be used to validate some computational thermal hydraulic codes. Experimental results for one and two phase regimes are presented as well as the proposed model to simulate the flow regimes with the RELAP5 code. (author)

  7. Experimental study of natural circulation circuit

    Energy Technology Data Exchange (ETDEWEB)

    Lemos, Wanderley F.; Su, Jian, E-mail: wlemos@lasme.coppe.ufrj.br, E-mail: sujian@lasme.coppe.ufrj.br [Coordenacao dos Programas de Pos-Graduacao de Engenharia (LASME/COPPE/UFRJ), Rio de Janeiro, RJ (Brazil). Lab. de Simulacao e Metodos Numericos; Faccini, Jose L.H., E-mail: faccini@ien.gov.br [Instituto de Engenharia Nuclear (LTE/IEN/CNEN-RJ), Rio de Janeiro, RJ (Brazil). Lab. de Termo-Hidraulica Experimental

    2011-07-01

    This work presents an experimental study about fluid flows behavior in natural circulation, under conditions of single-phase flow. The experiment was performed through experimental thermal-hydraulic circuit built at IEN. This test equipment has performance similar to passive system of residual heat removal present in Advanced Pressurized Water Reactors (APWR). This experimental study aims to observing and analyzing the natural circulation phenomenon, using this experimental circuit that was dimensioned and built based on concepts of similarity and scale. This philosophy allows the analysis of natural circulation behavior in single-phase flow conditions proportionally to the functioning real conditions of a nuclear reactor. The experiment was performed through procedures to initialization of hydraulic feeding of primary and secondary circuits and electrical energizing of resistors installed inside heater. Power controller has availability to adjust values of electrical power to feeding resistors, in order to portray several conditions of energy decay of nuclear reactor in a steady state. Data acquisition system allows the measurement and monitoring of the evolution of the temperature in various points through thermocouples installed in strategic points along hydraulic circuit. The behavior of the natural circulation phenomenon was monitored by graphical interface on computer screen, showing the temperature evolutions of measuring points and results stored in digital spreadsheets. The results stored in digital spreadsheets allowed the getting of data to graphic construction and discussion about natural circulation phenomenon. Finally, the calculus of Reynolds number allowed the establishment for a correlation of friction in function of geometric scales of length, heights and cross section of tubing, considering a natural circulation flow throughout in the region of hot leg. (author)

  8. Scaling Analysis of Natural Circulation Flow Loop

    International Nuclear Information System (INIS)

    To improve the thermal margin for the severe accident measures in high-power reactors, engineered corium cooling systems involving boiling-induced two-phase natural circulation have been proposed for decay heat removal. The boiling-induced natural circulation flow is generated in a coolant path between a hot vessel wall and cold coolant reservoir. In general, an increase in the natural circulation mass flow rate of the coolant leads to an increase in the critical heat flux (CHF) on the hot wall, thus enhancing the thermal margin. An ex-vessel core catcher under consideration, which is one of the engineered corium cooling system, is a passive system consisting of an inclined engineered cooling channel made of a single channel between the body of the core catcher and the inside wall of the reactor cavity. Under severe accident conditions, water is supplied from the IRWST to the engineered cooling channel. The water in the inclined channel absorbs the decay heat transferred from the corium through the carbon steel structure of the core catcher body and boils off as steam. The latter is subsequently released into the free volume of the containment above the corium spreading compartment. Water continues to flow from the IRWST to the cooling channel as a result of buoyancy-driven natural circulation. The engineered cooling channel is designed to provide effective long-term cooling and stabilization of the corium mixture in the core catcher body while facilitating steam venting. In this study, the scaling analysis was performed by solving the natural circulation flow loop equation for the cooling channel in the ex-vessel core catcher. The scaling analysis was performed by solving the natural circulation flow loop equation for the cooling channel in the ex-vessel core catcher. The boiling-induced natural circulation flow in the cooling channel of the core catcher has been modeled by considering the conservation of mass, momentum and energy in the two-phase mixture, along

  9. Selective expansion of human natural killer cells leads to enhanced alloreactivity

    NARCIS (Netherlands)

    Eissens, D.N.; Michelo, C.M.; Preijers, F.W.M.B.; Cranenbroek, B. van; Houwelingen, K.P. van; Meer, A. van der; Joosten, I.

    2014-01-01

    In allogeneic stem cell transplantation (SCT), natural killer (NK) cells lacking their cognate inhibitory ligand can induce graft-versus-leukemia responses, without the induction of severe graft-versus-host disease (GVHD). This feature can be exploited for cellular immunotherapy. In this study, we e

  10. Mass spectrometric analysis of the glycosphingolipid-enriched microdomains of rat natural killer cells

    Czech Academy of Sciences Publication Activity Database

    Man, Petr; Novák, Petr; Cebecauer, M.; Horváth, Ondřej; Fišerová, Anna; Havlíček, Vladimír; Bezouška, Karel

    2005-01-01

    Roč. 5, - (2005), s. 113-122. ISSN 1615-9853 R&D Projects: GA ČR GV312/98/K034 Institutional research plan: CEZ:AV0Z5020903 Keywords : activation receptor * mebrane microdomains * natural killer cells Subject RIV: EE - Microbiology, Virology Impact factor: 6.088, year: 2005

  11. Heat shock protein 70 (Hsp70) stimulates proliferation and cytolytic activity of natural killer cells

    NARCIS (Netherlands)

    Multhoff, G; Mizzen, L; Winchester, CC; Milner, CM; Wenk, S; Eissner, G; Kampinga, HH; Laumbacher, B; Johnson, J

    1999-01-01

    We previously demonstrated that lysis of tumor cells that express Hsp70, the highly stress-inducible member of the HSP70 family, on their plasma membrane is mediated by natural killer (NK) cells. Here, we studied the effects of different proteins of the HSP70 family in combination with interleukin 2

  12. Influence of in vivo hypobaric hypoxia on function of lymphocytes, neutrocytes, natural killer cells, and cytokines

    DEFF Research Database (Denmark)

    Klokker, M; Kharazmi, A; Galbo, H;

    1993-01-01

    of an increased concentration of lymphocytes. The absolute and relative concentration of CD16+ natural killer (NK) cells increased markedly during hypoxia and returned to pretest values after 2 h of recovery. The NK cell activity of blood mononuclear cells (BMNC, %lysis/fixed no. of BMNC) boosted...

  13. Increase in natural killer cell activity during diethylcarbamazine treatment of patients with filariasis

    DEFF Research Database (Denmark)

    Pedersen, B K; Bygbjerg, Ib Christian; Svenson, M

    1987-01-01

    Two patients, one with Bancroftian filariasis and the other with onchocerciasis, and two healthy controls were treated with diethylcarbamazine (DEC). The natural killer (NK) cell activity of the two patients increased during DEC treatment to 2.5 and 2.8 times, respectively, while that of the...

  14. Carotenoids located in human lymphocyte subpopulations and natural killer cells by Raman microspectroscopy

    NARCIS (Netherlands)

    Puppels, G.J.; Garritsen, H.S.P.; Kummer, J.A.; Greve, Jan

    1993-01-01

    The presence and subcellular location of carotenoids in human lymphocyte sub-populations (CD4+, CD8+, T-cell receptor-γδ+, and CD19+ ) and natural killer cells (CD16+ ) were studied by means of Raman microspectroscopy. In CD4+ lymphocytes a high concentration (10-3M) of carotenoids was found in the

  15. Use of natural circulation flow map

    International Nuclear Information System (INIS)

    Natural circulation in complex systems, considering the experimental simulators of PWR and the experience gained in analyzing natural circulation experiments performed in those systems are referred to. In particular, the NC scenarios occurring at different values of the primary system mass inventory are studied. Data have been gathered and analyzed coming from the experimental facilities (PWR simulators, or Integral Test Facilities, ITF) named Semiscale, Spes, Lobi, Bethsy, Pkl and Lstf. The case of PWR design, the NC should be seen as the fundamental mechanism for removing core following accidents or events that cause unavailability of primary circulation pumps. The NC phenomenon constitutes the basis for the layout of the primary system with core located in the bottom of vessel and steam generators a few meters above the top of the active fuel

  16. DBA-Lectin Reactivity Defines Mouse Uterine Natural Killer Cell Subsets with Biased Gene Expression 1

    Science.gov (United States)

    Chen, Zhilin; Zhang, Jianhong; Hatta, Kota; Lima, Patricia D. A.; Yadi, Hakim; Colucci, Francesco; Yamada, Aureo T.; Croy, B. Anne

    2012-01-01

    Endometrial decidualization, a process essential for blastocyst implantation in species with hemochorial placentation, is accompanied by an enormous but transient influx of Natural Killer (NK) cells. Mouse uterine (u)NK cell subsets have been defined by diameter and cytoplasmic granule number, reflecting stage of maturity and by histochemical reactivity with Periodic Acid Schiff’s (PAS) reagent, with or without co-reactivity with Dolichos biflorus agglutinin (DBA) lectin. We asked whether DBA− and DBA+ mouse uNK cells were equivalent using quantitative (q)RT-PCR analyses of flow separated, midpregnancy (gestation day (gd)10) cells and using immunohistochemistry. CD3E (CD3)-IL2RB (CD122)+DBA− cells were identified as the dominant Ifng transcript source. Skewed IFNG production by uNK cell subsets was confirmed by analysis of uNK cells from eYFP-tagged IFNG-reporter mice. In contrast, CD3E-IL2RB+DBA+ uNK cells expressed genes compatible with significantly greater potential for IL22 synthesis, angiogenesis and participation in regulation mediated by the renin-angiotensin system (RAS). CD3E-IL2RB+DBA+ cells were further divided into VEGFA+ and VEGFA− subsets. CD3E-IL2RB+DBA+ uNK cells but not CD3E-IL2RB+DBA− uNK cells arose from circulating, bone marrow-derived progenitor cells by gd6. These findings indicate the heterogeneous nature of mouse uNK cells and suggest that studies using only DBA + uNK cells will give biased data that does not fully represent the uNK cell population. PMID:22875907

  17. Quenching phenomena in natural circulation loop

    Energy Technology Data Exchange (ETDEWEB)

    Umekawa, Hisashi; Ozawa, Mamoru [Kansai Univ., Osaka (Japan); Ishida, Naoki [Daihatsu Motor Company, Osaka (Japan)

    1995-09-01

    Quenching phenomena has been investigated experimentally using circulation loop of liquid nitrogen. During the quenching under natural circulation, the heat transfer mode changes from film boiling to nucleate boiling, and at the same time flux changes with time depending on the vapor generation rate and related two-phase flow characteristics. Moreover, density wave oscillations occur under a certain operating condition, which is closely related to the dynamic behavior of the cooling curve. The experimental results indicates that the occurrence of the density wave oscillation induces the deterioration of effective cooling of the heat surface in the film and the transition boiling regions, which results in the decrease in the quenching velocity.

  18. Identification of distinct human invariant natural killer T-cell response phenotypes to alpha-galactosylceramide

    Directory of Open Access Journals (Sweden)

    Besra Gurdyal S

    2008-12-01

    Full Text Available Abstract Background Human CD1d-restricted, invariant natural killer T cells (iNKT are a unique class of T lymphocytes that recognise glycolipid antigens such as α-galactosylceramide (αGalCer and upon T cell receptor (TCR activation produce both Th1 and Th2 cytokines. iNKT cells expand when cultured in-vitro with αGalCer and interleukin 2 (IL-2 in a CD1d-restricted manner. However, the expansion ratio of human iNKT cells varies between individuals and this has implications for attempts to manipulate this pathway therapeutically. We have studied a panel of twenty five healthy human donors to assess the variability in their in-vitro iNKT cell expansion responses to stimulation with CD1d ligands and investigated some of the factors that may influence this phenomenon. Results Although all donors had comparable numbers of circulating iNKT cells their growth rates in-vitro over 14 days in response to a range of CD1d ligands and IL-2 were highly donor-dependent. Two reproducible donor response patterns of iNKT expansion were seen which we have called 'strong' or 'poor' iNKT responders. Donor response phenotype did not correlate with age, gender, frequency of circulating iNKT, or with the CD1d ligand utilised. Addition of exogenous recombinant human interleukin 4 (IL-4 to 'poor' responder donor cultures significantly increased their iNKT proliferative capacity, but not to levels equivalent to that of 'strong' responder donors. However in 'strong' responder donors, addition of IL-4 to their cultures did not significantly alter the frequency of iNKT cells in the expanded CD3+ population. Conclusion (i in-vitro expansion of human iNKT cells in response to CD1d ligand activation is highly donor variable, (ii two reproducible patterns of donor iNKT expansion were observed, which could be classified into 'strong' and 'poor' responder phenotypes, (iii donor iNKT response phenotypes did not correlate with age, gender, frequency of circulating iNKT cells, or

  19. Expansion of highly activated invariant natural killer T cells with altered phenotype in acute dengue infection.

    Science.gov (United States)

    Kamaladasa, A; Wickramasinghe, N; Adikari, T N; Gomes, L; Shyamali, N L A; Salio, M; Cerundolo, V; Ogg, G S; Malavige, G Neelika

    2016-08-01

    Invariant natural killer T (iNKT) cells are capable of rapid activation and production of cytokines upon recognition of antigenic lipids presented by CD1d molecules. They have been shown to play a significant role in many viral infections and were observed to be highly activated in patients with acute dengue infection. In order to characterize further their role in dengue infection, we investigated the proportion of iNKT cells and their phenotype in adult patients with acute dengue infection. The functionality of iNKT cells in patients was investigated by both interferon (IFN)-γ and interleukin (IL)-4 ex-vivo enzyme-linked immunospot (ELISPOT) assays following stimulation with alpha-galactosyl-ceramide (αGalCer). We found that circulating iNKT cell proportions were significantly higher (P = 0·03) in patients with acute dengue when compared to healthy individuals and were predominantly of the CD4(+) subset. iNKT cells of patients with acute dengue had reduced proportions expressing CD8α and CD161 when compared to healthy individuals. The iNKT cells of patients were highly activated and iNKT activation correlated significantly with dengue virus-specific immunoglobulin (Ig)G antibody levels. iNKT cells expressing Bcl-6 (P = 0·0003) and both Bcl-6 and inducible T cell co-stimulator (ICOS) (P = 0·006) were increased significantly in patients when compared to healthy individuals. Therefore, our data suggest that in acute dengue infection there is an expansion of highly activated CD4(+) iNKT cells, with reduced expression of CD161 markers. PMID:26874822

  20. The role of natural killer cells in multiple sclerosis and their therapeutic implications.

    Science.gov (United States)

    Chanvillard, Coralie; Jacolik, Raymond F; Infante-Duarte, Carmen; Nayak, Ramesh C

    2013-01-01

    Multiple sclerosis (MS) is assumed to be an autoimmune disease initiated by autoreactive T cells that recognize central nervous system antigens. Although adaptive immunity is clearly involved in MS pathogenesis, innate immunity increasingly appears to be implicated in the disease. We and others have presented evidence that natural killer (NK) cells may be involved in immunoregulation in MS, leading to the question of whether a particular NK cell subtype will account for this effect. Changes of NK cell functionality in MS were associated with MS activity, and depletion of NK cells exacerbated the course of disease in a murine model of MS, experimental autoimmune encephalomyelitis. Several studies described a deficiency and transient "valleys" in NK cell killing activity in human MS, which may coincide with symptomatic relapse. However, the molecular basis of the defect in killing activity has not been determined. We discuss results on the expression of perforin in CD16(+) NK cells and the existence of an inverse relationship between myelin loaded phagocytes and the proportion of CD16(+) NK cells expressing perforin in the circulation. This inverse relationship is consistent with a role for NK cell killing activity in dampening autoimmunity. On the other hand, it has been broadly reported that first line MS therapies, such as interferon-beta, glatiramer acetate as well as escalation therapies such as fingolimod, daclizumab, or mitoxantrone seem to affect NK cell functionality and phenotype in vivo. Therefore, in this review we consider evidence for the immunoregulatory role of NK cells in MS and its animal models. Furthermore, we discuss the effect of MS treatments on NK cell activity. PMID:23493880

  1. Natural circulation in pressurized water reactors

    International Nuclear Information System (INIS)

    Several analytical modelling have been done for steady-state and slow transients conditions, besides more sophisticated studies considering two and three dimensional effects in a very simple geometry. Under severe accident conditions for PWR a code to analyse natural circulation has been developed by Westinghouse. This paper discusses the problem of natural circulation in a complex geometry similar to that of nuclear power plants. A first experiment has been done at the integral test facility of 'Co-ordination of Special Projects-Ministry of Naval Affairs' (Coordenadoria para Projetos Especiais -Ministerio da Marinha, COPESP) for several flux conditions. The results obtained were compared with numerical simulations for the steady-state regime. 09 refs, 05 figs, 01 tab. (B.C.A.)

  2. The design of large natural circulation BWR's

    International Nuclear Information System (INIS)

    Boiling water reactors (BWR) with natural circulation are applied for capacities up to 60 MWe. Based on scale studies, however, it appears that larger production units are more efficient. It is recommended to investigate the bottlenecks in realizing larger reactors (>1000 MWe). The aim of the study on the title subject is to study to what extent the production capacity of BWRs with natural circulation can be increased. Based on data from the literature a simple analytic method has been chosen and existing BWR designs were compared. Capacities of 1300 MWe appear to be possible. These reactors will have a smaller pin diameter and a lower water supply temperature. Also steam separators with a minor pressure reduction must be available. The reliability of the stability measurement must be increased. Based on the results of this investigation the priorities for research on the design of future BWRs have been determined

  3. Natural Killer cell recognition of melanoma: new clues for a more effective immunotherapy

    Directory of Open Access Journals (Sweden)

    Raquel eTarazona

    2016-01-01

    Full Text Available Natural killer cells participate in the early immune response against melanoma and also contribute to the development of an adequate adaptive immune response by their crosstalk with dendritic cells and cytokine secretion. Melanoma resistance to conventional therapies together with its high immunogenicity justifies the development of novel therapies aimed to stimulate effective immune responses against melanoma. However, melanoma cells frequently escape to CD8 T cell recognition by the down-regulation of major histocompatibility complex class I molecules. In this scenario, Natural killer cells emerge as potential candidates for melanoma immunotherapy due to their capacity to recognize and destroy melanoma cells expressing low levels of major histocompatibility complex class I molecules. In addition, the possibility to combine immune checkpoint blockade with other NK cell potentiating strategies (e.g. cytokine induction of activating receptors has opened new perspectives in the potential use of adoptive NK cell-based immunotherapy in melanoma.

  4. Effects of OK-432 on murine bone marrow and the production of natural killer cells

    International Nuclear Information System (INIS)

    The streptococcal preparation, OK-432, which augments anti-tumor responses in humans and mice, has been shown to be a potent immunomodulator. Among its effects is a pronounced augmentation of natural killer (NK) activity. The hypothesis that OK-432 alters the rates of production and maturation of NK cells in the bone marrow was tested. Studies to determine the kinetic parameters of NK cell production in normal C57BL/6J mice using tritiated thymidine, 3H-TdR, as a DNA marker are described. We are now extending those studies to determine the effect of OK-432 on the bone marrow and on the production of NK cells in the marrow. Initial observations are reported which indicate that OK-432 has profound effects on the cellularity and mitotic activity of the bone marrow, and in particular, on cells with the characteristics of natural killer cells within the marrow. 17 refs., 3 figs., 4 tabs

  5. Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma

    OpenAIRE

    Barnig, C.; Cernadas, M; Dutile, S.; Liu, X.; Perrella, M A; Kazani, S.; Wechsler, M.E.; Israel, E; Levy, B.D.

    2013-01-01

    Asthma is a prevalent disease of chronic inflammation in which endogenous counter-regulatory signaling pathways are dysregulated. Recent evidence suggests that innate lymphoid cells (ILCs), including natural killer (NK) cells and type 2 innate lymphoid cells (ILC2), can participate in the regulation of allergic airways responses, in particular airway mucosal inflammation. Here, we have identified both NK cells and ILC2 in human lung and peripheral blood in healthy and asthmatic subjects. NK c...

  6. The Neurological Significance of Abnormal Natural Killer Cell Activity in Chronic Toxigenic Mold Exposures

    OpenAIRE

    Ebere Anyanwu; Campbell, Andrew W.; Joseph Jones; Ehiri, John E; Akpan I. Akpan

    2003-01-01

    Toxigenic mold activities produce metabolites that are either broad-spectrum antibiotics or mycotoxins that are cytotoxic. Indoor environmental exposure to these toxigenic molds leads to adverse health conditions with the main outcome measure of frequent neuroimmunologic and behavioral consequences. One of the immune system disorders found in patients presenting with toxigenic mold exposure is an abnormal natural killer cell activity. This paper presents an overview of the neurological signif...

  7. STAT5 Loss Awakens the Dark Force in Natural Killer Cells.

    Science.gov (United States)

    Ni, Jing; Cerwenka, Adelheid

    2016-04-01

    Natural killer cells (NK) are commonly considered to be potent antitumor effector cells. The study by Gotthardt and colleagues challenges this concept and reveals that STAT5-deficient/inhibited NK cells induce angiogenesis and promote tumor progression. These unexpected findings shed new light on potential adverse effects of JAK-STAT inhibitors in the clinics.Cancer Discov; 6(4); 347-9. ©2016 AACRSee related article by Gotthardt et al., p. 414. PMID:27045017

  8. The phylogenetic origins of natural killer receptors and recognition:relationships, possibilities and realities

    OpenAIRE

    Yoder, Jeffrey A.; Gary W. Litman

    2010-01-01

    Natural killer (NK) cells effect a form of innate immunity that recognizes and eliminates cells that are infected with certain viruses or have undergone malignant transformation. In mammals, this recognition can be mediated through immunoglobulin- (Ig) and/or lectin-type NK receptors (NKRs). NKR genes in mammals range from minimally polymorphic single copy genes to complex multigene families that exhibit high levels of haplotypic complexity and exhibit significant interspecific variation. Cer...

  9. Rôle des cellules Natural Killer dans l'asthme allergique

    OpenAIRE

    Plé, Coline

    2010-01-01

    The prevalence and severity of allergic diseases are increasing in western countries. Known pathophysiological mechanisms involve the induction of Th2 response by dendritic cells, leading to IgE production and inflammation. The innate immunity was recently highlighted in the control of adaptive immunity, which is antigen specific. However, the role of Natural Killer (NK) cells, innate cells mainly known for their anti-tumoral and anti-microbial functions, is still unknown in allergic patholog...

  10. Natural Killer T Cells in Adipose Tissue Are Activated in Lean Mice

    OpenAIRE

    Kondo, Taisuke; Toyoshima, Yujiro; Ishii, Yoshiyuki; Kyuwa, Shigeru

    2013-01-01

    Adipose tissues are closely connected with the immune system. It has been suggested that metabolic syndromes such as type 2 diabetes, arteriosclerosis and liver steatosis can be attributed to adipose tissue inflammation characterized by macrophage infiltration. To understand a physiological and pathological role of natural killer T (NKT) cells on inflammation in adipose tissue, we characterized a subset of NKT cells in abdominal and subcutaneous adipose tissues in C57BL/6J mice fed normal or ...

  11. Mechanisms of Innate Lymphoid Cell and Natural Killer T Cell Activation during Mucosal Inflammation

    OpenAIRE

    David Nau; Nora Altmayer; Jochen Mattner

    2014-01-01

    Mucosal surfaces in the airways and the gastrointestinal tract are critical for the interactions of the host with its environment. Due to their abundance at mucosal tissue sites and their powerful immunomodulatory capacities, the role of innate lymphoid cells (ILCs) and natural killer T (NKT) cells in the maintenance of mucosal tolerance has recently moved into the focus of attention. While NKT cells as well as ILCs utilize distinct transcription factors for their development and lineage dive...

  12. Hidden talents of natural killers: NK cells in innate and adaptive immunity

    OpenAIRE

    Cooper, Megan A.; Colonna, Marco; Yokoyama, Wayne M.

    2009-01-01

    Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells and producing immunoregulatory cytokines. Herein, we discuss recent studies that indicate that NK cells span the conventional boundaries between innate and adaptive immunity. For example, it was recently discovered that NK cells have the capacity for memory-like responses, a property that was previously thought to be limited to adaptive immunity. NK cells have also been identified in multiple tissues, and ...

  13. Phenotypic Studies of Natural Killer Cell Subsets in Human Transporter Associated with Antigen Processing Deficiency

    OpenAIRE

    Zimmer, Jacques; Bausinger, Huguette; Andrès, Emmanuel; Donato, Lionel; Hanau, Daniel; Hentges, François; Moretta, Alessandro; de la Salle, Henri

    2007-01-01

    Peripheral blood natural killer (NK) cells from patients with transporter associated with antigen processing (TAP) deficiency are hyporesponsive. The mechanism of this defect is unknown, but the phenotype of TAP-deficient NK cells is almost normal. However, we noticed a high percentage of CD56bright cells among total NK cells from two patients. We further investigated TAP-deficient NK cells in these patients and compared them to NK cells from two other TAP-deficient patients with no clinical ...

  14. Establishment of human T cell clones exhibiting natural killer-like activity

    OpenAIRE

    Alam, Shahabuddin; Katakura, Yoshinori; Shirahata, Sanetaka

    1999-01-01

    We have succeeded in establishing a method to reproducibly immortalize human T cells by oncogene(s) transfection (Alam, 1997). This study was based on our previous discoveries that these immortalized T cell lines contained T cells which showed cytotoxicity against K562 cells in MHC-nonrestricted manner. Then we attempted to obtain human T cell clones exhibiting natural killer-like activity. Here, we tried to establish clones from these immortalized T cell lines by limiting dilution after stim...

  15. DBA-Lectin Reactivity Defines Mouse Uterine Natural Killer Cell Subsets with Biased Gene Expression 1

    OpenAIRE

    Chen, Zhilin; Zhang, Jianhong; Hatta, Kota; Lima, Patricia D.A.; Yadi, Hakim; Colucci, Francesco; Yamada, Aureo T.; Croy, B. Anne

    2012-01-01

    Endometrial decidualization, a process essential for blastocyst implantation in species with hemochorial placentation, is accompanied by an enormous but transient influx of Natural Killer (NK) cells. Mouse uterine (u)NK cell subsets have been defined by diameter and cytoplasmic granule number, reflecting stage of maturity and by histochemical reactivity with Periodic Acid Schiff’s (PAS) reagent, with or without co-reactivity with Dolichos biflorus agglutinin (DBA) lectin. We asked whether DBA...

  16. Functional and molecular aspects of interferon action in human natural killer cells and other leucocytes

    OpenAIRE

    Gustafsson, Åke

    1985-01-01

    Interferons comprise a class of structurally related proteins which exert several regulatory effects in responsive cells. These effects include the establishment of an antiviral state, the inhibition of cellular proliferation and the alteration of different immune reactions. In particular, the IFN:s rapidly augment the lytic activity of the natural killer (NK) cells. In the present thesis, some of the functional and molecular mechanisms by which IFN:s act on NK cells and other leucocytes are ...

  17. Effect of human colostrum on interleukin-2 production and natural killer cell activity.

    OpenAIRE

    Sirota, L.; Straussberg, R; Notti, I.; Bessler, H

    1995-01-01

    The effect of human colostrum on the production of interleukin-2 (IL-2) and on natural killer (NK) cell activity by peripheral blood mononuclear cells (PBMC) was investigated in 50 healthy women. At concentrations as low as 0.5%, human colostrum stimulated IL-2 production; at a higher concentration (10%), IL-2 secretion was inhibited. A time and dose dependent inhibitory effect of colostrum on NK cytotoxicity was also observed. This inhibition could be reversed by the addition of human recomb...

  18. Application of Mass Cytometry (CyTOF) for Functional and Phenotypic Analysis of Natural Killer Cells.

    Science.gov (United States)

    Kay, Alexander W; Strauss-Albee, Dara M; Blish, Catherine A

    2016-01-01

    Mass cytometry is a novel platform for high-dimensional phenotypic and functional analysis of single cells. This system uses elemental metal isotopes conjugated to monoclonal antibodies to evaluate up to 42 parameters simultaneously on individual cells with minimal overlap between channels. The platform can be customized for analysis of both phenotypic and functional markers. Here, we will describe methods to stain, collect, and analyze intracellular functional markers and surface phenotypic markers on natural killer cells. PMID:27177653

  19. Use of the 51chromium release assay to study natural killer cells in mice infected with Babesia microti

    International Nuclear Information System (INIS)

    The chromium-51 release assay was used to measure levels of natural killer cell activity in mice infected with Babesia microti. In this microassay system serial dilutions of effector cells (natural killer cells) are mixed with a constant number of radiolabeled YAC tumor cell targets. The amount of radioactivity released into the supernate of the cultures is measured and a percent of 51Cr release is calculated. This value is an index cytotoxicity

  20. Current perspectives on natural killer cell education and tolerance: emerging roles for inhibitory receptors

    Directory of Open Access Journals (Sweden)

    Thomas LM

    2015-03-01

    Full Text Available L Michael Thomas Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA Abstract: Natural killer (NK cells are regulated through the coordinated functions of activating and inhibitory receptors. These receptors can act during the initial engagement of an NK cell with a target cell, or in subsequent NK cell engagements to maintain tolerance. Notably, each individual possesses a sizable minority-population of NK cells that are devoid of inhibitory receptors that recognize the surrounding MHC class I (ie, self-MHC. Since these NK cells cannot perform conventional inhibition, they are rendered less responsive through the process of NK cell education (also known as licensing in order to reduce the likelihood of auto-reactivity. This review will delineate current views on NK cell education, clarify various misconceptions about NK cell education, and, lastly, discuss the relevance of NK cell education in anti-cancer therapies. Keywords: natural killer cell education, natural killer cell inhibitory receptors, immunotherapy, cancer

  1. Dynamic changes of cytotoxic T lymphocytes (CTLs, natural killer (NK cells, and natural killer T (NKT cells in patients with acute hepatitis B infection

    Directory of Open Access Journals (Sweden)

    Liu Bo

    2011-05-01

    Full Text Available Abstract Background The goal of this study is to observe changes in HBcAg-specific cytotoxic T lymphocytes (CTLs, natural killer (NK and natural killer T (NKT cells from peripheral blood and to relate such changes on viral clearance and liver injury in patients with acute hepatitis B (AHB. Methods Dynamic profiles on the frequency of HLA-A0201-restricted HBcAg18-27 pentamer complex (MHC-Pentamer-specific CTLs and lymphocyte subsets in AHB patients were analyzed in addition to liver function tests, HBV serological markers, and HBV DNA levels. ELISPOT was used to detect interferon-gamma (INF-γ secretion in specific CTLs stimulated with known T cell epitope peptides associated with HBV surface protein, polymerase, and core protein. Results HBV-specific CTL frequencies in AHB patients were much higher than in patients with chronic hepatitis B (CHB (p +CD8+ T cell numbers in AHB patients was more than observed in the healthy control group from the first to the fourth week after admission (p = 0.008 and 0.01, respectively; the number of CD3+CD8+ T cells and frequency of HBcAg18-27-specific CTLs in AHB patients reached peak levels at the second week after admission. NK and NKT cell numbers were negatively correlated with the frequency of HBcAg-specific CTLs (r = -0.266, p = 0.05. Conclusions Patients with AHB possess a higher frequency of HBcAg-specific CTLs than CHB patients. The frequency of specific CTLs in AHB patients is correlated with HBeAg clearance indicating that HBV-specific CTLs play an important role in viral clearance and the self-limited process of the disease. Furthermore, NK and NKT cells are likely involved in the early, non-specific immune response to clear the virus.

  2. NCR1+ cells in dogs show phenotypic characteristics of natural killer cells.

    Science.gov (United States)

    Grøndahl-Rosado, Christine; Bønsdorff, Tina B; Brun-Hansen, Hege C; Storset, Anne K

    2015-03-01

    No specific markers for natural killer (NK) cells in dogs have currently been described. NCR1 (NKp46, CD355) has been considered a pan species NK cell marker and is expressed on most or all NK cells in all species investigated except for the pig which has both a NCR1(+) and a NCR1(-) population. In this study peripheral blood mononuclear cells (PBMC) from 14 healthy dogs, 37 dogs with a clinical diagnosis, including a dog diagnosed with LGL leukemia, and tissue samples from 8 dogs were evaluated for NCR1(+) expression by a cross reacting anti bovine NCR1 antibody. CD3(-)NCR1(+) cells were found in the blood of 93 % of healthy dogs and comprised up to 2.5 % of lymphocytes in PBMC. In a selection of healthy dogs, sampling and immunophenotyping were repeated throughout a period of 1 year revealing a substantial variation in the percentage of CD3(-)NCR1(+) over time. Dogs allocated to 8 disease groups had comparable amounts of CD3(-)NCR1(+) cells in PBMC to the healthy individuals. All organs examined including liver, spleen and lymph nodes contained CD3(-)NCR1(+) cells. Circulating CD3(-)NCR1(+) cells were further characterized as CD56(-)GranzymeB(+)CD8(-). A CD3(+)NCR1(+) population was observed in PBMC in 79 % of the healthy dogs examined representing at the most 4.8 % of the lymphocyte population. In canine samples examined for CD56 expression, CD56(+) cells were all CD3(+) and NCR1(-). To our knowledge, this is the first examination of NCR1 expression in the dog. The study shows that this NK cell associated receptor is expressed both on populations of CD3(+) and CD3(-) blood lymphocytes in dogs and the receptor is found on a CD3(+) GranzymeB(+) CD8(+) leukemia. Our results support that CD56 is expressed only on CD3(+) cells in dogs and shows that NCR1 defines a different CD3(+) lymphocyte population than CD56(+)CD3(+) cells in this species. CD3(-)NCR1(+) cells may represent canine NK cells. PMID:25434421

  3. Phenotype and functions of natural killer cells in critically-ill septic patients.

    Directory of Open Access Journals (Sweden)

    Jean-Marie Forel

    Full Text Available RATIONALE: Natural killer cells, as a major source of interferon-γ, contribute to the amplification of the inflammatory response as well as to mortality during severe sepsis in animal models. OBJECTIVE: We studied the phenotype and functions of circulating NK cells in critically-ill septic patients. METHODS: Blood samples were taken <48 hours after admission from 42 ICU patients with severe sepsis (n = 15 or septic shock (n = 14 (Sepsis group, non-septic SIRS (n = 13 (SIRS group, as well as 21 healthy controls. The immuno-phenotype and functions of NK cells were studied by flow cytometry. RESULTS: The absolute number of peripheral blood CD3-CD56(+ NK cells was similarly reduced in all groups of ICU patients, but with a normal percentage of NK cells. When NK cell cytotoxicity was evaluated with degranulation assays (CD107 expression, no difference was observed between Sepsis patients and healthy controls. Under antibody-dependent cell cytotoxicity (ADCC conditions, SIRS patients exhibited increased CD107 surface expression on NK cells (62.9[61.3-70]% compared to healthy controls (43.5[32.1-53.1]% or Sepsis patients (49.2[37.3-62.9]% (p = 0.002. Compared to healthy (10.2[6.3-13.1]%, reduced interferon-γ production by NK cells (K562 stimulation was observed in Sepsis group (6.2[2.2-9.9]%, p<0.01, and especially in patients with septic shock. Conversely, SIRS patients exhibited increased interferon-γ production (42.9[30.1-54.7]% compared to Sepsis patients (18.4[11.7-35.7]%, p<0.01 or healthy controls (26.8[19.3-44.9]%, p = 0.09 in ADCC condition. CONCLUSIONS: Extensive monitoring of the NK-cell phenotype and function in critically-ill septic patients revealed early decreased NK-cell function with impaired interferon-γ production. These results may aid future NK-based immuno-interventions. TRIAL REGISTRATION: NTC00699868.

  4. Station blackout analysis of natural circulation reactor

    International Nuclear Information System (INIS)

    Full text of publication follows: The natural circulation reactor is a vertical pressure tube type boiling light water cooled and heavy water moderated reactor. One of the important passive design features of this reactor is that the heat removal is achieved through natural circulation of primary coolant at all power level with no primary coolant pumps. There is no auxiliary feed pump available as Isolation Condenser (IC) is meant to remove decay heat. Station Blackout lead to feed water pump trip and loss of condenser vacuum which in turn results in to loss of feed water as well as the turbine trip on low condenser vacuum signal. This leads to bottle up of the system, leading to pressure rise in PHT. The bypass flow is not available due to loss of condenser vacuum. Reactor is tripping on high pressure signal. As the pressure continue to raise, IC valve starts opening at a pressure of 76.0 bar to limit the pressure rise. Relief valve may open in case of IC's capacity is not adequate. This analysis highlights the thermal hydraulic conditions following station blackout with IC's to limit the pressure rise. The paper discusses the thermal hydraulic transient analysis for evaluating the safety of the reactor; following station blackout with IC's using RELAP5/MOD3.2. Predictions are made for different parameters like pressure, temperature, steam quality and flow in different parts of the Primary Heat Transport (PHT) system. In this paper summary of analysis for event is presented. In this paper, various modeling complexities are brought out; evaluation of acceptance criteria is made and design implications of event are discussed. (authors)

  5. Effect of tunicamycin on sialomucin and natural killer susceptibility of rat mammary tumor ascites cells.

    Science.gov (United States)

    Bharathan, S; Moriarty, J; Moody, C E; Sherblom, A P

    1990-09-01

    The MAT-B1 and MAT-C1 ascites sublines of the 13762 rat mammary adenocarcinoma contain a dominant cell surface "complex" consisting of two glycoproteins: ascites sialoglycoprotein (ASGP)-1, a Mr 600,000-700,000 peanut agglutinin-binding sialomucin, and ASGP-2, a Mr 120,000 concancavalin A-binding glycoprotein (Sherblom et al., J. Biol. Chem., 255: 783-790, 1980; Sherblom and Carraway, J. Biol. Chem., 255: 12051-12059, 1980). Although both cell lines are resistant to lysis by natural killer cells, treatments which result in loss of cell surface ASGP-1 render the cells susceptible to natural killer cell lysis (Sherblom and Moody, Cancer Res., 46:4543-4546, 1986). Treatment of the ascites cells with 5 micrograms/ml tunicamycin for 24 h effectively inhibits glycosylation of ASGP-2 without affecting cell viability or total protein synthesis. Under these conditions, expression of ASGP-1 is depressed by at least 50% in both cell lines, as monitored by [3H]glucosamine incorporation and by binding of peanut agglutinin to intact cells. The size distribution of O-linked oligosaccharides in ASGP-1 from tunicamycin-treated versus control MAT-B1 cells is indistinguishable, as determined by Bio-Gel P-4 chromatography following alkaline-borohydride treatment. Complex isolated from either treated or control cells bands at the same density in a CsCl gradient containing Triton X-100 and contains a diffuse band corresponding to ASGP-2 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Tunicamycin-treated cells, consistent with the reduced expression of ASGP-1, are significantly more susceptible to natural killer cell-mediated lysis, when compared to untreated controls. The results suggest that N-linked glycosylation is a prerequisite for sialomucin synthesis and/or complex formation. PMID:2386935

  6. Natural Killer Cells Determine Development of Allergen-induced Eosinophilic Airway Inflammation in Mice

    OpenAIRE

    Korsgren, Magnus; Persson, Carl G.A.; Sundler, Frank; Bjerke, Torbjörn; Hansson, Tony; Chambers, Benedict J.; Hong, Seokmann; Van Kaer, Luc; Ljunggren, Hans-Gustaf; Korsgren, Olle

    1999-01-01

    The earliest contact between antigen and the innate immune system is thought to direct the subsequent antigen-specific T cell response. We hypothesized that cells of the innate immune system, such as natural killer (NK) cells, NK1.1+ T cells (NKT cells), and γ/δ T cells, may regulate the development of allergic airway disease. We demonstrate here that depletion of NK1.1+ cells (NK cells and NKT cells) before immunization inhibits pulmonary eosinophil and CD3+ T cell infiltration as well as in...

  7. Transplantable progenitors of natural killer cells are distinct from those of T and B lymphocytes.

    OpenAIRE

    Hackett, J; Bosma, G C; Bosma, M J; Bennett, M.; Kumar, V

    1986-01-01

    We have utilized a mouse mutant (C.B-17 scid) that lacks functional T and B lymphocytes to examine the relationship among transplantable progenitors of natural killer (NK) cells, T cells, and B cells. The NK-progenitor cells contained in the bone marrow were detected by their ability to generate mature NK cells, following transfer of bone marrow cells into NK cell-depleted and lethally irradiated mice. Regeneration of NK activity in the recipient mice was monitored by two different assays: th...

  8. Alteration of natural killer(NK) cells in atomic bomb survivors of hiroshima

    International Nuclear Information System (INIS)

    This paper reports on the alteration of natural killer(NK) cells and their responsiveness to IL-2 observed in 125 atomic-bomb survivors. It is found no difference in the number and activity of NK cells among different dose groups with the same age ATB. But there was of difference in NK activity in different age ATB groups with same dose, especially in the g roups 25 years, the old with doses of 0.01-1 Gy (P < 0.05). This result suggests that there is an obvious late effect of ionizing radiation on activity of NK cells in children

  9. Transcription factors involved in the regulation of natural killer cell development and function: an update

    Directory of Open Access Journals (Sweden)

    Martha Elia Luevano

    2012-10-01

    Full Text Available Natural Killer (NK cells belong to the innate immune system and are key effectors in the immune response against cancer and infection. Recent studies have contributed to the knowledge of events controlling NK cell fate. The use of knockout mice has enabled the discovery of key transcription factors (TFs essential for NK cell development and function. Yet, unwrapping the downstream targets of these TFs and their influence on NK cells remains a challenge. In this review we discuss the latest TFs described to be involved in the regulation of NK cell development and maturation.

  10. Suppression of tumor formation in lymph nodes by L-selectin–mediated natural killer cell recruitment

    OpenAIRE

    Chen, Shihao; Kawashima, Hiroto; Lowe, John B.; Lanier, Lewis L.; Fukuda, Minoru

    2005-01-01

    Natural killer (NK) cells are known to reject certain tumors in vivo; however, the ability of NK cells to prevent metastasis of tumors into secondary lymphoid organs has not been addressed. Here, we report that in tumor-bearing hosts, NK cells are recruited to regional lymph nodes in wild-type mice, but not in mice deficient for L-selectin or L-selectin ligands. By adoptive transfer and complete Freund's adjuvant stimulation experiments, we demonstrated that L-selectin on NK cells and L-selec...

  11. Extranodal Natural Killer/T-Cell Lymphoma: A Rare Nasal-Type Case

    OpenAIRE

    Esra Sarıbacak Can; Harika Okutan; Ünsal Han

    2016-01-01

    Nasal type extranodal natural killer (NK) NK-cell/T-cell lymphoma (NKTCL) is a rare extranodal lymphoma of NK-cell or T-cell origin that most commonly affects immunocompetent middle-aged men of Asian or Native American descent [1]. The pathogenesis is not understood completely, but it is related in part to infection of the tumor cells with Epstein-Barr virus (EBV) [2]. Around 6-7% of all non-Hodgkin’s lymphoma (NHL) in Southeast Asia accounts for NKTCL. However, the incid...

  12. Interferon-γ-Mediated Natural Killer Cell Activation by an Aqueous Panax ginseng Extract

    OpenAIRE

    Kazuyoshi Takeda; Ko Okumura

    2015-01-01

    Panax ginseng extracts are used in traditional herbal medicines, particularly in eastern Asia, but their effect on natural killer (NK) cell activity is not completely understood. This study aimed to examine the effects of P. ginseng extracts on the cytotoxic activity of NK cells. We orally administered P. ginseng extracts or ginsenosides to wild-type (WT) C57BL/6 (B6) and BALB/c mice and to B6 mice deficient in either recombination activating gene 2 (RAG-2) or interferon-γ (IFN-γ). We then te...

  13. Natural killer cells regulate Th1/Treg and Th17/Treg balance in chlamydial lung infection

    OpenAIRE

    Li, Jing; Dong, Xiaojing; Zhao, Lei; Wang, Xiao; Wang, Yan; Yang, Xi; Wang, Hong; Zhao, Weiming

    2016-01-01

    Abstract Natural killer (NK) cell is an important component in innate immunity, playing a critical role in bridging innate and adaptive immunity by modulating the function of other immune cells including T cells. In this study, we focused on the role of NK cells in regulating Th1/Treg and Th17/Treg balance during chlamydial lung infection. We found that NK cell‐depleted mice showed decreased Th1 and Th17 cells, which was correlated with reduced interferon‐γ, interleukin (IL)‐12, IL‐17 and IL‐...

  14. Human herpesvirus-6 enhances natural killer cell cytotoxicity via IL-15.

    OpenAIRE

    Flamand, L.; Stefanescu, I.(Argonne National Laboratory, Argonne, IL, 60439, USA); Menezes, J.

    1996-01-01

    The marked tropism of human herpesvirus-6 (HHV-6) for natural killer (NK) cells and T lymphocytes has led us to investigate the effect of HHV-6 on cellular cytotoxicity. We describe here how HHV-6 infection of peripheral blood mononuclear cells (PBMC) leads to upregulation of their NK cell cytotoxicity. The induction of NK cell activity by HHV-6 was abrogated by monoclonal antibodies (mAbs) to IL-15 but not by mAbs to other cytokines (IFN-alpha, IFN-gamma, TNF-alpha, TNF-beta, IL-2, IL-12) su...

  15. Feasibility research of CRDM natural circulation cooling

    International Nuclear Information System (INIS)

    Background: In the second generation pressurized water reactor, the Control Rod Drive Mechanism (CRDM) is mainly cooled by the blast blower, which consumes more energy and is of lower security. Based on the layout of the CRDM group in the Daya Bay nuclear power plant, the EMC-B type of CRDM is taken as research object. Purpose: The temperature distribution of the CRDM group was simulated to verify the feasibility of natural circulation cooling of air. Methods: Several Computational Fluid Dynamics (CFD) based programs were employed for this research. Firstly, Pro/ENGINEER was applied to establish the 3D model of the CRDM group; then the geometrical model was meshed with ICEM; finally, the flow field and temperature distribution were solved by using FLUENT. Results: The temperature field of the CRDM can be divided into three regions, and the temperature of the middle CRDM was highest, while the temperature of the region between the middle and outside regions was lowest due to the relative weak convection. The highest coil temperature is 198℃, below the limit value of 200℃. Conclusion: The CRDM and the coils may be cooled effectively by natural convection of air under given conditions. (authors)

  16. Natural Killer-like B Cells Prime Innate Lymphocytes against Microbial Infection.

    Science.gov (United States)

    Wang, Shuo; Xia, Pengyan; Chen, Yi; Huang, Guanling; Xiong, Zhen; Liu, Jing; Li, Chong; Ye, Buqing; Du, Ying; Fan, Zusen

    2016-07-19

    Natural killer (NK) cells and non-cytotoxic interferon-γ (IFN-γ)-producing group I innate lymphoid cells (ILC1s) produce large amounts of IFN-γ and cause activation of innate and adaptive immunity. However, how NKs and ILC1s are primed during infection remains elusive. Here we have shown that a lymphocyte subpopulation natural killer-like B (NKB) cells existed in spleen and mesenteric lymph nodes (MLNs). NKBs had unique features that differed from T and B cells, and produced interleukin-18 (IL-18) and IL-12 at an early phase of infection. NKB cells played a critical role in eradication of microbial infection via secretion of IL-18 and IL-12. Moreover, IL-18 deficiency abrogated the antibacterial effect of NKBs. Upon bacterial challenge, NKB precursors (NKBPs) rapidly differentiated to NKBs that activated NKs and ILC1s against microbial infection. Our findings suggest that NKBs might be exploited to develop effective therapies for treatment of infectious diseases. PMID:27421702

  17. ERAP1 regulates natural killer cell function by controlling the engagement of inhibitory receptors.

    Science.gov (United States)

    Cifaldi, Loredana; Romania, Paolo; Falco, Michela; Lorenzi, Silvia; Meazza, Raffaella; Petrini, Stefania; Andreani, Marco; Pende, Daniela; Locatelli, Franco; Fruci, Doriana

    2015-03-01

    The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by MHC class I (MHC-I) molecules. Herein, we demonstrate that genetic or pharmacological inhibition of ERAP1 on human tumor cell lines perturbs their ability to engage several classes of inhibitory receptors by their specific ligands, including killer cell Ig-like receptors (KIR) by classical MHC-I-peptide (pMHC-I) complexes and the lectin-like receptor CD94-NKG2A by nonclassical pMHC-I complexes, in each case leading to natural killer (NK) cell killing. The protective effect of pMHC-I complexes could be restored in ERAP1-deficient settings by the addition of known high-affinity peptides, suggesting that ERAP1 was needed to positively modify the affinity of natural ligands. Notably, ERAP1 inhibition enhanced the ability of NK cells to kill freshly established human lymphoblastoid cell lines from autologous or allogeneic sources, thereby promoting NK cytotoxic activity against target cells that would not be expected because of KIR-KIR ligand matching. Overall, our results identify ERAP1 as a modifier to leverage immune functions that may improve the efficacy of NK cell-based approaches for cancer immunotherapy. PMID:25592150

  18. Simultaneous measurement of natural killer cell cytotoxicity against each of three different target cell lines.

    Science.gov (United States)

    Blomberg, K

    1994-02-10

    A time-resolved fluorometric assay for the simultaneous measurement of natural killer cell activity against three different lanthanide diethylenetriaminopentaacetate (LaDTPA) labelled target cell lines is described. The target cell line K-562 was labelled with SmDTPA, the cell line Molt with TbDTPA and the cell line Raji with EuDTPA. After co-incubation of the three target cell lines with effector cells the fluorescence of the lanthanides released from the lysed target cells was measured in an enhancer solution in which they formed highly fluorescent complexes. It was possible to differentiate the specific release from the three target cell lines because the emission lines of the europium, samarium and terbium complexes formed in the enhancer solution are well separated from each other. The autofluorescence from culture media supplemented with serum was avoided by the use of time-resolved fluorometry. The results show that applying fluorometry based on the combination of spectral and temporal resolution to natural killer cell assays, makes possible the simultaneous determination of lysis in up to three target cell lines in complex culture medium. PMID:8308301

  19. Cytotoxic activity of allogeneic natural killer cells on U251 glioma cells in vitro.

    Science.gov (United States)

    Guo, Meng; Wu, Tingting; Wan, Lixin

    2016-07-01

    The present study aimed to observe the cytotoxic activity of allogeneic natural killer (NK) cells on U251 glioma cells and to investigate their mechanism of action to establish an effective treatment strategy for neuroglioma. Cell survival curves, colony formation assays and karyotype analysis were performed to investigate the characteristics of U251 glioma cells. The present study demonstrated that natural killer group 2, member D (NKG2D)‑major histocompatibility complex class I‑related chain A/B (MICA/B) interactions contributed to the cytotoxic effect of NK cells on K562 and U251 cells. In antibody‑blocking assays to inhibit NKG2D ligands, the cytotoxic activity was not completely attenuated, which suggested that other signaling pathways contribute to the cytotoxic activity of NK cells on tumor cells in addition to the NKG2D‑mediated activity. The present study identified that the expression levels of NKG2D ligands on the surface of target cells influenced the strength of the NK cell immune response. Furthermore, allogeneic NK cells were observed to kill glioma cells in vitro, and this anticancer activity is associated with the rate of NKG2D expression on the surface of glioma cells. PMID:27175912

  20. Changes in endometrial natural killer cell expression of CD94, CD158a and CD158b are associated with infertility.

    LENUS (Irish Health Repository)

    McGrath, Emma

    2012-02-01

    PROBLEM: Cycle-dependent fluctuations in natural killer (NK) cell populations in endometrium and circulation may differ, contributing to unexplained infertility. METHOD OF STUDY: NK cell phenotypes were determined by flow cytometry in endometrial biopsies and matched blood samples. RESULTS: While circulating and endometrial T cell populations remained constant throughout the menstrual cycle in fertile and infertile women, circulating NK cells in infertile women increased during the secretory phase. However, increased expression of CD94, CD158b (secretory phase), and CD158a (proliferative phase) by endometrial NK cells from infertile women was observed. These changes were not reflected in the circulation. CONCLUSION: In infertile women, changes in circulating NK cell percentages are found exclusively during the secretory phase and not in endometrium; cycle-related changes in NK receptor expression are observed only in infertile endometrium. While having exciting implications for understanding NK cell function in fertility, our data emphasize the difficulty in attaching diagnostic or prognostic significance to NK cell analyses in individual patients.

  1. Cigarette smoke alters the invariant natural killer T cell function and may inhibit anti-tumor responses.

    LENUS (Irish Health Repository)

    Hogan, Andrew E

    2011-09-01

    Invariant natural killer T (iNKT) cells are a minor subset of human T cells which express the invariant T cell receptor Vα24 Jα18 and recognize glycolipids presented on CD1d. Invariant NKT cells are important immune regulators and can initiate anti-tumor responses through early potent cytokine production. Studies show that iNKT cells are defective in certain cancers. Cigarette smoke contains many carcinogens and is implicated directly and indirectly in many cancers. We investigated the effects of cigarette smoke on the circulating iNKT cell number and function. We found that the iNKT cell frequency is significantly reduced in cigarette smoking subjects. Invariant NKT cells exposed to cigarette smoke extract (CSE) showed significant defects in cytokine production and the ability to kill target cells. CSE inhibits the upregulation of CD107 but not CD69 or CD56 on iNKT cells. These findings suggest that CSE has a specific effect on iNKT cell anti-tumor responses, which may contribute to the role of smoking in the development of cancer.

  2. CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver.

    Science.gov (United States)

    Stegmann, Kerstin A; Robertson, Francis; Hansi, Navjyot; Gill, Upkar; Pallant, Celeste; Christophides, Theodoros; Pallett, Laura J; Peppa, Dimitra; Dunn, Claire; Fusai, Giuseppe; Male, Victoria; Davidson, Brian R; Kennedy, Patrick; Maini, Mala K

    2016-01-01

    Natural killer cells (NK) are highly enriched in the human liver, where they can regulate immunity and immunopathology. We probed them for a liver-resident subset, distinct from conventional bone-marrow-derived NK. CXCR6+ NK were strikingly enriched in healthy and diseased liver compared to blood (p bright)CD16-CD57-), and expressed the tissue-residency marker CD69. CXCR6+ NK produced fewer cytotoxic mediators and pro-inflammatory cytokines than the non-liver-specific CXCR6- fraction. Instead CXCR6+ NK could upregulate TRAIL, a key death ligand in hepatitis pathogenesis. CXCR6 demarcated liver NK into two transcriptionally distinct populations: T-bet(hi)Eomes(lo)(CXCR6-) and T-bet(lo)Eomes(hi)(CXCR6+); the latter was virtually absent in the periphery. The small circulating CXCR6+ subset was predominantly T-bet(hi)Eomes(lo), suggesting its lineage was closer to CXCR6- peripheral than CXCR6+ liver NK. These data reveal a large subset of human liver-resident T-bet(lo)Eomes(hi) NK, distinguished by their surface expression of CXCR6, adapted for hepatic tolerance and inducible anti-viral immunity. PMID:27210614

  3. Independent review of SCDAP/RELAP5 natural circulation calculations

    International Nuclear Information System (INIS)

    A review and assessment of the uncertainties in the calculated response of reactor coolant system natural circulation using the SCDAP/RELAP5 computer code were completed. The SCDAP/RELAP5 calculation modeled a station blackout transient in the Surry nuclear power plant and concluded that primary system depressurization from natural circulation induced primary system failure is more likely than previously thought

  4. Independent review of SCDAP/RELAP5 natural circulation calculations

    Energy Technology Data Exchange (ETDEWEB)

    Martinez, G.M.; Gross, R.J.; Martinez, M.J.; Rightley, G.S.

    1994-01-01

    A review and assessment of the uncertainties in the calculated response of reactor coolant system natural circulation using the SCDAP/RELAP5 computer code were completed. The SCDAP/RELAP5 calculation modeled a station blackout transient in the Surry nuclear power plant and concluded that primary system depressurization from natural circulation induced primary system failure is more likely than previously thought.

  5. Natural Circulation Phenomena and Modelling for Advanced Water Cooled Reactors

    International Nuclear Information System (INIS)

    The role of natural circulation in advanced water cooled reactor design has been extended with the adoption of passive safety systems. Some designs utilize natural circulation to remove core heat during normal operation. Most passive safety systems used in evolutionary and innovative water cooled reactor designs are driven by natural circulation. The use of passive systems based on natural circulation can eliminate the costs associated with the installation, maintenance and operation of active systems that require multiple pumps with independent and redundant electric power supplies. However, considering the weak driving forces of passive systems based on natural circulation, careful design and analysis methods must be employed to ensure that the systems perform their intended functions. Several IAEA Member States with advanced reactor development programmes are actively conducting investigations of natural circulation to support the development of advanced water cooled reactor designs with passive safety systems. To foster international collaboration on the enabling technology of passive systems that utilize natural circulation, in 2004 the IAEA initiated a coordinated research project (CRP) on Natural Circulation Phenomena, Modelling and Reliability of Passive Systems that Utilize Natural Circulation. Three reports were published within the framework of this CRP. The first report (IAEA-TECDOC-1474) contains the material developed for the first IAEA training course on natural circulation in water cooled nuclear power plants. The second report (IAEA-TECDOC-1624) describes passive safety systems in a wide range of advanced water cooled nuclear power plant designs, with the goal of gaining insights into system design, operation and reliability. This third, and last, report summarizes the research studies completed by participating institutes during the CRP period.

  6. Efficacy of pegaspargase in extra nodal natural killer/T-cell lymphoma nasal type: A case report from China

    Directory of Open Access Journals (Sweden)

    Xingan Xiong

    2015-01-01

    Full Text Available Extranodal natural killer (NK/T-cell lymphoma, nasal type, is a rare and highly aggressive disease with a grim prognosis. There is no known satisfactory treatment. The author herein to report one case of L-asparaginase extranodal NK/T-cell lymphoma primary treated with L-asparaginase methotrexate and dexamethasone.

  7. Effects of dexamethasone on human natural killer cell cytotoxicity, interferon production, and interleukin-2 receptor expression induced by microbial antigens.

    OpenAIRE

    E. Piccolella; Lombardi, G.; Vismara, D; Del Gallo, F; Colizzi, V; Dolei, A; Dianzani, F

    1986-01-01

    Dexamethasone inhibits the expression of the interleukin-2 receptor, the synthesis of immune interferon, and the development of natural killer cells when added to peripheral blood mononuclear cells cultured with soluble microbial antigens (purified protein derivative and a polysaccharide extract from Candida albicans [MPPS]) or human recombinant interleukin-2.

  8. Therapeutic manipulation of natural killer (NK) T cells in autoimmunity: are we close to reality?

    Science.gov (United States)

    Simoni, Y; Diana, J; Ghazarian, L; Beaudoin, L; Lehuen, A

    2013-01-01

    T cells reactive to lipids and restricted by major histocompatibility complex (MHC) class I-like molecules represent more than 15% of all lymphocytes in human blood. This heterogeneous population of innate cells includes the invariant natural killer T cells (iNK T), type II NK T cells, CD1a,b,c-restricted T cells and mucosal-associated invariant T (MAIT) cells. These populations are implicated in cancer, infection and autoimmunity. In this review, we focus on the role of these cells in autoimmunity. We summarize data obtained in humans and preclinical models of autoimmune diseases such as primary biliary cirrhosis, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, psoriasis and atherosclerosis. We also discuss the promise of NK T cell manipulations: restoration of function, specific activation, depletion and the relevance of these treatments to human autoimmune diseases. PMID:23199318

  9. Natural Killer Cells Are Activated by Lactic Acid Bacteria-Matured Dendritic Cells

    DEFF Research Database (Denmark)

    Fink, Lisbeth Nielsen; Christensen, Hanne Risager; Frøkiær, Hanne

    of certain lactic acid bacteria has been shown to increase in vivo NK cytotoxicity. Here, we investigated how human gut flora-derived lactobacilli affect NK cells in vitro, by measuring proliferation and IFN-gamma production of human NK cells upon bacterial stimulation. Human peripheral blood NK...... encounter of NK cells with lactic acid bacteria will affect NK cell activation. Such activation of NK cells may potentially skew an on-going or subsequent immune response towards a Th1 response.......Natural killer (NK) cells are cells of the non-specific immune system lysing altered self-cells. A non-cytolytic subset of NK cells may serve a regulatory role by secreting cytokines. Bacteria translocating across the gastrointestinal mucosa are presumed to gain access to NK cells, as consumption...

  10. Natural Killer Cells—An Epigenetic Perspective of Development and Regulation

    Directory of Open Access Journals (Sweden)

    Alexander Schenk

    2016-03-01

    Full Text Available Based on their ability to recognize and eliminate various endo- and exogenous pathogens as well as pathological alterations, Natural Killer (NK cells represent an important part of the cellular innate immune system. Although the knowledge about their function is growing, little is known about their development and regulation on the molecular level. Research of the past decade suggests that modifications of the chromatin, which do not affect the base sequence of the DNA, also known as epigenetic alterations, are strongly involved in these processes. Here, the impact of epigenetic modifications on the development as well as the expression of important activating and inhibiting NK-cell receptors and their effector function is reviewed. Furthermore, external stimuli such as physical activity and their influence on the epigenetic level are discussed.

  11. Cytodiagnosis of extranodal natural killer/T-cell lymphoma, nasal type: Report of two cases

    Directory of Open Access Journals (Sweden)

    Kavita Mardi

    2014-01-01

    Full Text Available Extranodal natural killer (NK/T-cell lymphoma, nasal type (NK/T is relatively rare, associated with aggressive behavior and poor prognosis. Histopathological findings, immunohistochemical study, and Epstein-Barr virus-encoded ribonucleic acid in situ hybridization are essential for the diagnosis. There are a few case reports in the literature describing the cytological findings of these uncommon lymphomas. We herein describe cytological findings in two cases of extranodal NK/T-cell lymphoma, nasal type presenting as lacrimal gland and/or nasal masses. Fine-needle aspiration smears revealed small to medium-sized lymphoid cells showing irregular nuclear outline, moderate amounts of light basophilic cytoplasm containing fine azurophilic granules in most of the cells. Some of these atypical lymphoid cells showed tongue-like projections of cytoplasm from one or both sides of the cells. Histopathological examination revealed typical angoicentric, angiodestructive growth pattern of these lymphomas.

  12. Natural Killer Cells—An Epigenetic Perspective of Development and Regulation

    Science.gov (United States)

    Schenk, Alexander; Bloch, Wilhelm; Zimmer, Philipp

    2016-01-01

    Based on their ability to recognize and eliminate various endo- and exogenous pathogens as well as pathological alterations, Natural Killer (NK) cells represent an important part of the cellular innate immune system. Although the knowledge about their function is growing, little is known about their development and regulation on the molecular level. Research of the past decade suggests that modifications of the chromatin, which do not affect the base sequence of the DNA, also known as epigenetic alterations, are strongly involved in these processes. Here, the impact of epigenetic modifications on the development as well as the expression of important activating and inhibiting NK-cell receptors and their effector function is reviewed. Furthermore, external stimuli such as physical activity and their influence on the epigenetic level are discussed. PMID:26938533

  13. Extranodal natural killer/T-cell lymphoma, nasal type: epidemiology study

    Institute of Scientific and Technical Information of China (English)

    Yao Liao; Xiaobo Du; Qingfeng Zou

    2012-01-01

    Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTCL) is a rarely kind of non-Hodgkin lymphoma (NHL). It is much more frequent in Asian and Latin American countries than other part of the world. It typically affects nasal cavity. In China, one of its endemically places, ENKTCL accounts for 74%–96% of nasal NHL. Patients with ENKTCL usually show a highly aggressive clinical course, and its etiology is unclear. However, it is already proved that ENKTCL is associated with Epstein-Barr virus (EBV) infection, regardless patients', ethnicity and areas. Some studies show that the risk will increase among several occupations, such as farmer, who are frequently exposure to pesticides and chemical solvent and risk can be cut down if taking some protective measures.

  14. Effects of in vitro asbestos exposure on natural killer and antibody-dependent cellular cytotoxicity

    International Nuclear Information System (INIS)

    Human peripheral blood lymphocytes (PBL) were exposed in vitro to asbestos fibers. Antibody-dependent cellular cytotoxicity (ADCC) activity and natural killer (NK) activity were examined by a chromium-51 release assay. There was a statistically significant enhancement of ADCC and NK activity by chrysotile and crocidolite fibers when cultured together with PBL for a period of 42 hr in medium containing a concentration of at least 2.5% fetal calf serum. Isolation of large granular lymphocytes to measure NK activity, however, showed the opposite effect when exposed to asbestos fibers. Their results indicated that asbestos fibers can directly affect lymphoid cytotoxic responses in vitro and may provide clues to immunopathogenic mechanisms for the occurrence of neoplasms in vivo

  15. The neurological significance of abnormal natural killer cell activity in chronic toxigenic mold exposures.

    Science.gov (United States)

    Anyanwu, Ebere; Campbell, Andrew W; Jones, Joseph; Ehiri, John E; Akpan, Akpan I

    2003-11-13

    Toxigenic mold activities produce metabolites that are either broad-spectrum antibiotics or mycotoxins that are cytotoxic. Indoor environmental exposure to these toxigenic molds leads to adverse health conditions with the main outcome measure of frequent neuroimmunologic and behavioral consequences. One of the immune system disorders found in patients presenting with toxigenic mold exposure is an abnormal natural killer cell activity. This paper presents an overview of the neurological significance of abnormal natural killer cell (NKC) activity in chronic toxigenic mold exposure. A comprehensive review of the literature was carried out to evaluate and assess the conditions under which the immune system could be dysfunctionally interfered with leading to abnormal NKC activity and the involvement of mycotoxins in these processes. The functions, mechanism, the factors that influence NKC activities, and the roles of mycotoxins in NKCs were cited wherever necessary. The major presentations are headache, general debilitating pains, nose bleeding, fevers with body temperatures up to 40 degrees C (104 degrees F), cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, vertigo/dizziness, and in some cases, seizures. Although sleep is commonly considered a restorative process that is important for the proper functioning of the immune system, it could be disturbed by mycotoxins. Most likely, mycotoxins exert some rigorous effects on the circadian rhythmic processes resulting in sleep deprivation to which an acute and transient increase in NKC activity is observed. Depression, psychological stress, tissue injuries, malignancies, carcinogenesis, chronic fatigue syndrome, and experimental allergic encephalomyelitis could be induced at very low physiological concentrations by mycotoxin-induced NKC activity. In the light of this review, it is concluded that chronic exposures to toxigenic mold could lead to abnormal NKC activity with a wide range

  16. The Neurological Significance of Abnormal Natural Killer Cell Activity in Chronic Toxigenic Mold Exposures

    Directory of Open Access Journals (Sweden)

    Ebere Anyanwu

    2003-01-01

    Full Text Available Toxigenic mold activities produce metabolites that are either broad-spectrum antibiotics or mycotoxins that are cytotoxic. Indoor environmental exposure to these toxigenic molds leads to adverse health conditions with the main outcome measure of frequent neuroimmunologic and behavioral consequences. One of the immune system disorders found in patients presenting with toxigenic mold exposure is an abnormal natural killer cell activity. This paper presents an overview of the neurological significance of abnormal natural killer cell (NKC activity in chronic toxigenic mold exposure. A comprehensive review of the literature was carried out to evaluate and assess the conditions under which the immune system could be dysfunctionally interfered with leading to abnormal NKC activity and the involvement of mycotoxins in these processes. The functions, mechanism, the factors that influence NKC activities, and the roles of mycotoxins in NKCs were cited wherever necessary. The major presentations are headache, general debilitating pains, nose bleeding, fevers with body temperatures up to 40�C (104�F, cough, memory loss, depression, mood swings, sleep disturbances, anxiety, chronic fatigue, vertigo/dizziness, and in some cases, seizures. Although sleep is commonly considered a restorative process that is important for the proper functioning of the immune system, it could be disturbed by mycotoxins. Most likely, mycotoxins exert some rigorous effects on the circadian rhythmic processes resulting in sleep deprivation to which an acute and transient increase in NKC activity is observed. Depression, psychological stress, tissue injuries, malignancies, carcinogenesis, chronic fatigue syndrome, and experimental allergic encephalomyelitis could be induced at very low physiological concentrations by mycotoxin-induced NKC activity. In the light of this review, it is concluded that chronic exposures to toxigenic mold could lead to abnormal NKC activity with a wide

  17. Alloreactive natural killer cells for the treatment of acute myeloid leukemia: from stem cell transplantation to adoptive immunotherapy

    Directory of Open Access Journals (Sweden)

    Loredana eRuggeri

    2015-10-01

    Full Text Available Natural killer cells express activating and inhibitory receptors which recognize MHC class I alleles, termed Killer cell Immunoglobulin-like Receptors (KIRs. Preclinical and clinical data from haploidentical T-cell depleted stem cell transplantation have demonstrated that alloreactive KIR-L mismatched natural killer cells play a major role as effectors against acute myeloid leukemia. Outside the transplantation setting, several reports have proven the safety and feasibility of natural killer cell infusion in acute myeloid leukemia patients and, in some cases, provided evidence that transferred NK cells are functionally alloreactive and may have a role in disease control. Aim of the present work is to briefly summarize the most recent advances in the field by moving from the first preclinical and clinical demonstration of donor NK alloreactivity in the transplantation setting to the most recent attempts of exploiting the use of alloreactive NK cell infusion as a means of adoptive immunotherapy against acute myeloid leukemia. Altogether, these data highlight the pivotal role of NK cells for the development of novel immunological approaches in the clinical management of acute myeloid leukemia.

  18. Application of natural circulation systems: advantages and challenges - II

    International Nuclear Information System (INIS)

    Applications of natural circulation systems are provided for advanced light water reactor designs. Design features proposed for the passive advanced light water reactors include the use of passive, gravity-fed water supplies for emergency core cooling and natural circulation decay heat removal from the primary system and the containment, and natural circulation cooling within the core for all conditions. Examples are given from different types of advanced reactor designs for the use of passive safety systems under the operational, transient, and accident conditions. Challenges encountered in the design of passive safety systems for HPLWR are discussed in short, as an example case. (author)

  19. Natural circulation in an integral CANDU test facility

    International Nuclear Information System (INIS)

    Over 70 single- and two-phase natural circulation experiments have been completed in the RD-14M facility, an integral CANDU thermalhydraulic test loop. This paper describes the RD-14M facility and provides an overview of the impact of key parameters on the results of natural circulation experiments. Particular emphasis will be on phenomena which led to heat up at high system inventories in a small subset of experiments. Clarification of misunderstandings in a recently published comparison of the effectiveness of natural circulation flows in RD-14M to integral facilities simulating other reactor geometries will also be provided. (author)

  20. Study on instability of natural circulation induced by subcooled boiling

    International Nuclear Information System (INIS)

    The best estimate system analysis code RELAP5 was used to analyze the natural circulation systems. The instability boundaries of one natural circulation system were obtained under different conditions. According to present results, most of the boundary points were found in the low subcooled boiling zone. The natural circulation systems can tolerate high subcooled boiling, and the disturbance of bubbles departing from the wall and condensing in the subcooled boiling region may be the inherent source to induce the instability, then the flow oscillations can become self-sustained and evolve because of the phase differences among system driving force, resistance and flow rate. (authors)

  1. Killer Cell Immunoglobulin-like Receptor Genotype and Haplotype Investigation of Natural Killer Cells from an Australian Population of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients

    Science.gov (United States)

    Huth, T. K.; Brenu, E. W.; Staines, D. R.; Marshall-Gradisnik, S. M.

    2016-01-01

    Killer cell immunoglobulin-like receptor (KIR) genes encode for activating and inhibitory surface receptors, which are correlated with the regulation of Natural Killer (NK) cell cytotoxic activity. Reduced NK cell cytotoxic activity has been consistently reported in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients, and KIR haplotypes and allelic polymorphism remain to be investigated. The aim of this article was to conduct a pilot study to examine KIR genotypes, haplotypes, and allelic polymorphism in CFS/ME patients and nonfatigued controls (NFCs). Comparison of KIR and allelic polymorphism frequencies revealed no significant differences between 20 CFS/ME patients and 20 NFCs. A lower frequency of the telomeric A/B motif (P < 0.05) was observed in CFS/ME patients compared with NFCs. This pilot study is the first to report the differences in the frequency of KIR on the telomeric A/B motif in CFS/ME patients. Further studies with a larger CFS/ME cohort are required to validate these results. PMID:27346947

  2. Isolation and purification of natural killer cells subpopulations using mononuclear cells

    Directory of Open Access Journals (Sweden)

    Mosaffa N

    1999-06-01

    Full Text Available Natural Killer (NK cells are the main lymphocyte population expressing P75 B chain of the IL-2 receptor (IL-2R. Consequently, incubation of peripheral blood lymphocytes with IL-2 induce selective activation of NK cells and results in NK activity and generation of Lymphokine activated killer (LAK cells activity and proliferation. One of the early events during IL-2 activation of peripheral blood lymphocyte in both rodents and humans is adherence of some NK cells to plastic surface. The cells adherence to plastic after 24 hr of culture with IL-2 are almost exclusively CD56+, have the morphology large granular cells to yield a highly entiched population of activated NK cells that have been used for systemic adoptive immunotherapy. To test these hypothesis, we used highly purified population of human peripheral NK cells through the biological and nonimmunclogical phenotyping technique. Blood mononuclear cells were separated by centrifugation of ficol-hypaque gradient from normal blood donor (20-30 years age. We depleted after purification of nonadherent cells with nylonwool. We collected with rosette technique to remove cells with high affinity SRBC receptors. These cells separate in two parts A-NK and NA-NK by mononuclear celss activated supernatant media. The main objective results of this study show that the subpopulation of human NK cell which develope early adherent to plastic surface in the presence of supernatant mononuclear celss activation media was functionally more cytotoxic and killed K562 targets in single cell sytotoxicity manner and LDH activity assay than nonadherent NK cells and resting NK cells

  3. Transient characteristic analysis of integral pressurized water reactor from forced circulation to natural circulation

    International Nuclear Information System (INIS)

    Natural circulation of nuclear reactor has heat dumpling capacity, which can improve the inherent safety of reactor. In this paper, the conceptional design of integrated pressurized water reactor was studied and RELAP5/MOD3.4 was used to analyze transient characteristic in the process from forced circulation to natural circulation. What's more, the influence of reactor power, resistance, moment of inertia of main pump, and various operation strategies on transient characteristic in this conversion process were also studied. (authors)

  4. Assessment of human natural killer and lymphokine-activated killer cell cytotoxicity against Toxoplasma gondii trophozoites and brain cysts

    International Nuclear Information System (INIS)

    Because previous work has suggested that NK cells may be important in host resistance against the intracellular parasite Toxoplasma gondii we examined whether human NK cells and lymphokine-activated killer (LAK) cells have activity against trophozoites and cysts of this organism in vitro. A method to radiolabel Toxoplasma trophozoites with 51Cr was developed and direct cytotoxic activity was determined by using modifications of the standard 51Cr release assay. Viability of 51Cr-labeled trophozoites assessed by both methylene blue staining and trypan blue exclusion was greater than 90%. Significantly more 51Cr was released by anti-Toxoplasma antibody and C than by antibody in the absence of C. Incubation of trophozoites with freshly isolated human NK cells or NK cells activated with either rIL-2 or rIFN-alpha did not result in significant release of 51Cr (specific lysis was 0 to 2.3%). In contrast, the average specific lysis of radiolabeled trophozoites by LAK cells was significant. In a series of separate experiments, preincubation of radiolabeled trophozoites with heat-inactivated normal or Toxoplasma antibody-positive human serum increased the cytotoxicity of LAK cells from a mean specific lysis of 15% +/- 4.5 to 39% +/- 8.5, respectively, as assessed by 51Cr release. Because previous work has shown that radioisotope release from parasites may be nonspecific, separate experiments were performed to determine the cytotoxicity of LAK cells against antibody-coated trophozoites by using ethidium bromide-acridine orange staining to assess effector cell damage. LAK cells had a mean specific lysis of 51% against antibody-coated trophozoites by ethidium bromide-acridine orange staining. Preincubation with heat-inactivated Toxoplasma-antibody positive human serum did not increase activity of rIL-2-activated NK cells against 51CR-labeled trophozoites

  5. Natural Circulation Characteristics of a Symmetric Loop under Inclined Conditions

    Directory of Open Access Journals (Sweden)

    Xingtuan Yang

    2014-01-01

    Full Text Available Natural circulation is an important process for primary loops of some marine integrated reactors. The reactor works under inclined conditions when severe accidents happen to the ship. In this paper, to investigate the characteristics of natural circulation, experiments were conducted in a symmetric loop under the inclined angle of 0~45°. A CFD model was also set up to predict the behaviors of the loop beyond the experimental scope. Total circulation flow rate decreases with the increase of inclined angle. Meanwhile one circulation is depressed while the other is enhanced, and accordingly the disparity between the branch circulations arises and increases with the increase of inclined angle. Circulation only takes place in one branch circuit at large inclined angle. Also based on the CFD model, the influences of flow resistance distribution and loop configuration on natural circulation are predicted. The numerical results show that to design the loop with the configuration of big altitude difference and small width, it is favorable to reduce the influence of inclination; however too small loop width will cause severe reduction of circulation ability at large angle inclination.

  6. Activation mechanisms of invariant natural killer T cells (iNKTs

    Directory of Open Access Journals (Sweden)

    Baena, Andrés

    2016-01-01

    Full Text Available A great amount of knowledge on natural killer T cells (iNKTs is now available, but a consensus about their activation mechanisms has not been reached. These cells recognize different glycolipid antigens through the CD1d molecule. Such antigens may be endogenous, derived from bacteria (foreign and synthetic, the latter have been developed for clinical applications. There exists much interest in understanding how these different glycolipid compounds induce different types of polarization, but it has been difficult to reach a consensus due to the fact that responses depend on different factors such as: the nature of the molecule, the internalization process and the presentation of the glycolipids. Moreover, activation of iNKT cells is determined by the type and state of the antigen presenting cell, the co-stimulatory molecules, the transactivation mechanisms and the location of the glycolipid-CD1d complexes on the plasma membrane, such as the lipid rafts. This review explores the evidence about the factors that affect activation of iNKT cells in order to understand their immune-modulatory potential.

  7. Gut-Targeted Immunonutrition Boosting Natural Killer Cell Activity Using Saccharomyces boulardii Lysates in Immuno-Compromised Healthy Elderly Subjects

    OpenAIRE

    Naito, Yasuhiro; Marotta, Francesco; Kantah, Makoto K.; Zerbinati, Nicola; Kushugulova, Almagul; Zhumadilov, Zhaxybay; Illuzzi, Nicola; Sapienza, Chiara; Takadanohara, Hiroshi; Kobayashi, Riyichi; Catanzaro, Roberto

    2014-01-01

    The aim of this study was to assess the immunomodulatory effect of KC-1317 (a symbiotic mixture containing Saccharomyces boulardii lysate in a cranberry, colostrum-derived lactoferrin, fragaria, and lactose mixture) supplementation in immune-compromised but otherwise healthy elderly subjects. A liquid formulation of KC-1317 was administered in a randomized controlled trial (RCT) fashion to healthy volunteers (65–79 years) previously selected for low natural killer (NK) cell activity, and this...

  8. Functional Perturbation of Classical Natural Killer and Innate Lymphoid Cells in the Oral Mucosa during SIV Infection

    OpenAIRE

    Li, Haiying; Reeves, R. Keith

    2013-01-01

    Despite the fact that the majority of human pathogens are transmitted across mucosal surfaces, including the oral mucosae, oral immunity is poorly understood. Furthermore, because the normal flora of the oral cavity is vast and significantly diverse, host immunity must balance a complex system of tolerance and pathogen recognition. Due to the rapid recognition and response to pathogens, the innate immune system, including natural killer (NK) cells, likely plays a critical role in mediating th...

  9. Consolidative treatment after salvage chemotherapy improves prognosis in patients with relapsed extranodal natural killer/T-cell lymphoma

    OpenAIRE

    Man Nie; Xi-wen Bi; Wen-wen Zhang; Peng Sun; Yi Xia; Pan-pan Liu; Hui-qiang Huang; Wen-qi Jiang; Zhi-ming Li

    2016-01-01

    The optimal treatment strategy for relapsed natural killer/T-cell lymphoma (NKTCL) remains largely unknown. We retrospectively reviewed the treatment modalities and prognosis of 56 relapsed NKTCL patients. Chemotherapy was the initial salvage treatment, followed by radiotherapy (RT) or autologous hematopoietic stem cell transplantation (AHSCT) as consolidative therapy, depending on the status of remission and the pattern of relapse. For patients with locoregional relapse alone, consolidative ...

  10. Identification, characterisation and expression analysis of natural killer receptor genes in Chlamydia pecorum infected koalas (Phascolarctos cinereus)

    OpenAIRE

    Morris, Katrina M.; Mathew, Marina; Waugh, Courtney; Ujvari, Beata; Timms, Peter; Polkinghorne, Adam; Belov, Katherine

    2015-01-01

    Background Koalas (Phascolarctos cinereus), an iconic Australian marsupial, are being heavily impacted by the spread of Chlamydia pecorum, an obligate intracellular bacterial pathogen. Koalas vary in their response to this pathogen, with some showing no symptoms, while others suffer severe symptoms leading to infertility, blindness or death. Little is known about the pathology of this disease and the immune response against it in this host. Studies have demonstrated that natural killer (NK) c...

  11. Activity and Phenotype of Natural Killer Cells in Peptide Transporter (TAP)-deficient Patients (Type I Bare Lymphocyte Syndrome)

    OpenAIRE

    Zimmer, Jacques; Donato, Lionel; Hanau, Daniel; Cazenave, Jean-Pierre; Tongio, Marie-Marthe; Moretta, Alessandro; Salle, Henri de la

    1998-01-01

    In this paper we describe the function and phenotype of natural killer (NK) lymphocytes from HLA class I–deficient patients. These cells are, as has been previously reported, unable to lyse HLA class I− K562 cells, but are able to perform antibody-dependent cellular cytotoxicity (ADCC), although with lower efficiency as compared to NK cells from normal individuals. Transporter associated to antigen processing (TAP)− NK cells proliferate when cultured in the presence of lymphoblastoid B cells ...

  12. Alterations in Natural Killer Cell Receptor Profiles During HIV Type 1 Disease Progression Among Chronically Infected South African Adults

    OpenAIRE

    Wong, Ambrose H.W.; Williams, Katie; Reddy, Sharon; Wilson, Douglas; Giddy, Janet; Alter, Galit; Ghebremichael, Musie; Carrington, Mary N; Ndung'u, Thumbi; Walker, Bruce D.; Altfeld, Marcus; Carr, William H.

    2010-01-01

    Recent studies suggest that innate immune responses by natural killer (NK) cells play a significant role in restricting human immunodeficiency virus type-1 (HIV-1) pathogenesis. Our aim was to characterize changes in NK cells associated with HIV-1 clade C disease progression. Here we used multiparametric flow cytometry (LSRII) to quantify phenotype and function of NK cells in a cross-sectional analysis of cryopreserved blood samples from a cohort of 41 chronically HIV-1-infected, treatment-na...

  13. Live cell linear dichroism imaging reveals extensive membrane ruffling within the docking structure of natural killer cell immune synapses

    DEFF Research Database (Denmark)

    Benninger, Richard K P; Vanherberghen, Bruno; Young, Stephen;

    2009-01-01

    We have applied fluorescence imaging of two-photon linear dichroism to measure the subresolution organization of the cell membrane during formation of the activating (cytolytic) natural killer (NK) cell immune synapse (IS). This approach revealed that the NK cell plasma membrane is convoluted into...... absent from the center of the mature synapse. Understanding the role of such extensive membrane ruffling in the assembly of cytolytic synapses is an intriguing new goal....

  14. Evaluation of CD56dim and CD56bright natural killer cells in peripheral blood of women with IVF failures

    OpenAIRE

    Farahnaz Mardanian; Moones Kazeroonizadeh; Bahman Rashidi

    2015-01-01

    Background: Infertility is an increasing medical and social problem. In vitro fertilization (IVF) has become a common and accessible treatment for a wide variety of indications that have variable outcomes. Natural killer (NK) cells have been identified as relevant immunological factors involved in reproductive success or failure. Objective: The aim of this study was to compare the percentage of peripheral blood CD56+ (CD56dim and CD56bright) cells and the level of NK cell in patients with ...

  15. Malignant monoblasts can function as effector cells in natural killer cell and antibody-dependent cellular cytotoxicity assays

    DEFF Research Database (Denmark)

    Hokland, P; Hokland, M; Ellegaard, J

    1981-01-01

    This is the first report describing natural killer (NK) and antibody-dependent cellular cytotoxicity (ADCC) of malignant monoblasts. Pure acute monoblastic leukemia was diagnosed in bone marrow aspirations from two patients by use of conventional cytochemical methods as well as multiple immunologic...... modulation was seen in ADCC. These findings are discussed in the light of our present knowledge of lymphoid NK cells. Udgivelsesdato: 1981-May...

  16. TRAIL-mediated killing of acute lymphoblastic leukemia by plasmacytoid dendritic cell-activated natural killer cells

    OpenAIRE

    Lelaidier, Martin; Dìaz-Rodriguez, Yildian; Cordeau, Martine; Cordeiro, Paulo; Haddad, Elie; Herblot, Sabine; Duval, Michel

    2015-01-01

    Acute lymphoblastic leukemia (ALL) still frequently recurs after hematopoietic stem cell transplantation (HSCT), underscoring the need to improve the graft-versus-leukemia (GvL) effect. Natural killer (NK) cells reconstitute in the first months following HSCT when leukemia burden is at its lowest, but ALL cells have been shown to be resistant to NK cell-mediated killing. We show here that this resistance is overcome by NK cell stimulation with TLR-9-activated plasmacytoid dendritic cells (pDC...

  17. Model for large scale circulation of nuclides in nature, 1

    Energy Technology Data Exchange (ETDEWEB)

    Ohnishi, Teruaki

    1988-12-01

    A model for large scale circulation of nuclides was developed, and a computer code named COCAIN was made which simulates this circulation system-dynamically. The natural environment considered in the present paper consists of 2 atmospheres, 8 geospheres and 2 lithospheres. The biosphere is composed of 4 types of edible plants, 5 cattles and their products, 4 water biota and 16 human organs. The biosphere is assumed to be given nuclides from the natural environment mentioned above. With the use of COCAIN, two numerical case studies were carried out; the one is the study on nuclear pollution in nature by the radioactive nuclides originating from the past nuclear bomb tests, and the other is the study on the response of environment and biota to the pulse injection of nuclides into one compartment. From the former case study it was verified that this model can well explain the observation and properly simulate the large scale circulation of nuclides in nature.

  18. Model for large scale circulation of nuclides in nature, 1

    International Nuclear Information System (INIS)

    A model for large scale circulation of nuclides was developed, and a computer code named COCAIN was made which simulates this circulation system-dynamically. The natural environment considered in the present paper consists of 2 atmospheres, 8 geospheres and 2 lithospheres. The biosphere is composed of 4 types of edible plants, 5 cattles and their products, 4 water biota and 16 human organs. The biosphere is assumed to be given nuclides from the natural environment mentioned above. With the use of COCAIN, two numerical case studies were carried out; the one is the study on nuclear pollution in nature by the radioactive nuclides originating from the past nuclear bomb tests, and the other is the study on the response of environment and biota to the pulse injection of nuclides into one compartment. From the former case study it was verified that this model can well explain the observation and properly simulate the large scale circulation of nuclides in nature. (author)

  19. Suppression of a Natural Killer Cell Response by Simian Immunodeficiency Virus Peptides.

    Directory of Open Access Journals (Sweden)

    Jamie L Schafer

    2015-09-01

    Full Text Available Natural killer (NK cell responses in primates are regulated in part through interactions between two highly polymorphic molecules, the killer-cell immunoglobulin-like receptors (KIRs on NK cells and their major histocompatibility complex (MHC class I ligands on target cells. We previously reported that the binding of a common MHC class I molecule in the rhesus macaque, Mamu-A1*002, to the inhibitory receptor Mamu-KIR3DL05 is stabilized by certain simian immunodeficiency virus (SIV peptides, but not by others. Here we investigated the functional implications of these interactions by testing SIV peptides bound by Mamu-A1*002 for the ability to modulate Mamu-KIR3DL05+ NK cell responses. Twenty-eight of 75 SIV peptides bound by Mamu-A1*002 suppressed the cytolytic activity of primary Mamu-KIR3DL05+ NK cells, including three immunodominant CD8+ T cell epitopes previously shown to stabilize Mamu-A1*002 tetramer binding to Mamu-KIR3DL05. Substitutions at C-terminal positions changed inhibitory peptides into disinhibitory peptides, and vice versa, without altering binding to Mamu-A1*002. The functional effects of these peptide variants on NK cell responses also corresponded to their effects on Mamu-A1*002 tetramer binding to Mamu-KIR3DL05. In assays with mixtures of inhibitory and disinhibitory peptides, low concentrations of inhibitory peptides dominated to suppress NK cell responses. Consistent with the inhibition of Mamu-KIR3DL05+ NK cells by viral epitopes presented by Mamu-A1*002, SIV replication was significantly higher in Mamu-A1*002+ CD4+ lymphocytes co-cultured with Mamu-KIR3DL05+ NK cells than with Mamu-KIR3DL05- NK cells. These results demonstrate that viral peptides can differentially affect NK cell responses by modulating MHC class I interactions with inhibitory KIRs, and provide a mechanism by which immunodeficiency viruses may evade NK cell responses.

  20. Identification of natural killer cell receptor genes in the genome of the marsupial Tasmanian devil (Sarcophilus harrisii).

    Science.gov (United States)

    van der Kraan, Lauren E; Wong, Emily S W; Lo, Nathan; Ujvari, Beata; Belov, Katherine

    2013-01-01

    Within the mammalian immune system, natural killer (NK) cells contribute to the first line of defence against infectious agents and tumours. Their activity is regulated, in part, by cell surface NK cell receptors. NK receptors can be divided into two unrelated, but functionally analogous superfamilies based on the structure of their extracellular ligand-binding domains. Receptors belonging to the C-type lectin superfamily are predominantly encoded in the natural killer complex (NKC), while receptors belonging to the immunoglobulin superfamily are predominantly encoded in the leukocyte receptor complex (LRC). Natural killer cell receptors are emerging as a rapidly evolving gene family which can display significant intra- and interspecific variation. To date, most studies have focused on eutherian mammals, with significantly less known about the evolution of these receptors in marsupials. Here, we describe the identification of 43 immunoglobulin domain-containing LRC genes in the genome of the Tasmanian devil (Sarcophilus harrisii), the largest remaining marsupial carnivore and only the second marsupial species to be studied. We also identify orthologs of NKC genes KLRK1, CD69, CLEC4E, CLEC1B, CLEC1A and an ortholog of an opossum NKC receptor. Characterisation of these regions in a second, distantly related marsupial provides new insights into the dynamic evolutionary histories of these receptors in mammals. Understanding the functional role of these genes is also important for the development of therapeutic agents against Devil Facial Tumour Disease, a contagious cancer that threatens the Tasmanian devil with extinction. PMID:23007952

  1. Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium.

    Science.gov (United States)

    Maltez, Vivien I; Tubbs, Alan L; Cook, Kevin D; Aachoui, Youssef; Falcone, E Liana; Holland, Steven M; Whitmire, Jason K; Miao, Edward A

    2015-11-17

    Defective neutrophils in patients with chronic granulomatous disease (CGD) cause susceptibility to extracellular and intracellular infections. Microbes must first be ejected from intracellular niches to expose them to neutrophil attack, so we hypothesized that inflammasomes detect certain CGD pathogens upstream of neutrophil killing. Here, we identified one such ubiquitous environmental bacterium, Chromobacterium violaceum, whose extreme virulence was fully counteracted by the NLRC4 inflammasome. Caspase-1 protected via two parallel pathways that eliminated intracellular replication niches. Pyroptosis was the primary bacterial clearance mechanism in the spleen, but both pyroptosis and interleukin-18 (IL-18)-driven natural killer (NK) cell responses were required for liver defense. NK cells cleared hepatocyte replication niches via perforin-dependent cytotoxicity, whereas interferon-γ was not required. These insights suggested a therapeutic approach: exogenous IL-18 restored perforin-dependent cytotoxicity during infection by the inflammasome-evasive bacterium Listeria monocytogenes. Therefore, inflammasomes can trigger complementary programmed cell death mechanisms, directing sterilizing immunity against intracellular bacterial pathogens. PMID:26572063

  2. Toxoplasma gondii infection regulates the balance of activating and inhibitory receptors on decidual natural killer cells.

    Directory of Open Access Journals (Sweden)

    Xiaoyan Xu

    Full Text Available Inhibitory receptors and activating receptor expressed on decidual natural killer (dNK cells are generally believed to be important in abnormal pregnancy outcomes and induced adverse pregnancy. However, if Toxoplasma gondii (T. gondii infection induced abnormal pregnancy was related to dNK cells changes is not clear. In this study, we used human dNK cells co-cultured with human extravillous cytotrophoblast (EVT cells following YFP-Toxoplasma gondii (YFP-T. gondii infection in vitro and established animal pregnant infection model. Levels of inhibitory receptors KIR2DL4 and ILT-2, their ligand HLA-G, and activating receptor NKG2D in human decidua, and NKG2A and its ligand Qa-1 and NKG2D in mice uterine were analyzed by real-time PCR and flow cytometry with levels of NKG2D significantly higher than those of KIR2DL4 and ILT-2 in vitro and in invo. The level of NKG2D was positively correlated with cytotoxic activity of dNK cells in vitro. Numbers of abnormal pregnancies were significantly greater in the infected group than in the control group. This result demonstrated that the increased NKG2D expression and imbalance between inhibitory receptors of dNK cells and HLA-G may contribute to abnormal pregnancy outcomes observed upon maternal infection with T. gondii.

  3. Donor liver natural killer cells alleviate liver allograft acute rejection in rats

    Institute of Scientific and Technical Information of China (English)

    Jian-Dong Yu; Tian-Zhu Long; Guo-Lin Li; Li-Hong Lv; Hao-Ming Lin; Yong-Heng Huang; Ya-Jin Chen; Yun-Le Wan

    2011-01-01

    BACKGROUND: Liver enriched natural killer (NK) cells are of high immune activity. However, the function of donor liver NK cells in allogeneic liver transplantation (LTx) remains unclear. METHODS: Ten Gy of whole body gamma-irradiation (WBI) from a 60Co source at 0.6 Gy/min was used for depleting donor-derived leukocytes, and transfusion of purified liver NK cells isolated from the same type rat as donor (donor type liver NK cells, dtlNKs) through portal vein was performed immediately after grafting the irradiated liver. Post-transplant survival observation on recipients and histopathological detection of liver grafts were adoptive to evaluate the biological impact of donor liver NK cells on recipients' survival in rat LTx. RESULTS: Transfusion of dtlNKs did not shorten the survival time among the recipients of spontaneous tolerance model (BN to LEW rat) after rat LTx, but prolonged the liver graft survival among the recipients depleted of donor-derived leukocytes in the acute rejection model (LEW to BN rat). Compared to the recipients in the groups which received the graft depleted of donor-derived leukocytes, better survival and less damage in the allografts were also found among the recipients in the two different strain combinations of liver allograft due to transfusion of dtlNKs. CONCLUSIONS: Donor liver NK cells alone do not exacerbate liver allograft acute rejection. Conversely, they can alleviate it, and improve the recipients' survival.

  4. Attenuation of natural killer cell functions by capsaicin through a direct and TRPV1-independent mechanism.

    Science.gov (United States)

    Kim, Hun Sik; Kwon, Hyung-Joon; Kim, Gye Eun; Cho, Mi-Hyang; Yoon, Seung-Yong; Davies, Alexander J; Oh, Seog Bae; Lee, Heuiran; Cho, Young Keol; Joo, Chul Hyun; Kwon, Seog Woon; Kim, Sun Chang; Kim, Yoo Kyum

    2014-07-01

    The assessment of the biological activity of capsaicin, the compound responsible for the spicy flavor of chili pepper, produced controversial results, showing either carcinogenicity or cancer prevention. The innate immune system plays a pivotal role in cancer pathology and prevention; yet, the effect of capsaicin on natural killer (NK) cells, which function in cancer surveillance, is unclear. This study found that capsaicin inhibited NK cell-mediated cytotoxicity and cytokine production (interferon-γ and tumor necrosis factor-α). Capsaicin impaired the cytotoxicity of NK cells, thereby inhibiting lysis of standard target cells and gastric cancer cells by modulating calcium mobilization in NK cells. Capsaicin also induced apoptosis in gastric cancer cells, but that effect required higher concentrations and longer exposure times than those required to trigger NK cell dysfunction. Furthermore, capsaicin inhibited the cytotoxicity of isolated NK cells and of an NK cell line, suggesting a direct effect on NK cells. Antagonists of transient receptor potential vanilloid subfamily member 1 (TRPV1), a cognate capsaicin receptor, or deficiency in TRPV1 expression failed to prevent the defects induced by capsaicin in NK cells expressing functional TRPV1. Thus, the mechanism of action of capsaicin on NK cells is largely independent of TRPV1. Taken together, capsaicin may have chemotherapeutic potential but may impair NK cell function, which plays a central role in tumor surveillance. PMID:24743513

  5. Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application.

    Science.gov (United States)

    Hayashi, Toshiaki; Hideshima, Teru; Akiyama, Masaharu; Podar, Klaus; Yasui, Hiroshi; Raje, Noopur; Kumar, Shaji; Chauhan, Dharminder; Treon, Steven P; Richardson, Paul; Anderson, Kenneth C

    2005-01-01

    Thalidomide and immunomodulatory drugs (IMiDs), which target multiple myeloma (MM) cells and the bone marrow microenvironment, can overcome drug resistance. These agents also have immunomodulatory effects. Specifically, we have reported that thalidomide increased serum interleukin-2 (IL-2) levels and natural killer (NK) cell numbers in the peripheral blood of responding MM patients. In this study, we investigated the mechanisms whereby IMiDs augment NK cell cytotoxicity. NK cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) of peripheral blood mononuclear cells cultured with IMiDs were examined in the presence or absence of anti-IL-2 antibody, ciclosporin A or depletion of CD56-positive cells. IMiDs-induced signalling pathways, triggering IL-2 transcription in T cells, were also delineated. IMiDs facilitated the nuclear translocation of nuclear factor of activated T cells-2 and activator protein-1 via activation of phosphoinositide-3 kinase signalling, with resultant IL-2 secretion. IMiDs enhanced both NK cell cytotoxicity and ADCC induced by triggering IL-2 production from T cells. These studies defined the mechanisms whereby IMiDs trigger NK cell-mediated tumour-cell lysis, further supporting their therapeutic use in MM. PMID:15638853

  6. Role of natural killer and dendritic cell crosstalk in immunomodulation by commensal bacteria probiotics.

    Science.gov (United States)

    Rizzello, Valeria; Bonaccorsi, Irene; Dongarrà, Maria Luisa; Fink, Lisbeth Nielsen; Ferlazzo, Guido

    2011-01-01

    A cooperative dialogue between natural killer (NK) cells and dendritic cells (DCs) has been elucidated in the last years. They help each other to acquire their complete functions, both in the periphery and in the secondary lymphoid organs. Thus, NK cells' activation by dendritic cells allows the killing of transformed or infected cells in the periphery but may also be important for the generation of adaptive immunity. Indeed, it has been shown that NK cells may play a key role in polarizing a Th1 response upon interaction with DCs exposed to microbial products. This regulatory role of DC/NK cross-talk is of particular importance at mucosal surfaces such as the intestine, where the immune system exists in intimate association with commensal bacteria such as lactic acid bacteria (LAB). We here review NK/DC interactions in the presence of gut-derived commensal bacteria and their role in bacterial strain-dependent immunomodulatory effects. We particularly aim to highlight the ability of distinct species of commensal bacterial probiotics to differently affect the outcome of DC/NK cross-talk and consequently to differently influence the polarization of the adaptive immune response. PMID:21660136

  7. Natural Killer (NK- and T-Cell Engaging Antibody-Derived Therapeutics

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    Christoph Stein

    2012-06-01

    Full Text Available Unmodified antibodies (abs have been successful in the treatment of hematologic malignancies, but less so for the treatment of solid tumors. They trigger anti-tumor effects through their Fc-domains, and one way to improve their efficacy is to optimize their interaction with the effectors through Fc-engineering. Another way to empower abs is the design of bispecific abs and related fusion proteins allowing a narrower choice of effector cells. Here we review frequently chosen classes of effector cells, as well as common trigger molecules. Natural Killer (NK- and T-cells are the most investigated populations in therapeutical approaches with bispecific agents until now. Catumaxomab, the first bispecific ab to receive drug approval, targets the tumor antigen Epithelial Cell Adhesion Molecule (EpCAM and recruits T-cells via a binding site for the cell surface protein CD3. The next generation of recombinant ab-derivatives replaces the broadly reactive Fc-domain by a binding domain for a single selected trigger. Blinatumomab is the first clinically successful member of this class, targeting cancer cells via CD19 and engaging T-cells by CD3. Other investigators have developed related recombinant fusion proteins to recruit effectors, such as NK-cells and macrophages. The first such agents currently in preclinical and clinical development will be discussed.

  8. All-trans retinoic acid negatively regulates cytotoxic activities of nature killer cell line 92

    International Nuclear Information System (INIS)

    NK cells are key components of innate immune systems and their activities are regulated by cytokines and hormones. All-trans retinoic acid (ATRA), as a metabolite of vitamin A and an immunomodulatory hormone, plays an important role in regulating immune responses. In the present study, we investigated the effect of ATRA on human NK cell line NK92. We found that ATRA dose-dependently suppressed cytotoxic activities of NK92 cells without affecting their proliferation. To explore the mechanisms underlying the ATRA influence on NK92 cells, we examined the production of cytokines (TNF-α, IFN-γ), gene expression of cytotoxic-associated molecules (perforin, granzyme B, nature killer receptors (NCRs), and NKG2D), and the activation of NF-κB pathways related with immune response. Our results demonstrated that ATRA suppressed NF-κB activity and prevented IκBα degradation in a dose-dependent way, inhibited IFN-γ production and gene expression of granzyme B and NKp46. Our findings suggest that ATRA is a negative regulator of NK92 cell activation and may act as a potential regulator of anti-inflammatory functions in vivo

  9. The Natural Killer Cell Cytotoxic Function Is Modulated by HIV-1 Accessory Proteins

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    Edward Barker

    2011-07-01

    Full Text Available Natural killer (NK cells’ major role in the control of viruses is to eliminate established infected cells. The capacity of NK cells to kill virus-infected cells is dependent on the interactions between ligands on the infected cell and receptors on the NK cell surface. Because of the importance of ligand-receptor interactions in modulating the NK cell cytotoxic response, HIV has developed strategies to regulate various NK cell ligands making the infected cell surprisingly refractory to NK cell lysis. This is perplexing because the HIV-1 accessory protein Vpr induces expression of ligands for the NK cell activating receptor, NKG2D. In addition, the accessory protein Nef removes the inhibitory ligands HLA-A and -B. The reason for the ineffective killing by NK cells despite the strong potential to eliminate infected cells is due to HIV-1 Vpu’s ability to down modulate the co-activation ligand, NTB-A, from the cell surface. Down modulation of NTB-A prevents efficient NK cell degranulation. This review will focus on the mechanisms through which the HIV-1 accessory proteins modulate their respective ligands, and its implication for NK cell killing of HIV-infected cells.

  10. Oxygen Modulates Human Decidual Natural Killer Cell Surface Receptor Expression and Interactions with Trophoblasts1

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    Wallace, Alison E.; Goulwara, Sonu S.; Whitley, Guy S.; Cartwright, Judith E.

    2014-01-01

    Decidual natural killer (dNK) cells have been shown to both promote and inhibit trophoblast behavior important for decidual remodeling in pregnancy and have a distinct phenotype compared to peripheral blood NK cells. We investigated whether different levels of oxygen tension, mimicking the physiological conditions of the decidua in early pregnancy, altered cell surface receptor expression and activity of dNK cells and their interactions with trophoblast. dNK cells were isolated from terminated first-trimester pregnancies and cultured in oxygen tensions of 3%, 10%, and 21% for 24 h. Cell surface receptor expression was examined by flow cytometry, and the effects of secreted factors in conditioned medium (CM) on the trophoblast cell line SGHPL-4 were assessed in vitro. SGHPL-4 cells treated with dNK cell CM incubated in oxygen tensions of 10% were significantly more invasive (P oxygen tensions of 3% or 21%. After 24 h, a lower percentage of dNK cells expressed CD56 at 21% oxygen (P oxygen (P oxygen tensions, with large patient variation. This study demonstrates dNK cell phenotype and secreted factors are modulated by oxygen tension, which induces changes in trophoblast invasion and endovascular-like differentiation. Alterations in dNK cell surface receptor expression and secreted factors at different oxygen tensions may represent regulation of function within the decidua during the first trimester of pregnancy. PMID:25232021

  11. Decreased Cytotoxicity of Peripheral and Peritoneal Natural Killer Cell in Endometriosis

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    Jeung, InCheul; Cheon, Keunyoung; Kim, Mee-Ran

    2016-01-01

    Endometriosis causes significant chronic pelvic pain, dysmenorrhea, and infertility and affects 10% of all women. In endometriosis, ectopic endometrium surviving after retrograde menstruation exhibits an abnormal immune response characterized by increased levels of activated macrophages and inflammatory cytokines. Particularly, dysfunctional natural killer (NK) cells play an important role in the pathogenesis of the disease by either facilitating or inhibiting the survival, implantation, and proliferation of endometrial cells. NK cells in the peritoneum and peritoneal fluid exhibit reduced levels of cytotoxicity in women with endometriosis. Several cytokines and inhibitory factors in the serum and peritoneal fluid also dysregulate NK cell cytotoxicity. Additionally, increased numbers of immature peripheral NK cells and induction of NK cell apoptosis are evident in the peritoneal fluid of women with endometriosis. The high rate of endometriosis recurrence after pharmaceutical or surgical treatment, which is associated with dysfunctional NK cells, indicates that new immunomodulatory management strategies are required. A good understanding of immune dysfunction would enable improvement of current treatments for endometriosis. PMID:27294113

  12. Natural Killer Cell Evasion Is Essential for Infection by Rhesus Cytomegalovirus.

    Science.gov (United States)

    Sturgill, Elizabeth R; Malouli, Daniel; Hansen, Scott G; Burwitz, Benjamin J; Seo, Seongkyung; Schneider, Christine L; Womack, Jennie L; Verweij, Marieke C; Ventura, Abigail B; Bhusari, Amruta; Jeffries, Krystal M; Legasse, Alfred W; Axthelm, Michael K; Hudson, Amy W; Sacha, Jonah B; Picker, Louis J; Früh, Klaus

    2016-08-01

    The natural killer cell receptor NKG2D activates NK cells by engaging one of several ligands (NKG2DLs) belonging to either the MIC or ULBP families. Human cytomegalovirus (HCMV) UL16 and UL142 counteract this activation by retaining NKG2DLs and US18 and US20 act via lysomal degradation but the importance of NK cell evasion for infection is unknown. Since NKG2DLs are highly conserved in rhesus macaques, we characterized how NKG2DL interception by rhesus cytomegalovirus (RhCMV) impacts infection in vivo. Interestingly, RhCMV lacks homologs of UL16 and UL142 but instead employs Rh159, the homolog of UL148, to prevent NKG2DL surface expression. Rh159 resides in the endoplasmic reticulum and retains several NKG2DLs whereas UL148 does not interfere with NKG2DL expression. Deletion of Rh159 releases human and rhesus MIC proteins, but not ULBPs, from retention while increasing NK cell stimulation by infected cells. Importantly, RhCMV lacking Rh159 cannot infect CMV-naïve animals unless CD8+ cells, including NK cells, are depleted. However, infection can be rescued by replacing Rh159 with HCMV UL16 suggesting that Rh159 and UL16 perform similar functions in vivo. We therefore conclude that cytomegaloviral interference with NK cell activation is essential to establish but not to maintain chronic infection. PMID:27580123

  13. Sequential chemoradiotherapy for stage I/II nasal natural killer/T cell lymphoma

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    Noh, Young Joo [Ulsan University Hospital, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Ahn, Yong Chan; Kim, Won Seog; Ko, Young Hyeh [Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2004-09-15

    Authors would report the results of sequential CHOP chemotherapy (cyclophosphamide, adriamycin, vincristine, and prednisone) and involved field radiotherapy (IFRT) for early stage nasal natural killer/T-cell lymphoma (NKTCL). Fourteen among 17 patients, who were registered at the Samsung Medical Center tumor registry with stage I and II nasal NKTCL from March 1995 to December 1999 received this treatment protocol. Three to four cycles of CHOP chemotherapy were given at 3 weeks' interval, which was followed by local IFRT including the known tumor extent and the adjacent draining lymphatics. Favorable responses after chemotherapy (before IFRT) were achievable only in seven patients (5 CR's + 2 PR's: 50%), while seven patients showed disease progression. There were six patients with local failures, two with distant relapses, and none with regional lymphatic failure. The actuarial overall survival and progression-free survival at 3 years were 50.0% and 42.9%. All the failures and deaths occurred within 13 months of the treatment start. The factors that correlated with the improved survival were the absence of 'B' symptoms, the favorable response to chemotherapy and overall treatment, and the low risk by international prognostic index on univariate analyses. Compared with the historic treatment results by IFRT either alone or followed by chemotherapy, the current trial failed to demonstrate advantages with respect to the failure pattern and survival. Development of new treatment strategy in combining IFRT and chemotherapy is required for improving outcomes.

  14. Regulation of IL-2 induced proliferation and cytotoxicity in human natural killer cells by monoclonal antibodies

    International Nuclear Information System (INIS)

    Natural killer (NK) activity is mediated by a subpopulation of cells termed large granular lymphocytes (LGL), which exhibit cytotoxic activity against a variety of tumor targets. LGL express OKT8, OKT9, OKT10, OKT11, 3G8 (FcγR), OKM1, NKH1. The addition of recombinant IL-2 (rIL-2), increases cytotoxicity, induces IFN-γ production and leads to LGL proliferation. Since monoclonal antibodies (MoAb) represent highly specific probes to analyze possible surface molecules, they have studied the role of various MoAbs in the regulation of cytotoxicity, proliferation, and secretory function of purified LGL. LGL were isolated from nonadherent human peripheral blood leukocytes on discontinuous Percoll density gradients, followed by 290C E-rosette depletion of contaminating T cells. These preparations were ≥ 85% LGL and contained ≥ 5% OKT3+ cells. Using a limiting dilution assay, purified LGL were incubated with rIL-2 and the MoAbs (10 μg/ml) for 7 days. These cells were tested for cytotoxicity against K562 in a 51Cr- release assay, and for proliferation as determined by 3H-thymidine incorporation. Results indicate that the OKT9 antibody inhibited both the cytotoxicity and proliferation. MoAb against LGl markers (OKT11, OKT8, OKM1, 3G8, and NKH1) had no effect on cytotoxicity or proliferation. Unlike the T cell receptor complex (with OKT3), the surface molecules examined do not regulate LGL lysis or proliferation

  15. Prognostic significance of peripheral monocyte count in patients with extranodal natural killer/T-cell lymphoma

    International Nuclear Information System (INIS)

    Extranodal natural killer/T-cell lymphoma (ENKL) has heterogeneous clinical manifestations and prognosis. This study aims to evaluate the prognostic impact of absolute monocyte count (AMC) in ENKL, and provide some immunologically relevant information for better risk stratification in patients with ENKL. Retrospective data from 163 patients newly diagnosed with ENKL were analyzed. The absolute monocyte count (AMC) at diagnosis was analyzed as continuous and dichotomized variables. Independent prognostic factors of survival were determined by Cox regression analysis. The AMC at diagnosis were related to overall survival (OS) and progression-free survival (PFS) in patients with ENKL. Multivariate analysis identified AMC as independent prognostic factors of survival, independent of International Prognostic Index (IPI) and Korean prognostic index (KPI). The prognostic index incorporating AMC and absolute lymphocyte count (ALC), another surrogate factor of immune status, could be used to stratify all 163 patients with ENKL into different prognostic groups. For patients who received chemotherapy followed by radiotherapy (102 cases), the three AMC/ALC index categories identified patients with significantly different survivals. When superimposed on IPI or KPI categories, the AMC/ALC index was better able to identify high-risk patients in the low-risk IPI or KPI category. The baseline peripheral monocyte count is shown to be an effective prognostic indicator of survival in ENKL patients. The prognostic index related to tumor microenvironment might be helpful to identify high-risk patients with ENKL

  16. The role of natural killer cells in the early period of infection in murine cutaneous leishmaniasis

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    M.D. Laurenti

    1999-03-01

    Full Text Available In order to study the role of natural killer (NK cells during the early period of Leishmania infection, BALB/c mice were selectively and permanently depleted of NK cells by injection with 90Sr and subsequently infected with Leishmania (Leishmania amazonensis (HSJD-1 strain. 90Sr is known to selectively deplete NK cells, leaving an intact T- and B-cell compartment and preserving the ability to produce both interferon alpha and IL-2. This method of depletion has advantages when compared with depletion using anti-NK cell monoclonal antibodies because the effect is permanent and neither activates complement nor provokes massive cell death. In the present study, after one month of treatment with 90Sr, the depletion of NK cells was shown by a more than ten-fold reduction in the cytotoxic activity of these cells: 2 x 106 spleen cells from NK-depleted animals were required to reach the same specific lysis of target cells effected by 0.15 x 106 spleen cells from normal control animals. The histopathology of the skin lesion at 7 days after Leishmania infection showed more parasites in the NK cell-depleted group. This observation further strengthens a direct role of NK cells during the early period of Leishmania infection.

  17. Therapeutic potential and challenges of Natural killer cells in treatment of solid tumors

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    Andrea eGras Navarro

    2015-04-01

    Full Text Available Natural killer (NK cells are innate lymphoid cells that hold tremendous potential for effective immunotherapy for a broad range of cancers. Due to the mode of NK cell killing requiring one–to-one target engagement and site directed release of cytolytic granules, the therapeutic potential of NK cells has been most extensively explored in hematological malignancies. However, their ability to precisely kill antibody coated cells, cancer stem cells (CSCs and genotoxically altered cells, while maintaining tolerance to healthy cells makes them appealing therapeutic effectors for all cancer forms, including metastases. Due to their release of pro-inflammatory cytokines, NK cells may potently reverse the anti-inflammatory tumor microenvironment (TME and augment adaptive immune responses by promoting differentiation, activation and/ or recruitment of accessory immune cells to sites of malignancy. Nevertheless, integrated and coordinated mechanisms of subversion of NK cell activity against the tumor and its microenvironment exist. Although our understanding of the receptor ligand interactions that regulate NK cell functionality has evolved remarkably, the diversity of ligands and receptors is complex, as is their mechanistic foundations in regulating NK cell function. In this article, we review the literature and highlight how the TME manipulates the NK cell phenotypes, genotypes and tropism to evade tumor recognition and elimination. We discuss counter strategies that may be adopted to augment the efficacy of NK cell anti-tumor surveillance, the clinical trials that have been undertaken so far in solid malignancies, critically weighing the challenges and opportunities with this approach.

  18. NKp80 Defines a Critical Step during Human Natural Killer Cell Development

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    Aharon G. Freud

    2016-07-01

    Full Text Available Human natural killer (NK cells develop in secondary lymphoid tissues (SLTs through distinct stages. We identified two SLT lineage (Lin−CD34−CD117+/−CD94+CD16− “stage 4” subsets according to expression of the C-type lectin-like surface-activating receptor, NKp80: NKp80− (stage “4a” and NKp80+ (stage “4b”. Whereas stage 4b cells expressed more of the transcription factors T-BET and EOMES, produced interferon-gamma, and were cytotoxic, stage 4a cells expressed more of the transcription factors RORγt and AHR and produced interleukin-22, similar to SLT Lin−CD34−CD117+CD94−CD16− “stage 3” cells, whose phenotype overlaps with that of group 3 innate lymphoid cells (ILC3s. Co-culture with dendritic cells or transplantation into immunodeficient mice produced mature NK cells from stage 3 and stage 4a populations. These data identify NKp80 as a marker of NK cell maturity in SLTs and support a model of human NK cell development through a stage 4a intermediate with ILC3-associated features.

  19. Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity.

    Science.gov (United States)

    Yin, Jie; Leavenworth, Jianmei W; Li, Yang; Luo, Qi; Xie, Huafeng; Liu, Xinhua; Huang, Shan; Yan, Han; Fu, Zheng; Zhang, Liyun Y; Zhang, Litao; Hao, Junwei; Wu, Xudong; Deng, Xianming; Roberts, Charles W M; Orkin, Stuart H; Cantor, Harvey; Wang, Xi

    2015-12-29

    Changes of histone modification status at critical lineage-specifying gene loci in multipotent precursors can influence cell fate commitment. The contribution of these epigenetic mechanisms to natural killer (NK) cell lineage determination from common lymphoid precursors is not understood. Here we investigate the impact of histone methylation repressive marks (H3 Lys27 trimethylation; H3K27(me3)) on early NK cell differentiation. We demonstrate that selective loss of the histone-lysine N-methyltransferase Ezh2 (enhancer of zeste homolog 2) or inhibition of its enzymatic activity with small molecules unexpectedly increased generation of the IL-15 receptor (IL-15R) CD122(+) NK precursors and mature NK progeny from both mouse and human hematopoietic stem and progenitor cells. Mechanistic studies revealed that enhanced NK cell expansion and cytotoxicity against tumor cells were associated with up-regulation of CD122 and the C-type lectin receptor NKG2D. Moreover, NKG2D deficiency diminished the positive effects of Ezh2 inhibitors on NK cell commitment. Identification of the contribution of Ezh2 to NK lineage specification and function reveals an epigenetic-based mechanism that regulates NK cell development and provides insight into the clinical application of Ezh2 inhibitors in NK-based cancer immunotherapies. PMID:26668377

  20. Interferon-γ-Mediated Natural Killer Cell Activation by an Aqueous Panax ginseng Extract

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    Kazuyoshi Takeda

    2015-01-01

    Full Text Available Panax ginseng extracts are used in traditional herbal medicines, particularly in eastern Asia, but their effect on natural killer (NK cell activity is not completely understood. This study aimed to examine the effects of P. ginseng extracts on the cytotoxic activity of NK cells. We orally administered P. ginseng extracts or ginsenosides to wild-type (WT C57BL/6 (B6 and BALB/c mice and to B6 mice deficient in either recombination activating gene 2 (RAG-2 or interferon-γ (IFN-γ. We then tested the cytotoxic activity of NK cells (of spleen and liver mononuclear cells against NK-sensitive YAC-1 cells. Oral administration of P. ginseng aqueous extract augmented the cytotoxicity of NK cells in WT B6 and BALB/c mice and in RAG-2-deficient B6 mice, but not in IFN-γ-deficient B6 mice. This effect was only observed with the aqueous extract of P. ginseng. Interestingly, the ginsenosides Rb1 and Rg1 did not augment NK cell cytotoxicity. These results demonstrated that the aqueous P. ginseng extract augmented NK cell activation in vivo via an IFN-γ-dependent pathway.

  1. Suppression of natural killer cell activity by surgical stress in cancer patients and the underlying mechanisms.

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    Yoshihara,Hisashi

    1986-04-01

    Full Text Available The influence of surgical stress on the natural killer (NK activity of peripheral blood lymphocytes in patients with carcinoma of the lung or gastrointestinal system was studied. The peripheral blood lymphocytes of the patients showed a marked decrease in NK activity against K-562 cells as target cells 1-2 days after surgery. The activity remained lowered for 2 weeks after thoractomy and for 1 week after laparotomy. No appreciable suppression of NK activity was observed with normal human peripheral blood lymphocytes preincubated with postoperative patient sera. Peripheral blood mononuclear cells obtained postoperatively from patients lost NK activity after ultraviolet irradiation, without any detectable loss of viability. Such irradiated mononuclear cells showed inhibition of NK activity after a 24-hour preincubation with peripheral blood lymphocytes from normal subjects. Similar suppressive activity was demonstrable in a fraction of mononuclear cells with adhesiveness to plastic petri dishes, while non-adherent cells had no such activity. When added immediately to the cytotoxicity assay system without the 24-hour preincubation, patient mononuclear cells caused no inhibition of NK activity, whereas adherent cells from normal subjects enhanced NK activity. The findings seems to indicate that, following surgical stress, plastic dish-adherent peripheral blood mononuclear cells become deprived of NK helper activity and exert suppression, thus causing postoperative depression of NK activity.

  2. Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.

    Science.gov (United States)

    Jiang, Lu; Gu, Zhao-Hui; Yan, Zi-Xun; Zhao, Xia; Xie, Yin-Yin; Zhang, Zi-Guan; Pan, Chun-Ming; Hu, Yuan; Cai, Chang-Ping; Dong, Ying; Huang, Jin-Yan; Wang, Li; Shen, Yang; Meng, Guoyu; Zhou, Jian-Feng; Hu, Jian-Da; Wang, Jin-Fen; Liu, Yuan-Hua; Yang, Lin-Hua; Zhang, Feng; Wang, Jian-Min; Wang, Zhao; Peng, Zhi-Gang; Chen, Fang-Yuan; Sun, Zi-Min; Ding, Hao; Shi, Ju-Mei; Hou, Jian; Yan, Jin-Song; Shi, Jing-Yi; Xu, Lan; Li, Yang; Lu, Jing; Zheng, Zhong; Xue, Wen; Zhao, Wei-Li; Chen, Zhu; Chen, Sai-Juan

    2015-09-01

    Natural killer/T-cell lymphoma (NKTCL) is a malignant proliferation of CD56(+) and cytoCD3(+) lymphocytes with aggressive clinical course, which is prevalent in Asian and South American populations. The molecular pathogenesis of NKTCL has largely remained elusive. We identified somatic gene mutations in 25 people with NKTCL by whole-exome sequencing and confirmed them in an extended validation group of 80 people by targeted sequencing. Recurrent mutations were most frequently located in the RNA helicase gene DDX3X (21/105 subjects, 20.0%), tumor suppressors (TP53 and MGA), JAK-STAT-pathway molecules (STAT3 and STAT5B) and epigenetic modifiers (MLL2, ARID1A, EP300 and ASXL3). As compared to wild-type protein, DDX3X mutants exhibited decreased RNA-unwinding activity, loss of suppressive effects on cell-cycle progression in NK cells and transcriptional activation of NF-κB and MAPK pathways. Clinically, patients with DDX3X mutations presented a poor prognosis. Our work thus contributes to the understanding of the disease mechanism of NKTCL. PMID:26192917

  3. Local Production of Interferon Gamma by Invariant Natural Killer T cells Modulates Acute Lyme Carditis

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    Olson, Chris M.; Bates, Tonya C.; Izadi, Hooman; Radolf, Justin D.; Huber, Sally A.; Boyson, Jonathan E.; Anguita, Juan

    2009-01-01

    The Lyme disease spirochete, Borrelia burgdorferi, is the only known human pathogen that directly activates invariant natural killer T (iNKT) cells. The number and activation kinetics of iNKT cells vary greatly among different strains of mice. We now report the role of the iNKT cell response in the pathogenesis of Lyme disease using C57Bl/6 mice, a strain with optimal iNKT cell activation that is resistant to the development of spirochetal-induced inflammation. During experimental infection of B6 mice with B. burgdorferi, iNKT cells localize to the inflamed heart where they are activated by CD1d-expressing macrophages. Activation of iNKT cells in vivo results in the production of IFNγ, which we demonstrate ameliorates the severity of murine Lyme carditis by at least two mechanisms. First, IFNγ enhances the recognition of B. burgdorferi by macrophages, leading to increased phagocytosis of the spirochete. Secondly, IFNγ activation of macrophages increases the surface expression of CD1d, thereby facilitating further iNKT activation. Collectively, our data demonstrate that in the resistant background, B6, iNKT cells modulate the severity of murine Lyme carditis through the action of IFNγ, which appears to self-renew through a positive feedback loop during infection. PMID:19265151

  4. Targeting natural killer cell reactivity by employing antibody to NKp46: implications for type 1 diabetes.

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    Rami Yossef

    Full Text Available Natural killer (NK cells belong to the innate lymphoid cells. Their cytotoxic activity is regulated by the delicate balance between activating and inhibitory signals. NKp46 is a member of the primary activating receptors of NK cells. We previously reported that the NKp46 receptor is involved in the development of type 1 diabetes (T1D. Subsequently, we hypothesized that blocking this receptor could prevent or hinder disease development. To address this goal, we developed monoclonal antibodies for murine NKp46. One mAb, named NCR1.15, recognizes the mouse homologue protein of NKp46, named Ncr1, and was able to down-regulate the surface expression of NKp46 on primary murine NK cells following antibody injection in vivo. Additionally, NCR1.15 treatments were able to down-regulate cytotoxic activity mediated by NKp46, but not by other NK receptors. To test our primary assumption, we examined T1D development in two models, non-obese diabetic mice and low-dose streptozotocin. Our results show a significantly lower incidence of diabetic mice in the NCR1.15-treated group compared to control groups. This study directly demonstrates the involvement of NKp46 in T1D development and suggests a novel treatment strategy for early insulitis.

  5. Impact of natural killer cells on chronic hepatitis C and hepatocellular carcinoma.

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    Tatsumi, Tomohide; Takehara, Tetsuo

    2016-03-01

    Natural killer (NK) cells are involved in the pathogenesis of hepatitis C viral (HCV) infection and hepatocellular carcinoma (HCC). Recent immunological progresses have revealed the molecular mechanisms of activation or inhibition of NK cells. In patients infected with HCV, the percentages of NK cells are decreased and the NK receptor expression and function of NK cells including cytotoxicity and cytokine production are altered. These alterations in NK cells are associated with persistent infection with HCV, liver injury, liver fibrosis and liver carcinogenesis. In HCV treatment, NK cells play a role in the eradication of HCV in both interferon (IFN)-based therapy and IFN-free therapy using direct-acting antivirals (DAA). In HCC patients, the exhaustion of NK cells that represents lower cytotoxicity and impaired cytokine production may contribute to the progression of HCC. Several immunotherapies targeting NK cells have been reported. NK cell transfer and NK-activating gene therapy have been demonstrated to be effective in mouse liver cancer models and several clinical trials are ongoing. Recently, the role of major histocompatibility complex class I-related chain A (MICA), a human ligand of NKG2D, has attracted attention in the development of HCC. The expression of MICA could be controlled by anti-HCC drugs including sorafenib. A new chemo-immunotherapy may be expected in the treatment of HCC. In this review, we summarize the impact of NK cells on chronic hepatitis C and HCC. PMID:26574168

  6. Modified procedure for labelling target cells in a europium release assay of natural killer cell activity.

    Science.gov (United States)

    Pacifici, R; Di Carlo, S; Bacosi, A; Altieri, I; Pichini, S; Zuccaro, P

    1993-05-01

    Lanthanide europium chelated to diethylenetriaminopentaacetate (EuDTPA) can be used to label target cells such as tumor cells and lymphocytes (Blomberg et al., 1986a,b; Granberg et al., 1988). This procedure has permitted the development of new non-radioactive methods for the detection of target cell cytolysis by natural killer (NK) cells (Blomberg et al., 1986a,b), cytotoxic T lymphocytes (CTL) (Granberg et al., 1988) or complement-mediated cytolysis (Cui et al., 1992). However, we had no success with this method because of a lack of comparability between human NK cell activity simultaneously measured by a classical 51Cr release assay (Seaman et al., 1981) and EuDTPA release assay (Blomberg et al., 1986a). Furthermore, cell division and cell viability were significantly impaired by the suggested concentrations of EuCl3. In this paper, we present a modified non-cytotoxic method for target cell labelling with EuDTPA while cells are growing in culture medium. PMID:8486925

  7. NKp80 Defines a Critical Step during Human Natural Killer Cell Development.

    Science.gov (United States)

    Freud, Aharon G; Keller, Karen A; Scoville, Steven D; Mundy-Bosse, Bethany L; Cheng, Stephanie; Youssef, Youssef; Hughes, Tiffany; Zhang, Xiaoli; Mo, Xiaokui; Porcu, Pierluigi; Baiocchi, Robert A; Yu, Jianhua; Carson, William E; Caligiuri, Michael A

    2016-07-12

    Human natural killer (NK) cells develop in secondary lymphoid tissues (SLTs) through distinct stages. We identified two SLT lineage (Lin)(-)CD34(-)CD117(+/-)CD94(+)CD16(-) "stage 4" subsets according to expression of the C-type lectin-like surface-activating receptor, NKp80: NKp80(-) (stage "4a") and NKp80(+) (stage "4b"). Whereas stage 4b cells expressed more of the transcription factors T-BET and EOMES, produced interferon-gamma, and were cytotoxic, stage 4a cells expressed more of the transcription factors RORγt and AHR and produced interleukin-22, similar to SLT Lin(-)CD34(-)CD117(+)CD94(-)CD16(-) "stage 3" cells, whose phenotype overlaps with that of group 3 innate lymphoid cells (ILC3s). Co-culture with dendritic cells or transplantation into immunodeficient mice produced mature NK cells from stage 3 and stage 4a populations. These data identify NKp80 as a marker of NK cell maturity in SLTs and support a model of human NK cell development through a stage 4a intermediate with ILC3-associated features. PMID:27373165

  8. The mature activating natural killer cell immunologic synapse is formed in distinct stages.

    Science.gov (United States)

    Orange, Jordan S; Harris, K Eliza; Andzelm, Milena M; Valter, Markus M; Geha, Raif S; Strominger, Jack L

    2003-11-25

    Natural killer (NK) cells form a structure at their interface with a susceptible target cell called the activating NK cell immunologic synapse (NKIS). The mature activating NKIS contains a central and peripheral supramolecular activation cluster (SMAC), and includes polarized surface receptors, filamentous actin (F-actin) and perforin. Evaluation of the NKIS in human NK cells revealed CD2, CD11a, CD11b and F-actin in the peripheral SMAC (pSMAC) with perforin in the central SMAC. The accumulation of F-actin and surface receptors was rapid and depended on Wiskott-Aldrich syndrome protein-driven actin polymerization. The accumulation at and arrangement of these molecules in the pSMAC was not affected by microtubule depolymerization. The polarization of perforin, however was slower and required intact actin, Wiskott-Aldrich syndrome protein, and microtubule function. Thus the process of CD2, CD11a, CD11b, and F-actin accumulation in the pSMAC and perforin accumulation in the central SMAC of the NKIS are sequential processes with distinct cytoskeletal requirements. PMID:14612578

  9. Intrahepatic natural killer T cell populations are increased in human hepatic steatosis

    Institute of Scientific and Technical Information of China (English)

    Michael Adler; Sarah Taylor; Kamalu Okebugwu; Herman Yee; Christine Fielding; George Fielding; Michael Poles

    2011-01-01

    AIM: To determine if natural killer T cell (NKT) populations are affected in nonalcoholic fatty liver disease(NAFLD).METHODS: Patients undergoing bariatric surgery underwent liver biopsy and blood sampling during surgery.The biopsy was assessed for steatosis and immunocyte infiltration. Intrahepatic lymphocytes (IHLs) were isolated from the remainder of the liver biopsy,and peripheral blood mononuclear cells (PBMCs) were isolated from the blood. Expression of surface proteins on both IHLs and PBMCs were quantified using flow cytometry.RESULTS: Twenty-seven subjects participated in this study. Subjects with moderate or severe steatosis had a higher percentage of intrahepatic CD3+/CD56+ NKT cells (38.6%) than did patients with mild steatosis(24.1%, P = 0.05) or those without steatosis (21.5%, P= 0.03). Patients with moderate to severe steatosis alsohad a higher percentage of NKT cells in the blood (12.3%) as compared to patients with mild steatosis (2.5% P =0.02) and those without steatosis (5.1%, P = 0.05).CONCLUSION: NKT cells are significantly increased in the liver and blood of patients with moderate to severe steatosis and support the role of NKT cells in NAFLD.

  10. Natural Killer Cell Function and Dysfunction in Hepatitis C Virus Infection

    Directory of Open Access Journals (Sweden)

    Kayla A. Holder

    2014-01-01

    Full Text Available Viruses must continually adapt against dynamic innate and adaptive responses of the host immune system to establish chronic infection. Only a small minority (~20% of those exposed to hepatitis C virus (HCV spontaneously clear infection, leaving approximately 200 million people worldwide chronically infected with HCV. A number of recent research studies suggest that establishment and maintenance of chronic HCV infection involve natural killer (NK cell dysfunction. This relationship is illustrated in vitro by disruption of typical NK cell responses including both cell-mediated cytotoxicity and cytokine production. Expression of a number of activating NK cell receptors in vivo is also affected in chronic HCV infection. Thus, direct in vivo and in vitro evidence of compromised NK function in chronic HCV infection in conjunction with significant epidemiological associations between the outcome of HCV infection and certain combinations of NK cell regulatory receptor and class I human histocompatibility linked antigen (HLA genotypes indicate that NK cells are important in the immune response against HCV infection. In this review, we highlight evidence suggesting that selective impairment of NK cell activity is related to establishment of chronic HCV infection.

  11. Mechanisms of Innate Lymphoid Cell and Natural Killer T Cell Activation during Mucosal Inflammation

    Directory of Open Access Journals (Sweden)

    David Nau

    2014-01-01

    Full Text Available Mucosal surfaces in the airways and the gastrointestinal tract are critical for the interactions of the host with its environment. Due to their abundance at mucosal tissue sites and their powerful immunomodulatory capacities, the role of innate lymphoid cells (ILCs and natural killer T (NKT cells in the maintenance of mucosal tolerance has recently moved into the focus of attention. While NKT cells as well as ILCs utilize distinct transcription factors for their development and lineage diversification, both cell populations can be further divided into three polarized subpopulations reflecting the distinction into Th1, Th2, and Th17 cells in the adaptive immune system. While bystander activation through cytokines mediates the induction of ILC and NKT cell responses, NKT cells become activated also through the engagement of their canonical T cell receptors (TCRs by (glycolipid antigens (cognate recognition presented by the atypical MHC I like molecule CD1d on antigen presenting cells (APCs. As both innate lymphocyte populations influence inflammatory responses due to the explosive release of copious amounts of different cytokines, they might represent interesting targets for clinical intervention. Thus, we will provide an outlook on pathways that might be interesting to evaluate in this context.

  12. Clinical Relevance of Natural Killer Cells Following Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Jeanne M Palmer, Kamalakannan Rajasekaran, Monica S Thakar, Subramaniam Malarkannan

    2013-01-01

    Full Text Available Natural killer (NK cells are one of the first cells to recover following allogeneic hematopoietic stem cell transplantation (HSCT, and are believed to play an important role in facilitating engraftment or preventing post-transplant infection and tumor recurrence. Recent studies have provided novel insights into the mechanisms by which NK cells mediate these highly clinically relevant immunological functions. In particular, the ability of NK cells to reduce the risk of graft versus host disease (GVHD and increase the graft versus leukemia effect (GVL in the setting of human leukocyte antigen (HLA-haploidentical HSCT highlights their clinical potentials. NK cells also mediate anti-viral protection, in particular against cytomegalovirus (CMV, an infection that causes significant morbidity and mortality following transplant. Another crucial function of NK cells is providing protection against bacterial infections at the mucosal barriers. NK cells achieve this by promoting anti-microbial defenses and regeneration of epithelial cells. These recent exciting findings provide a strong basis for the formulation of novel NK cell-based immunotherapies. In this review, we summarize the recent advances related to the mechanisms, functions, and future clinical prospects of NK cells that can impact post-transplant outcomes.

  13. Comparison of the quantities and subset distributions of natural killer cells among different races

    Institute of Scientific and Technical Information of China (English)

    FENG Yan-meng; ZHANG Rui-jun; ZHU Hong; PENG Hong; ZHOU Xiao-ping; HONG Kun-xue; LIU Jian-li; CHEN Jian-ping; SHAO Yi-ming

    2010-01-01

    Background Natural killer (NK) cells play critical roles in host immune defense, while the quantities and subset distributions may vary among different races. To address the difference, we compared these variables among Chinese Han, the Caucasians and the Blacks. The study may provide critical background information for both basic research and clinical investigation.Methods Blood samples collected from populations of different races were tested within 12 hours after collection and subsets of NK cells were characterized using flow cytometry.Results The absolute NK count in the Chinese Han was significantly higher than that in the Caucasian. The Han and Caucasian groups showed higher percentages of cytotoxic subset compared to that of the Black group. The percentage of cytokine-producing subset of Chinese Han group was lower than that of Caucasian and Black groups. Black group had a higher percentage of function-unknown NK subset than that of the Hah and Caucasian groups.Conclusion Our data indicated that NK cell count and the distribution of different subsets varied among different races,which should be taken into consideration in related investigations.

  14. β-endorphin augments the cytolytic activity and interferon production of natural killer cells

    International Nuclear Information System (INIS)

    The in vitro effects of the neurohormone β-endorphin (b-end) on natural killer (NK) activity and interferon (IFN) production mediated by large granular lymphocytes (LGL) were investigated. LGL-enriched fractions from peripheral blood mononuclear cells (PBMC) from normal human volunteers were obtained by fractionation over discontinuous Percoll gradients. LGL were preincubated with or without various concentrations of b-end or the closely related peptides α-endorphin (a-end), γ-endorphin (g-end), or D-ALA2-β-endorphin (D-ALA2-b-end), a synthetic b-end analogue. NK activity was assayed on 51Cr-labeled K562 target cells. Preincubation of LGL effectors (but not K562 targets) for 2 to 18 hr with concentrations of b-end between 10-7 M and 10-10 M produced significant augmentation of NK cytolytic activity (mean percentage increase: 63%). The classic opiate antagonist naloxone blocked the enhancing effect when used at a 100-fold molar excess relative to b-end. These findings demonstrate that b-end enhances NK activity and IFN production of purified LGL, and suggests that b-end might bind to an opioid receptor on LGL that can be blocked by naloxone. These results lend support to the concepts of regulation of the immune response by neurohormones and the functional relationship between the nervous and immune systems

  15. Leukocytosis and natural killer cell function parallel neurobehavioral fatigue induced by 64 hours of sleep deprivation.

    Science.gov (United States)

    Dinges, D F; Douglas, S D; Zaugg, L; Campbell, D E; McMann, J M; Whitehouse, W G; Orne, E C; Kapoor, S C; Icaza, E; Orne, M T

    1994-05-01

    The hypothesis that sleep deprivation depresses immune function was tested in 20 adults, selected on the basis of their normal blood chemistry, monitored in a laboratory for 7 d, and kept awake for 64 h. At 2200 h each day measurements were taken of total leukocytes (WBC), monocytes, granulocytes, lymphocytes, eosinophils, erythrocytes (RBC), B and T lymphocyte subsets, activated T cells, and natural killer (NK) subpopulations (CD56/CD8 dual-positive cells, CD16-positive cells, CD57-positive cells). Functional tests included NK cytotoxicity, lymphocyte stimulation with mitogens, and DNA analysis of cell cycle. Sleep loss was associated with leukocytosis and increased NK cell activity. At the maximum sleep deprivation, increases were observed in counts of WBC, granulocytes, monocytes, NK activity, and the proportion of lymphocytes in the S phase of the cell cycle. Changes in monocyte counts correlated with changes in other immune parameters. Counts of CD4, CD16, CD56, and CD57 lymphocytes declined after one night without sleep, whereas CD56 and CD57 counts increased after two nights. No changes were observed in other lymphocyte counts, in proliferative responses to mitogens, or in plasma levels of cortisol or adrenocorticotropin hormone. The physiologic leukocytosis and NK activity increases during deprivation were eliminated by recovery sleep in a manner parallel to neurobehavioral function, suggesting that the immune alterations may be associated with biological pressure for sleep. PMID:7910171

  16. PWR hot leg natural circulation modeling with MELCOR code

    International Nuclear Information System (INIS)

    Previous MELCOR and SCDAP/RELAP5S nodalizations for simulating the counter-current, natural circulation behavior of vapor flow within the RCS hot legs and SG U-tubes when core damage progress can not be applied to the steady state and water-filled conditions during the initial period of accident progression because of the artificially high loss coefficients in the hot legs and SG U-tubes which were chosen from results of COMMIX calculation and the Westinghouse natural circulation experiments in a 1/7-scale facility for simulating steam natural circulation behavior in the vessel and in the hot leg and SG during the TMLB' scenrio. The objective of this study is to develop a natural circulation modeling which can be used both for the liquid flow condition at steady state and for the vapor flow condition at the later period of in-vessel core damage. For this, the drag forces resulting from the momentum exchange effects between the two vapor streams in the hot leg was modeled as a pressure drop by pump model. This hot leg natural circulation modeling of MELCOR was able to reproduce similar mass flow rates with those predicted by previous models

  17. Experimental study of two-phase natural circulation circuit

    International Nuclear Information System (INIS)

    This paper reports an experimental study on the behavior of fluid flow in natural circulation under single-and two-phase flow conditions. The natural circulation circuit was designed based on concepts of similarity and scale in proportion to the actual operating conditions of a nuclear reactor. This test equipment has similar performance to the passive system for removal of residual heat presents in Advanced Pressurized Water Reactors (A PWR). The experiment was carried out by supplying water to primary and secondary circuits, as well as electrical power resistors installed inside the heater. Power controller has available to adjust the values for supply of electrical power resistors, in order to simulate conditions of decay of power from the nuclear reactor in steady state. Data acquisition system allows the measurement and control of the temperature at different points by means of thermocouples installed at several points along the circuit. The behavior of the phenomenon of natural circulation was monitored by a software with graphical interface, showing the evolution of temperature measurement points and the results stored in digital format spreadsheets. Besides, the natural circulation flow rate was measured by a flowmeter installed on the hot leg. A flow visualization technique was used the for identifying vertical flow regimes of two-phase natural circulation. Finally, the Reynolds Number was calculated for the establishment of a friction factor correlation dependent on the scale geometrical length, height and diameter of the pipe. (author)

  18. A Flashing Simulator for Natural Circulation Heated Systems

    International Nuclear Information System (INIS)

    Many of the next generation of nuclear reactors rely on natural circulation, either as the primary mode of heat removal or as a passive safety mechanism. Flashing-induced instabilities are of concern during startup of natural-circulation loops and small-scale natural-circulation light water reactors. (Flashing refers to the beginning of (adiabatic) boiling in the unheated riser when there is no boiling upstream.) A simulator with significantly enhanced modeling and simulation capabilities is being developed to analyze flashing and flashing-induced instabilities. The model allows an arbitrary number of nodes in both the heated section (allowing axially varying heat flux) and in the unheated riser section. Preliminary simulations using the model show that it can capture the location of flashing in the experiments conducted on the Dodewaard reactor very well

  19. PWR hot leg natural circulation modeling with MELCOR code

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jae Hong; Lee, Jong In [Korea Institute of Nuclear Safety, Taejon (Korea, Republic of)

    1997-12-31

    Previous MELCOR and SCDAP/RELAP5 nodalizations for simulating the counter-current, natural circulation behavior of vapor flow within the RCS hot legs and SG U-tubes when core damage progress can not be applied to the steady state and water-filled conditions during the initial period of accident progression because of the artificially high loss coefficients in the hot legs and SG U-tubes which were chosen from results of COMMIX calculation and the Westinghouse natural circulation experiments in a 1/7-scale facility for simulating steam natural circulation behavior in the vessel and circulation modeling which can be used both for the liquid flow condition at steady state and for the vapor flow condition at the later period of in-vessel core damage. For this, the drag forces resulting from the momentum exchange effects between the two vapor streams in the hot leg was modeled as a pressure drop by pump model. This hot leg natural circulation modeling of MELCOR was able to reproduce similar mass flow rates with those predicted by previous models. 6 refs., 2 figs. (Author)

  20. The anti-canine distemper virus activities of ex vivo-expanded canine natural killer cells.

    Science.gov (United States)

    Park, Ji-Yun; Shin, Dong-Jun; Lee, Soo-Hyeon; Lee, Je-Jung; Suh, Guk-Hyun; Cho, Duck; Kim, Sang-Ki

    2015-04-17

    Natural killer (NK) cells play critical roles in induction of antiviral effects against various viruses of humans and animals. However, few data on NK cell activities during canine distemper virus (CDV) infections are available. Recently, we established a culture system allowing activation and expansion of canine non-B, non-T, large granular NK lymphocytes from PBMCs of normal dogs. In the present study, we explored the ability of such expanded NK cells to inhibit CDV infection in vitro. Cultured CD3-CD5-CD21- NK cells produced large amounts of IFN-γ, exhibited highly upregulated expression of mRNAs encoding NK-cell-associated receptors, and demonstrated strong natural killing activity against canine tumor cells. Although the expanded NK cells were dose-dependently cytotoxic to both normal and CDV-infected Vero cells, CDV infection rendered Vero cells more susceptible to NK cells. Pretreatment with anti-CDV serum from hyperimmunized dogs enhanced the antibody-dependent cellular cytotoxicity (ADCC) of NK cells against CDV-infected Vero cells. The culture supernatants of NK cells, added before or after infection, dose-dependently inhibited both CDV replication and development of CDV-induced cytopathic effects (CPEs) in Vero cells. Anti-IFN-γ antibody neutralized the inhibitory effects of NK cell culture supernatants on CDV replication and CPE induction in Vero cells. Such results emphasize the potential significance of NK cells in controlling CDV infection, and indicate that NK cells may play roles both during CDV infection and in combating such infections, under certain conditions. PMID:25680810

  1. Underground Adaptation to a Hostile Environment: Acute Myeloid Leukemia vs. Natural Killer Cells

    Science.gov (United States)

    Dulphy, Nicolas; Chrétien, Anne-Sophie; Khaznadar, Zena; Fauriat, Cyril; Nanbakhsh, Arash; Caignard, Anne; Chouaib, Salem; Olive, Daniel; Toubert, Antoine

    2016-01-01

    Acute myeloid leukemia (AML) is a heterogeneous group of malignancies which incidence increases with age. The disease affects the differentiation of hematopoietic stem or precursor cells in the bone marrow and can be related to abnormal cytogenetic and/or specific mutational patterns. AML blasts can be sensitive to natural killer (NK) cell antitumor response. However, NK cells are frequently defective in AML patients leading to tumor escape. NK cell defects affect not only the expression of the activating NK receptors, including the natural cytotoxicity receptors, the NK group 2, member D, and the DNAX accessory molecule-1, but also cytotoxicity and IFN-γ release. Such perturbations in NK cell physiology could be related to the adaptation of the AML to the immune pressure and more generally to patient’s clinical features. Various mechanisms are potentially involved in the inhibition of NK-cell functions in AML, including defects in the normal lymphopoiesis, reduced expression of activating receptors through cell-to-cell contacts, and production of immunosuppressive soluble agents by leukemic blasts. Therefore, the continuous cross-talk between AML and NK cells participates to the leukemia immune escape and eventually to patient’s relapse. Methods to restore or stimulate NK cells seem to be attractive strategies to treat patients once the complete remission is achieved. Moreover, our capacity in stimulating the NK cell functions could lead to the development of preemptive strategies to eliminate leukemia-initiating cells before the emergence of the disease in elderly individuals presenting preleukemic mutations in hematopoietic stem cells. PMID:27014273

  2. Effects of pitching and rolling upon natural circulation

    International Nuclear Information System (INIS)

    In view of the characteristics of the separate arranged PWR primary loop in nuclear power ship, the different influences of pitching and rolling on natural circulation ability have been analyzed. A calculation program is compiled and the variations of the natural circulation ability at two kinds of rocking states are calculated and compared based on the parameters of a certain nuclear power ship. The results show that for separate arranged PWR pitching has bigger effect on the primary loop's coolant flow rate and PWR output power than rolling. The reason of the different effects result from different rocking has been emphatically analyzed

  3. Stress-Induced In Vivo Recruitment of Human Cytotoxic Natural Killer Cells Favors Subsets with Distinct Receptor Profiles and Associates with Increased Epinephrine Levels.

    Directory of Open Access Journals (Sweden)

    Marc B Bigler

    Full Text Available Acute stress drives a 'high-alert' response in the immune system. Psychoactive drugs induce distinct stress hormone profiles, offering a sought-after opportunity to dissect the in vivo immunological effects of acute stress in humans.3,4-methylenedioxymethamphetamine (MDMA, methylphenidate (MPH, or both, were administered to healthy volunteers in a randomized, double-blind, placebo-controlled crossover-study. Lymphocyte subset frequencies, natural killer (NK cell immune-phenotypes, and changes in effector function were assessed, and linked to stress hormone levels and expression of CD62L, CX3CR1, CD18, and stress hormone receptors on NK cells.MDMA/MPH > MDMA > MPH robustly induced an epinephrine-dominant stress response. Immunologically, rapid redistribution of peripheral blood lymphocyte-subsets towards phenotypically mature NK cells occurred. NK cytotoxicity was unaltered, but they expressed slightly reduced levels of the activating receptor NKG2D. Preferential circulation of mature NK cells was associated with high epinephrine receptor expression among this subset, as well as expression of integrin ligands previously linked to epinephrine-induced endothelial detachment.The acute epinephrine-induced stress response was characterized by rapid accumulation of mature and functional NK cells in the peripheral circulation. This is in line with studies using other acute stressors and supports the role of the acute stress response in rapidly mobilizing the innate immune system to counteract incoming threats.

  4. Effect of synthetic compound B 58 on natural killer and cytostatic cell activity in the mouse spleen

    Energy Technology Data Exchange (ETDEWEB)

    Malaitsev, V.V.; Bogdanova, I.M.; Spivak, N.Ya.; Bogdashin, I.V.; Zueva, V.S.

    1987-11-01

    The authors study the effect of compound B 58, a synthetic interferon inducer, on activity of natural killer cells (NKC) and cytostatic effectors in the mouse spleen. NKC activity in the spleen was determined in the 4-hour microtoxicity test against VAC-1 target cells labeled with /sup 51/Cr. /sup 3/H-thymidine was added to the effectors and targets. An increase in activity of the cellular mechanisms of natural antitumor resistance arising under the influence of compound B 58 is shown.

  5. Serglycin determines secretory granule repertoire and regulates natural killer cell and cytotoxic T lymphocyte cytotoxicity.

    Science.gov (United States)

    Sutton, Vivien R; Brennan, Amelia J; Ellis, Sarah; Danne, Jill; Thia, Kevin; Jenkins, Misty R; Voskoboinik, Ilia; Pejler, Gunnar; Johnstone, Ricky W; Andrews, Daniel M; Trapani, Joseph A

    2016-03-01

    The anionic proteoglycan serglycin is a major constituent of secretory granules in cytotoxic T lymphocyte (CTL)/natural killer (NK) cells, and is proposed to promote the safe storage of the mostly cationic granule toxins, granzymes and perforin. Despite the extensive defects of mast cell function reported in serglycin gene-disrupted mice, no comprehensive study of physiologically relevant CTL/NK cell populations has been reported. We show that the cytotoxicity of serglycin-deficient CTL and NK cells is severely compromised but can be partly compensated in both cell types when they become activated. Reduced intracellular granzyme B levels were noted, particularly in CD27(+) CD11b(+) mature NK cells, whereas serglycin(-/-) TCR-transgenic (OTI) CD8 T cells also had reduced perforin stores. Culture supernatants from serglycin(-/-) OTI T cells and interleukin-2-activated NK contained increased granzyme B, linking reduced storage with heightened export. By contrast, granzyme A was not significantly reduced in cells lacking serglycin, indicating differentially regulated trafficking and/or storage for the two granzymes. A quantitative analysis of different granule classes by transmission electronmicroscopy showed a selective loss of dense-core granules in serglycin(-/-) CD8(+) CTLs, although other granule types were maintained quantitatively. The findings of the present study show that serglycin plays a critical role in the maturation of dense-core cytotoxic granules in cytotoxic lymphocytes and the trafficking and storage of perforin and granzyme B, whereas granzyme A is unaffected. The skewed retention of cytotoxic effector molecules markedly reduces CTL/NK cell cytotoxicity, although this is partly compensated for as a result of activating the cells by physiological means. PMID:26756195

  6. Activation of human natural killer cells by the soluble form of cellular prion protein

    International Nuclear Information System (INIS)

    Cellular prion protein (PrPC) is widely expressed in various cell types, including cells of the immune system. However, the specific roles of PrPC in the immune system have not been clearly elucidated. In the present study, we investigated the effects of a soluble form of recombinant PrPC protein on human natural killer (NK) cells. Recombinant soluble PrPC protein was generated by fusion of human PrPC with the Fc portion of human IgG1 (PrPC-Fc). PrPC-Fc binds to the surface of human NK cells, particularly to CD56dim NK cells. PrPC-Fc induced the production of cytokines and chemokines and the degranulation of granzyme B from NK cells. In addition, PrPC-Fc facilitated the IL-15-induced proliferation of NK cells. PrPC-Fc induced phosphorylation of ERK-1/2 and JNK in NK cells, and inhibitors of the ERK or the JNK pathways abrogated PrPC-Fc-induced cytokine production in NK cells. In conclusion, the soluble form of recombinant PrPC-Fc protein activates human NK cells via the ERK and JNK signaling pathways. - Highlights: • Recombinant soluble PrPC (PrPC-Fc) was generated by fusion of human PrPC with IgG1 Fc portion. • PrPC-Fc protein induces the production of cytokines and degranulation from human NK cells. • PrPC-Fc protein enhances the IL-15-induced proliferation of human NK cells. • PrPC-Fc protein activates human NK cells via the ERK and JNK signaling pathways

  7. Activation of human natural killer cells by the soluble form of cellular prion protein

    Energy Technology Data Exchange (ETDEWEB)

    Seong, Yeon-Jae [Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon (Korea, Republic of); Hafis Clinic, Seoul (Korea, Republic of); Sung, Pil Soo; Jang, Young-Soon; Choi, Young Joon [Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon (Korea, Republic of); Park, Bum-Chan [Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Park, Su-Hyung [Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, KAIST, Daejeon (Korea, Republic of); Park, Young Woo [Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Shin, Eui-Cheol, E-mail: ecshin@kaist.ac.kr [Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon (Korea, Republic of)

    2015-08-21

    Cellular prion protein (PrP{sup C}) is widely expressed in various cell types, including cells of the immune system. However, the specific roles of PrP{sup C} in the immune system have not been clearly elucidated. In the present study, we investigated the effects of a soluble form of recombinant PrP{sup C} protein on human natural killer (NK) cells. Recombinant soluble PrP{sup C} protein was generated by fusion of human PrP{sup C} with the Fc portion of human IgG{sub 1} (PrP{sup C}-Fc). PrP{sup C}-Fc binds to the surface of human NK cells, particularly to CD56{sup dim} NK cells. PrP{sup C}-Fc induced the production of cytokines and chemokines and the degranulation of granzyme B from NK cells. In addition, PrP{sup C}-Fc facilitated the IL-15-induced proliferation of NK cells. PrP{sup C}-Fc induced phosphorylation of ERK-1/2 and JNK in NK cells, and inhibitors of the ERK or the JNK pathways abrogated PrP{sup C}-Fc-induced cytokine production in NK cells. In conclusion, the soluble form of recombinant PrP{sup C}-Fc protein activates human NK cells via the ERK and JNK signaling pathways. - Highlights: • Recombinant soluble PrP{sup C} (PrP{sup C}-Fc) was generated by fusion of human PrP{sup C} with IgG1 Fc portion. • PrP{sup C}-Fc protein induces the production of cytokines and degranulation from human NK cells. • PrP{sup C}-Fc protein enhances the IL-15-induced proliferation of human NK cells. • PrP{sup C}-Fc protein activates human NK cells via the ERK and JNK signaling pathways.

  8. Innate lymphoid cells and natural killer T cells in the gastrointestinal tract immune system

    Directory of Open Access Journals (Sweden)

    Enrique Montalvillo

    2014-05-01

    Full Text Available The gastrointestinal tract is equipped with a highly specialized intrinsic immune system. However, the intestine is exposed to a high antigenic burden that requires a fast, nonspecific response -so-called innate immunity- to maintain homeostasis and protect the body from incoming pathogens. In the last decade multiple studies helped to unravel the particular developmental requirements and specific functions of the cells that play a role in innate immunity. In this review we shall focus on innate lymphoid cells, a newly discovered, heterogeneous set of cells that derive from an Id2-dependent lymphoid progenitor cell population. These cells have been categorized on the basis of the pattern of cytokines that they secrete, and the transcription factors that regulate their development and functions. Innate lymphoid cells play a role in the early response to pathogens, the anatomical contention of the commensal flora, and the maintenance of epithelial integrity. Amongst the various innate lymphoid cells we shall lay emphasis on a subpopulation with several peculiarities, namely that of natural killer T cells, a subset of T lymphocytes that express both T-cell and NK-cell receptors. The most numerous fraction of the NKT population are the so-called invariant NKT or iNKT cells. These iNKT cells have an invariant TCR and recognize the glycolipidic structures presented by the CD1d molecule, a homolog of class-I MHC molecules. Following activation they rapidly acquire cytotoxic activity and secrete both Th1 and Th2 cytokines, including IL-17. While their specific role is not yet established, iNKT cells take part in a great variety of intestinal immune responses ranging from oral tolerance to involvement in a number of gastrointestinal conditions.

  9. Natural killer cells promote early CD8 T cell responses against cytomegalovirus.

    Directory of Open Access Journals (Sweden)

    Scott H Robbins

    2007-08-01

    Full Text Available Understanding the mechanisms that help promote protective immune responses to pathogens is a major challenge in biomedical research and an important goal for the design of innovative therapeutic or vaccination strategies. While natural killer (NK cells can directly contribute to the control of viral replication, whether, and how, they may help orchestrate global antiviral defense is largely unknown. To address this question, we took advantage of the well-defined molecular interactions involved in the recognition of mouse cytomegalovirus (MCMV by NK cells. By using congenic or mutant mice and wild-type versus genetically engineered viruses, we examined the consequences on antiviral CD8 T cell responses of specific defects in the ability of the NK cells to control MCMV. This system allowed us to demonstrate, to our knowledge for the first time, that NK cells accelerate CD8 T cell responses against a viral infection in vivo. Moreover, we identify the underlying mechanism as the ability of NK cells to limit IFN-alpha/beta production to levels not immunosuppressive to the host. This is achieved through the early control of cytomegalovirus, which dramatically reduces the activation of plasmacytoid dendritic cells (pDCs for cytokine production, preserves the conventional dendritic cell (cDC compartment, and accelerates antiviral CD8 T cell responses. Conversely, exogenous IFN-alpha administration in resistant animals ablates cDCs and delays CD8 T cell activation in the face of NK cell control of viral replication. Collectively, our data demonstrate that the ability of NK cells to respond very early to cytomegalovirus infection critically contributes to balance the intensity of other innate immune responses, which dampens early immunopathology and promotes optimal initiation of antiviral CD8 T cell responses. Thus, the extent to which NK cell responses benefit the host goes beyond their direct antiviral effects and extends to the prevention of innate

  10. Phenotypic studies of natural killer cell subsets in human transporter associated with antigen processing deficiency.

    Directory of Open Access Journals (Sweden)

    Jacques Zimmer

    Full Text Available Peripheral blood natural killer (NK cells from patients with transporter associated with antigen processing (TAP deficiency are hyporesponsive. The mechanism of this defect is unknown, but the phenotype of TAP-deficient NK cells is almost normal. However, we noticed a high percentage of CD56(bright cells among total NK cells from two patients. We further investigated TAP-deficient NK cells in these patients and compared them to NK cells from two other TAP-deficient patients with no clinical symptoms and to individuals with chronic inflammatory diseases other than TAP deficiency (chronic lung diseases or vasculitis. Peripheral blood mononuclear cells isolated from venous blood were stained with fluorochrome-conjugated antibodies and the phenotype of NK cells was analyzed by flow cytometry. In addition, (51Chromium release assays were performed to assess the cytotoxic activity of NK cells. In the symptomatic patients, CD56(bright NK cells represented 28% and 45%, respectively, of all NK cells (higher than in healthy donors. The patients also displayed a higher percentage of CD56(dimCD16(- NK cells than controls. Interestingly, this unusual NK cell subtype distribution was not found in the two asymptomatic TAP-deficient cases, but was instead present in several of the other patients. Over-expression of the inhibitory receptor CD94/NKG2A by TAP-deficient NK cells was confirmed and extended to the inhibitory receptor ILT2 (CD85j. These inhibitory receptors were not involved in regulating the cytotoxicity of TAP-deficient NK cells. We conclude that expansion of the CD56(bright NK cell subtype in peripheral blood is not a hallmark of TAP deficiency, but can be found in other diseases as well. This might reflect a reaction of the immune system to pathologic conditions. It could be interesting to investigate the relative distribution of NK cell subsets in various respiratory and autoimmune diseases.

  11. In vitro augmentation of natural killer cell activity by manganese chloride

    International Nuclear Information System (INIS)

    The in vitro cultivation of murine spleen cells with MnCl2 resulted in the enhancement of natural killer (NK) cell activity as measured in a 4-h 51Cr-release assay. Optimal enhancement of NK activity was observed at concentrations of 10-20 μg MnCl2/culture (72-144 μM Mn2+). Enhancement of NK activity by MnCl2 was not associated with any changes in the number or viability of cells following culture. The addition of antiasialo GM1 antibody and complement to spleen cell cultures completely abrogated the enhancement of NK activity by MnCl2. The enhancement of NK activity by MnCl2 in vitro was accompanied by interferon induction. The addition of rabbit antimouse interferon to spleen cells cultured with MnCl2 reduced NK activity. NK activity in cultures treated with MnCl2 was also reduced upon removal of plastic adherent cells. However, restoration of enhanced NK activity by addition of adherent cells to nonadherent cells in the presence of MnCl2 was not observed. Similar effects of NK activity were observed with polyinosinic-polycytidylic acid (Poly I x C), a known interferon inducer and NK enhancer. The results demonstrate that murine splenic NK activity is enhanced in vitro by MnCl2 and that this enhancement may be mediated by interferon induction. The results also suggest that in vitro enhancement of NK activity by MnCl2, as with Poly I x C, may require participation of an adherent cell population for NK augmentation

  12. Immunosuppressive effects of triclosan, nonylphenol, and DDT on human natural killer cells in vitro.

    Science.gov (United States)

    Udoji, Felicia; Martin, Tamara; Etherton, Rachel; Whalen, Margaret M

    2010-01-01

    Human natural killer (NK) cells are a first-line immune defense against tumor cells and virally-infected cells. If their function is impaired, it leaves an individual more susceptible to cancer development or viral infection. The ability of compounds that contaminate the environment to suppress the function of NK cells could contribute to the increased risk of cancer development. There are a wide spectrum of compounds that significantly contaminate water and food that are consumed by humans, leading to accumulation of some of these compounds in human tissues. In the current study, we examined the ability of three such compounds to diminish the function of human NK cells. Triclosan (TC) is an antimicrobial agent used in a large number of antibacterial soaps. Nonylphenol (NP) is a degradation product of compounds used as surfactants and as stabilizers in plastics. 4,4'-Dichlorodiphenyltrichloroethane (DDT) is a pesticide that is mainly used to control mosquitoes. The compounds were examined for their ability to suppress NK function following exposures of 1 h, 24 h, 48 h, and 6 days. Each agent was able to substantially decrease NK lytic function within 24 h. At a concentration of 5 microM, both TC and NP inhibited NK lytic function by 87 and 30%, respectively; DDT decreased function by 55% at 2.5 microM. The negative effects of each of these compounds persisted and/or intensified following a brief (1 h) exposure to the compounds, indicating that the impairment of function cannot be eliminated by removal of the compound under in vitro conditions. PMID:20297919

  13. Natural killer cells in obesity: impaired function and increased susceptibility to the effects of cigarette smoke.

    LENUS (Irish Health Repository)

    O'Shea, Donal

    2010-01-01

    BACKGROUND: Obese individuals who smoke have a 14 year reduction in life expectancy. Both obesity and smoking are independently associated with increased risk of malignancy. Natural killer cells (NK) are critical mediators of anti-tumour immunity and are compromised in obese patients and smokers. We examined whether NK cell function was differentially affected by cigarette smoke in obese and lean subjects. METHODOLOGY AND PRINCIPAL FINDINGS: Clinical data and blood were collected from 40 severely obese subjects (BMI>40 kg\\/m(2)) and 20 lean healthy subjects. NK cell levels and function were assessed using flow cytometry and cytotoxicity assays. The effect of cigarette smoke on NK cell ability to kill K562 tumour cells was assessed in the presence or absence of the adipokines leptin and adiponectin. NK cell levels were significantly decreased in obese subjects compared to lean controls (7.6 vs 16.6%, p = 0.0008). NK function was also significantly compromised in obese patients (30% +\\/- 13% vs 42% +\\/-12%, p = 0.04). Cigarette smoke inhibited NK cell ability to kill tumour cell lines (p<0.0001). NK cells from obese subjects were even more susceptible to the inhibitory effects of smoke compared to lean subjects (33% vs 28%, p = 0.01). Cigarette smoke prevented NK cell activation, as well as perforin and interferon-gamma secretion upon tumour challenge. Adiponectin but not leptin partially reversed the effects of smoke on NK cell function in both obese (p = 0.002) and lean controls (p = 0.01). CONCLUSIONS\\/SIGNIFICANCE: Obese subjects have impaired NK cell activity that is more susceptible to the detrimental effects of cigarette smoke compared to lean subjects. This may play a role in the increase of cancer and infection seen in this population. Adiponectin is capable of restoring NK cell activity and may have therapeutic potential for immunity in obese subjects and smokers.

  14. Reconstitution models to evaluate natural killer T cell function in tumor control.

    Science.gov (United States)

    Gebremeskel, Simon; Slauenwhite, Drew; Johnston, Brent

    2016-01-01

    Natural killer T (NKT) cells are glycolipid-reactive T lymphocytes that function in immunosurveillance and immune regulation. However, reduced tumor control in NKT cell-deficient Jα18(-/-) mice may be confounded by an overall reduction in T-cell receptor (TCR) repertoire diversity in these animals. Mechanistic studies are also hindered by a lack of tools to target molecules specifically in NKT cells. To address these issues, we developed protocols to expand functional NKT cells and stably reconstitute them in Jα18(-/-) mice. In vivo delivery of α-galactosylceramide (α-GalCer)-loaded dendritic cells expanded NKT cells in wild-type mice without skewing CD4 or TCR Vβ expression profiles. Expanded NKT cells exhibited enhanced cytokine responses upon re-stimulation with glycolipid or CD3 ligation. Adoptive transfer of recently expanded wild-type or interferon (IFN)-γ(-/-) NKT cells protected recipient Jα18(-/-) mice from B16 melanoma metastasis without the need for additional glycolipid stimulation. However, NKT cell reconstitution in recipient Jα18(-/-) mice was short lived. Long-term reconstitution was only achieved when expanded NKT cells were transferred into sublethally irradiated recipients. Thirty days after transfer, NKT cell numbers, phenotype and α-GalCer-induced cytokine responses were equivalent to naive wild-type mice. Jα18(-/-) recipients reconstituted with wild-type or IFN-γ(-/-) NKT cells were both protected from B16 melanoma metastasis following α-GalCer treatment, and NK cell transactivation was intact in mice reconstituted with IFN-γ(-/-) NKT cells. These studies validate the use of reconstitution protocols to investigate the mechanisms of NKT cell immune function, demonstrating that NKT cell-derived IFN-γ and the altered TCR repertoire in Jα18(-/-) mice do not impact NKT cell-mediated antitumor responses. PMID:26095148

  15. Cytotoxicity of Human Cord Blood Natural Killer Cells is Enhanced by Recombinant Interleukin-15

    Directory of Open Access Journals (Sweden)

    Shiva Saghafi

    2010-06-01

    Full Text Available Hematopoietic cord blood (CB stem cell transplantation has more advantages to other cell sources because of lower Graft Versus Host Disease (GVHD. Interleukin-15(IL-15 is an immunoregulatory cytokine, known to enhance cytolytic function of cord Natural Killer (NK cells. The aim of this study was to investigate the effect of IL-15 on NK cytotoxicity simultaneously in different cell death stages.We compared the ability of IL-15 to enhance the NK cytotoxicity of CB in comparison to adult blood Mononuclear Cells (MNCs against K562 target cells by co-staining with AnnexinV-FITC and Propidium Iodide after 3.5 h incubation at 37C and 5% CO2 by using flow cytometric method. We also evaluated phenotypic changes after treatment by IL-15 in both cell sources.Our results indicated that CB samples had lower level of apoptosis, while necrosis was negligible; also by escalating Effector: Target (E: T, we got higher level of apoptosis and necrosis in peripheral blood (PB. NK activity of cord and adult MNCs was enhanced by incubation with IL-15 (10 ng/ml for 72 h with significantly higher results of PB in comparison to CB (pTaken together, these results indicated that NK cytotoxicity of CB MNCs could be augmented by human recombinant (hr IL-15, but this activity did not reach to same level of PB counterparts.We established that CD25 expression on CB MNCs could be increased with IL-15, in 72-hour cultures, but to a lesser degree compared to that on corresponding adult PB MNCs.

  16. The Proangiogenic Phenotype of Natural Killer Cells in Patients with Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Antonino Bruno

    2013-02-01

    Full Text Available The tumor microenvironment can polarize innate immune cells to a proangiogenic phenotype. Decidual natural killer (dNK cells show an angiogenic phenotype, yet the role for NK innate lymphoid cells in tumor angiogenesis remains to be defined. We investigated NK cells from patients with surgically resected non-small cell lung cancer (NSCLC and controls using flow cytometric and functional analyses. The CD56+CD16- NK subset in NSCLC patients, which represents the predominant NK subset in tumors and a minor subset in adjacent lung and peripheral blood, was associated with vascular endothelial growth factor (VEGF, placental growth factor (PIGF, and interleukin-8 (IL-8/CXCL8 production. Peripheral blood CD56+CD16- NK cells from patients with the squamous cell carcinoma (SCC subtype showed higher VEGF and PlGF production compared to those from patients with adenocarcinoma (AdC and controls. Higher IL-8 production was found for both SCC and AdC compared to controls. Supernatants derived from NSCLC CD56+CD16- NK cells induced endothelial cell chemotaxis and formation of capillary-like structures in vitro, particularly evident in SCC patients and absent from controls. Finally, exposure to transforming growth factor-β1 (TGFβ1, a cytokine associated with dNK polarization, upregulated VEGF and PlGF in peripheral blood CD56+CD16- NK cells from healthy subjects. Our data suggest that NK cells in NSCLC act as proangiogenic cells, particularly evident for SCC and in part mediated by TGFβ1.

  17. Natural killer cells in obesity: impaired function and increased susceptibility to the effects of cigarette smoke.

    LENUS (Irish Health Repository)

    O'Shea, Donal

    2012-02-01

    BACKGROUND: Obese individuals who smoke have a 14 year reduction in life expectancy. Both obesity and smoking are independently associated with increased risk of malignancy. Natural killer cells (NK) are critical mediators of anti-tumour immunity and are compromised in obese patients and smokers. We examined whether NK cell function was differentially affected by cigarette smoke in obese and lean subjects. METHODOLOGY AND PRINCIPAL FINDINGS: Clinical data and blood were collected from 40 severely obese subjects (BMI>40 kg\\/m(2)) and 20 lean healthy subjects. NK cell levels and function were assessed using flow cytometry and cytotoxicity assays. The effect of cigarette smoke on NK cell ability to kill K562 tumour cells was assessed in the presence or absence of the adipokines leptin and adiponectin. NK cell levels were significantly decreased in obese subjects compared to lean controls (7.6 vs 16.6%, p = 0.0008). NK function was also significantly compromised in obese patients (30% +\\/- 13% vs 42% +\\/-12%, p = 0.04). Cigarette smoke inhibited NK cell ability to kill tumour cell lines (p<0.0001). NK cells from obese subjects were even more susceptible to the inhibitory effects of smoke compared to lean subjects (33% vs 28%, p = 0.01). Cigarette smoke prevented NK cell activation, as well as perforin and interferon-gamma secretion upon tumour challenge. Adiponectin but not leptin partially reversed the effects of smoke on NK cell function in both obese (p = 0.002) and lean controls (p = 0.01). CONCLUSIONS\\/SIGNIFICANCE: Obese subjects have impaired NK cell activity that is more susceptible to the detrimental effects of cigarette smoke compared to lean subjects. This may play a role in the increase of cancer and infection seen in this population. Adiponectin is capable of restoring NK cell activity and may have therapeutic potential for immunity in obese subjects and smokers.

  18. Kinome analysis of receptor-induced phosphorylation in human natural killer cells.

    Directory of Open Access Journals (Sweden)

    Sebastian König

    Full Text Available BACKGROUND: Natural killer (NK cells contribute to the defense against infected and transformed cells through the engagement of multiple germline-encoded activation receptors. Stimulation of the Fc receptor CD16 alone is sufficient for NK cell activation, whereas other receptors, such as 2B4 (CD244 and DNAM-1 (CD226, act synergistically. After receptor engagement, protein kinases play a major role in signaling networks controlling NK cell effector functions. However, it has not been characterized systematically which of all kinases encoded by the human genome (kinome are involved in NK cell activation. RESULTS: A kinase-selective phosphoproteome approach enabled the determination of 188 kinases expressed in human NK cells. Crosslinking of CD16 as well as 2B4 and DNAM-1 revealed a total of 313 distinct kinase phosphorylation sites on 109 different kinases. Phosphorylation sites on 21 kinases were similarly regulated after engagement of either CD16 or co-engagement of 2B4 and DNAM-1. Among those, increased phosphorylation of FYN, KCC2G (CAMK2, FES, and AAK1, as well as the reduced phosphorylation of MARK2, were reproducibly observed both after engagement of CD16 and co-engagement of 2B4 and DNAM-1. Notably, only one phosphorylation on PAK4 was differentally regulated. CONCLUSIONS: The present study has identified a significant portion of the NK cell kinome and defined novel phosphorylation sites in primary lymphocytes. Regulated phosphorylations observed in the early phase of NK cell activation imply these kinases are involved in NK cell signaling. Taken together, this study suggests a largely shared signaling pathway downstream of distinct activation receptors and constitutes a valuable resource for further elucidating the regulation of NK cell effector responses.

  19. Effects of phenytoin and carbamazepine on human natural killer cell activity and genotoxicity in vitro.

    Science.gov (United States)

    Margaretten, N C; Hincks, J R; Warren, R P; Coulombe, R A

    1987-01-01

    Human peripheral blood mononuclear cells (PBMC) were isolated from healthy volunteers and exposed in vitro to phenytoin or carbamazepine, two widely used antiepileptic drugs (AED). This study investigated the effects of these drugs on natural killer (NK) cell activity and antibody-dependent cell-mediated cytotoxicity (ADCC), which are both thought to protect against developing neoplasms. Also, the genotoxicity of phenytoin on human PBMC was investigated by gravity-flow alkaline elution. Concentrations of phenytoin considered therapeutic (10 and 20 micrograms/ml) and a dose considered acutely toxic (40 micrograms/ml) were used while carbamazepine levels of 8 micrograms/ml (therapeutic) and 10 and 16 micrograms/ml (acutely toxic) were tested. Phenytoin at all three concentrations significantly suppressed NK cell activity in a dose-dependent manner. Carbamazepine had no significant effect on NK cell activity at the dose levels studied. Incubation in propylene glycol, the diluent for carbamazepine, significantly decreased NK cell activity compared to saline. Phenytoin also significantly depressed interferon augmentation of NK cell cytotoxicity in a dose dependent manner. ADCC activity was significantly depressed with 20 and 40 micrograms/ml phenytoin. Alkaline elution showed a slight but significant increase in DNA single-strand breaks of PBMC exposed to 40 micrograms/ml phenytoin for 18 or 72 hr. These results show phenytoin may induce pronounced immunosuppression of NK cell and ADCC activity in patients receiving antiepileptic therapy and that this agent has a potential for genotoxic side effects. Phenytoin may also increase the potential for neoplasm development by a direct interaction with cellular DNA and/or an indirect mechanism by immunosuppression. PMID:3798446

  20. Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer.

    Science.gov (United States)

    Mimura, Kousaku; Kamiya, Takahiro; Shiraishi, Kensuke; Kua, Ley-Fang; Shabbir, Asim; So, Jimmy; Yong, Wei-Peng; Suzuki, Yoshiyuki; Yoshimoto, Yuya; Nakano, Takashi; Fujii, Hideki; Campana, Dario; Kono, Koji

    2014-09-15

    To develop more effective therapies for patients with advanced gastric cancer, we examined the potential of ex vivo expanded natural killer (NK) cells. We assessed the expression of ligands for NK Group 2 Member D (NKG2D, an important NK activation molecule) in primary tumors from 102 patients with gastric cancer by immunohistochemistry and determined their prognostic value. We then examined the in vitro and in vivo cytotoxicity of NK cells from healthy donors and patients with gastric cancer. The cytotoxicity of resting and of interleukin (IL)-2-activated NK cells was compared to that of NK cells expanded for 7 days by coculture with the K562-mb15-4.1BBL cell line. As a result, the expression of NKG2D ligands in primary tumors was correlated with favorable presenting features and outcomes, suggesting that gastric cancer may be sensitive to NK cell cytotoxicity. Although resting NK cells showed minimal cytotoxicity against gastric cancer cells, K562-mb15-4.1BBL-expanded NK cells were highly cytotoxic and significantly more powerful than IL-2-activated NK cells. Cytotoxicity was correlated with NKG2D ligand expression and could be modulated by mitogen-activated protein kinase and AKT-PI3 kinase inhibitors. The cytotoxicity of expanded NK cells against HER2-positive gastric cancer cells could be increased by Herceptin and further augmented by Lapatinib. Finally, expanded NK cells exhibited strong antitumor activity in immunodeficient mice engrafted with a gastric cancer cell line. In conclusion, gastric cancer tumors express NKG2D ligands and are highly susceptible to killing by NK cells stimulated by K562-mb15-4.1BBL. These results provide a strong rationale for clinical testing of these NK cells in patients and suggest their use to augment the effects of antibody therapy. PMID:24615495

  1. Natural killer cells and neuroblastoma: tumor recognition, escape mechanisms, and possible novel immunotherapeutic approaches.

    Science.gov (United States)

    Bottino, Cristina; Dondero, Alessandra; Bellora, Francesca; Moretta, Lorenzo; Locatelli, Franco; Pistoia, Vito; Moretta, Alessandro; Castriconi, Roberta

    2014-01-01

    Neuroblastoma (NB) is the most common extra-cranial solid tumor of childhood and arises from developing sympathetic nervous system. Most primary tumors localize in the abdomen, the adrenal gland, or lumbar sympathetic ganglia. Amplification in tumor cells of MYCN, the major oncogenic driver, patients' age over 18 months, and the presence at diagnosis of a metastatic disease (stage IV, M) identify NB at high risk of treatment failure. Conventional therapies did not significantly improve the overall survival of these patients. Moreover, the limited landscape of somatic mutations detected in NB is hampering the development of novel pharmacological approaches. Major efforts aim to identify novel NB-associated surface molecules that activate immune responses and/or direct drugs to tumor cells and tumor-associated vessels. PVR (Poliovirus Receptor) and B7-H3 are promising targets, since they are expressed by most high-risk NB, are upregulated in tumor vasculature and are essential for tumor survival/invasiveness. PVR is a ligand of DNAM-1 activating receptor that triggers the cytolytic activity of natural killer (NK) cells against NB. In animal models, targeting of PVR with an attenuated oncolytic poliovirus induced tumor regression and elimination. Also B7-H3 was successfully targeted in preclinical studies and is now being tested in phase I/II clinical trials. B7-H3 down-regulates NK cytotoxicity, providing NB with a mechanism of escape from immune response. The immunosuppressive potential of NB can be enhanced by the release of soluble factors that impair NK cell function and/or recruitment. Among these, TGF-β1 modulates the cytotoxicity receptors and the chemokine receptor repertoire of NK cells. Here, we summarize the current knowledge on the main cell surface molecules and soluble mediators that modulate the function of NK cells in NB, considering the pros and cons that must be taken into account in the design of novel NK cell-based immunotherapeutic approaches

  2. Natural killer cells in baboons and humans subjected to total lymphoid irradiation and subsequent renal transplantation

    International Nuclear Information System (INIS)

    This study investigates the functional ability and numbers of natural killer (NK) cells in peripheral blood of the chacma baboon and humans which were subjected to varying doses of total lymphoid irradiation (TLI) and subsequent renal transplantation. NK cell activity was determined by measuring the amount of 51Cr release from K562 target cells when placed in contact with baboon or human peripheral blood lymphocytes. The anti-human antibody Leu11b was shown to cross-react with determinants on baboon effector cells. Concomitant measurements of large granular lymphocytes (LGL) were also made. Normal values for NK cell activity Leu11b+ cells and LGL in the baboon were 73.4+-39.6 Vmax units, 6.8+-3.8% and 6.0+-3.2% respectively. After TLI, NK cell activity was elevated 3 to 4 fold of pre-TLI values and remained at these supranormal levels. The effects of surgery caused a transient depression of activity. Normal values for NK cell activity, Leu11b+ cells and LGL in humans were 280+-212 Vmax units, 6.7+-2.5% and 7.6+-2.5% respectively. A significant depression of NK cell activity was observed in renal allograft patients receiving combination doses of immunosuppressive drugs. Those patients that received tolerogenic doses of TLI prior to transplant followed by immunosuppressive drug regimens had a significant and persistent elevation of NK cell activity. Baboons and humans showed no relationship between NK cell function and Leu11b+ cells or LGL. The latter two parameters did not significantly change in response to TLI or transplantation. It was concluded that TLI gives rise to activated NK cells which results in elevated function unrelated to cell numbers. This dissertation has demonstrated that one advantage of TLI lies in the selective suppression of immunity - while graft tolerance is easily induced

  3. Evaluation of role of natural killer cells in radiation-induced leukemogenesis in mice

    International Nuclear Information System (INIS)

    The relationship of the leukemogenic and natural killer (NK)-suppressive effects of fractionated doses of gamma-radiation in mice was studied. A/J mice were relatively resistant; CBA/J, BALB/c, and C57BL/6 were susceptible to both the NK-suppressive and leukemogenic effects, and young (1 mo old) C57BL/6 mice were more susceptible than were 2- and 3-month-old C57BL/6 mice to both effects. Age-dependent susceptibility to radiation-induced leukemogenesis also was observed in C57BL/6 (bg/bg) (beige) mice. No differences in incidence and latent period of lymphoma development were found between C57BL/6 (+/+) and beige mice. Bone marrow cells (BMC) from normal C57BL/6 donors reconstituted the NK reactivity of irradiated C57BL/6 (+/+) or beige recipients and inhibited leukemogenesis. Although BMC of beige donors did not reconstitute the NK reactivity of irradiated C57BL/6 (+/+) or beige recipients, these cells were as efficient for antileukemic protection as were BMC from C57BL/6 (+/+) mice. The bone marrow of irradiated mice contained preleukemia cells that produced leukemias when transplanted iv into recipients preirradiated with 400 R. Inoculation (iv) of spleen cells (SpC) from syngeneic nude mice plus preleukemia bone marrow cells (PBMC) were able to inhibit leukemia formation in the 400 R-irradiated recipients. SpC from beige mice, normal C57BL/6 (+/+) mice, or C57BL/6 (+/+) mice treated with anti-asialo GM1 serum had no influence on the development of leukemia after their transplantation with PBMC

  4. Histone deacetylase inhibitors enhance expression of NKG2D ligands in Ewing sarcoma and sensitize for natural killer cell-mediated cytolysis

    Directory of Open Access Journals (Sweden)

    Berghuis Dagmar

    2012-02-01

    Full Text Available Abstract Background Ewing sarcoma patients have a poor prognosis despite multimodal therapy. Integration of combination immunotherapeutic strategies into first-/second-line regimens represents promising treatment options, particularly for patients with intrinsic or acquired resistance to conventional therapies. We evaluated the susceptibility of Ewing sarcoma to natural killer cell-based combination immunotherapy, by assessing the capacity of histone deacetylase inhibitors to improve immune recognition and sensitize for natural killer cell cytotoxicity. Methods Using flow cytometry, ELISA and immunohistochemistry, expression of natural killer cell receptor ligands was assessed in chemotherapy-sensitive/-resistant Ewing sarcoma cell lines, plasma and tumours. Natural killer cell cytotoxicity was evaluated in Chromium release assays. Using ATM/ATR inhibitor caffeine, the contribution of the DNA damage response pathway to histone deacetylase inhibitor-induced ligand expression was assessed. Results Despite comparable expression of natural killer cell receptor ligands, chemotherapy-resistant Ewing sarcoma exhibited reduced susceptibility to resting natural killer cells. Interleukin-15-activation of natural killer cells overcame this reduced sensitivity. Histone deacetylase inhibitor-pretreatment induced NKG2D-ligand expression in an ATM/ATR-dependent manner and sensitized for NKG2D-dependent cytotoxicity (2/4 cell lines. NKG2D-ligands were expressed in vivo, regardless of chemotherapy-response and disease stage. Soluble NKG2D-ligand plasma concentrations did not differ between patients and controls. Conclusion Our data provide a rationale for combination immunotherapy involving immune effector and target cell manipulation in first-/second-line treatment regimens for Ewing sarcoma.

  5. Severe accident natural circulation studies at the INEL

    International Nuclear Information System (INIS)

    Severe accident natural circulation flows have been investigated at the Idaho National Engineering Laboratory to better understand these flows and their potential impacts on the progression of a pressurized water reactor severe accident. Parameters affecting natural circulation in the reactor vessel and hot legs were identified and ranked based on their perceived importance. Reviews of the scaling of the 1/7-scale experiments performed by Westinghouse were undertaken. RELAP5/MOD3 calculations of two of the experiments showed generally good agreement between the calculated and observed behavior. Analyses of hydrogen behavior in the reactor vessel showed that hydrogen stratification is not likely to occur, and that an initially stratified layer of hydrogen would quickly mix with a recirculating steam flow. An analysis of the upper plenum behavior in the Three Mile Island, Unit 2 reactor concluded that vapor temperatures could have been significantly higher than the temperatures seen by the control rod drive lead screws, supporting the premise that a strong natural circulation flow was likely present during the accident. SCDAP/RELAP5 calculations of a commercial pressurized water reactor severe accident without operator actions showed that the natural circulation flows enhance the likelihood of ex-vessel piping failures long before failure of the reactor vessel lower head

  6. Experimental study of flow instability in elongated natural circulation system

    International Nuclear Information System (INIS)

    The visual experimental study with water as the working substance was performed to investigate the operation behavior of a natural circulation system with elongated loops and long horizontal sections at atmospheric pressure, and the transient operation behavior and instability mechanism of typical experimental phenomenon (P= 1.46 kW) were given. The results show that the single natural circulation in elongated system with the great resistance coefficient is difficult to appear, but the heat can be removed by two-phase intermittent boiling. The driven force caused by the sub-cooled boiling can not drive the fluid to produce the effective natural circulation because of the great loop resistance, and the circular flow occurs only when the fluid in heat section produces the saturation boiling. The big loop resistance and flashing because of pressure drop in boiling process make the elongated natural circulation difficult to maintain a stable flow driven head and they are the fundamental reasons of intermittent boiling and strong flow instability. (authors)

  7. Thermalhydraulic instability analysis of a two phase natural circulation loop

    International Nuclear Information System (INIS)

    This work presents an analysis of a loop operating in natural circulation regime. Experiments were done in a rectangular closed circuit in one and two-phase flows. Numerical analysis were performed initially with the CIRNAT code and afterwards with RELAP5/MOD2. The limitations of CIRNAT were studied and new developments for this code are proposed. (author)

  8. Coolant rate distribution in horizontal steam generator under natural circulation

    Energy Technology Data Exchange (ETDEWEB)

    Blagovechtchenski, A.; Leontieva, V.; Mitrioukhin, A. [St. Petersburg State Technical Univ. (Russian Federation)

    1997-12-31

    In the presentation the major factors determining the conditions of NCC (Natural Coolant Circulation) in the primary circuit and in particular conditions of coolant rate distribution on the horizontal tubes of PGV-1000 in NPP with VVER-1000 under NCC are considered. 5 refs.

  9. Validation of SSC using the FFTF natural-circulation tests

    International Nuclear Information System (INIS)

    As part of the Super System Code (SSC) validation program, the 100% power FFTF natural circulation test has been simulated using SSC. A detailed 19 channel, 2 loop model was used in SSC. Comparisons showed SSC calculations to be in good agreement with the Fast Flux Test Facility (FFTF), test data. Simulation of the test was obtained in real time

  10. Severe accident natural circulation studies at the INEL

    Energy Technology Data Exchange (ETDEWEB)

    Bayless, P.D.; Brownson, D.A.; Dobbe, C.A.; Jones, K.R.; O`Brien, J.E.; Pafford, D.J.; Schlenker, L.D.; Tung, V.X.

    1995-02-01

    Severe accident natural circulation flows have been investigated at the Idaho National Engineering Laboratory to better understand these flows and their potential impacts on the progression of a pressurized water reactor severe accident. Parameters affecting natural circulation in the reactor vessel and hot legs were identified and ranked based on their perceived importance. Reviews of the scaling of the 1/7-scale experiments performed by Westinghouse were undertaken. RELAP5/MOD3 calculations of two of the experiments showed generally good agreement between the calculated and observed behavior. Analyses of hydrogen behavior in the reactor vessel showed that hydrogen stratification is not likely to occur, and that an initially stratified layer of hydrogen would quickly mix with a recirculating steam flow. An analysis of the upper plenum behavior in the Three Mile Island, Unit 2 reactor concluded that vapor temperatures could have been significantly higher than the temperatures seen by the control rod drive lead screws, supporting the premise that a strong natural circulation flow was likely present during the accident. SCDAP/RELAP5 calculations of a commercial pressurized water reactor severe accident without operator actions showed that the natural circulation flows enhance the likelihood of ex-vessel piping failures long before failure of the reactor vessel lower head.

  11. Natural circulation flow behavior at reduced inventory conditions

    International Nuclear Information System (INIS)

    The flow instability behaviour of a natural circulation loop was studied at reduced inventory conditions, which is important during a LOCA situation in a nuclear reactor with non-availability of circulating pumps. For this, experiments were conducted at low steam drum levels. Large amplitude U-tube type oscillations were observed at low power condition when the system was mostly under single-phase condition. With rise in power when boiling was initiated in the loop, low quality Type I density-wave instabilities were observed. The characteristics of Type I instabilities are found to be quite different from the oscillations observed under single-phase conditions. (author)

  12. Natural Circulation Modeling in MTR Fuel Geometry in Research Reactors

    International Nuclear Information System (INIS)

    In many research reactors the reactor can operate under either forced or natural convection modes. Under forced convection, the primary cooling system removes the heat generated in the reactor core through a heat exchanger to the secondary cooling system, which releases this thermal energy through the cooling tower to the atmosphere. Under natural convection operating mode, the generated nuclear power imply heats up the pool water, and is ultimately dissipated through the pool surface to the containment atmosphere. Hence, the large pool provides a heat sink for the energy generated within the core. The pool surface is open to the containment atmosphere, where thermal energy exchange via evaporation and convection heat transfer can occur. In case of electrical supply failure or mechanical / electrical failure in the pumps, a Loss of Flow Accident (LOFA) will occur. In this case natural circulation mechanism may be the only mechanism that can be use to remove the decay heat from the core. Modeling and modeling validation of natural circulation is an important issue in designing and commissioning of nuclear reactors. Most of the designers are using commercial codes like RELAP5, TRAC and THYDE-W to simulate the behavior of the core under natural circulation. Validation of those cods is done by comparing between different codes and comparing the calculated results with results from scaled experimental systems. In the last two decades, CFD calculations are also used for calculations and validation of the commercial codes. In case of research reactors and in case of Loss of Flow Accident, a simple analytical model can be use for preliminary and advanced calculations of the reactors. The purpose of this paper is to present and validate a simple model for thermohydraulic calculation of research reactor in natural circulation mode

  13. A relevância das células natural killer (NK) e killer immunoglobulin-like receptors (KIR) no transplante de células-tronco hematopoéticas (TCTH) The relevance of natural killer (NK) cells and killer immunoglobulin-like receptors (KIR) in hematopoietic stem cell transplantation (HSCT)

    OpenAIRE

    Aline Almeida-Oliveira; Hilda R. Diamond

    2008-01-01

    As células natural killer (NK) foram identificadas há mais de 30 anos por sua capacidade de matar células tumorais e infectadas por vírus sem precisar de sensibilização prévia. No entanto, a forma como as células NK matam seus alvos ficou desconhecida por muito tempo. Na década de 90, a partir de várias observações, foi proposto que as células NK matariam células com a expressão diminuída de antígeno leucocitário humano (HLA), protegendo as células autólogas normais, o que ficou conhecido com...

  14. Sensitivity of locally recurrent rat mammary tumour cell lines to syngeneic polymorphonuclear cell, macrophage and natural killer cell cytolysis.

    OpenAIRE

    Aeed, P. A.; Welch, D. R.

    1988-01-01

    Using a recently developed model for studying the biology of locally recurrent (LR) mammary tumours in the 13762NF rat mammary adenocarcinoma system, we examined the sensitivity to polymorphonuclear cell, macrophage and natural killer cell cytolysis. The parental MTF7(T20) cell line; the 'primary' tumours which arose following subcutaneous inoculation into the mammary fat pad, sc1 and sc3; and the local recurrences (following surgical excision) LR1 and LR1a from sc1, and LR3 from sc3 were all...

  15. Natural killer function following allogeneic bone marrow transplantation. Very early reemergence but strong dependence of cytomegalovirus infection

    DEFF Research Database (Denmark)

    Hokland, M; Jacobsen, N; Ellegaard, J;

    1988-01-01

    Natural killer (NK) cell function was followed sequentially after allogeneic bone marrow transplantation (BMT) using three approaches: (1) chromium-release assay with purified mononuclear effector cells, (2) chromium-release assay with whole blood effectors, and 3) enumeration of lymphocytes......) infections (primary or reactivated). In contrast, the presence of graft-versus-host (GVH) disease did not associate with consistent changes in the NK parameters measured here. After the first month of increase, NK declined reaching levels near those observed in their respective bone marrow donors at day 90...

  16. Inhibition of in vitro natural killer activity by the third component of complement: role for the C3a fragment.

    OpenAIRE

    Charriaut, C; Senik, A; Kolb, J P; Barel, M; Frade, R

    1982-01-01

    Purified human native third component of complement, C3, was found to inhibit in vitro natural killer (NK) cell cytotoxicity in both mouse and human systems. The effect was dose and time dependent, a 50% inhibition being reached with 190 nM C3 (35 micrograms/ml) added during the NK assay or after a 30-min preincubation of the effector cells with this C3 concentration. C3 was shown to act at the effector-cell population level because pretreatment of the target cells did not modify the NK lysis...

  17. An Essential Role for Tumor Necrosis Factor in Natural Killer Cell–mediated Tumor Rejection in the Peritoneum

    OpenAIRE

    Smyth, Mark J.; Kelly, Janice M.; Baxter, Alan G.; Körner, Heinrich; Sedgwick, Jonathon D.

    1998-01-01

    Natural killer (NK) cells are thought to provide the first line of defence against tumors, particularly major histocompatibility complex (MHC) class I− variants. We have confirmed in C57BL/6 (B6) mice lacking perforin that peritoneal growth of MHC class I− RMA-S tumor cells in unprimed mice is controlled by perforin-dependent cytotoxicity mediated by CD3− NK1.1+ cells. Furthermore, we demonstrate that B6 mice lacking tumor necrosis factor (TNF) are also significantly defective in their reject...

  18. Invariant Natural Killer T cells are not affected by lysosomal storage in patients with Niemann-Pick disease type C

    OpenAIRE

    Speak, Anneliese O; Platt, Nicholas; Salio, Mariolina; te Vruchte, Danielle Taylor; Smith, David A.; Shepherd, Dawn; Veerapen, Natacha; Besra, Gurdyal; Yanjanin, Nicole M.; Simmons, Louise; Imrie, Jackie; Wraith, James E.; Lachmann, Robin; Hartung, Ralf; Runz, Heiko

    2012-01-01

    Invariant Natural Killer T (iNKT) cells are a specialised subset of T cells that are restricted to the MHC class I like molecule, CD1d. The ligands for iNKT cells are lipids, with the canonical superagonist being α-galactosylceramide, a non-mammalian glycosphingolipid. Trafficking of CD1d through the lysosome is required for the development of murine iNKT cells. Niemann-Pick type C (NPC) disease is a lysosomal storage disorder caused by dysfunction in either of two lysosomal proteins, NPC1 or...

  19. Trichinella pseudospiralis larvae express natural killer (NK) cell-associated asialo-GM1 antigen and stimulate pulmonary NK activity.

    OpenAIRE

    Niederkorn, J. Y.; Stewart, G L; Ghazizadeh, S; Mayhew, E.; Ross, J; Fischer, B.

    1988-01-01

    Natural killer (NK) cell function was evaluated in mice infected with either Trichinella pseudospiralis or T. spiralis larvae. T. pseudospiralis-infected mice consistently demonstrated augmented pulmonary NK cell-mediated clearance of YAC-1 tumor cells in vivo but failed to display enhanced splenic NK cell-mediated lysis of the same tumor cells in vitro. Attempts to alter NK cell function in vivo by the injection of anti-asialo-GM1 antibody resulted in anaphylaxis and death of the hosts infec...

  20. Met-ase: Cloning and distinct chromosomal location of a serine protease preferentially expressed in human natural killer cells

    Energy Technology Data Exchange (ETDEWEB)

    Smyth, M.J.; Trapani, J.A. (Austin Research Institute, Austin Hospital, Victoria (Australia)); Sayers, T.J.; Wiltrout, T. (NCI-Frederick Cancer Research and Development Center, Frederick, MD (United States)); Powers, J.C. (Georgia Institute of Technology, Atlanta, GA (United States))

    1993-12-01

    A cDNA clone encoding a human NK serine protease was obtained by screening a [lambda]-gt10 library from the Lopez NK leukemia with the rat natural killer Met-ase (RNK-Met-1) cDNA clone. In Northern blot analysis human Met-ase (Hu-Met-1) cDNA hybridized with a 0.9-kb mRNA in two human NK leukemia cell lines, unstimulated human PBMC, and untreated purified CD3[sup [minus

  1. Decidual Cell Regulation of Natural Killer Cell–Recruiting Chemokines: Implications for the Pathogenesis and Prediction of Preeclampsia

    OpenAIRE

    Lockwood, Charles J.; Huang, S. Joseph; Chen, Chie-Pein; Huang, Yingqun; Xu, Jie; Faramarzi, Saeed; Kayisli, Ozlem; Kayisli, Umit; Koopman, Louise; Smedts, Dineke; Buchwalder, Lynn F.; Schatz, Frederick

    2013-01-01

    First trimester human decidua is composed of decidual cells, CD56brightCD16− decidual natural killer (dNK) cells, and macrophages. Decidual cells incubated with NK cell–derived IFN-γ and either macrophage-derived TNF-α or IL-1β synergistically enhanced mRNA and protein expression of IP-10 and I-TAC. Both chemokines recruit CXCR3-expressing NK cells. This synergy required IFN-γ receptor 1 and 2 mediation via JAK/STAT and NFκB signaling pathways. However, synergy was not observed on neutrophil,...

  2. The Fetal Allograft Revisited: Does the Study of an Ancient Invertebrate Species Shed Light on the Role of Natural Killer Cells at the Maternal-Fetal Interface?

    Directory of Open Access Journals (Sweden)

    Breton F. Barrier

    2008-07-01

    Full Text Available Human pregnancy poses a fundamental immunological problem because the placenta and fetus are genetically different from the host mother. Classical transplantation theory has not provided a plausible solution to this problem. Study of naturally occurring allogeneic chimeras in the colonial marine invertebrate, Botryllus schlosseri, has yielded fresh insight into the primitive development of allorecognition, especially regarding the role of natural killer (NK cells. Uterine NK cells have a unique phenotype that appears to parallel aspects of the NK-like cells in the allorecognition system of B. schlosseri. Most notably, both cell types recognize and reject “missing self” and both are involved in the generation of a common vascular system between two individuals. Chimeric combination in B. schlosseri results in vascular fusion between two individual colonies; uterine NK cells appear essential to the establishment of adequate maternal-fetal circulation. Since human uterine NK cells appear to de-emphasize primary immunological function, it is proposed that they may share the same evolutionary roots as the B. schlosseri allorecognition system rather than a primary origin in immunity.

  3. Liquid Fluoride Salt Experimentation Using a Small Natural Circulation Cell

    Energy Technology Data Exchange (ETDEWEB)

    Yoder Jr, Graydon L [ORNL; Heatherly, Dennis Wayne [ORNL; Williams, David F [ORNL; Elkassabgi, Yousri M. [Texas A& M University, Kingsville; Caja, Joseph [Electrochemical Systems, Inc.; Caja, Mario [ORNL; Jordan, John [Texas A& M University, Kingsville; Salinas, Roberto [Texas A& M University, Kingsville

    2014-04-01

    A small molten fluoride salt experiment has been constructed and tested to develop experimental techniques for application in liquid fluoride salt systems. There were five major objectives in developing this test apparatus: Allow visual observation of the salt during testing (how can lighting be introduced, how can pictures be taken, what can be seen) Determine if IR photography can be used to examine components submerged in the salt Determine if the experimental configuration provides salt velocity sufficient for collection of corrosion data for future experimentation Determine if a laser Doppler velocimeter can be used to quantify salt velocities. Acquire natural circulation heat transfer data in fluoride salt at temperatures up to 700oC All of these objectives were successfully achieved during testing with the exception of the fourth: acquiring velocity data using the laser Doppler velocimeter. This paper describes the experiment and experimental techniques used, and presents data taken during natural circulation testing.

  4. Transient and stability analysis in single-phase natural circulation

    Energy Technology Data Exchange (ETDEWEB)

    Mousavian, Seyed Khalil E-mail: kh_mousavian@mehr.sharif.edu; Misale, Mario; D' Auria, Francesco; Salehi, Mahmoud A

    2004-07-01

    This paper presents the mathematical modeling of single-phase natural circulation of the University of Genoa's rectangular loop (LOOP no. 1) by a computer program and using RELAP5 system code. The mass, momentum and energy conservation equations in transient form were solved numerically using the finite difference method. One-dimensional linear stability analysis was performed for the single-phase natural circulation loop and the numerical perturbation technique was used in this analysis. The Nyquist criterion was employed to find the stability map of the LOOP no. 1. The obtained transient results using the first order upwind scheme of the fluid temperatures in various sectors of the LOOP no. 1 are compared with the results obtained from the RELAP5 system code and available experimental data.

  5. Bond graph model for prediction of PWR natural circulation

    International Nuclear Information System (INIS)

    In operation of a Pressurized Water Reactor, natural circulation is an efficient, passive heat transfer mechanism for cooling. It is often employed for heat removal in operational transients, especially in long-term decay-heat removal operation. To simulate the dynamics of natural circulation, a bond graph representation of the PWR primary system and causal manipulation of the field equations has been modeled. The bond graph method calls for establishing the dynamic equations of multiport systems in state-variable form. Using the analogy of circuit elements in electrical networks, a bond graph consists of multiport capacitances, inertances, dissipations, sources of effort and flow, transformers, gyrators, and ideal junction elements. By treating each component in a PWR primary loop as a multiport element in the bond graph, a set of state-space equations representing the thermal/hydraulic responses of the loop is obtained. The state equations are then solved iteratively by using the program DYSIS developed by MIT

  6. Development of thermohydraulic software for PWR reactors with natural circulation

    International Nuclear Information System (INIS)

    The basics concepts about the development of software for steady state analysis of a reactor with natural circulations, in the primary circuit, are exposed. The reactor type is pressurized light water. The equations, correlations and flux diagrams of the source code of the software developed are shown. The source code of the software was written in FORTRAN 77 making use of modular technique, this save development effort and release of news versions is simplified. (author)

  7. Decay heat removal in HTGR by natural circulation

    International Nuclear Information System (INIS)

    The coolability of 1000MWt HTGR under complete loss of forced flow conditions was investigated. A dynamic simulator for nuclear power plants (DSNP) program was developed to study the evolution of natural circulation during loss of forced flow (LOF). It was concluded that a passive cooling device, having 0.3% heat removal capacity of nominal decay heat rate, is sufficient for emergency cooling of the proposed plant under total LOF. (author)

  8. A relevância das células natural killer (NK e killer immunoglobulin-like receptors (KIR no transplante de células-tronco hematopoéticas (TCTH The relevance of natural killer (NK cells and killer immunoglobulin-like receptors (KIR in hematopoietic stem cell transplantation (HSCT

    Directory of Open Access Journals (Sweden)

    Aline Almeida-Oliveira

    2008-08-01

    Full Text Available As células natural killer (NK foram identificadas há mais de 30 anos por sua capacidade de matar células tumorais e infectadas por vírus sem precisar de sensibilização prévia. No entanto, a forma como as células NK matam seus alvos ficou desconhecida por muito tempo. Na década de 90, a partir de várias observações, foi proposto que as células NK matariam células com a expressão diminuída de antígeno leucocitário humano (HLA, protegendo as células autólogas normais, o que ficou conhecido como hipótese do missing-self. Esta teoria foi confirmada através da descoberta de vários receptores, principalmente os da família killer immunoglobulin-like receptors (KIR, que reconhecem moléculas de HLA de classe I. Estes novos conceitos levaram à busca da importância dos receptores KIR no transplante de células-tronco hematopoéticas (TCTH. Foi sugerido que as disparidades de HLA entre o doador e o paciente poderiam ser reconhecidas por células NK levando à aloreatividade, o que ajudaria no efeito enxerto contra leucemia. No entanto, apesar de alguns resultados promissores, até hoje, os diferentes estudos sobre o assunto não chegaram a um consenso. Nesta revisão, será abordada a relevância das células NK e dos receptores KIR nos diferentes tipos de TCTH.Natural killer (NK cells were identified over 30 years ago by their ability to kill cancer and virally infected cells without prior sensitization. For years the recognition mechanisms of target cells were unknown, until the 1990s when the "missing-self" hypothesis was proposed. According to this theory, although tolerant to normal autologous cells, NK cells can recognize and attack cells that have down-regulated human leukocyte antigen (HLA class I molecules. The discovery of killer immunoglobulin-like receptors (KIR that specifically recognize HLA class I molecules corroborated this hypothesis. These new concepts point to the importance of studying KIR in hematopoietic stem

  9. Natural circulation in PWR for asymmetric secondary conditions

    International Nuclear Information System (INIS)

    Natural circulation in the primary loop of PWRs offers an essential means of removing the shutdown decay heat during accidents and is an important safety issue due to its passive mechanism. The flow is driven by the buoyancy force arisen by the average coolant density difference between the heat source and the heat sink. In order to examine the thermal-hydraulic behavior and heat removal capability by the natural circulation of system in transients or accident conditions, the experimental facility (SNUF) is constructed on the model of KORI unit 1 and 2 with the scaling factor of 1/710 by volume. With SNUF, a series of experiments is performed to understand the characteristics of natural circulation. Form the steady-state experiments, it is turned out that the loop mass flow rate is in pro potion to core power and to reciprocal of loop temperature difference. From the transient experiments, the core heat can be removed for active secondary heat sinks including the condition that one steam generator degrades its heat removal capability such as feed line break accident or loss of normal feedwater

  10. OPG's approach of crediting natural circulation in outage heat sinks

    International Nuclear Information System (INIS)

    A review of crediting natural circulation as a backup means of removing the reactor core decay heat during an outage in Ontario Power Generation's nuclear stations was completed in 2000. The objective was to define the configurations and conditions under which natural circulation can be confidently credited as an effective heat transport mechanism for use in shutdown heat sink management. The project was an interdisciplinary program, and involved analyses in the areas of heat transport system thermalhydaulics, fuel and fuel channel thermal and mechanical behaviour, radiation physics, and probabilistic risks. The assessment shows that it is economically acceptable to credit natural circulation as a backup means of removing the core decay heat whenever the no fuel failure criteria are met. The economic risks associated with such a potential use decrease with time after shutdown. The waiting times after shutdown when there would be various levels of risks of damaging the pressure tubes and fuel bundles were derived for use in planning maintenance activities so as to minimize the economic risks. (author)

  11. Study on diffusion and natural circulation of two component gases

    International Nuclear Information System (INIS)

    When a primary coolant pipe of a High Temperature Gas Cooled Reactor (HTGR) ruptures, helium gas in the reactor core blows out into the container, and the primary coolant system reduces the pressure. After the reactor core and the container pressures are balanced, air is expected to ingress into the reactor core from a broken part by natural circulation and diffusion. It seems to be probable that the graphite structures is oxidized by the air. It is difficult to predict the air ingress rate, because complicated natural circulations take place in the reactor core, and diffusion paths are also complicated. In order to study the basic features of the air ingress during the early stage of the primary pipe rupture accident of the high temperature gas cooled reactor, the natural circulation of the two component gases was studied experimentally and analytically. The experiment was performed with a reversed U-shaped round pipe with one pipe heated and the other cooled. The analytical results were in good agreement with the experimental ones. (author)

  12. Scaling laws for single-phase natural circulation loops

    International Nuclear Information System (INIS)

    The power-to-volume scaling laws used for the construction of scaled test facilities simulating the primary system of nuclear power plants result in loops of the same elevation (and length) with reduced diameters. The adequacy of these scaling laws for simulating single-phase natural circulation was tested in three rectangular loops, each having the same elevation but different loop diameters of 6mm, 11mm and 23.2mm respectively. The experiments showed that the power-to-volume scaling principles adequately describe the steady state behaviour. The stability behaviour observed in the loop 23.2mm in diameter, however, could not be reproduced in the smaller diameter loops. Subsequent theoretical investigation of the single-phase natural circulation phenomenon showed that the transient and stability behaviour can be simulated only if the diameter ratio Dp/Dm is also simulated. The theoretical investigation suggested the following scaling laws for single-phase natural circulation: (Grm)p=(Grm)m LpLm=DpDm=HpHm=(Lh)p(Lh)m (Stm)p=(Stm)m For simulating the steady state behaviour alone, it is sufficient to simulate the product Grm(D/L). ((orig.))

  13. The tumor antigen N-glycolyl-GM3 is a human CD1d ligand capable of mediating B cell and natural killer T cell interaction.

    Science.gov (United States)

    Gentilini, M Virginia; Pérez, M Eugenia; Fernández, Pablo Mariano; Fainboim, Leonardo; Arana, Eloísa

    2016-05-01

    The expression of N-glycolyl-monosialodihexosyl-ganglioside (NGcGM3) in humans is restricted to cancer cells; therefore, it is a tumor antigen. There are measurable quantities of circulating anti-NGcGM3 antibodies (aNGcGM3 Abs) in human serum. Interestingly, some people have circulating Ag-specific immunoglobulins G (IgGs) that are capable of complement mediated cytotoxicity against NGcGM3 positive cells, which is relevant for tumor surveillance. In light of the chemical nature of Ag, we postulated it as a candidate ligand for CD1d. Furthermore, we hypothesize that the immune mechanism involved in the generation of these Abs entails cross talk between B lymphocytes (Bc) and invariant natural killer T cells (iNKT). Combining cellular techniques, such as flow cytometry and biochemical assays, we demonstrated that CD1d binds to NGcGM3 and that human Bc present NGcGM3 in a CD1d context according to two alternative strategies. We also showed that paraformaldehyde treatment of cells expressing CD1d affects the presentation. Finally, by co-culturing primary human Bc with iNKT and measuring Ki-67 expression, we detected a reproducible increment in the proliferation of the iNKT population when Ag was on the medium. Our findings identify a novel, endogenous, human CD1d ligand, which is sufficiently competent to stimulate iNKT. We postulate that CD1d-restricted Bc presentation of NGcGM3 drives effective iNKT activation, an immunological mechanism that has not been previously described for humans, which may contribute to understanding aNGcGM3 occurrence. PMID:26969612

  14. Significant Increase in Cytotoxic T Lymphocytes and Natural Killer Cells by Triphala: A Clinical Phase I Study

    Science.gov (United States)

    Phetkate, Pratya; Kummalue, Tanawan; U-pratya, Yaowalak; Kietinun, Somboon

    2012-01-01

    Background. Searching for drugs or herbal formulations to improve the immunity of HIV/AIDS positive people is an important issue for researchers in this field. Triphala, a Thai herbal formulation, is reported to have immunomodulatory effects in mice. However, it has not yet been investigated for immunostimulatory and side effects in healthy human volunteers. Objective. To evaluate the immunostimulatory and side effects of Triphala in a clinical phase I study. Materials and Methods. All volunteers took Triphala, 3 capsules per day for 2 weeks. Complete physical examination, routine laboratory analysis, and immunological studies were performed before ingestion and after initial meeting for 4 consecutive weeks. Results. We found that Triphala demonstrated significant immunostimulatory effects on cytotoxic T cells (CD3−CD8+) and natural killer cells (CD16+CD56+). Both of them increased significantly when compared with those of the control samples. However, no significant change in cytokine secretion was detected. All volunteers were healthy and showed no adverse effects throughout the duration of the study. Conclusion. Triphala has significant immunostimulatory effects on cellular immune response, especially cytotoxic T cells and natural killer cells. Increases in the absolute number of these cells may provide a novel adjuvant therapy for HIV/AIDS positive people in terms of immunological improvement. PMID:23243435

  15. Computer simulation of natural circulation in FFTF secondary loops

    International Nuclear Information System (INIS)

    A thermal/hydraulic model of the FFTF secondary heat transport loop has been calibrated against transient natural circulation test data collected March to May 1979. The tests verified that the transition to natural convective flow could be effected from near isothermal conditions without excessive cooling at the air dump heat exchangers. Key empirical parameters of pressure drop and heat loss were found to be at 88% and 81% of pretest estimates, respectively. Pretest piping thermal transport and flow calculational models required no further revision to produce good agreement with test data

  16. Circulational characteristics of a natural circulation circuit of a weakly boiling reactor large-scale model

    International Nuclear Information System (INIS)

    A large-scale model for determining circulational characteristics of a natural circulation circuit of weakly boiling (core outlet steam content below 4%) tank tpype water cooled reactors is described. The model consists of 61 elecrtroheated fuel elements 14 mm in-diameter and 3 m height. Outlet pressure can vary within 1.7-5.0 MPa inlet water subcooling is 20-90 deg C, weight outlet balance steam content from-9 to 3.2 %. Results of the experiments performed for checking the algorithms developed for thermohydraulic calculation of steady-state characteristics of the investigated circuit are given. It is concluded that for one-phase coolant estimated and experimental values for pressure head and hydraulic resistance agree well with

  17. Stability analysis on natural circulation boiling water reactors

    International Nuclear Information System (INIS)

    The purpose of the study is a stability analysis of the simplified boiling water reactor concept. A fluid dynamics code, DYNOS, was developed and successfully validated against FRIGG and DESIRE data and a stability benchmark on the Ringhals 1 forced circulation BWR. Three simplified desings were considered in the analysis: The SWRIOOO by Siemens and the SBWR and ESBWR from the General Electric Co. For all three design operational characteristics, i.e. power versus flow rate maps, were calculated. The effects which different geometric and operational parameters, such as the riser height, inlet subcooling etc., have on the characteristics have been investigated. Dynamic simulations on the three simplified design revealed the geysering and the natural circulation oscillations modes only. They were, however, only encountered at pressure below 0.6 MPa. Stability maps for all tree simplified BWRs were calculated and plotted. The study concluded that a fast pressurisation of the reactor vessel is necessary to eliminate the possibility of geysering or natural circulation oscillations mode instability. (au)

  18. Stability analysis on natural circulation boiling water reactors

    Energy Technology Data Exchange (ETDEWEB)

    Metz, Peter

    1999-05-01

    The purpose of the study is a stability analysis of the simplified boiling water reactor concept. A fluid dynamics code, DYNOS, was developed and successfully validated against FRIGG and DESIRE data and a stability benchmark on the Ringhals 1 forced circulation BWR. Three simplified desings were considered in the analysis: The SWRIOOO by Siemens and the SBWR and ESBWR from the General Electric Co. For all three design operational characteristics, i.e. power versus flow rate maps, were calculated. The effects which different geometric and operational parameters, such as the riser height, inlet subcooling etc., have on the characteristics have been investigated. Dynamic simulations on the three simplified design revealed the geysering and the natural circulation oscillations modes only. They were, however, only encountered at pressure below 0.6 MPa. Stability maps for all tree simplified BWRs were calculated and plotted. The study concluded that a fast pressurisation of the reactor vessel is necessary to eliminate the possibility of geysering or natural circulation oscillations mode instability. (au) 26 tabs., 88 ills.

  19. Prostate tumor-derived exosomes down-regulate NKG2D expression on natural killer cells and CD8+ T cells: mechanism of immune evasion.

    Directory of Open Access Journals (Sweden)

    Marie Lundholm

    Full Text Available Tumor-derived exosomes, which are nanometer-sized extracellular vesicles of endosomal origin, have emerged as promoters of tumor immune evasion but their role in prostate cancer (PC progression is poorly understood. In this study, we investigated the ability of prostate tumor-derived exosomes to downregulate NKG2D expression on natural killer (NK and CD8+ T cells. NKG2D is an activating cytotoxicity receptor whose aberrant loss in cancer plays an important role in immune suppression. Using flow cytometry, we found that exosomes produced by human PC cells express ligands for NKG2D on their surface. The NKG2D ligand-expressing prostate tumor-derived exosomes selectively induced downregulation of NKG2D on NK and CD8+ T cells in a dose-dependent manner, leading to impaired cytotoxic function in vitro. Consistent with these findings, patients with castration-resistant PC (CRPC showed a significant decrease in surface NKG2D expression on circulating NK and CD8+ T cells compared to healthy individuals. Tumor-derived exosomes are likely involved in this NKG2D downregulation, since incubation of healthy lymphocytes with exosomes isolated from serum or plasma of CRPC patients triggered downregulation of NKG2D expression in effector lymphocytes. These data suggest prostate tumor-derived exosomes as down-regulators of the NKG2D-mediated cytotoxic response in PC patients, thus promoting immune suppression and tumor escape.

  20. The effect of sex on immune cells in healthy aging: Elderly women have more robust natural killer lymphocytes than do elderly men.

    Science.gov (United States)

    Al-Attar, Ahmad; Presnell, Steven R; Peterson, Charlotte A; Thomas, D Travis; Lutz, Charles T

    2016-06-01

    Immune gender differences have been reported, but are little studied in elderly humans. We compared monocyte and lymphocyte subsets, along with soluble immune mediators in healthy men and women over the age of 70. We also measured natural killer (NK) lymphocyte cytotoxic granule exocytosis, chemokine synthesis, and cytokine synthesis in response to a variety of stimuli. Elderly women had significantly more circulating B cells than men, whereas men had more CD4 central memory T cells and higher monocyte levels. Plasma adiponectin levels were higher in women, plasma retinol-binding protein 4 levels were higher in men, but there were no significant gender differences in C-reactive protein, IL-15, or sphingosine-1-phosphate. Women had a higher ratio of immature CD56(bright) NK cells to mature CD56(dim) NK cells, indicating a gender difference in NK cell maturation in the elderly. Comparing sexes, female mature NK cells had more vigorous cytotoxic granule responses to K562 leukemia cells and IFN-γ responses to NKp46 crosslinking. Moreover, female NK cells were more likely to produce MIP-1β in response to a variety of stimuli. These data show that gender influences NK cell activity in elderly humans. PMID:27059724

  1. Hepatosplenic T-Cell Lymphoma: A Clinicopathologic Review With an Emphasis on Diagnostic Differentiation From Other T-Cell/Natural Killer-Cell Neoplasms.

    Science.gov (United States)

    Shi, Yang; Wang, Endi

    2015-09-01

    Hepatosplenic T-cell lymphoma is a rare, aggressive T-cell lymphoma, characterized by hepatosplenic sinusoidal infiltration of monotonous, medium-sized, nonactivated cytotoxic T cells, usually of γ/δ T-cell receptor type. Hepatosplenic T-cell lymphoma occurs more frequently in immunocompromised patients, especially in those receiving long-term immunosuppressive therapy. Patients usually manifest hepatosplenomegaly without lymphadenopathy. The bone marrow is also involved in two-thirds of cases and is often accompanied by circulating lymphoma cells, which, along with anemia and thrombocytopenia, may raise suspicion for acute leukemia. The differential diagnosis includes aggressive natural killer-cell leukemia, T-large granular lymphocytic leukemia, T-lymphoblastic leukemia, enteropathy-associated T-cell lymphoma type II, primary cutaneous γ/δ T-cell lymphoma, other peripheral T-cell lymphomas, myelodysplastic syndrome, and infectious mononucleosis. The diagnosis is usually established from the combination of clinical findings, histologic features, and immunophenotype, although cytogenetic/molecular studies are occasionally needed. Hepatosplenic T-cell lymphoma exhibits a dismal clinical course with a poor response to currently available therapies. PMID:26317456

  2. Expression of Interferon γ by Decidual Cells and Natural Killer Cells at the Human Implantation Site: Implications for Preeclampsia, Spontaneous Abortion, and Intrauterine Growth Restriction.

    Science.gov (United States)

    Chen, Chie-Pein; Piao, Longzhu; Chen, Xilin; Yu, Jianhua; Masch, Rachel; Schatz, Frederick; Lockwood, Charles J; Huang, S Joseph

    2015-11-01

    Human first-trimester decidual cells (FTDCs) chemoattract CXCR3-expressing circulating CD56(bright)CD16(-) natural killer (NK) cells, which increase uteroplacental blood flow by remodeling spiral arteries and arterioles. This recruitment reflects elevated FTDC expression of NK cell-recruiting induced protein 10 and interferon (IFN)-inducible T-cell-α chemoattractant produced in response to the synergistic effects of tumor necrosis factor α (TNF-α) and IFN-γ stimulation. Decidual macrophages express TNF-α, whereas the cellular origin of IFN-γ is unclear. Therefore, this study aims to identify the cell source(s) of IFN-γ in human first trimester decidua. Immunostaining of decidual sections revealed that both FTDCs and decidual NK (dNK) cells express IFN-γ. Although individual dNK cells express higher IFN-γ levels, the more numerous FTDCs account for greater proportion of total IFN-γ immunostaining. Freshly isolated FTDCs express greater IFN-γ staining than dNK cells as measured by flow cytometry, whereas incubation of dNK cells with documented NK cell activators significantly increases IFN-γ above FTDC levels. Confluent FTDCs intrinsically produce, but paradoxically respond to, exogenous IFN-γ. PMID:25963913

  3. Paucity of CD4+ natural killer T (NKT lymphocytes in sooty mangabeys is associated with lack of NKT cell depletion after SIV infection.

    Directory of Open Access Journals (Sweden)

    Namita Rout

    Full Text Available Lack of chronic immune activation in the presence of persistent viremia is a key feature that distinguishes nonpathogenic simian immunodeficiency virus (SIV infection in natural hosts from pathogenic SIV and HIV infection. To elucidate novel mechanisms downmodulating immune activation in natural hosts of SIV infection, we investigated natural killer T (NKT lymphocytes in sooty mangabeys. NKT lymphocytes are a potent immunoregulatory arm of the innate immune system that recognize glycolipid antigens presented on the nonpolymorphic MHC-class I-like CD1d molecules. In a cross-sectional analysis of 50 SIV-negative and 50 naturally SIV-infected sooty mangabeys, ligand alpha-galactosylceramide loaded CD1d tetramers co-staining with Valpha24-positive invariant NKT lymphocytes were detected at frequencies >or=0.002% of circulating T lymphocytes in approximately half of the animals. In contrast to published reports in Asian macaques, sooty mangabey NKT lymphocytes consisted of CD8(+ and CD4/CD8 double-negative T lymphocytes that were CXCR3-positive and CCR5-negative suggesting that they trafficked to sites of inflammation without being susceptible to SIV infection. Consistent with these findings, there was no difference in the frequency or phenotype of NKT lymphocytes between SIV-negative and SIV-infected sooty mangabeys. On stimulation with alpha-galactosylceramide loaded on human CD1d molecules, sooty mangabey NKT lymphocytes underwent degranulation and secreted IFN-gamma, TNF-alpha, IL-2, IL-13, and IL-10, indicating the presence of both effector and immunoregulatory functional capabilities. The unique absence of CD4(+ NKT lymphocytes in sooty mangabeys, combined with their IL-10 cytokine-secreting ability and preservation following SIV infection, raises the possibility that NKT lymphocytes might play a role in downmodulating immune activation in SIV-infected sooty mangabeys.

  4. Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome.

    Science.gov (United States)

    Sohlberg, Ebba; Pfefferle, Aline; Andersson, Sandra; Baumann, Bettina C; Hellström-Lindberg, Eva; Malmberg, Karl-Johan

    2015-10-27

    5-azacytidine (5-aza) is a hypomethylating agent approved for the treatment of high-risk myelodysplastic syndrome (MDS). It is assumed to act by demethylating tumor suppressor genes and via direct cytotoxic effects on malignant cells. In vitro treatment with hypomethylating agents has profound effects on the expression of killer-cell immunoglobulin-like (KIR) receptors on natural killer (NK) cells, as these receptors are epigenetically regulated via methylation of the promoters. Here we investigated the influence of 5-aza on the NK-cell repertoire during cytokine-induced proliferation in vitro and homeostatic proliferation in vivo in patients with high-risk MDS. In vitro treatment of NK cells from both healthy donors and MDS patients with low doses of 5-aza led to a significant increase in expression of multiple KIRs, but only in cells that had undergone several rounds of cell division. Proliferating 5-aza exposed NK cells exhibited increased IFN-γ production and degranulation towards tumor target cells. MDS patients had lower proportions of educated KIR-expressing NK cells than healthy controls but after systemic treatment with 5-aza, an increased proportion of Ki-67+ NK cells expressed multiple KIRs suggesting uptake of 5-aza in cycling cells in vivo. Hence, these results suggest that systemic treatment with 5-aza may shape the NK cell repertoire, in particular during homeostatic proliferation, thereby boosting NK cell-mediated recognition of malignant cells. PMID:26497557

  5. Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome

    Science.gov (United States)

    Sohlberg, Ebba; Pfefferle, Aline; Andersson, Sandra; Baumann, Bettina C.; Hellström-Lindberg, Eva; Malmberg, Karl-Johan

    2015-01-01

    5-azacytidine (5-aza) is a hypomethylating agent approved for the treatment of high-risk myelodysplastic syndrome (MDS). It is assumed to act by demethylating tumor suppressor genes and via direct cytotoxic effects on malignant cells. In vitro treatment with hypomethylating agents has profound effects on the expression of killer-cell immunoglobulin-like (KIR) receptors on natural killer (NK) cells, as these receptors are epigenetically regulated via methylation of the promoters. Here we investigated the influence of 5-aza on the NK-cell repertoire during cytokine-induced proliferation in vitro and homeostatic proliferation in vivo in patients with high-risk MDS. In vitro treatment of NK cells from both healthy donors and MDS patients with low doses of 5-aza led to a significant increase in expression of multiple KIRs, but only in cells that had undergone several rounds of cell division. Proliferating 5-aza exposed NK cells exhibited increased IFN-γ production and degranulation towards tumor target cells. MDS patients had lower proportions of educated KIR-expressing NK cells than healthy controls but after systemic treatment with 5-aza, an increased proportion of Ki-67+ NK cells expressed multiple KIRs suggesting uptake of 5-aza in cycling cells in vivo. Hence, these results suggest that systemic treatment with 5-aza may shape the NK cell repertoire, in particular during homeostatic proliferation, thereby boosting NK cell-mediated recognition of malignant cells. PMID:26497557

  6. Signaling at the inhibitory natural killer cell immune synapse regulates lipid raft polarization but not class I MHC clustering.

    Science.gov (United States)

    Fassett, M S; Davis, D M; Valter, M M; Cohen, G B; Strominger, J L

    2001-12-01

    Natural killer (NK) cell cytotoxicity is determined by a balance of positive and negative signals. Negative signals are transmitted by NK inhibitory receptors (killer immunoglobulin-like receptors, KIR) at the site of membrane apposition between an NK cell and a target cell, where inhibitory receptors become clustered with class I MHC ligands in an organized structure known as an inhibitory NK immune synapse. Immune synapse formation in NK cells is poorly understood. Because signaling by NK inhibitory receptors could be involved in this process, the human NK tumor line YTS was transfected with signal-competent and signal-incompetent KIR2DL1. The latter were generated by truncating the KIR2DL1 cytoplasmic tail or by introducing mutations in the immunoreceptor tyrosine-based inhibition motifs. The KIR2DL1 mutants retained their ability to cluster class I MHC ligands on NK cell interaction with appropriate target cells. Therefore, receptor-ligand clustering at the inhibitory NK immune synapse occurs independently of KIR2DL1 signal transduction. However, parallel examination of NK cell membrane lipid rafts revealed that KIR2DL1 signaling is critical for blocking lipid raft polarization and NK cell cytotoxicity. Moreover, raft polarization was inhibited by reagents that disrupt microtubules and actin filaments, whereas synapse formation was not. Thus, NK lipid raft polarization and inhibitory NK immune synapse formation occur by fundamentally distinct mechanisms. PMID:11724921

  7. Postoperative Regulatory T-Cells and Natural Killer Cells in Stage I Nonsmall Cell Lung Cancer Underwent Video-assisted Thoracoscopic Lobectomy or Thoracotomy

    Directory of Open Access Journals (Sweden)

    Sai Zhang

    2015-01-01

    Full Text Available Background: Regulatory T-cells (Treg play key roles in suppressing cell-mediated immunity in cancer patients. Little is known about perioperative Treg fluctuations in nonsmall cell lung cancer (NSCLC. Video-assisted thoracoscopic (VATS lobectomy, as a minimal invasive procedure for treating NSCLC, may have relatively less impact on the patient′s immune system. This study aimed to observe perioperative dynamics of circulating Treg and natural killer (NK cell levels in NSCLC patients who underwent major lobectomy by VATS or thoracotomy. Methods: Totally, 98 consecutive patients with stage I NSCLC were recruited and assigned into VATS or thoracotomy groups. Peripheral blood samples were taken on 1-day prior to operation, postoperative days (PODs 1, 3, 7, 30, and 90. Circulating Treg and NK cell counts were assayed by flow cytometry, defined as CD4 + CD25 + CD127 low cells in CD4 + lymphocytes and CD56 + 16 + CD3− cells within CD45 + leukocytes respectively. With SPSS software version 21.0 (SPSS Inc., USA, differences between VATS and thoracotomy groups were determined by one-way analysis of variance (ANOVA, and differences between preoperative baseline and PODs in each group were evaluated by one-way ANOVA Dunnett t-test. Results: In both groups, postoperative Treg percentages were lower than preoperative status. No statistical difference was found between VATS and thoracotomy groups on PODs 1, 3, 7, and 30. On POD 90, Treg percentage in VATS group was significantly lower than in thoracotomy group (5.26 ± 2.75 vs. 6.99 ± 3.60, P = 0.012. However, a higher level of NK was found on all PODs except on POD 90 in VATS group, comparing to thoracotomy group. Conclusions: Lower Treg level on POD 90 and higher NK levels on PODs 1, 3, 7, 30 in VATS group might imply better preserved cell-mediated immune function in NSCLC patients, than those in thoracotomy group.

  8. Automated scoping methodology for liquid metal natural circulation small reactor

    International Nuclear Information System (INIS)

    Highlights: • Automated scoping methodology for natural circulation small modular reactor is developed. • In-house code is developed to carry out system analysis and core geometry generation during scoping. • Adjustment relations are obtained to correct the critical core geometry out of diffusion theory. • Optimized design specification is found using objective function value. • Convex hull volume is utilized to quantify the impact of different constraints on the scope range. - Abstract: A novel scoping method is proposed that can automatically generate design variable range of the natural circulation driven liquid metal cooled small reactor. From performance requirements based upon Generation IV system roadmap, appropriate structure materials are selected and engineering constraints are compiled based upon literature. Utilizing ASME codes and standards, appropriate geometric sizing criteria on constituting components are developed to ensure integrity of the system during its lifetime. In-house one dimensional thermo-hydraulic system analysis code is developed based upon momentum integral model and finite element methods to deal with non-uniform descritization of temperature nodes for convection and thermal diffusion equation of liquid metal coolant. In order to quickly generate critical core dimensions out of given unit cell information, an adjustment relation that relates the critical geometry estimated from one-group diffusion and that from MCNP code is constructed and utilized throughout the process. For the selected unit cell dimension ranges, burnup calculations are carried out to check the cores can generate energy over the reactor lifetime. Utilizing random method, sizing criteria, and in-house analysis codes, an automated scoping methodology is developed. The methodology is applied to nitride fueled integral type lead cooled natural circulation reactor concept to generate design scopes which satisfies given constraints. Three dimensional convex

  9. Selected examples of natural circulation for small break loca and some severe accidents

    International Nuclear Information System (INIS)

    In all light water reactors (LWRs), natural circulation is an important passive heat removal system. The March 1979 accident at TMI-2 brought into question the capability of natural circulation cooling remove core decay heat, especially during accident situations. Because natural circulation is expected to be an essential core heat rejection mechanism during certain kinds of accidents or transients in a PWR (e.g., small break LOCAs or operational transients involving loss of pumped circulation), a thorough understanding of natural circulation processes and factors that influence the natural circulation response of the reactor system is necessary. In this paper, natural circulation and related major phenomena are discussed with examples for small break LOCA and severe accident cases, e.g., TMLB station black-out. Descriptions of three modes of natural circulation are provided: Single-phase natural circulation, two-phase natural circulation, and reflux condensation/boiling condensation. The basic phenomena associated with the three types of natural circulation being considered for severe accidents are also addressed: In-vessel natural circulation, hot leg countercurrent flow, coolant loop flows. (author)

  10. Methodology for studies of natural circulation in closed circuits

    International Nuclear Information System (INIS)

    This work presents the results obtained from the analysis of stability of the phenomenon of the natural circulation for one-dimension single-phase flow in a closed loop, by a computer program with the method of finite element. The Navier-Stokes equations in cartesian geometry were used for the balance of mass, momentum and one equation for energy. The formulation has been implemented in a computer code developed at the Nuclear Engineering Institute(IEN-CNEN-RJ) and is now available either for futures analysis or design of nuclear systems. (author)

  11. Acute pain induces an instant increase in natural killer cell cytotoxicity in humans and this response is abolished by local anaesthesia

    DEFF Research Database (Denmark)

    Greisen, J.; Hokland, Marianne; Grøfte, Thorbjørn;

    1999-01-01

    We have investigated the effect of pain without tissue injury on natural killer (NK) cell activity in peripheral blood in humans and the effect of local anaesthesia on the response. Ten subjects were investigated during two sessions. First, self-controlled painful electric stimulation was applied...

  12. Genomic Analyses Reveal Global Functional Alterations That Promote Tumor Growth and Novel Tumor Suppressor Genes in Natural Killer-Cell Malignancies

    DEFF Research Database (Denmark)

    Kucuk, Can; Iqbal, Javeed; J. deLeeuw, Ronald;

    Background: Natural Killer (NK)-cell lymphomas/leukemias (NKL) account for 1-2 % of all non-Hodgkin lymphomas. Although the incidence of NKL is relatively low, the clinical course of these lymphomas is highly aggressive. To elucidate the recurrent genomic abnormalities and the associated changes ...

  13. Infection with foot-and-mouth disease virus (FMDV) induces a natural killer (NK) cell response in cattle that is lacking following vaccination

    Science.gov (United States)

    Natural killer (NK) cells play a role in innate antiviral immunity by directly lysing virus-infected cells and producing antiviral cytokines such as interferon gamma (IFNgamma). We developed a system for characterizing the bovine NK response to foot-and-mouth disease virus (FMDV), which causes a dis...

  14. Green Tea Catechin Metabolites Exert Immunoregulatory Effects on CD4(+) T Cell and Natural Killer Cell Activities.

    Science.gov (United States)

    Kim, Yoon Hee; Won, Yeong-Seon; Yang, Xue; Kumazoe, Motofumi; Yamashita, Shuya; Hara, Aya; Takagaki, Akiko; Goto, Keiichi; Nanjo, Fumio; Tachibana, Hirofumi

    2016-05-11

    Tea catechins, such as (-)-epigallocatechin-3-O-gallate (EGCG), have been shown to effectively enhance immune activity and prevent cancer, although the underlying mechanism is unclear. Green tea catechins are instead converted to catechin metabolites in the intestine. Here, we show that these green tea catechin metabolites enhance CD4(+) T cell activity as well as natural killer (NK) cell activity. Our data suggest that the absence of a 4'-hydroxyl on this phenyl group (B ring) is important for the effect on immune activity. In particular, 5-(3',5'-dihydroxyphenyl)-γ-valerolactone (EGC-M5), a major metabolite of EGCG, not only increased the activity of CD4(+) T cells but also enhanced the cytotoxic activity of NK cells in vivo. These data suggest that EGC-M5 might show immunostimulatory activity. PMID:27112424

  15. Gut-targeted immunonutrition boosting natural killer cell activity using Saccharomyces boulardii lysates in immuno-compromised healthy elderly subjects.

    Science.gov (United States)

    Naito, Yasuhiro; Marotta, Francesco; Kantah, Makoto K; Zerbinati, Nicola; Kushugulova, Almagul; Zhumadilov, Zhaxybay; Illuzzi, Nicola; Sapienza, Chiara; Takadanohara, Hiroshi; Kobayashi, Riyichi; Catanzaro, Roberto

    2014-04-01

    The aim of this study was to assess the immunomodulatory effect of KC-1317 (a symbiotic mixture containing Saccharomyces boulardii lysate in a cranberry, colostrum-derived lactoferrin, fragaria, and lactose mixture) supplementation in immune-compromised but otherwise healthy elderly subjects. A liquid formulation of KC-1317 was administered in a randomized controlled trial (RCT) fashion to healthy volunteers (65-79 years) previously selected for low natural killer (NK) cell activity, and this parameter was checked at the completion of the study. A significant improvement in NK cell activity of KC-1317 consumers was observed as compared to placebo at the end of 2 months. Although preliminary, these beneficial immune-modulatory effects of KC-1317 in aged individuals might indicate its employment within a wider age-management strategy. PMID:24059806

  16. Effects of 5-azacytidine on natural killer cell activating receptor expression in patients with refractory anemia with excess of blasts

    Directory of Open Access Journals (Sweden)

    Régis T. Costello

    2015-01-01

    Full Text Available Epigenetic drugs modify DNA methylation and are used in refractory anemia with excess of blasts (RAEB. These drugs may reactivate anti-oncogene expression and restore a normal phenotype instead of inducing antitumor toxicity, although they also have immunosuppressive effects on T-lymphocytes [1] In RAEB and acute myeloid leukemia, a defect in natural killer (NK cell cytotoxicity has been shown, which relies on abnormal expression of activating receptors. Previous study has shown that 5-azacytidine impaired mRNA synthesis and induced apoptosis in NK cells [2]. In this study we investigated the effect of the demethylating drug 5-azacytidine (Vidaza® on NK receptors with the hypothesis that demethylation of the promoters of activating NK receptor genes induces gene reactivation and thus may increase their expression.

  17. Homing of radiolabelled recombinant interleukin-2 activated natural killer cells and their efficacy in adoptive immunotherapy against murine fibrosarcoma

    Indian Academy of Sciences (India)

    Anuradha Rai; Ashim K Chakravarty

    2007-12-01

    Natural killer (NK) cells are spontaneously cytotoxic against tumour target cells. Their number was found to be four times more in the spleen of tumour-bearing Swiss albino mice. After activation with recombinant interleukin-2 (rIL-2), NK cells were tested and found to seek out the tumour site when injected intravenously in tumour-bearing mice. Their potential for fighting tumours in vivo was further seen following adoptive transfer of rIL-2 activated NK (A-NK) cells in tumour-bearing mice. After surgical removal of tumour load, adoptive transfer of A-NK cells inhibited tumour recurrence in 92.3% cases, thereby suggesting the use of this protocol for therapeutic purposes to obtain a better outcome.

  18. Effects of 5-azacytidine on natural killer cell activating receptor expression in patients with refractory anemia with excess of blasts

    Science.gov (United States)

    Costello, Régis T.; Leclercq, Amélie; Treut, Thérèse Le; Sanchez, Carole; Mercier, Delphine; Sébahoun, Gérard

    2015-01-01

    Epigenetic drugs modify DNA methylation and are used in refractory anemia with excess of blasts (RAEB). These drugs may reactivate anti-oncogene expression and restore a normal phenotype instead of inducing antitumor toxicity, although they also have immunosuppressive effects on T-lymphocytes [1] In RAEB and acute myeloid leukemia, a defect in natural killer (NK) cell cytotoxicity has been shown, which relies on abnormal expression of activating receptors. Previous study has shown that 5-azacytidine impaired mRNA synthesis and induced apoptosis in NK cells [2]. In this study we investigated the effect of the demethylating drug 5-azacytidine (Vidaza®) on NK receptors with the hypothesis that demethylation of the promoters of activating NK receptor genes induces gene reactivation and thus may increase their expression. PMID:25709892

  19. Effects of 5-azacytidine on natural killer cell activating receptor expression in patients with refractory anemia with excess of blasts.

    Science.gov (United States)

    Costello, Régis T; Leclercq, Amélie; Treut, Thérèse Le; Sanchez, Carole; Mercier, Delphine; Sébahoun, Gérard

    2015-01-01

    Epigenetic drugs modify DNA methylation and are used in refractory anemia with excess of blasts (RAEB). These drugs may reactivate anti-oncogene expression and restore a normal phenotype instead of inducing antitumor toxicity, although they also have immunosuppressive effects on T-lymphocytes [1] In RAEB and acute myeloid leukemia, a defect in natural killer (NK) cell cytotoxicity has been shown, which relies on abnormal expression of activating receptors. Previous study has shown that 5-azacytidine impaired mRNA synthesis and induced apoptosis in NK cells [2]. In this study we investigated the effect of the demethylating drug 5-azacytidine (Vidaza(®)) on NK receptors with the hypothesis that demethylation of the promoters of activating NK receptor genes induces gene reactivation and thus may increase their expression. PMID:25709892

  20. Nutritional immunology: function of natural killer cells and their modulation by resveratrol for cancer prevention and treatment.

    Science.gov (United States)

    Leischner, Christian; Burkard, Markus; Pfeiffer, Matthias M; Lauer, Ulrich M; Busch, Christian; Venturelli, Sascha

    2016-01-01

    Natural killer (NK) cells as part of the innate immune system represent the first line of defence against (virus-) infected and malignantly transformed cells. The emerging field of nutritional immunology focuses on compounds featuring immune-modulating activities in particular on NK cells, which e.g. can be exploited for cancer prevention and treatment. The plant-based nutrition resveratrol is a ternary hydroxylated stilbene, which is present in many foods and beverages, respectively. In humans it comprises a large variety of distinct biological activities. Interestingly, resveratrol strongly modulates the immune response including the activity of NK cells. This review will give an overview on NK cell functions and summarize the resveratrol-mediated modulation thereof. PMID:27142426

  1. Development of an in vitro system for the analysis of ultraviolet radiation-induced suppression of natural killer cell activity

    International Nuclear Information System (INIS)

    Previous studies have shown that natural killer (NK) cell activity was suppressed in volunteer subjects exposed to ultraviolet radiation (UVR) from solarium lamps. The present studies were carried out to determine the spectrum of UVR responsible for suppression of NK activity and to develop in vitro methods to analyze the effectiveness of sunscreen agents in prevention of UVR-mediated suppression of NK activity and other aspects of immune function. These studies suggest that when the greater proportion of UV-A in solar radiation and its greater penetration into skin is taken into account, UV-A may have equivalent or greater direct immunosuppressive effects than UV-B. The mechanisms of their immunosuppressive effects may, however, differ. The in vitro system described here would appear to provide a simple test system for further analysis of UVR-induced immunosuppression. (Author)

  2. Numerical simulation of losses along a natural circulation helium loop

    Science.gov (United States)

    Knížat, Branislav; Urban, František; Mlkvik, Marek; RidzoÅ, František; Olšiak, Róbert

    2016-06-01

    A natural circulation helium loop appears to be a perspective passive method of a nuclear reactor cooling. When designing this device, it is important to analyze the mechanism of an internal flow. The flow of helium in the loop is set in motion due to a difference of hydrostatic pressures between cold and hot branch. Steady flow at a requested flow rate occurs when the buoyancy force is adjusted to resistances against the flow. Considering the fact that the buoyancy force is proportional to a difference of temperatures in both branches, it is important to estimate the losses correctly in the process of design. The paper deals with the calculation of losses in branches of the natural circulation helium loop by methods of CFD. The results of calculations are an important basis for the hydraulic design of both exchangers (heater and cooler). The analysis was carried out for the existing model of a helium loop of the height 10 m and nominal heat power 250 kW.

  3. Preliminary Analysis on Reactivity Insertion Transient of Natural Circulation Reactor

    International Nuclear Information System (INIS)

    When a malfunction of the reactor control system occurs, there's a chance that the positive reactivity is inserted into the core, resulting in the increase of the core power. With the combination of the failure of the related safety features, this may raise the temperature of the core material beyond the design limit to break its integrity. For the fast nuclear reactors like FFTF and CRBRP, the overpower trip is initiated when the power reaches 115% of rated value to keep the fuel from melting. In this study, the system response to the reactivity insertion transient on a liquid metal cooled natural circulation reactor is analyzed utilizing an in-house code based on a momentum integral model. Utilizing an in-house system analysis code, a set of numerical simulation is carried out on the reactivity ramp insertion transients which showed that the role of reactivity feedback is significant in mitigating the time to failure, and the evolution of the natural circulation mass flow is rather slow to generate meaningful feedback effect. It is also observed that in terms of the peak cladding temperature, smaller reactivity insertion transient generated more severe outcome owing to increased accumulation of the thermal energy within fuel pins. Thus, it may require an extra attention to carefully monitor and capture the mild transients to avoid potential drastic results

  4. Endometrial aspiration biopsy: a non-invasive method of obtaining functional lymphoid progenitor cells and mature natural killer cells.

    LENUS (Irish Health Repository)

    McMenamin, Moya

    2012-09-01

    The aim of this study was to compare the efficacy of endometrial aspiration biopsy (EAB) with the more traditional dilatation and curettage (D&C) for the procurement of lymphoid progenitor cells and uterine natural killer (NK) populations in endometrial tissue. This prospective observational study conducted in a tertiary referral university hospital examined endometrium obtained from 32 women admitted for laparoscopic gynaecological procedures. Each participant had endometrium sampled using both EAB and D&C. Both methods were assessed as a source of uterine NK and lymphoid progenitor cells. Similar proportions of mature CD45+CD56+ NK cells (range 25.4-36.2%) and CD45+CD34+ lymphoid progenitors (range 1.2-2.0%) were found in tissue obtained using both EAB and D&C. These cells were adequate for flow cytometric analysis, magnetic bead separation and culture. Colony formation by the CD34+ population demonstrated maturational potential. Tissues obtained via endometrial biopsy and D&C are equivalent, by analysis of uterine NK and lymphoid progenitor cells. The aim of this study was to compare two methods of endometrial sampling - endometrial aspiration biopsy and traditional dilatation and curettage - for the procurement of haematopoietic stem cells and uterine natural killer (NK) populations in endometrial tissue. Thirty-two women who had gynaecological procedures in a tertiary referral hospital participated in this study and had endometrial tissue collected via both methods. Similar populations of mature NK cells and haematopoietic stem cells were found in tissue obtained using both endometrial aspiration biopsy and dilatation and curettage. Tissue obtained via endometrial aspiration biopsy was adequate for the culture and growth of haematopoietic stem cells. We conclude that tissue obtained via endometrial biopsy and dilatation and curettage is equivalent, by analysis of uterine NK and haematopoietic stem cells using flow cytometry. This has implications for further

  5. Study on reverse flow characteristics under natural circulation in inverted U-tube steam generator

    International Nuclear Information System (INIS)

    Natural circulation is important for application in the nuclear power industry. Aiming at the steam generator of AP1000 pressurized water reactor loop, the mathematical model was established to analysis the reverse flow of single-phase water in the inverted U-tubes of a steam generator in a natural circulation system. The length distribution and the mass flow rates in both tubes with normal and reverse flow were determined respectively. The research results show that the reverse flow may result in sharp decrease of gravity pressure head, circulation mass flow rate and heat release rate of natural circulation. It has adverse influence on natural circulation. (authors)

  6. Valuation of BWR stability operating in natural circulation conditions

    International Nuclear Information System (INIS)

    Nowadays, the design of reactors having appropriate stability margins, the adoption of operating procedures avoiding possible unstable regions and the development of mitigation strategies to cope with inadvertent instability occurrences have strongly limited safety concerns in this regard. However, despite the obvious need for plant-specific Probabilistic Safety Assessment (PSA), BWR (boiling water reactor) transients of general interest can be identified and characterized as for example, overpressurization events, Large Break Loss of Coolant Accidents (LBLOCAs), feedwater temperature decrease, increase of core flow, main circulation pump flow rate increase, control rod withdrawal and others. Simulations of these complex scenarios have been improved by the utilization of coupled thermal-hydraulic (TH) and neutron kinetics (NK) system codes. In this work, the RELAP5/MOD3.3 thermal-hydraulic system code and the PARCS/2.4 3D neutron kinetic code have been adopted to predict the Peach Bottom BWR stability during recirculation pumps trip while the reactor is operating in a special region of power and core flow map. In the recirculation pump trip event, the stopping of the recirculation pumps causes a sharp decrease in the core flow, which generates a considerable negative reactivity insertion that tends to reduce power and, consequently, the amount of steam generated. The BWR reactor stability has been valuated during natural circulation conditions after the pumps trip event. The time evolution of the power and the related thermal-hydraulic parameters were investigated to analyse the behavior of the reactor for this special operation condition. (author)

  7. Phenomenon of Local Natural Circulation in a Circuit of Nuclear Power Plant

    International Nuclear Information System (INIS)

    The report presents results of experimental research performed at the BN-350 reactor facility, which have allowed identifying a local natural circulation phenomenon arising in some sections of heat removal loops. The nature of this phenomenon and features of its interaction with total-circuit natural circulation is described. In particular, specific features and degree of possible influence of local natural circulation on operational modes of reactor facility are analyzed. (author)

  8. Investigations into natural circulation driven heat removal systems

    International Nuclear Information System (INIS)

    Passive safety systems can make an important contribution to decay heat removal in existing and next Generation NPP. Two-phase natural circulation systems have under certain circumstances instabilities which have to be analysed in detail. For this reason the test facility GENEVA has been constructed and commissioned at the TU Dresden. The experiments described in the experimental matrix will be started this year. First experimental data showed flow instabilities e.g. flashing as expected. Generic studies are necessary to examine two-phase flow and especially two-phase flow instabilities in further detail. The influence of subcooling and the diameters of downcomer and riser are of particular interest. These will help to evaluate the system behaviour of passive heat removal systems as well as their safety and reliability for nuclear reactors. (orig.)

  9. Thermal hydraulic modeling of a natural circulation loop

    International Nuclear Information System (INIS)

    The experiment was carried out on the test loop HRTL-5, which simulates the geometry and system design of a 5 MW nuclear heating reactor. The analysis was based on a one-dimensional two-phase flow drift model with conservation equations for mass, steam, energy and momentum. Clausius-Clapeyron equation was used for the calculation of flashing front in the riser. A set of ordinary equations, which describes the behavior of two-phase flow in the natural circulation system, was derived through integration of the above conservation equations for the subcooled boiling region, bulk boiling region in the heated section and for the riser. The method of time-domain was used for the calculation. Both static and dynamic results are presented. System pressure, inlet subcooling and heat flux are varied as input parameters. The results show that subcooled boiling in the heated section and void flashing in the riser have significant influence on the distribution of the void fraction, mass flow rate and flow instability of the system, especially at low pressure. The response of mass flow rate, after a small disturbance in the heat flux is shown, and based on it the instability map of the system is given through experiment and calculation. There exists three regions in the instability map of the investigated natural circulation system, namely, the stable two-phase flow region, the unstable bulk and subcooled boiling flow region and the stable subcooled boiling and single phase flow region. The mechanism of two-phase flow oscillation is interpreted. (orig.)

  10. ESBWR - Robust design for natural circulation and stability performance effectiveness

    International Nuclear Information System (INIS)

    ESBWR is a 4500 MWt Generation III+ natural circulation reactor with an array of robust design features and passive safety systems to deliver highly effective plant performance during normal operation and to keep the reactor safe during postulated transients and accidents. With the submittal of the latest revision of the Design Control Document (DCD) to US Nuclear Regulatory Commission, ESBWR is nearing the completion of the US design certification process. This paper focuses on the natural circulation-driven plant performance aspects during normal operation, and stability evaluation of the robust ESBWR design. The TRACG computer code is used for the analysis of ESBWR plant performance, safety analysis, and stability margins. The paper describes the evaluation of ESBWR stability performance during normal power operation including operation in the Core Power-Feed Water Temperature Operating Domain. For ESBWR the normal power operation condition has the highest power/flow ratio and is limiting from the perspective of stability. The paper includes results from detailed evaluation of the most limiting decay ratio for out-of-phase regional oscillations calculated by perturbing the core inlet flow rate in this out-of-phase mode about the line of symmetry for the azimuthal harmonic mode. The paper also summarizes the ESBWR regional mode stability evaluations during a limiting transient (Loss of Feedwater Heating), and during ATWS (Anticipated Transient without Scram). Nominal decay ratios of limiting Channel oscillation, Core wide oscillation and Regional oscillation are within the maximum acceptance criterion of 0.8, at 95% content and 95% confidence. These stability evaluation results indicate decay ratio is within design limits. The paper also describes the evaluation of ESBWR stability performance during plant startup, and summarizes the defense-in-depth stability solution for ESBWR. (authors)

  11. Thermal hydraulic modeling of a natural circulation loop

    Science.gov (United States)

    Jiang, S. Y.; Wu, X. X.; Zhang, Y. J.; Jia, H. J.

    The experiment was carried out on the test loop HRTL-5, which simulates the geometry and system design of a 5MW nuclear heating reactor. The analysis was based on a one-dimensional two-phase flow drift model with conservation equations for mass, steam, energy and momentum. Clausius-Clapeyron equation was used for the calculation of flashing front in the riser. A set of ordinary equations, which describes the behavior of two-phase flow in the natural circulation system, was derived through integration of the above conservation equations for the subcooled boiling region, bulk boiling region in the heated section and for the riser. The method of time-domain was used for the calculation. Both static and dynamic results are presented. System pressure, inlet subcooling and heat flux are varied as input parameters. The results show that subcooled boiling in the heated section and void flashing in the riser have significant influence on the distribution of the void fraction, mass flow rate and flow instability of the system, especially at low pressure. The response of mass flow rate, after a small disturbance in the heat flux is shown, and based on it the instability map of the system is given through experiment and calculation. There exists three regions in the instability map of the investigated natural circulation system, namely, the stable two-phase flow region, the unstable bulk and subcooled boiling flow region and the stable subcooled boiling and single phase flow region. The mechanism of two-phase flow oscillation is interpreted.

  12. Experimental studies in a single-phase parallel channel natural circulation system. Preliminary results

    Energy Technology Data Exchange (ETDEWEB)

    Bodkha, Kapil; Pilkhwal, D.S.; Jana, S.S.; Vijayan, P.K. [Bhabha Atomic Research Centre, Mumbai (India). Reactor Engineering Div.

    2016-03-15

    Natural circulation systems find extensive applications in industrial engineering systems. One of the applications is in nuclear reactor where the decay heat is removed by natural circulation of the fluid under off-normal conditions. The upcoming reactor designs make use of natural circulation in order to remove the heat from core under normal operating conditions also. These reactors employ multiple vertical fuel channels with provision of on-power refueling/defueling. Natural circulation systems are relatively simple, safe and reliable when compared to forced circulation systems. However, natural circulation systems are prone to encounter flow instabilities which are highly undesirable for various reasons. Presence of parallel channels under natural circulation makes the system more complicated. To examine the behavior of parallel channel system, studies were carried out for single-phase natural circulation flow in a multiple vertical channel system. The objective of the present work is to study the flow behavior of the parallel heated channel system under natural circulation for different operating conditions. Steady state and transient studies have been carried out in a parallel channel natural circulation system with three heated channels. The paper brings out the details of the system considered, different cases analyzed and preliminary results of studies carried out on a single-phase parallel channel system.

  13. Experimental studies in a single-phase parallel channel natural circulation system. Preliminary results

    International Nuclear Information System (INIS)

    Natural circulation systems find extensive applications in industrial engineering systems. One of the applications is in nuclear reactor where the decay heat is removed by natural circulation of the fluid under off-normal conditions. The upcoming reactor designs make use of natural circulation in order to remove the heat from core under normal operating conditions also. These reactors employ multiple vertical fuel channels with provision of on-power refueling/defueling. Natural circulation systems are relatively simple, safe and reliable when compared to forced circulation systems. However, natural circulation systems are prone to encounter flow instabilities which are highly undesirable for various reasons. Presence of parallel channels under natural circulation makes the system more complicated. To examine the behavior of parallel channel system, studies were carried out for single-phase natural circulation flow in a multiple vertical channel system. The objective of the present work is to study the flow behavior of the parallel heated channel system under natural circulation for different operating conditions. Steady state and transient studies have been carried out in a parallel channel natural circulation system with three heated channels. The paper brings out the details of the system considered, different cases analyzed and preliminary results of studies carried out on a single-phase parallel channel system.

  14. The Role of Amnion Membrane-Derived Mesenchymal Stem Cells on Differentiation and Expansion of Natural Killer Cell Progenitors Originated From Umbilical Cord Blood Mononuclear Cells

    Directory of Open Access Journals (Sweden)

    Ahmadi

    2015-11-01

    Full Text Available Background Natural killer (NK cells are members of the innate immune system. Their unique properties, including recognition of viral infected and tumor cells without major histocompatibility complex (MHC restriction or prior sensitization, make them a suitable choice for immunotherapy. Low numbers of NK cells in circulating blood is the most important obstacle for this goal. Objectives The aim of this study was to make an optimum in vitro condition to proliferate and differentiate cord blood (CB-NK cell progenitors to mature NK cells, which can be used for cell therapy. Materials and Methods In our study, CB-Mononuclear Cells’ (MNCs CD3+ lymphocytes were positive depleted using immunomagnetic microbeads. This CD3-depleted (CD3-dep CB - MNCs compartment was used for in vitro expansion with or without a layer of amnion membrane mesenchymal stem cells (MSCs in combination with cytokines that are essential for NK cells expansion (IL-2, IL-3, IL-15, and FLT3 ligand. The expansion period lasted for one week. On day seven, immunophenotype and fold expansion of differentiated cells were measured. Results Combination of cytokines and MSC layer yielded significant fold expansion in comparison with cytokines without feeder conditions (day 7: 5.2 ± 1.12 and 2 ± 0.78, respectively, P < 0.05. CD3-/CD56+ cells percentage increased during the culture period in MSCs/with cytokine and cytokine/without feeder, respectively (day 0: 4.4 ± 0.42% and day 7: 22.9 ± 3.6% and 13.9 ± 1.92 % for MSC/with cytokine and cytokine without feeder, respectively. Conclusions Our results suggested that CB-NK cells progenitors could proliferate and differentiate on feeder layer of amnion membrane MSCs in combination with specific cytokines to produce NK cells for immunotherapy.

  15. Targeted delivery of lipid antigen to macrophages via the CD169/sialoadhesin endocytic pathway induces robust invariant natural killer T cell activation

    OpenAIRE

    Kawasaki, Norihito; Vela, Jose Luis; Nycholat, Corwin M.; Rademacher, Christoph; Khurana, Archana; van Rooijen, Nico; Crocker, Paul R.; Kronenberg, Mitchell; Paulson, James C.

    2013-01-01

    Invariant natural killer T (iNKT) cells induce a protective immune response triggered by foreign glycolipid antigens bound to CD1d on antigen-presenting cells (APCs). A limitation of using glycolipid antigens to stimulate immune responses in human patients has been the inability to target them to the most effective APCs. Recent studies have implicated phagocytic CD169+ macrophages as major APCs in lymph nodes for priming iNKT cells in mice immunized with glycolipid antigen in particulate form...

  16. Effects of first-line chemotherapy on natural killer cells in adult T-cell leukemia–lymphoma and peripheral T-cell lymphoma

    OpenAIRE

    Ogura, Michinori; Ishida, Takashi; Tsukasaki, Kunihiro; Takahashi, Takeshi; Utsunomiya, Atae

    2016-01-01

    Purpose Natural killer (NK) cells are well known to be the most important effector cells mediating antibody-dependent cellular cytotoxicity (ADCC) which is an important mechanism of action of antibody drugs. We evaluated the effects of chemotherapy on the cell number and activity of NK cells from patients who received the vincristine–cyclophosphamide–doxorubicin–prednisone (VCAP), doxorubicin–ranimustine–prednisone (AMP), and vindesine–etoposide–carboplatin–prednisone (VECP) (mLSG15) or mLSG1...

  17. Fc gamma receptor activation induces the tyrosine phosphorylation of both phospholipase C (PLC)-gamma 1 and PLC-gamma 2 in natural killer cells

    OpenAIRE

    1992-01-01

    Crosslinking of the low affinity immunoglobulin G (IgG) Fc receptor (Fc gamma R type III) on natural killer (NK) cells initiates antibody- dependent cellular cytotoxicity. During this process, Fc gamma R stimulation results in the rapid activation of phospholipase C (PLC), which hydrolyzes membrane phosphoinositides, generating inositol-1,4,5- trisphosphate and sn-1,2-diacylglycerol as second messengers. We have recently reported that PLC activation after Fc gamma R stimulation can be inhibit...

  18. Curcuminoids and ω-3 fatty acids with anti-oxidants potentiate cytotoxicity of natural killer cells against pancreatic ductal adenocarcinoma cells and inhibit interferon γ production

    OpenAIRE

    Milan eFiala; Ramesh eHalder; Anasheh eAlmasi; Bien eSagong; Jessica eLeung; Anahid eJewett

    2015-01-01

    Pancreatic cancer has a poor prognosis attributed in part to immune suppression and deactivation of natural killer (NK) cells. Curcuminoids have a potential for improving the therapy of pancreatic cancer given promising results in cancer models and a clinical trial, but their oral absorption is limited. Our objective in this study is to show curcuminoid anti-oncogenic effects alone and together with human NK cells. We tested curcuminoids in an emulsion of ω-3 fatty acids and anti-oxidants (S...

  19. PET/CT aids the staging of and radiotherapy planning for early-stage extranodal natural killer/T-cell lymphoma, nasal type: A case series

    OpenAIRE

    MacDonald Shannon L; Mulroy Liam; Wilke Derek R; Burrell Steven

    2011-01-01

    Abstract Extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, is a rare form of non-Hodgkin lymphoma. Treatment of ENKTL primarily relies on radiation; thus, proper delineation of target volumes is critical. Currently, the ideal modalities for delineation of gross tumor volume for ENKTL are unknown. We describe three consecutive cases of localized ENKTL that presented to the Nova Scotia Cancer Centre in Halifax, Nova Scotia. All patients had a planning CT and MRI as well as a planni...

  20. Symposium 3: Vitamin D and immune function: from pregnancy to adolescence: Vitamin D, invariant natural killer T-cells and experimental autoimmune disease

    OpenAIRE

    Cantorna, Margherita T.; Zhao, Jun; Yang, Linlin

    2012-01-01

    Vitamin D is an important regulator of the immune system in general and multiple sclerosis in particular. Experimentally (i), invariant natural killer T (iNKT) cells have been shown to be important suppressors of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE; an animal model of multiple sclerosis). Conversely, in experimental allergic asthma iNKT cells are required for disease induction and are therefore pathogenic. The active form of vitamin D (calcitriol) suppre...

  1. Genetically modified natural killer cells specifically recognizing the tumor-associated antigens ErbB2/HER2 and EpCAM

    OpenAIRE

    Uherek B; Tonn T; Müller T.; Uherek C; Klingemann H-G; Wels WS

    2007-01-01

    The continuously growing natural killer (NK) cell line NK-92 is highly cytotoxic against malignant cells of various origin without affecting normal human cells. Based on this selectivity, the potential of NK-92 cells for adoptive therapy is currently being investigated in phase I clinical studies. To further enhance the antitumoral activity of NK-92 cells and expand the range of tumor entities suitable for NK-92-based therapies, here by transduction with retroviral vectors we have generated g...

  2. Invariant Natural Killer T-Cell Control of Type 1 Diabetes: A Dendritic Cell Genetic Decision of a Silver Bullet or Russian Roulette

    OpenAIRE

    Driver, John P.; Scheuplein, Felix; Chen, Yi-Guang; Grier, Alexandra E.; Wilson, S. Brian; Serreze, David V.

    2009-01-01

    OBJECTIVE In part, activation of invariant natural killer T (iNKT)-cells with the superagonist α-galactosylceramide (α-GalCer) inhibits the development of T-cell–mediated autoimmune type 1 diabetes in NOD mice by inducing the downstream differentiation of antigen-presenting dendritic cells (DCs) to an immunotolerogenic state. However, in other systems iNKT-cell activation has an adjuvant-like effect that enhances rather than suppresses various immunological responses. Thus, we tested whether ...

  3. HIV-1 infection leads to increased HLA-E expression resulting in impaired function of natural killer cells.

    Science.gov (United States)

    Nattermann, Jacob; Nischalke, Hans Dieter; Hofmeister, Valesko; Kupfer, Bernd; Ahlenstiel, Golo; Feldmann, Georg; Rockstroh, Jiirgen; Weiss, Elisabeth H; Sauerbruch, Tilman; Spengler, Ulrich

    2005-01-01

    HIV has evolved several strategies to evade recognition by the host immune system including down-regulation of major histocompatibility complex (MHC) class I molecules. However, reduced expression of MHC class I molecules may stimulate natural killer (NK) cell lysis in cells of haematopoietic lineage. Here, we describe how HIV counteracts stimulation of NK cells by stabilizing surface expression of the non-classical MHC class I molecule, HLA-E. We demonstrate enhanced expression of HLA-E on lymphocytes from HIV-infected patients and show that in vitro infection of lymphocytes with HIV results in up-regulation of HLA-E expression and reduced susceptibility to NK cell cytotoxicity. Using HLA-E transfected K-562 cells, we identified the well-known HIV T-cell epitope p24 aa14-22a as a ligand for HLA-E that stabilizes surface expression of HLA-E, favouring inhibition of NK cell cytotoxicity. These results propose HIV-mediated up-regulation of HLA-E expression as an additional evasion strategy targeting the antiviral activities of NK cells, which may contribute to the capability of the virus in establishing chronic infection. PMID:15751767

  4. Mice lacking natural killer T cells are more susceptible to metabolic alterations following high fat diet feeding.

    Directory of Open Access Journals (Sweden)

    Brittany V Martin-Murphy

    Full Text Available Current estimates suggest that over one-third of the adult population has metabolic syndrome and three-fourths of the obese population has non-alcoholic fatty liver disease (NAFLD. Inflammation in metabolic tissues has emerged as a universal feature of obesity and its co-morbidities, including NAFLD. Natural Killer T (NKT cells are a subset of innate immune cells that abundantly reside within the liver and are readily activated by lipid antigens. There is general consensus that NKT cells are pivotal regulators of inflammation; however, disagreement exists as to whether NKT cells exert pathogenic or suppressive functions in obesity. Here we demonstrate that CD1d(-/- mice, which lack NKT cells, were more susceptible to weight gain and fatty liver following high fat diet (HFD feeding. Compared with their WT counterparts, CD1d(-/- mice displayed increased adiposity and greater induction of inflammatory genes in the liver suggestive of the precursors of NAFLD. Calorimetry studies revealed a significant increase in food intake and trends toward decreased metabolic rate and activity in CD1d(-/- mice compared with WT mice. Based on these findings, our results suggest that NKT cells play a regulatory role that helps to prevent diet-induced obesity and metabolic dysfunction and may play an important role in mechanisms governing cross-talk between metabolism and the immune system to regulate energy balance and liver health.

  5. Genistein inhibits human TNF-α-induced porcine endothelial cell adhesiveness for human monocytes and natural killer cells

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Cellular immune response is a major barrier to xenotransplantation. Human tumor necrosis factor-α (hTNF-α) possesses cross-species activity and directly amplifies the immune rejection via the upregulation of adhesion molecules on porcine endothelium. We investigated the role of protein tyrosine phosphorylation in the induction of expression of E-sclectin and vascular cell adhesion molecule-1 (VCAM-1), and the augmentation of adhesion of human peripheral blood monocytes (PBMo) and natural killer cells (PBNK), after rhTNF-α-stimulation of porcine aortic endothelial cells (PAEC) in vitro, rhTNF-α-increased adhesiveness of PAEC for both PBMo and PBNK was dose-dependently reduced by pretreatment of PAEC with the selective protein tyrosine kinase (PTK) inhibitor genistein. The inhibitory effect occurred at the early time of PAEC activation triggered by rhTNF-α, and was completely reversible. PTK activity assay indicated that genistein also suppressed rhTNF-α stimulated activation of protein tyrosine kinases (PTKs) in PAEC in a dose-dependent manner. Flow cytometric analysis showed that genistein inhibited the upregulation of E-selectin and VCAM-1 by rhTNF-α. These results suggest that PTKs may regulate the expression of E-selectin and VCAM-1 on PAEC and the adherence of PBMo and PBNK induced by rhTNF-α. Moreover, dietary genistein, used as an adhesion antagonist, may contribute to managing the cell-mediated rejection in the clinical application.

  6. [The natural killer activity and indices of the interferon status of patients with recurrent genital herpes being treated with ridostin].

    Science.gov (United States)

    Cheknev, S B; Mikovskaia, O I; Meshkova, E N; Khaldin, A A; Samgin, M A; Malinovskaia, V V

    1994-01-01

    Natural killer cell activity (NK) in parallel with the interferon (IFN)-alpha and IFN-gamma production as well as with a level of IFN in the blood serum were studied in 15 patients with relapsing herpes genitalis (RHG). Rhidostin, well known as an IFN-alpha inducer, was used in a dose of 2 mg once daily for 3 days subcutaneously up to a total dose of 8 mg of the preparation. The NK cell activity and IFN-alpha production were shown to decrease in RHG more significantly in the stage of remission than during the relapse of the process. As a result of rhidostin therapy the NK cell activity was restored simultaneously with the positive clinical effect of the drug. Rhidostin was found to be an efficient modifier of the IFN system functioning in patients with RHG. The above data allow a conclusion that rhidostin exhibiting an independent antiviral and immunostimulating action might be useful in patients with a remission of RHG for prevention of its relapses. PMID:8091753

  7. Cytomegalovirus m154 hinders CD48 cell-surface expression and promotes viral escape from host natural killer cell control.

    Directory of Open Access Journals (Sweden)

    Angela Zarama

    2014-03-01

    Full Text Available Receptors of the signalling lymphocyte-activation molecules (SLAM family are involved in the functional regulation of a variety of immune cells upon engagement through homotypic or heterotypic interactions amongst them. Here we show that murine cytomegalovirus (MCMV dampens the surface expression of several SLAM receptors during the course of the infection of macrophages. By screening a panel of MCMV deletion mutants, we identified m154 as an immunoevasin that effectively reduces the cell-surface expression of the SLAM family member CD48, a high-affinity ligand for natural killer (NK and cytotoxic T cell receptor CD244. m154 is a mucin-like protein, expressed with early kinetics, which can be found at the cell surface of the infected cell. During infection, m154 leads to proteolytic degradation of CD48. This viral protein interferes with the NK cell cytotoxicity triggered by MCMV-infected macrophages. In addition, we demonstrate that an MCMV mutant virus lacking m154 expression results in an attenuated phenotype in vivo, which can be substantially restored after NK cell depletion in mice. This is the first description of a viral gene capable of downregulating CD48. Our novel findings define m154 as an important player in MCMV innate immune regulation.

  8. Scorpion venom activates natural killer cells in hepatocellular carcinoma via the NKG2D-MICA pathway.

    Science.gov (United States)

    Chen, Han; Zhidan, Wang; Xia, Ren; Zhaoxia, Wang; Qing, Jia; Qiang, Guo; Haipeng, Yin; Hengxiao, Wang

    2016-06-01

    Previous studies have demonstrated that polypeptides extracted from scorpion venom (PESV) inhibited cell proliferation in several tumors, however, the effect on dysfunctional and exhausted natural killer cells which contribute to tumor escape from immune surveillance remain to be elucidated. In this study, we determined the effect of PESV on NK infiltration into H22 cells orthotopic transplantation tumors and on the expression of MHC class I chain-related proteins A (MICA) in HepG2 cells. We found that tumor growth in mice was significantly inhibited by PESV and the survival time of tumor-bearing mice treated with PESV was significantly prolonged. Moreover, levels of tumor-infiltrating NK cells, NKG2D protein, perforin and granzyme B mRNA were significantly increased in the group treated with PESV compared with the tumor-bearing control group. In addition, In addition, up-regulation of MICA by PESV enhances the susceptibility of HepG2 cells to NK lysis in vitro. These results indicate that the inhibitory effects of PESV on hepatic carcinoma are likely mediated by up-regulation of NK cell activity via the MICA-NKG2D pathway. PMID:27089390

  9. Early activation of natural killer and B cells in response to primary dengue virus infection in A/J mice

    International Nuclear Information System (INIS)

    Dengue virus (DEN) causes the most prevalent arthropod-borne viral illness in humans worldwide. Immune mechanisms that are involved in protection and pathogenesis of DEN infection have not been fully elucidated due largely to the lack of an adequate animal model. Therefore, as a first step, we characterized the primary immune response in immunocompetent inbred A/J mice that were infected intravenously with a non-mouse-adapted DEN type 2 (DEN2) strain. A subset (55%) of infected mice developed paralysis by 14 days post-infection (p.i.), harbored infectious DEN in the central nervous system (CNS), and had an elevated hematocrit and a decreased white blood cell (WBC) count. Immunologic studies detected (i) increased numbers of CD69+ splenic natural killer (NK) and B cells at day 3 p.i., (ii) DEN-specific IgM and IgG responses by days 3 and 7 p.i., respectively, and (iii) splenocyte production of IFNγ at day 14 p.i. We conclude that the early activities of NK cells, B cells and IgM, and later actions of IFNγ and IgG likely play a role in the defense against DEN infection

  10. The Transcription Factor AHR Prevents the Differentiation of a Stage 3 Innate Lymphoid Cell Subset to Natural Killer Cells

    Directory of Open Access Journals (Sweden)

    Tiffany Hughes

    2014-07-01

    Full Text Available Accumulating evidence indicates that human natural killer (NK cells develop in secondary lymphoid tissue (SLT through a so-called “stage 3” developmental intermediate minimally characterized by a CD34−CD117+CD94− immunophenotype that lacks mature NK cell function. This stage 3 population is heterogeneous, potentially composed of functionally distinct innate lymphoid cell (ILC types that include interleukin-1 receptor (IL-1R1-positive, IL-22-producing ILC3s. Whether human ILC3s are developmentally related to NK cells is a subject of ongoing investigation. Here, we show that antagonism of the aryl hydrocarbon receptor (AHR or silencing of AHR gene expression promotes the differentiation of tonsillar IL-22-producing IL-1R1hi human ILC3s to CD56brightCD94+ interferon (IFN-γ-producing cytolytic mature NK cells expressing eomesodermin (EOMES and T-Box Protein 21 (TBX21 or TBET. Hence, we demonstrate the lineage plasticity of human ILCs by identifying AHR as a transcription factor that prevents IL-1R1hi ILC3s from differentiating into NK cells.

  11. Elevated lead levels and adverse effects on natural killer cells in children from an electronic waste recycling area.

    Science.gov (United States)

    Zhang, Yu; Huo, Xia; Cao, Junjun; Yang, Tian; Xu, Long; Xu, Xijin

    2016-06-01

    Lead (Pb) has been proved to exert immunotoxicity to influence immune homeostasis in humans. To monitor the internal Pb level and evaluate its effect on natural killer (NK) cells and cytokine/chemokine concentrations, we recruited 285 preschool children from Guiyu, one of the largest electronic waste (e-waste) destinations and recycling areas in the world, and known to have high concentrations of Pb in the air, soil, water, sediment and plants. A total of 126 preschool children were selected from Haojiang as a reference group. Results showed that children in Guiyu, the exposed area, had higher blood Pb levels and lower percentages of NK cells than children from the reference area. A significantly negative association was found between the percentage of NK cells and increasing Pb levels. Moreover, children in Guiyu area had higher platelet counts and IL-1β concentrations, and lower levels of IL-2, IL-27, MIP-1α and MIP-1β were observed in the exposed children. These changes might not be conducive to the development and differentiation of NK cells. Taken together, the elevated Pb levels result in the lower percentages of NK cells, but also alter the levels of platelets, IL-1β and IL-27, which might be unconducive to the activity and function of NK cells. PMID:26895538

  12. Lysophospholipid presentation by CD1d and recognition by a human Natural Killer T-cell receptor

    Energy Technology Data Exchange (ETDEWEB)

    López-Sagaseta, Jacinto; Sibener, Leah V.; Kung, Jennifer E.; Gumperz, Jenny; Adams, Erin J. (UC); (UW-MED)

    2014-10-02

    Invariant Natural Killer T (iNKT) cells use highly restricted {alpha}{beta} T cell receptors (TCRs) to probe the repertoire of lipids presented by CD1d molecules. Here, we describe our studies of lysophosphatidylcholine (LPC) presentation by human CD1d and its recognition by a native, LPC-specific iNKT TCR. Human CD1d presenting LPC adopts an altered conformation from that of CD1d presenting glycolipid antigens, with a shifted {alpha}1 helix resulting in an open A pocket. Binding of the iNKT TCR requires a 7-{angstrom} displacement of the LPC headgroup but stabilizes the CD1d-LPC complex in a closed conformation. The iNKT TCR CDR loop footprint on CD1d-LPC is anchored by the conserved positioning of the CDR3{alpha} loop, whereas the remaining CDR loops are shifted, due in part to amino-acid differences in the CDR3{beta} and J{beta} segment used by this iNKT TCR. These findings provide insight into how lysophospholipids are presented by human CD1d molecules and how this complex is recognized by some, but not all, human iNKT cells.

  13. Mutation of the Traj18 gene segment using TALENs to generate Natural Killer T cell deficient mice.

    Science.gov (United States)

    Zhang, Jingjing; Bedel, Romain; Krovi, S Harsha; Tuttle, Kathryn D; Zhang, Bicheng; Gross, James; Gapin, Laurent; Matsuda, Jennifer L

    2016-01-01

    Invariant Natural Killer T (iNKT) cells are a unique subset of T lymphocytes that have been implicated in both promoting and suppressing a multitude of immune responses. In mice, iNKT cells express T cell antigen receptors (TCRs) comprising a unique TCRα rearrangement between the Trav11 and Traj18 gene segments. When paired with certain Trbv TCRβ chains, these TCRs recognize lipid antigens presented by the major histocompatibility complex (MHC) class I-like molecule, CD1d. Until recently, the sole model of iNKT deficiency targeted the Jα18, which is absolutely required to form the TCR with the appropriate antigenic specificity. However, these mice were demonstrated to have a large reduction in TCR repertoire diversity, which could confound results arising from studies using these mice. Here, we have created a new NKT-deficient mouse strain using transcription activator-like effector nuclease (TALEN) technology to only disrupt the expression of Jα18, leaving the remaining Jα repertoire unperturbed. We confirm that these mice lack iNKT cells and do not respond to lipid antigen stimulation while the development of conventional T cells, regulatory T cells, and type Ib NKT cells is normal. This new mouse strain will serve as a new model of iNKT cell deficiency to facilitate our understanding of iNKT biology. PMID:27256918

  14. Diabetes, Epstein-Barr virus and extranodal natural killer/T-cell lymphoma in India: Unravelling the plausible nexus

    Science.gov (United States)

    Spadigam, Anita; Dhupar, Anita; Syed, Shaheen; Saluja, Tajindra Singh

    2016-01-01

    The International Diabetes Federation Diabetes Atlas estimates a staggering 590 million people affected with diabetes mellitus (DM) within the next two decades globally, of which Type 2 DM will constitute more than 90%. The associated insulin resistance, hyperinsulinemia, and hyperglycemia pose a further significant risk for developing diverse malignant neoplasms. Diabetes and malignancy are multifactorial heterogeneous diseases. The immune dysfunction secondary to Type 2 diabetes also reactivates latent infections with high morbidity and mortality rates. Epstein-Barr virus (EBV), a ubiquitous human herpes virus-4, is an oncogenic virus; its recrudescence in the immunocompromised condition activates the expression of EBV latency genes, thus immortalizing the infected cell and giving rise to lymphomas and carcinomas. Extranodal natural killer/T-cell lymphoma (ENKTCL), common in South-East Asia and Latin America; is a belligerent type of non-Hodgkin lymphoma (NHL) almost invariably associated with EBV. An analysis of articles sourced from the PubMed database and Google Scholar web resource until February 2014, suggests an increasing incidence of NHL in Asia/India and of ENKTCL in India, over the last few decades. This article reviews the epidemiological evidence linking various neoplasms with Type 2 DM and prognosticates the emergence of ENKTCL as a common lymphoreticular malignancy secondary to Type 2 diabetes, in the Indian population in the next few decades. PMID:27051150

  15. Delta-Like Ligand (DLL)1 Expression in Early Mouse Decidua and Its Localization to Uterine Natural Killer Cells

    Science.gov (United States)

    Yamada, Aureo T.; Croy, B. Anne

    2012-01-01

    Uterine vascular changes, critical for pregnancy success, occur at each implant site during endometrial decidualization. Mesometrial decidualization recruits high numbers of angiogenic, uterine Natural Killer (uNK) cells that trigger midpregnancy spiral arterial remodeling. We postulated that uNK cells contribute to early decidual angiogenesis as endothelial-cell extrinsic sources of Delta-like ligand 1 (DLL1), a molecule that induces endothelial tip cell differentiation and orthogonal vascular growth in other tissues. Virgin uteri expressed Dll1 mesometrially and anti-mesometrially and relative expression increased in both anatomic regions as pregnancy progressed. Analyses of transcripts from gd10.5 uNK cells flow sorted on the basis of expression of Dolichos biflorus agglutinin (DBA) lectin revealed that DBA+ but not DBA- uNK cells expressed Dll1. Immunostaining at gd4.5 found DLL1-expressing cells rare. At gd6.5, DBA+ uNK cells at all stages of maturation expressed DLL1. By gd10.5, DLL1 immunoreactivity was strongly expressed by some but not all DBA+ uNK cells and more weakly by DBA- cells. DLL1+ cells were mesometrially stratified and concentrated within central decidua basalis. Our data suggest that uNK cells have the potential to induce endothelial tip cell differentiation and to promote non-planar vascular growth within early decidua basalis. PMID:23284862

  16. Potential for Natural Killer Cell-Mediated Antibody-Dependent Cellular Cytotoxicity for Control of Human Cytomegalovirus

    Directory of Open Access Journals (Sweden)

    Rebecca J. Aicheler

    2013-12-01

    Full Text Available Human cytomegalovirus (HCMV is an important pathogen that infects the majority of the population worldwide, yet, currently, there is no licensed vaccine. Despite HCMV encoding at least seven Natural Killer (NK cell evasion genes, NK cells remain critical for the control of infection in vivo. Classically Antibody-Dependent Cellular Cytotoxicity (ADCC is mediated by CD16, which is found on the surface of the NK cell in a complex with FcεRI-γ chains and/or CD3ζ chains. Ninety percent of NK cells express the Fc receptor CD16; thus, they have the potential to initiate ADCC. HCMV has a profound effect on the NK cell repertoire, such that up to 10-fold expansions of NKG2C+ cells can be seen in HCMV seropositive individuals. These NKG2C+ cells are reported to be FcεRI-γ deficient and possess variable levels of CD16+, yet have striking ADCC functions. A subset of HCMV cell surface proteins will induce robust antibody responses that could render cells susceptible to ADCC. We will consider how the strong anti-HCMV function of NKG2C+ FcεRI-γ-deficient NK cells could potentially be harnessed in the clinic to treat patients suffering from HCMV disease and in the development of an efficacious HCMV vaccine.

  17. [Extranodal natural killer/T-cell lymphoma, nasal type developing central nervous system and epididymis involvement immediately after concurrent chemoradiotherapy].

    Science.gov (United States)

    Sasaki, Yuya; Yonezawa, Akihito; Kinoshita, Yoshihiro; Kitagawa, Tomoya; Mori, Minako; Onaka, Takashi; Imada, Kazunori

    2015-12-01

    A 66-year-old man showed central nervous system (CNS) and epididymis involvement after concurrent chemoradiotherapy for extranodal natural killer/T-cell lymphoma, nasal type (ENKL). The patient experienced continuous nasal obstruction. CT revealed a mass in the nasal cavity and paranasal sinuses. Biopsy of the nasal cavity mass showed it to be ENKL. Based on bone marrow biopsy and 18F-FDG PET/CT findings, the clinical stage was suspected to be IIE. The sites involved were the nasal cavity, paranasal sinuses, and cervical lymph nodes. We performed concurrent chemoradiotherapy consisting of a 67% dose of DeVIC and involved field radiation therapy towards his head and neck. Head and neck CT confirmed a therapeutic response. After receiving concurrent chemoradiotherapy, the patient complained of perineal discomfort. Ultrasonography revealed swelling of the left epididymis. Left epididymis biopsy showed ENKL involvement and lumbar puncture revealed CNS involvement. The findings of this case suggest that evaluation of CNS involvement might be an essential part of the initial workup for some ENKL patients. PMID:26725358

  18. Possible Immune Regulation of Natural Killer T Cells in a Murine Model of Metal Ion-Induced Allergic Contact Dermatitis

    Science.gov (United States)

    Kumagai, Kenichi; Horikawa, Tatsuya; Shigematsu, Hiroaki; Matsubara, Ryota; Kitaura, Kazutaka; Eguchi, Takanori; Kobayashi, Hiroshi; Nakasone, Yasunari; Sato, Koichiro; Yamada, Hiroyuki; Suzuki, Satsuki; Hamada, Yoshiki; Suzuki, Ryuji

    2016-01-01

    Metal often causes delayed-type hypersensitivity reactions, which are possibly mediated by accumulating T cells in the inflamed skin, called irritant or allergic contact dermatitis. However, accumulating T cells during development of a metal allergy are poorly characterized because a suitable animal model is unavailable. We have previously established novel murine models of metal allergy and found accumulation of both metal-specific T cells and natural killer (NK) T cells in the inflamed skin. In our novel models of metal allergy, skin hypersensitivity responses were induced through repeated sensitizations by administration of metal chloride and lipopolysaccharide into the mouse groin followed by metal chloride challenge in the footpad. These models enabled us to investigate the precise mechanisms of the immune responses of metal allergy in the inflamed skin. In this review, we summarize the immune responses in several murine models of metal allergy and describe which antigen-specific responses occur in the inflamed skin during allergic contact dermatitis in terms of the T cell receptor. In addition, we consider the immune regulation of accumulated NK T cells in metal ion–induced allergic contact dermatitis. PMID:26771600

  19. Natural killer (NK cells for cancer immunotherapy: pluripotent stem cells-derived NK cells as an immunotherapeutic perspective

    Directory of Open Access Journals (Sweden)

    Cristina eEguizabal

    2014-09-01

    Full Text Available Natural killer (NK cells play an essential role in the fight against tumor development. Over the last years, the progress made in the NK cell biology field and in deciphering how NK cell function is regulated, is driving efforts to utilize NK cell-based immunotherapy as a promising approach for the treatment of malignant diseases. Therapies involving NK cells may be accomplished by activating and expanding endogenous NK cells by means of cytokine treatment or by transferring exogenous cells by adoptive cell therapy and/or by hematopoietic stem cell transplantation (HSCT. NK cells that are suitable for adoptive cell therapy can be derived from different sources, including ex vivo expansion of autologous NK cells, unstimulated or expanded allogeneic NK cells from peripheral blood, derived from CD34+ hematopoietic progenitors from peripheral blood and umbilical cord blood, and NK cell lines. Besides, genetically modified NK cells expressing chimeric antigen receptors (CARs or cytokines genes may also have a relevant future as therapeutic tools. Recently, it has been described the derivation of large numbers of functional and mature NK cells from pluripotent stem cells (PSCs, both embryonic stem cells (ESCs and induced pluripotent stem cells (iPSCs, which adds another tool to the expanding NK cell-based cancer immunotherapy arsenal.

  20. Testosterone increases susceptibility to amebic liver abscess in mice and mediates inhibition of IFNγ secretion in natural killer T cells.

    Science.gov (United States)

    Lotter, Hannelore; Helk, Elena; Bernin, Hannah; Jacobs, Thomas; Prehn, Cornelia; Adamski, Jerzy; González-Roldán, Nestor; Holst, Otto; Tannich, Egbert

    2013-01-01

    Amebic liver abscess (ALA), a parasitic disease due to infection with the protozoan Entamoeba histolytica, occurs age and gender dependent with strong preferences for adult males. Using a mouse model for ALA with a similar male bias for the disease, we have investigated the role of female and male sexual hormones and provide evidence for a strong contribution of testosterone. Removal of testosterone by orchiectomy significantly reduced sizes of abscesses in male mice, while substitution of testosterone increased development of ALA in female mice. Activation of natural killer T (NKT) cells, which are known to be important for the control of ALA, is influenced by testosterone. Specifically activated NKT cells isolated from female mice produce more IFNγ compared to NKT cells derived from male mice. This high level production of IFNγ in female derived NKT cells was inhibited by testosterone substitution, while the IFNγ production in male derived NKT cells was increased by orchiectomy. Gender dependent differences were not a result of differences in the total number of NKT cells, but a result of a higher activation potential for the CD4(-) NKT cell subpopulation in female mice. Taken together, we conclude that the hormone status of the host, in particular the testosterone level, determines susceptibility to ALA at least in a mouse model of the disease. PMID:23424637

  1. Natural killer T cells and non-alcoholic fatty liver disease: Fat chews on the immune system

    Institute of Scientific and Technical Information of China (English)

    Michael Kremer; Ian N Hines

    2008-01-01

    Natural killer T cells (NKT) are an important subset of T lymphocytes. They are unique in their ability to produce both T helper 1 and T helper 2 associated cytokines, thus being capable of steering the immune system into either inflammation or tolerance. Disruption of NKT cell numbers or function results in severe deficits in immune surveillance against pathogens and tumor cells. Growing experimental evidence suggests that hepatosteatosis may reduce resident hepatic as well as peripheral NICE cells. Those models of hepatosteatosis and the change in NKT cell numbers are associated with a disruption of cytokine homeostasis, resulting in a more pronounced release of proinflammatory cytokines which renders the steatotic liver highly susceptible to secondary insults. In this letter to the editor, we focus on recently published data in the World Journal of Gastroenterology by Xu and colleagues demonstrating reduced peripheral NKT ceils in patients with non-alcoholic fatty liver disease, compare those findings with ours and others in different animal models of hepatosteatosis, and hypothesize about the potential underlying mechanism.

  2. Sea buckthorn (Hippophae rhamnoides L.) oil protects against chronic stress-induced inhibitory function of natural killer cells in rats.

    Science.gov (United States)

    Diandong, Hou; Feng, Gu; Zaifu, Liang; Helland, Timothy; Weixin, Fu; Liping, Cai

    2016-03-01

    Chronic stress can suppress natural killer (NK) cell activity; this may also be related to the effect of stress on the neuroendocrine-immune network. Sea buckthorn (SBT) (Hippophae rhamnoides L.) is a thorny nitrogen fixing deciduous shrub, native to both Europe and Asia. It has been used as a medicinal plant in Tibetan and Mongolian traditional medicines. SBT has multifarious medical properties, including anti-fatigue as well as immunoregulatory effects. This study reports the effects of SBT oil with regard to the cytotoxicity and quantity of NK cells in the blood of a chronic-stress rat model, in addition to its mechanisms on the neuroendocrine-immune network. These results show that SBT oil, given by gavage to rats with chronic stress, could increase the following: body weight, NK cell quantities, and cytotoxicity, as well as the expression of perforin and granzyme B. The results also show that SBT oil in rats with chronic stress could suppress cortisol, ACTH, IL-1β and TNF-α levels, in addition to increasing 5-HT and IFN-γ serum levels. This leads to suggest that SBT oil, in rats with chronic stress, can increase NK cell cytotoxicity by upregulating the expression of perforin and granzyme B, thus causing associated effects of SBT oil on the neuroendocrine-immune network. PMID:26684638

  3. Possible Immune Regulation of Natural Killer T Cells in a Murine Model of Metal Ion-Induced Allergic Contact Dermatitis

    Directory of Open Access Journals (Sweden)

    Kenichi Kumagai

    2016-01-01

    Full Text Available Metal often causes delayed-type hypersensitivity reactions, which are possibly mediated by accumulating T cells in the inflamed skin, called irritant or allergic contact dermatitis. However, accumulating T cells during development of a metal allergy are poorly characterized because a suitable animal model is unavailable. We have previously established novel murine models of metal allergy and found accumulation of both metal-specific T cells and natural killer (NK T cells in the inflamed skin. In our novel models of metal allergy, skin hypersensitivity responses were induced through repeated sensitizations by administration of metal chloride and lipopolysaccharide into the mouse groin followed by metal chloride challenge in the footpad. These models enabled us to investigate the precise mechanisms of the immune responses of metal allergy in the inflamed skin. In this review, we summarize the immune responses in several murine models of metal allergy and describe which antigen-specific responses occur in the inflamed skin during allergic contact dermatitis in terms of the T cell receptor. In addition, we consider the immune regulation of accumulated NK T cells in metal ion–induced allergic contact dermatitis.

  4. Inositol hexaphosphate-induced enhancement of natural killer cell activity correlates with suppression of colon carcinogenesis in rats

    Institute of Scientific and Technical Information of China (English)

    Zheng Zhang; Yang Song; Xiu-Li Wang

    2005-01-01

    AIM: To investigate the anti-neoplastic effect of inositol hexaphosphate (InsP6 or phytic acid) on dimethylhydrazine (DMH)-induced colon tumor in rats and its effect on blood natural killer (NK) cell activity.METHODS: Healthy Wistar rats, 4 wk old, were divided into control group (fed with common food) and TnsP6 group (fed with common food+2% sodium inositol hexaphosphate in the drinking water), 15 rats in each group. Both groups were injected with 1,2-dimethylhydrazine subcutaneously (20 mg/kg body weight) once a week for 20 wk. Rats were killed after 21 wk. The whole large intestine was isolated to determine the general condition of tumors and to test blood NK cell activity by lactate-dehydrogenaserelease assay.RESULTS: Administration of InsP6 significantly increased blood NK cell activity in DMH-induced colorectal tumor in rats. InsP6 group had a smaller tumor size on average and a smaller number of tumors than the control group. Its mortality was also higher than that in control. However, the variables of body weight and tumor incidence were not significantly different between the two groups.CONCLUSION: InsP6 can increase blood NK cell activity in DMH-induced colon tumor in rats and inhibit tumor growth and metastasis in rats.

  5. A New Biological Feature of Natural Killer Cells: The Recognition of Solid Tumor-Derived Cancer Stem Cells

    Science.gov (United States)

    Tallerico, Rossana; Garofalo, Cinzia; Carbone, Ennio

    2016-01-01

    Natural killer (NK) cells are classified as a member of the innate lymphoid cells (ILCs) group 1. ILCs have been recently identified and grouped on the basis of their phenotypical and functional characteristics. They are effectors of innate immunity and are involved in secondary lymphoid organ generation and tissue remodeling. NK cells are powerful cytotoxic lymphocytes able to recognize and eliminate tumor- and virus-infected cells by limiting their spread and tissue damage. The recognition of tumor cells is mediated by both activating and inhibitory receptors. While in hematological malignancies the role played by NK cells is widely known, their role in recognizing solid tumors remains unclear. Recently, tumor cell populations have been divided into two compartments: cancer-initiating cells (CICs) or cancer stem cells (CSCs) and senescent tumor cells. Here, CSC will be used. CSCs are a small subset of malignant cells with stem-like properties that are involved in tumor maintenance and recurrence due to their ability to survive to traditional therapies; they are, moreover, poorly recognized by T lymphocytes. Recent data showed that NK cells recognize in vitro cancer-initiating cells derived from colon cancer, glioblastoma, and melanoma. However, more in vivo studies are urgently required to fully understand whether these new antitumor NK cells with cytotoxic capability may be considered in the design of new immunotherapeutic interventions. PMID:27242786

  6. Study on the activity and phenotype of decidual natural killer cells in patients with unexplained habitual abortions

    Institute of Scientific and Technical Information of China (English)

    Dong Ruiying; Li Hongrong; Lu Jiming; Liu Haiying; Li Xiaomei; Cui Baoxia; Jiang Sen

    2004-01-01

    Objective:To determine the activity and phenotype of decidual natural killer (NK) cells in patients with unexplained habitual abortions (UHA).Methods:A total of 32 patients with UHA were studied, and 20 cases of normal pregnant women were selected as control group. The levels of CD56+CD3- NK cells and their CD56+CD16-, CD56+CD16+ subsets in decidua were detected using two-color flow cytometric analysis.The NK cells activity was measured by a chromium-51(51Cr) release cytotoxicity assay,with K562 human myeloid leukaemia cells as targets.Results:Compared with control group, the proportion of CD56+CD3- NK cells in decidual mononuclear cells(DMC) of UHA patients had no difference, but the CD56+CD16- NK cell subset decreased and the CD56+CD16+ subset increased significantly (P<0.05). The decidual NK cells activities of UHA patients were higher than those of normal controls (P<0.05).Conclusions:NK cell is predominant lymphocyte in normal decidua and plays an important role in maintaining successful pregnancy. Abnormally raised activity and disbalanced CD56+CD16+, CD56+CD16- subsets of decidual NK cell are associated with UHA and may play a role in reproductive failure.

  7. TRAIL-mediated killing of acute lymphoblastic leukemia by plasmacytoid dendritic cell-activated natural killer cells.

    Science.gov (United States)

    Lelaidier, Martin; Dìaz-Rodriguez, Yildian; Cordeau, Martine; Cordeiro, Paulo; Haddad, Elie; Herblot, Sabine; Duval, Michel

    2015-10-01

    Acute lymphoblastic leukemia (ALL) still frequently recurs after hematopoietic stem cell transplantation (HSCT), underscoring the need to improve the graft-versus-leukemia (GvL) effect. Natural killer (NK) cells reconstitute in the first months following HSCT when leukemia burden is at its lowest, but ALL cells have been shown to be resistant to NK cell-mediated killing. We show here that this resistance is overcome by NK cell stimulation with TLR-9-activated plasmacytoid dendritic cells (pDCs). NK cell priming with activated pDCs resulted in TRAIL and CD69 up-regulation on NK cells and IFN-γ production. NK cell activation was dependent on IFN-α produced by pDCs, but was not reproduced by IFN-α alone. ALL killing was further enhanced by inhibition of KIR engagement. We showed that ALL lysis was mainly mediated by TRAIL engagement, while the release of cytolytic granules was involved when ALL expressed NK cell activating receptor ligands. Finally, adoptive transfers of activated-pDCs in ALL-bearing humanized mice delayed the leukemia onset and cure 30% of mice. Our data therefore demonstrate that TLR-9 activated pDCs are a powerful tool to overcome ALL resistance to NK cell-mediated killing and to reinforce the GvL effect of HSCT. These results open new therapeutic avenues to prevent relapse in children with ALL. PMID:26320191

  8. A think tank of TINK/TANKs: tumor-infiltrating/tumor-associated natural killer cells in tumor progression and angiogenesis.

    Science.gov (United States)

    Bruno, Antonino; Ferlazzo, Guido; Albini, Adriana; Noonan, Douglas M

    2014-08-01

    Tumor-infiltrating leukocytes are often induced by the cancer microenvironment to display a protumor, proangiogenic phenotype. This "polarization" has been described for several myeloid cells, in particular macrophages. Natural killer (NK) cells represent another population of innate immune cells able to infiltrate tumors. The role of NK in tumor progression and angiogenesis has not yet been fully investigated. Several studies have shown that tumor-infiltrating NK (here referred to as "TINKs") and tumor-associated NK (altered peripheral NK cells, which here we call "TANKs") are compromised in their ability to lysew tumor cells. Recent data have suggested that they are potentially protumorigenic and can also acquire a proangiogenic phenotype. Here we review the properties of TINKs and TANKs and compare their activities to that of NK cells endowed with a physiological proangiogenic phenotype, in particular decidual NK cells. We speculate on the potential origins of TINKs and TANKs and on the immune signals involved in their differentiation and polarization. The TINK and TANK phenotype has broad implications in the immune response to tumors, ranging from a deficient control of cancer and cancer stem cells to an altered crosstalk with other relevant players of the immune response, such as dendritic cells, to induction of cancer angiogenesis. With this recently acquired knowledge that has not yet been put into perspective, we point out new potential avenues for therapeutic intervention involving NK cells as a target or an ally in oncology. PMID:25178695

  9. Mutation of the Traj18 gene segment using TALENs to generate Natural Killer T cell deficient mice

    Science.gov (United States)

    Zhang, Jingjing; Bedel, Romain; Krovi, S. Harsha; Tuttle, Kathryn D.; Zhang, Bicheng; Gross, James; Gapin, Laurent; Matsuda, Jennifer L.

    2016-01-01

    Invariant Natural Killer T (iNKT) cells are a unique subset of T lymphocytes that have been implicated in both promoting and suppressing a multitude of immune responses. In mice, iNKT cells express T cell antigen receptors (TCRs) comprising a unique TCRα rearrangement between the Trav11 and Traj18 gene segments. When paired with certain Trbv TCRβ chains, these TCRs recognize lipid antigens presented by the major histocompatibility complex (MHC) class I-like molecule, CD1d. Until recently, the sole model of iNKT deficiency targeted the Jα18, which is absolutely required to form the TCR with the appropriate antigenic specificity. However, these mice were demonstrated to have a large reduction in TCR repertoire diversity, which could confound results arising from studies using these mice. Here, we have created a new NKT-deficient mouse strain using transcription activator-like effector nuclease (TALEN) technology to only disrupt the expression of Jα18, leaving the remaining Jα repertoire unperturbed. We confirm that these mice lack iNKT cells and do not respond to lipid antigen stimulation while the development of conventional T cells, regulatory T cells, and type Ib NKT cells is normal. This new mouse strain will serve as a new model of iNKT cell deficiency to facilitate our understanding of iNKT biology. PMID:27256918

  10. Sodium Experiments on Natural Circulation Decay Heat Removal and 3D Simulation of Plenum Thermal Hydraulics

    International Nuclear Information System (INIS)

    Natural circulation decay heat removal is one of the significant issues for fast reactor safety, especially in long term station blackout events. Several sodium experiments were carried out using a 7-subassembly core model for core thermal hydraulics under natural circulation conditions and for onset transients of natural circulation in a decay heat removal system (DHRS) including natural draft. Significant heat removal via inter-wrapper flow was confirmed in the experiments. Solidification of sodium in an air cooler is one of key issues in loss of heat sink events. Natural circulation characteristics under long-term decay heat removal were also obtained. Multi-dimensional phenomena, e.g., thermal stratification and bypass flow in plenums and/or heat exchangers, may influence the natural circulation. Thus, 3D simulation method was developed for entire region in the primary loop. Comparison of temperature distributions in a DHRS heat exchanger between experiment and analysis was done. (author)

  11. Some questions of fast reactor residual heat removal using coolant natural circulation in the circuits

    International Nuclear Information System (INIS)

    A calculation procedure designed for entire plant dynamics has been used for transients leading the reactor plant of BN-600 type into a natural circulation mode. A detailed description of the mathematical model and comparison of calculated and experimental results are presented. Some peculiarities of coolant natural circulation development in the BN-350 reactor circuits are considered. (author)

  12. Static Instability Analysis of the Natural Circulation Flow in a Passive Containment Cooling System

    International Nuclear Information System (INIS)

    When a severe accident occurs in a nuclear power plant, the containment pressure can increase up to 4 bar and, then, it can threaten the containment's integrity. To avoid such over-pressure in the containment, a passive containment cooling systems (PCCS) has been developed instead of existing active cooling systems. The PCCS can cool down the containment by using a natural circulation flow and, thus, flow instabilities may easily occur. It should be confirmed that both static and dynamic flow instabilities do not occur due to the system characteristics. In this study, mathematical models for the single- and two-phase natural circulation flows in a PCCS are developed. Using the flow models, static instability of the natural circulation flow is investigated. In this study, mathematical models for the single- and two-phase natural circulation flows in a PCCS are developed. Using the models, both single- and two-phase natural circulation flows were investigated in terms of static instability. It is shown that, for both cases, there is only one steady-state mass flow rate which satisfies the integrated momentum equation and the pressure drop along the natural circulation loop increases monotonically according to the mass flow rate. Therefore, it can be said that static instability doesn't exist in the PCCS natural circulation loop. Additional research is needed to investigate the dynamic instability of the PCCS natural circulation flow

  13. NK-92: an 'off-the-shelf therapeutic' for adoptive natural killer cell-based cancer immunotherapy.

    Science.gov (United States)

    Suck, Garnet; Odendahl, Marcus; Nowakowska, Paulina; Seidl, Christian; Wels, Winfried S; Klingemann, Hans G; Tonn, Torsten

    2016-04-01

    Natural killer (NK) cells are increasingly considered as immunotherapeutic agents in particular in the fight against cancers. NK cell therapies are potentially broadly applicable and, different from their T cell counterparts, do not cause graft-versus-host disease. Efficacy and clinical in vitro or in vivo expansion of primary NK cells will however always remain variable due to individual differences of donors or patients. Long-term storage of clinical NK cell lots to allow repeated clinical applications remains an additional challenge. In contrast, the established and well-characterized cell line NK-92 can be easily and reproducibly expanded from a good manufacturing practice (GMP)-compliant cryopreserved master cell bank. Moreover, no cost-intensive cell purification methods are required. To date, NK-92 has been intensively studied. The cells displayed superior cytotoxicity against a number of tumor types tested, which was confirmed in preclinical mouse studies. Subsequent clinical testing demonstrated safety of NK-92 infusions even at high doses. Despite the phase I nature of the trials conducted so far, some efficacy was noted, particularly against lung tumors. Furthermore, to overcome tumor resistance and for specific targeting, NK-92 has been engineered to express a number of different chimeric antigen receptors (CARs), including targeting, for example, CD19 or CD20 (anti-B cell malignancies), CD38 (anti-myeloma) or human epidermal growth factor receptor 2 (HER2; ErbB2; anti-epithelial cancers). The concept of an NK cell line as an allogeneic cell therapeutic produced 'off-the-shelf' on demand holds great promise for the development of effective treatments. PMID:26559813

  14. Natural killer T cells activated by a lipopeptidophosphoglycan from Entamoeba histolytica are critically important to control amebic liver abscess.

    Science.gov (United States)

    Lotter, Hannelore; González-Roldán, Nestor; Lindner, Buko; Winau, Florian; Isibasi, Armando; Moreno-Lafont, Martha; Ulmer, Artur J; Holst, Otto; Tannich, Egbert; Jacobs, Thomas

    2009-05-01

    The innate immune response is supposed to play an essential role in the control of amebic liver abscess (ALA), a severe form of invasive amoebiasis due to infection with the protozoan parasite Entamoeba histolytica. In a mouse model for the disease, we previously demonstrated that Jalpha18(-/-) mice, lacking invariant natural killer T (iNKT) cells, suffer from more severe abscess development. Here we show that the specific activation of iNKT cells using alpha-galactosylceramide (alpha-GalCer) induces a significant reduction in the sizes of ALA lesions, whereas CD1d(-/-) mice develop more severe abscesses. We identified a lipopeptidophosphoglycan from E. histolytica membranes (EhLPPG) as a possible natural NKT cell ligand and show that the purified phosphoinositol (PI) moiety of this molecule induces protective IFN-gamma but not IL-4 production in NKT cells. The main component of EhLPPG responsible for NKT cell activation is a diacylated PI, (1-O-[(28:0)-lyso-glycero-3-phosphatidyl-]2-O-(C16:0)-Ins). IFN-gamma production by NKT cells requires the presence of CD1d and simultaneously TLR receptor signalling through MyD88 and secretion of IL-12. Similar to alpha-GalCer application, EhLPPG treatment significantly reduces the severity of ALA in ameba-infected mice. Our results suggest that EhLPPG is an amebic molecule that is important for the limitation of ALA development and may explain why the majority of E. histolytica-infected individuals do not develop amebic liver abscess. PMID:19436711

  15. Natural convection and natural circulation flow and limits in advanced reactor concepts

    International Nuclear Information System (INIS)

    Existing reactor designs and new concepts rely to varying degrees on heat removal processes driven by natural convection as a potentially important design feature or ultimate heat removal mechanism. This is independent of whether the nuclear core is cooled by water, gas or liquid metal, since in many shut down or emergency conditions forced cooling is assumed or predicted to be lost. However, using natural convection to advantage is possible, since it can provide significant cost-savings by the elimination of pumps and ancillary equipment and also can result in simplified and hence higher reliability safety systems. It is highly desirable to build on the inherent or existing heat removal processes than to graft design or add them on afterwards. The limits to the heat removal are set by the natural circulation flow and heat removal capability, so these need to be predicted with accuracy. The capability limit is determined by well-known physically linked parameters, including the flow rates, driving heads, heat sinks, fluid thermal expansion, and flow thermal and hydraulic stability. In natural convection plants, there are opportunities for the limits to be set by the absolute power output available from naturally convective flow, and the onset of instability in that flow. We are interested in the ultimate or maximum power output both in order to minimize power generation costs, and to determine how far the natural circulation designs can be developed. This paper reviews some of the fundamental equations and analytical solutions for natural convection flows, and examines their application to determine the limits of heat removal as a means of establishing simple criteria and fundamental design limits. This type of physical analysis can be used to investigate the flow and stability limits for a thermally expandable fluid, which encompasses the extremes of both low and supercritical pressure applications. To illustrate the approach, simple analytical expressions are

  16. Immunophenotypic and Clinical Differences Between the Nasal and Extranasal Subtypes of Upper Aerodigestive Tract Natural Killer/T-Cell Lymphoma

    International Nuclear Information System (INIS)

    Purpose: To investigate, in a large cohort of patients, the immunophenotypic and clinical differences of nasal and extranasal extranodal nasal-type natural killer/T-cell lymphoma of the upper aerodigestive tract (UADT-NKTCL) and examine the relevance of the immunophenotype on the clinical behavior, prognosis, and treatment. Methods and Materials: A total of 231 patients with UADT-NKTCL were recruited. One hundred eighty-one patients had primary location in the nasal cavity (nasal UADT-NKTCL), and 50 patients had primary extranasal UADT-NKTCL. Results: Patients with extranasal UADT-NKTCL had more adverse clinical features, including advanced-stage disease, regional lymph node involvement, B symptoms, and poor performance status, than patients with nasal UADT-NKTCL. In addition, CD56 and granzyme B were less frequently expressed in extranasal UADT-NKTCL. The 5-year overall survival rate was 74.1% for the entire group and 76.0% for early-stage disease. The 5-year overall survival rate for extranasal UADT-NKTCL was similar or superior to that of nasal UADT-NKTCL for all disease stages (76.9% vs 73.4%, P=.465), stage I disease (75.9% vs 79.2%, P=.786), and stage II disease (83.3% vs 50.3%, P=.018). CD56 expression and a Ki-67 proliferation rate ≥50% predicted poorer survival for extranasal UADT-NKTCL but not for nasal UADT-NKTCL. Conclusions: Patients with nasal and extranasal UADT-NKTCL have significantly different clinical features, immunophenotypes, and prognosis. Extranasal UADT-NKTCL should be considered as a distinct subgroup apart from the most commonly diagnosed prototype of nasal UADT-NKTCL

  17. The critical role of IL-15-PI3K-mTOR pathway in Natural Killer cell effector functions

    Directory of Open Access Journals (Sweden)

    Neethi eNandagopal

    2014-04-01

    Full Text Available Natural killer (NK cells were so named for their uniqueness in killing certain tumor and virus-infected cells without prior sensitization. Their functions are modulated in vivo by several soluble immune mediators; IL-15 being the most potent among them in enabling NK cell homeostasis, maturation and activation. During microbial infections, NK cells stimulated with IL-15 display enhanced cytokine responses. This priming effect has previously been shown with respect to increased IFN-γ production in NK cells upon IL-12 and IL-15/IL-2 co-stimulation. In this study, we explored if this effect of IL-15 priming can be extended to various other cytokines and observed enhanced NK cell responses to stimulation with IL-4, IL-21, IFN-α and IL-2 in addition to IL-12. Notably, we also observed elevated IFN-γ production in primed NK cells upon stimulation through the Ly49H activation receptor. Currently, the fundamental processes required for priming and whether these signaling pathways work collaboratively or independently for NK cell functions are poorly understood. To identify the key signaling events for NK cell priming, we examined IL-15 effects on NK cells in which the pathways emanating from IL-15 receptor activation were blocked with specific inhibitors. Our results demonstrate that the PI3K-AKT-mTOR pathway is critical for cytokine responses in IL-15 primed NK cells. Furthermore, this pathway is also implicated in a broad range of IL-15 induced NK cell effector functions such as proliferation and cytotoxicity. Likewise, NK cells from mice treated with rapamycin to block the mTOR pathway displayed defects in proliferation, IFN-γ and granzyme B productions resulting in elevated viral burdens upon MCMV infection. Taken together, our data demonstrates the requirement of PI3K-mTOR pathway for enhanced NK cell functions by IL-15, thereby coupling the metabolic sensor mTOR to NK cell anti-viral responses.

  18. Probing natural killer cell education by Ly49 receptor expression analysis and computational modelling in single MHC class I mice.

    Directory of Open Access Journals (Sweden)

    Sofia Johansson

    Full Text Available Murine natural killer (NK cells express inhibitory Ly49 receptors for MHC class I molecules, which allows for "missing self" recognition of cells that downregulate MHC class I expression. During murine NK cell development, host MHC class I molecules impose an "educating impact" on the NK cell pool. As a result, mice with different MHC class I expression display different frequency distributions of Ly49 receptor combinations on NK cells. Two models have been put forward to explain this impact. The two-step selection model proposes a stochastic Ly49 receptor expression followed by selection for NK cells expressing appropriate receptor combinations. The sequential model, on the other hand, proposes that each NK cell sequentially expresses Ly49 receptors until an interaction of sufficient magnitude with self-class I MHC is reached for the NK cell to mature. With the aim to clarify which one of these models is most likely to reflect the actual biological process, we simulated the two educational schemes by mathematical modelling, and fitted the results to Ly49 expression patterns, which were analyzed in mice expressing single MHC class I molecules. Our results favour the two-step selection model over the sequential model. Furthermore, the MHC class I environment favoured maturation of NK cells expressing one or a few self receptors, suggesting a possible step of positive selection in NK cell education. Based on the predicted Ly49 binding preferences revealed by the model, we also propose, that Ly49 receptors are more promiscuous than previously thought in their interactions with MHC class I molecules, which was supported by functional studies of NK cell subsets expressing individual Ly49 receptors.

  19. Expression and Functional Role of α7 Nicotinic Receptor in Human Cytokine-stimulated Natural Killer (NK) Cells.

    Science.gov (United States)

    Zanetti, Samanta R; Ziblat, Andrea; Torres, Nicolás I; Zwirner, Norberto W; Bouzat, Cecilia

    2016-08-01

    The homomeric α7 nicotinic receptor (nAChR) is one of the most abundant nAChRs in the central nervous system where it contributes to cognition, attention, and working memory. α7 nAChR is also present in lymphocytes, dendritic cells (DCs), and macrophages and it is emerging as an important drug target for intervention in inflammation and sepsis. Natural killer (NK) cells display cytotoxic activity against susceptible target cells and modulate innate and adaptive immune responses through their interaction with DCs. We here show that human NK cells also express α7 nAChR. α7 nAChR mRNA is detected by RT-PCR and cell surface expression of α7 nAChR is detected by confocal microscopy and flow cytometry using α-bungarotoxin, a specific antagonist. Both mRNA and protein levels increase during NK stimulation with cytokines (IL-12, IL-18, and IL-15). Exposure of cytokine-stimulated NK cells to PNU-282987, a specific α7 nAChR agonist, increases intracellular calcium concentration ([Ca(2+)]i) mainly released from intracellular stores, indicating that α7 nAChR is functional. Moreover, its activation by PNU-282987 plus a specific positive allosteric modulator greatly enhances the Ca(2+) responses in NK cells. Stimulation of NK cells with cytokines and PNU-282987 decreases NF-κB levels and nuclear mobilization, down-regulates NKG2D receptors, and decreases NKG2D-dependent cell-mediated cytotoxicity and IFN-γ production. Also, such NK cells are less efficient to trigger DC maturation. Thus, our results demonstrate the anti-inflammatory role of α7 nAChR in NK cells and suggest that modulation of its activity in these cells may constitute a novel target for regulation of the immune response. PMID:27284006

  20. Evaluation of CD56dim and CD56bright natural killer cells in peripheral blood of women with IVF failures

    Directory of Open Access Journals (Sweden)

    Farahnaz Mardanian

    2015-09-01

    Full Text Available Background: Infertility is an increasing medical and social problem. In vitro fertilization (IVF has become a common and accessible treatment for a wide variety of indications that have variable outcomes. Natural killer (NK cells have been identified as relevant immunological factors involved in reproductive success or failure. Objective: The aim of this study was to compare the percentage of peripheral blood CD56+ (CD56dim and CD56bright cells and the level of NK cell in patients with IVF failure with those of successful IVF control women. Materials and Methods: We assessed the level of CD56dim CD16+ and CD56bright CD16- cells in 50 women under IVF treatment and compared between successful IVF and IVF failure with the flowcytometry technique. Results: Of studied women, 68% did not response to IVF therapy and 32% had successful IVF, the level of CD56dim CD16+ cells in women with IVF failure was significantly higher than successful IVF (p<0.0001 but the level of CD56bright CD16- cells was not significantly different between women with IVF failure and successful IVF (p=0.28. Conclusion: The results of present study demonstrated that the level of NK cells as a risk factor is associated with pregnancy loss in women with IVF failure. However, number of sample in this study is low and further studies with more sample size are needed to be done. We suggest considering treatment option for women undergoing repeated IVF failure with increased percentage of CD56dim cells and the level of peripheral blood NK cell.

  1. Clinical significance of peripheral blood CD4 + natural killer T cells in chronic hepatitis B virus infection

    Institute of Scientific and Technical Information of China (English)

    JIANG Rong-long; LU Qiao-sheng; FENG Xiao-rong; LUO Kang-xian; HOU Jin-lin; FU Ning

    2001-01-01

    To understand the clinical significance of CD4+ natural killer T (NK-T) cells in chronic hepatitis B virus (HBV) infection. Methods: Peripheral blood mononuclear cells (PBMCs) from individuals with chronic HBV infection were separated routinely. After Induction with IL-12/IL-2 for 12 d, the proportion of CD4+NK-T cells in peripheral blood was determined by fluorescence activated cell sorter (FACS) analysis, and the cytotoxicity of peripheral blood lymphocytes (PBLs) was tested with a 4 h 51Cr release assay. Results: After IL-12/IL-2 induction, the proportion of CD4+ NK-T cells was (18.1±4.20)%, (6.95±2.85)% and (1.50±1.30)% in the healthy control, CAH and AsC respectively. That in the peripheral blood of chronic HBV infected individuals was lower than that in the healthy control. CD8+ NK-T cells was (2.70±1.10)%, (2.20±1.40)% and (3.10±0.70)%respectively. In vitro cytotoxicity assays against Wish cells revealed that the PBLs cytotoxicity reduced in chronic HBV infected individuals (P<0.05), and that in AsC group was significantly lower in comparison with CHB and healthy control groups. The cytotoxicity of CD4+ NK-T cells against Wish cells could be abolished by treating PBLs with either anti-CD4 Ab or anti-CD56 Ab and complement, and partially depleted by anti-CD8 Ab. Conclusion:The abnormal cellular immune function of chronic HBV infected individuals may be associated with the deficiency of CD4+ NK-T cells.

  2. Natural Killer Cells and Helicobacter pylori Infection: Bacterial Antigens and Interleukin-12 Act Synergistically To Induce Gamma Interferon Production

    Science.gov (United States)

    Yun, Cheol H.; Lundgren, Anna; Azem, Josef; Sjöling, Åsa; Holmgren, Jan; Svennerholm, Ann-Mari; Lundin, B. Samuel

    2005-01-01

    Helicobacter pylori is known to induce a local immune response, which is characterized by activation of lymphocytes and the production of IFN-γ in the stomach mucosa. Since not only T cells, but also natural killer (NK) cells, are potent producers of gamma interferon (IFN-γ), we investigated whether NK cells play a role in the immune response to H. pylori infection. Our results showed that NK cells were present in both the gastric and duodenal mucosae but that H. pylori infection did not affect the infiltration of NK cells into the gastrointestinal area. Furthermore, we could show that NK cells could be activated directly by H. pylori antigens, as H. pylori bacteria, as well as lysate from H. pylori, induced the secretion of IFN-γ by NK cells. NK cells were also activated without direct contact when separated from the bacteria by an epithelial cell layer, indicating that the activation of NK cells by H. pylori can also occur in vivo, in the infected stomach mucosa. Moreover, the production of IFN-γ by NK cells was greatly enhanced when a small amount of interleukin-12 (IL-12) was added, and this synergistic effect was associated with increased expression of the IL-12 receptor β2. It was further evident that bacterial lysate alone was sufficient to induce the activation of cytotoxicity-related molecules. In conclusion, we demonstrated that NK cells are present in the gastroduodenal mucosa of humans and that NK cells produce high levels of IFN-γ when stimulated with a combination of H. pylori antigen and IL-12. We propose that NK cells play an active role in the local immune response to H. pylori infection. PMID:15731046

  3. Helicobacter pylori cholesteryl α-glucosides contribute to its pathogenicity and immune response by natural killer T cells.

    Directory of Open Access Journals (Sweden)

    Yuki Ito

    Full Text Available Approximately 10-15% of individuals infected with Helicobacter pylori will develop ulcer disease (gastric or duodenal ulcer, while most people infected with H. pylori will be asymptomatic. The majority of infected individuals remain asymptomatic partly due to the inhibition of synthesis of cholesteryl α-glucosides in H. pylori cell wall by α1,4-GlcNAc-capped mucin O-glycans, which are expressed in the deeper portion of gastric mucosa. However, it has not been determined how cholesteryl α-glucosyltransferase (αCgT, which forms cholesteryl α-glucosides, functions in the pathogenesis of H. pylori infection. Here, we show that the activity of αCgT from H. pylori clinical isolates is highly correlated with the degree of gastric atrophy. We investigated the role of cholesteryl α-glucosides in various aspects of the immune response. Phagocytosis and activation of dendritic cells were observed at similar degrees in the presence of wild-type H. pylori or variants harboring mutant forms of αCgT showing a range of enzymatic activity. However, cholesteryl α-glucosides were recognized by invariant natural killer T (iNKT cells, eliciting an immune response in vitro and in vivo. Following inoculation of H. pylori harboring highly active αCgT into iNKT cell-deficient (Jα18(-/- or wild-type mice, bacterial recovery significantly increased in Jα18(-/- compared to wild-type mice. Moreover, cytokine production characteristic of Th1 and Th2 cells dramatically decreased in Jα18(-/- compared to wild-type mice. These findings demonstrate that cholesteryl α-glucosides play critical roles in H. pylori-mediated gastric inflammation and precancerous atrophic gastritis.

  4. Dephosphorylation of the adaptor LAT and phospholipase C-γ by SHP-1 inhibits natural killer cell cytotoxicity.

    Science.gov (United States)

    Matalon, Omri; Fried, Sophia; Ben-Shmuel, Aviad; Pauker, Maor H; Joseph, Noah; Keizer, Danielle; Piterburg, Marina; Barda-Saad, Mira

    2016-01-01

    Natural killer (NK) cells discriminate between healthy cells and virally infected or transformed self-cells by tuning activating and inhibitory signals received through cell surface receptors. Inhibitory receptors inhibit NK cell function by recruiting and activating the tyrosine phosphatase Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-1 (SHP-1) to the plasma membrane. However, to date, the guanine nucleotide exchange factor VAV1 is the only direct SHP-1 substrate identified in NK cells. We reveal that the adaptor protein linker for activation of T cells (LAT) as well as phospholipase C-γ1 (PLC-γ1) and PLC-γ2 are SHP-1 substrates. Dephosphorylation of Tyr(132) in LAT by SHP-1 in NK cells abrogated the recruitment of PLC-γ1 and PLC-γ2 to the immunological synapse between the NK cell and a cancer cell target, which reduced NK cell degranulation and target cell killing. Furthermore, the ubiquitylation of LAT by the E3 ubiquitin ligases c-Cbl and Cbl-b, which was induced by LAT phosphorylation, led to the degradation of LAT in response to the engagement of inhibitory receptors on NK cells, which abrogated NK cell cytotoxicity. Knockdown of the Cbl proteins blocked LAT ubiquitylation, which promoted NK cell function. Expression of a ubiquitylation-resistant mutant LAT blocked inhibitory receptor signaling, enabling cells to become activated. Together, these data identify previously uncharacterized SHP-1 substrates and inhibitory mechanisms that determine the response of NK cells. PMID:27221712

  5. Functional perturbation of classical natural killer and innate lymphoid cells in the oral mucosa during SIV infection

    Directory of Open Access Journals (Sweden)

    Haiying eLi

    2013-01-01

    Full Text Available Despite the fact that the majority of human pathogens are transmitted across mucosal surfaces, including the oral mucosae, oral immunity is poorly understood. Furthermore, because the normal flora of the oral cavity is vast and significantly diverse, host immunity must balance a complex system of tolerance and pathogen recognition. Due to the rapid recognition and response to pathogens, the innate immune system, including natural killer (NK cells, likely plays a critical role in mediating this balance. Because logistical and ethical restraints limit access to significant quantities of human mucosal tissues, nonhuman primate models offer one of the best opportunities to study mucosal NK cells. In this study we have identified both classical NK cells, as well as innate lymphoid cells (ILCs in tonsillar and buccal tissues and oral-draining lymph nodes. Identified by mutually exclusive expression of NKG2A and NKp44, NK cells and ILCs in the oral mucosa are generally phenotypically and functionally analogous to their gut counterparts. NKG2A+ NK cells were more cytotoxic while NKp44+ ILCs produced copious amounts of IL-17 and TNF-α. However, in contrast to gut, oral NK cells and ILCs both produced large quantities of IFN-γ and the beta-chemokine, MIP-1β. Also in contrast to what we have previously found in gut tissues of SIV-infected macaques, we found no reduction in NK cells during chronic SIV infection, but rather an expansion of ILCs in oral-draining lymph nodes and tonsils. These data suggest that the lentivirus-induced depletion of the NK cell/ILC compartment in the gut may be absent in the oral mucosa, but the inherent differences and SIV-induced alterations are likely to have significant impact on preventing oral opportunistic infections in lentiviral disease. Furthermore, these data extend our understanding of the oral innate immune system in general and could aid future studies evaluating the regulation of both normal oral flora and

  6. Clinical significance of cyclooxygenase-2 expression in extranodal natural killer (NK)/T-cell lymphoma, nasal type

    International Nuclear Information System (INIS)

    Purpose: To determine whether there are any differences in therapeutic response, patterns of systemic recurrence, and prognosis of patients with extranodal natural killer (NK)/T-cell lymphoma, nasal type, by the cyclooxygenase-2 (COX-2) expression. Patients and Methods: Thirty-four patients with Ann Arbor Stage I and II extranodal NK/T-cell lymphoma who underwent chemotherapy or radiotherapy, or both, were retrospectively reviewed. These patients were divided into two groups according to their immunohistochemical staining for COX-2 expressions: a COX-2-negative group (n = 10 patients) and a COX-2-positive group (n = 24 patients). The treatment response, patterns of treatment failure, and survival data for the patients were compared between the COX-2-positive and negative groups. Results: There was no significant difference in the clinical profiles between the COX-2-negative and COX-2-positive groups. All patients (100%) in the COX-2-negative group achieved complete response after initial treatment, whereas only 14 patients (58%) in the COX-2-positive group achieved complete response (p = 0.03). Compared with the patients in the COX-2-negative group, those in the COX-2-positive group had a significantly lower 2-year systemic recurrence-free survival rate (100% for the COX-2-negative group vs. 54% for the COX-2-positive group) (p = 0.02) and a decreased 5-year overall survival rate (70% for the COX-2-negative group vs. 32% for the COX-2-positive group) (p = 0.06). Conclusion: Cyclooxygenase-2 expression can serve as a predictive factor for poor treatment response, higher systemic recurrence, and unfavorable prognosis in patients with extranodal NK/T-cell lymphoma, nasal type

  7. Natural killer cell (NK) subsets and NK-like T-cell populations in acute myeloid leukemias and myelodysplastic syndromes.

    Science.gov (United States)

    Aggarwal, N; Swerdlow, S H; TenEyck, S P; Boyiadzis, M; Felgar, R E

    2016-07-01

    The impact of the immune microenvironment on the behavior and therapeutic strategies for hematopoietic and lymphoid neoplasms is being increasingly recognized. Many functional studies of natural killer (NK) cell cytotoxic responses in myelodysplasia (MDS) and acute myeloid leukemia (AML) exist, but with limited data on these lymphocyte proportions and related T-cell subsets. The proportions of these cells and their prognostic implications were therefore investigated in 89 AML, 51 MDS, and 20 control marrows by flow cytometry. The median proportion of NK cells (relative to the total lymphocytes) was lower in AML versus controls (P = 0.01). Among AML, a lower proportion of NK cells predicted better survival, whereas a higher NK cell proportion was associated with the poor prognostic AML category (P = 0.002). NK cell proportions were similar in MDS, MDS subgroups, and control marrows. The relative proportion of the mature NK cell subset (CD56(dim) CD16/57(bright) ) was lower in AML and MDS versus controls (P = 0.006, P = 0.0002, respectively). The proportion of mature NK cells was not a prognostic indicator although fewer were seen in poor prognosis AML. In contrast, a lower proportion of mature NK cells correlated with worse survival in MDS (P = 0.027). A higher proportion of NK-like T-cells (of total lymphoid cells) was found in MDS compared to controls (P = 0.01). A lower proportion of NK-like T-cells predicted better survival in AML but not in MDS. Thus, the proportions of NK, NK-cell subsets, and NK-like T-cells vary in myeloid neoplasms, may potentially impact immunomodulatory therapies, and may impact outcome. © 2016 International Clinical Cytometry Society. PMID:26648320

  8. Decidual cell regulation of natural killer cell-recruiting chemokines: implications for the pathogenesis and prediction of preeclampsia.

    Science.gov (United States)

    Lockwood, Charles J; Huang, S Joseph; Chen, Chie-Pein; Huang, Yingqun; Xu, Jie; Faramarzi, Saeed; Kayisli, Ozlem; Kayisli, Umit; Koopman, Louise; Smedts, Dineke; Buchwalder, Lynn F; Schatz, Frederick

    2013-09-01

    First trimester human decidua is composed of decidual cells, CD56(bright)CD16(-) decidual natural killer (dNK) cells, and macrophages. Decidual cells incubated with NK cell-derived IFN-γ and either macrophage-derived TNF-α or IL-1β synergistically enhanced mRNA and protein expression of IP-10 and I-TAC. Both chemokines recruit CXCR3-expressing NK cells. This synergy required IFN-γ receptor 1 and 2 mediation via JAK/STAT and NFκB signaling pathways. However, synergy was not observed on neutrophil, monocyte, and NK cell-recruiting chemokines. Immunostaining of first trimester decidua localized IP-10, I-TAC, IFN-γR1, and -R2 to vimentin-positive decidual cells versus cytokeratin-positive interstitial trophoblasts. Flow cytometry identified high CXCR3 levels on dNK cells and minority peripheral CD56(bright)CD16(-) pNK cells and intermediate CXCR3 levels on the majority of CD56(dim)CD16(+) pNK cells. Incubation of pNK cells with either IP-10 or I-TAC elicited concentration-dependent enhanced CXCR3 levels and migration of both pNK cell subsets that peaked at 10 ng/mL, whereas each chemokine at a concentration of 50 ng/mL inhibited CXCR3 expression and pNK cell migration. Deciduae from women with preeclampsia, a leading cause of maternal and fetal morbidity and mortality, displayed significantly lower dNK cell numbers and higher IP-10 and I-TAC levels versus gestational age-matched controls. Significantly elevated IP-10 levels in first trimester sera from women eventually developing preeclampsia compared with controls, identifying IP-10 as a novel, robust early predictor of preeclampsia. PMID:23973270

  9. Spontaneous and natural cytotoxicity receptor-mediated cytotoxicity are effector functions of distinct natural killer subsets in hepatitis C virus-infected chimpanzees.

    Science.gov (United States)

    Verstrepen, B E; Nieuwenhuis, I G; Mooij, P; Bogers, W M; Boonstra, A; Koopman, G

    2016-07-01

    In humans, CD16 and CD56 are used to identify functionally distinct natural killer (NK) subsets. Due to ubiquitous CD56 expression, this marker cannot be used to distinguish between NK cell subsets in chimpanzees. Therefore, functional analysis of distinct NK subsets during hepatitis C virus (HCV) infection has never been performed in these animals. In the present study an alternative strategy was used to identify four distinct NK subsets on the basis of the expression of CD16 and CD94. The expression of activating and inhibiting surface receptors showed that these subsets resemble human NK subsets. CD107 expression was used to determine degranulation of the different subsets in naive and HCV-infected chimpanzees. In HCV-infected chimpanzees increased spontaneous cytotoxicity was observed in CD94(high/dim) CD16(pos) and CD94(low) CD16(pos) subsets. By contrast, increased natural cytotoxicity receptor (NCR)- mediated degranulation after NKp30 and NKp44 triggering was demonstrated in the CD94(dim) CD16(neg) subset. Our findings suggest that spontaneous and NCR-mediated cytotoxicity are effector functions of distinct NK subsets in HCV-infected chimpanzees. PMID:26850369

  10. An experimental approach to improve the basin type solar still using an integrated natural circulation loop

    International Nuclear Information System (INIS)

    Highlights: • A new experimental approach to improve the conventional solar still performances is proposed. • A passive natural circulation loop is integrated to the conventional solar still. • Natural circulation of humid-air in a closed loop is studied by the present study. • Natural circulation capability in driving air convection in the still was demonstrated. • Air convection created inside the still increase the evaporation heat and mass transfer. - Abstract: In this paper, a new experimental approach is proposed to enhance the performances of the conventional solar still using the natural circulation effect inside the still. The idea consists in generating air flow by a rectangular natural circulation loop appended to the rear side of the still. The proposed still was tested during summer period and the experimental data presented in this paper concerns four typical days. The convective heat transfer coefficient is evaluated and compared with Dunkle’s model. The comparison shows that convective heat transfer is considerably improved by the air convection created inside the still. The natural circulation phenomenon in the still is studied and a good agreement between the experimental data and Vijajan’s laminar correlation is found. Therefore, natural circulation phenomenon is found to have a good effect on the still performances where the still daily productivity is of 3.72 kg/m2 and the maximum efficiency is of 45.15%

  11. Phase II Study of Haploidentical Natural Killer Cell Infusion for Treatment of Relapsed or Persistent Myeloid Malignancies Following Allogeneic Hematopoietic Cell Transplantation.

    Science.gov (United States)

    Shaffer, Brian C; Le Luduec, Jean-Benoit; Forlenza, Christopher; Jakubowski, Ann A; Perales, Miguel-Angel; Young, James W; Hsu, Katharine C

    2016-04-01

    We conducted a phase 2 study to determine the efficacy of HLA-haploidentical related donor natural killer (NK) cells after cyclophosphamide-based lymphodepletion in patients with relapsed or progressive acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) following allogeneic hematopoietic cell transplantation (HCT). Eight patients (2 with MDS and 6 with AML) were treated with cyclophosphamide 50 mg/kg on day -3 and day -2 before infusion of NK cells isolated from a haploidentical related donor. One patient also received fludarabine 25 mg/m(2)/day for 4 days. Six doses of 1 million units of interleukin-2 (IL-2) were administered on alternating days beginning on day -1. The median number of NK cells infused was 10.6 × 10(6)/kg (range, 4.3 to 22.4 × 10(6)/kg), and the median number of CD3 cells infused was 2.1 × 10(3)/kg (range, 1.9 to 40 × 10(3)/kg). NK infusions were well tolerated, with a median time to neutrophil recovery of 19 days (range, 7 days to not achieved) and no incidence of graft-versus-host disease after NK infusion. One patient with AML and 1 patient with MDS achieved a complete response, but relapsed at 1.7 and 1.8 months, respectively. One patient with MDS experienced resolution of dysplastic features but persistence of clonal karyotype abnormalities; this patient was stable at 65 months after NK cell therapy. The median duration of survival was 12.9 months (range, 0.8 to 65.3 months). Chimerism analysis of CD3(-)/CD56(+) peripheral blood cells did not detect any circulating haploidentical NK cells after infusion. NK phenotyping was performed in 7 patients during and after IL-2 infusion. We found a slight trend toward greater expression of KIR2DL2/2DL3/2DS2 (5% versus 28%; P = .03) at 14 days in patients who survived longer than 6 months from NK cell infusion (n = 4) compared with those who died within 6 months of NK cell therapy (n = 3). In summary, our data support the safety of haploidentical NK cell

  12. Natural circulation in water cooled nuclear power plants: Phenomena, models, and methodology for system reliability assessments

    International Nuclear Information System (INIS)

    In recent years it has been recognized that the application of passive safety systems (i.e. those whose operation takes advantage of natural forces such as convection and gravity), can contribute to simplification and potentially to improved economics of new nuclear power plant designs. Further, the IAEA Conference on The Safety of Nuclear Power: Strategy for the Future which was convened in 1991 noted that for new plants 'the use of passive safety features is a desirable method of achieving simplification and increasing the reliability of the performance of essential safety functions, and should be used wherever appropriate'. Considering the weak driving forces of passive systems based on natural circulation, careful design and analysis methods must be employed to assure that the systems perform their intended functions. To support the development of advanced water cooled reactor designs with passive systems, investigations of natural circulation are an ongoing activity in several IAEA Member States. Some new designs also utilize natural circulation as a means to remove core power during normal operation. In response to the motivating factors discussed above, and to foster international collaboration on the enabling technology of passive systems that utilize natural circulation, an IAEA Coordinated Research Project (CRP) on Natural Circulation Phenomena, Modelling and Reliability of Passive Systems that Utilize Natural Circulation was started in early 2004. Building on the shared expertise within the CRP, this publication presents extensive information on natural circulation phenomena, models, predictive tools and experiments that currently support design and analyses of natural circulation systems and highlights areas where additional research is needed. Therefore, this publication serves both to provide a description of the present state of knowledge on natural circulation in water cooled nuclear power plants and to guide the planning and conduct of the CRP in

  13. Fundamental study on thermo-hydraulics during start-up in natural circulation boiling water reactors. 3. Effects of system pressure on geysering and natural circulation oscillation

    International Nuclear Information System (INIS)

    The authors have been investigating the fundamentals of thermo-hydraulic instabilities which may appear during the start-up in natural circulation BWRs in order to understand their driving mechanisms and to examine the methods preventing their occurrence with an aim of establishing a rational start-up procedure and reactor configuration. In this paper, based on our proposed driving mechanisms of geysering and natural circulation oscillation, the effects of system pressure on their occurrences and features are investigated experimentally. It is made clear that an increase in the system pressure suppresses their occurrences. From the results, a consideration is drawn to understand the differences in the start-ups between thermal natural circulation boilers using fossil fuel and the Dodewaard reactor. Lastly, a rational start-up procedure to prevent their instabilities from occurring is recommended and a new idea of separator is proposed. (author)

  14. Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function.

    Directory of Open Access Journals (Sweden)

    Venkateswara Rao Simhadri

    Full Text Available NKp30, a natural cytotoxicity receptor expressed on NK cells is critically involved in direct cytotoxicity against various tumor cells and directs both maturation and selective killing of dendritic cells. Recently the intracellular protein BAT3, which is involved in DNA damage induced apoptosis, was identified as a ligand for NKp30. However, the mechanisms underlying the exposure of the intracellular ligand BAT3 to surface NKp30 and its role in NK-DC cross talk remained elusive. Electron microscopy and flow cytometry demonstrate that exosomes released from 293T cells and iDCs express BAT3 on the surface and are recognized by NKp30-Ig. Overexpression and depletion of BAT3 in 293T cells directly correlates with the exosomal expression level and the activation of NK cell-mediated cytokine release. Furthermore, the NKp30-mediated NK/DC cross talk resulting either in iDC killing or maturation was BAT3-dependent. Taken together this puts forward a new model for the activation of NK cells through intracellular signals that are released via exosomes from accessory cells. The manipulation of the exosomal regulation may offer a novel strategy to induce tumor immunity or inhibit autoimmune diseases caused by NK cell-activation.

  15. Analysis of hot leg natural circulation under station blackout severe accident

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Under severe accidents, natural circulation flows are important to influence the accident progression and result in a pressurized water reactor (PWR). In a station blackout accident with no recovery of steam generator (SG) auxiliary feedwater (TMLB' severe accident scenario), the hot leg countercurrent natural circulation flow is analyzed by using a severe-accident code, to better understand its potential impacts on the creep-rupture timing among the surge line, the hot leg, and SG tubes. The results show that the natural circulation may delay the failure time of the hot leg.The recirculation ratio and the hot mixing factor are also calculated and discussed.

  16. Cloning and chromosomal assignment of a human cDNA encoding a T cell- and natural killer cell-specific trypsin-like serine protease

    International Nuclear Information System (INIS)

    A cDNA clone encoding a human T cell- and natural killer cell-specific serine protease was obtained by screening a phage λgt10 cDNA library from phytohemagglutinin-stimulated human peripheral blood lymphocytes with the mouse Hanukah factor cDNA clone. In an RNA blot-hybridization analysis, this human Hanukah factor cDNA hybridized with a 1.3-kilobase band in allogeneic-stimulated cytotoxic T cells and the Jurkat cell line, but this transcript was not detectable in normal muscle, liver, tonsil, or thymus. By dot-blot hybridization, this cDNA hybridized with RNA from three cytolytic T-cell clones and three noncytolytic T-cell clones grown in vitro as well as with purified CD16+ natural killer cells and CD3+, CD16- T-cell large granular lymphocytes from peripheral blood lymphocytes (CD = cluster designation). The nucleotide sequence of this cDNA clone encodes a predicted serine protease of 262 amino acids. The active enzyme is 71% and 77% similar to the mouse sequence at the amino acid and DNA level, respectively. The human and mouse sequences conserve the active site residues of serine proteases--the trypsin-specific Asp-189 and all 10 cysteine residues. The gene for the human Hanukah factor serine protease is located on human chromosome 5. The authors propose that this trypsin-like serine protease may function as a common component necessary for lysis of target cells by cytotoxic T lymphocytes and natural killer cells

  17. High-level expression of soluble form of mouse natural killer cell receptor NKR-P1C(B6) in Escherichia coli

    Czech Academy of Sciences Publication Activity Database

    Rozbeský, Daniel; Kavan, Daniel; Chmelík, Josef; Novák, Petr; Vaněk, Ondřej; Bezouška, Karel

    2011-01-01

    Roč. 77, č. 2 (2011), s. 178-184. ISSN 1046-5928 R&D Projects: GA ČR GA303/09/0477; GA ČR GD305/09/H008; GA ČR GAP207/10/1040; GA AV ČR IAA500200620; GA MŠk LC07017; GA MŠk LC545; GA MŠk 1M0505 Institutional research plan: CEZ:AV0Z50200510 Keywords : Natural killer cell * NKR-P1C receptor * NK1.1 antigen Subject RIV: EC - Immunology Impact factor: 1.587, year: 2011

  18. Cultured Mycelium Cordyceps sinensis allevi¬ates CCl4-induced liver inflammation and fibrosis in mice by activating hepatic natural killer cells

    OpenAIRE

    Peng, Yuan; Huang, Kai; Shen, Li; Tao, Yan-Yan; Liu, Cheng-Hai

    2015-01-01

    Aim: Recent evidence shows that cultured mycelium Cordyceps sinensis (CMCS) effectively protects against liver fibrosis in mice. Here, we investigated whether the anti-fibrotic action of CMCS was related to its regulation of the activity of hepatic natural killer (NK) cells in CCl4-treated mice. Methods: C57BL/6 mice were injected with 10% CCl4 (2 mL/kg, ip) 3 times per week for 4 weeks, and received CMCS (120 mg·kg−1·d−1, ig) during this period. In another part of experiments, the mice were ...

  19. Curcuminoids and ω-3 fatty acids with anti-oxidants potentiate cytotoxicity of natural killer cells against pancreatic ductal adenocarcinoma cells and inhibit interferon γ production

    OpenAIRE

    Halder, Ramesh C.; Almasi, Anasheh; Sagong, Bien; Leung, Jessica; Jewett, Anahid; Fiala, Milan

    2015-01-01

    Pancreatic cancer has a poor prognosis attributed in part to immune suppression and deactivation of natural killer (NK) cells. Curcuminoids have a potential for improving the therapy of pancreatic cancer given promising results in cancer models and a clinical trial, but their oral absorption is limited. Our objective in this study is to show curcuminoid anti-oncogenic effects alone and together with human NK cells. We tested curcuminoids in an emulsion of ω-3 fatty acids and anti-oxidants (“S...

  20. Glucagon-like peptide-1 (GLP-1) and the regulation of human invariant natural killer T cells: lessons from obesity, diabetes and psoriasis.

    LENUS (Irish Health Repository)

    Hogan, A E

    2011-11-01

    The innate immune cells, invariant natural killer T cells (iNKT cells), are implicated in the pathogenesis of psoriasis, an inflammatory condition associated with obesity and other metabolic diseases, such as diabetes and dyslipidaemia. We observed an improvement in psoriasis severity in a patient within days of starting treatment with an incretin-mimetic, glucagon-like peptide-1 (GLP-1) receptor agonist. This was independent of change in glycaemic control. We proposed that this unexpected clinical outcome resulted from a direct effect of GLP-1 on iNKT cells.

  1. High Pretreatment D-Dimer Levels Correlate with Adverse Clinical Features and Predict Poor Survival in Patients with Natural Killer/T-Cell Lymphoma

    OpenAIRE

    Bi, Xi-wen; Wang, Liang; Zhang, Wen-Wen; Sun, Peng; Yan, Shu-Mei; Liu, Pan-pan; Li, Zhi-Ming; Jiang, Wen-qi

    2016-01-01

    Pretreatment plasma D-dimer levels have been reported to predict survival in several types of malignancies. The aim of this study was to evaluate the prognostic value of D-dimer levels in patients with newly diagnosed natural killer/T-cell lymphoma (NKTCL). The cut-off value of D-dimer to predict survival was set as 1.2 μg/mL based on the receiver operating curve analysis. Patients with a D-dimer level ≥ 1.2 μg/mL had significantly more adverse clinical features, including poor performance st...

  2. Soluble interleukin-2 receptors inhibit interleukin 2-dependent proliferation and cytotoxicity: explanation for diminished natural killer cell activity in cutaneous T-cell lymphomas in vivo?

    OpenAIRE

    Dummer, R.; Posseckert, G.; F. NESTLE; Witzgall, R.; Burger, M.; Becker, J C; Schäfer, E; Wiede, J.; Sebald, Walter; Burg, G

    2012-01-01

    In patients with cutaneous T-cell lymphomas (CTCL), soluble interleukin-2 receptor serum levels (sIL-2R) were determined by ELISA technique, and natural killer cell (NK) activity, by a 4-h chromium-51 release assay. Decrease of NK activity correlated with the augmentation of serum sIL-2R. After a 4-d stimulation with interleukin 2 CTCL patients' peripheral mononuclear cells (PMC) showed an increase of cytotoxic activity similar to that in healthy donors' PMC. Normal donors' PMC demonstrated a...

  3. Expansion of Natural Killer Cells in Peripheral Blood in a Japanese Elderly with Human T-Cell Lymphotropic Virus Type 1-Related Skin Lesions

    OpenAIRE

    Shinsaku Imashuku; Naoko Kudo; Kagekatsu Kubo; Kouichi Ohshima

    2014-01-01

    Natural killer (NK) cells were proposed to play an important role in the pathogenesis of human T-cell lymphotropic virus type 1- (HTLV-1-) associated neurologic disease. Our patient was a 77-year-old Japanese man, who had been treated for infective dermatitis associated with HTLV-1 for nearly 10 years. When referred to us, he had facial eczema/edema as well as extensive dermatitis at the neck/upper chest and nuchal area/upper back regions. Dermal lesions had CD3+CD4+ cells, but no NK cells. F...

  4. MHC class I–deficient natural killer cells acquire a licensed phenotype after transfer into an MHC class I–sufficient environment

    OpenAIRE

    Elliott, Julie M.; Wahle, Joseph A.; Yokoyama, Wayne M.

    2010-01-01

    In MHC class I–deficient hosts, natural killer (NK) cells are hyporesponsive to cross-linking of activation receptors. Functional competence requires engagement of a self–major histocompatability complex (MHC) class I–specific inhibitory receptor, a process referred to as “licensing.” We previously suggested that licensing is developmentally determined in the bone marrow. In this study, we find that unlicensed mature MHC class I–deficient splenic NK cells show gain-of-function and acquire a l...

  5. A generalised correlation for the steady state flow in single-phase natural circulation loops

    International Nuclear Information System (INIS)

    To establish the heat transport capability of natural circulation loops, it is essential to know the flow rate. A generalized correlation for steady state flow valid for uniform and non-uniform diameter loops has been theoretically derived

  6. Startup transient simulation for natural circulation boiling water reactors in PUMA facility

    International Nuclear Information System (INIS)

    In view of the importance of instabilities that may occur at low-pressure and -flow conditions during the startup of natural circulation boiling water reactors, startup simulation experiments were performed in the Purdue University Multi-Dimensional Integral Test Assembly (PUMA) facility. The simulations used pressure scaling and followed the startup procedure of a typical natural circulation boiling water reactor. Two simulation experiments were performed for the reactor dome pressures ranging from 55 kPa to 1 MPa, where the instabilities may occur. The experimental results show the signature of condensation-induced oscillations during the single-phase-to-two-phase natural circulation transition. The results also suggest that a rational startup procedure is needed to overcome the startup instabilities in natural circulation boiling water reactor designs

  7. Natural Circulation Characteristics at Low-Pressure Conditions through PANDA Experiments and ATHLET Simulations

    Directory of Open Access Journals (Sweden)

    Domenico Paladino

    2008-01-01

    Full Text Available Natural circulation characteristics at low pressure/low power have been studied by performing experimental investigations and numerical simulations. The PANDA large-scale facility was used to provide valuable, high quality data on natural circulation characteristics as a function of several parameters and for a wide range of operating conditions. The new experimental data allow for testing and improving the capabilities of the thermal-hydraulic computer codes to be used for treating natural circulation loops in a range with increased attention. This paper presents a synthesis of a part of the results obtained within the EU-Project NACUSP “natural circulation and stability performance of boiling water reactors.” It does so by using the experimental results produced in PANDA and by showing some examples of numerical simulations performed with the thermal-hydraulic code ATHLET.

  8. Number and subtypes of natural killer cells in patients with allergic rhinitis in comparison to healthy subjects

    Directory of Open Access Journals (Sweden)

    Mehrnaz Mesdaghi

    2010-04-01

    Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Allergic rhinitis is a common disorder with great morbidity. Its prevalence has increased during recent years, therefore attracting attentions to its mechanisms. Type 2 cytokines play a major role in allergies. It has been proposed that Natural killer (NK cells may be able to produce type 2 cytokines. This study was done to evaluate NK cells number and subtypes in patients with allergic rhinitis, comparing healthy subjects."n"nMethods: In a case control study, patients with allergic rhinitis were compared to healthy non-atopic subjects. Allergic rhinitis was diagnosed according to ARIA guidelines. NK cells quantity was studied by staining of peripheral blood mono nuclear cells with anti-CD16-FITC and anti-CD56-PE and evaluated by two color flowcytometry. Intracellular cytokines were evaluated by tri-color flowcytometry. NK cells were separated by magnetic beads, and cultured for 72 hours. Secretion of IL-4, IL-5, IL-10, IL-13, and IFN-γ was measured by ELISA, in stimulated and unstimulated conditions."n"nResults: Patients had more CD16+ CD56+ NK cells than control group. IL-4+ NK cells were significantly higher in patients (p<0.001, but the number of IFN-γ+ NK cells was not different. Cytokine secretion

  9. Post-irradiation viability and cytotoxicity of natural killer cells isolated from human peripheral blood using different methods.

    Science.gov (United States)

    Hietanen, Tenho; Pitkänen, Maunu; Kapanen, Mika; Kellokumpu-Lehtinen, Pirkko-Liisa

    2016-01-01

    Purpose We compared the pre- and post-irradiation viability and cytotoxicity of human peripheral natural killer cell (NK) populations obtained using different isolation methods. Material and methods Three methods were used to enrich total NK cells from buffy coats: (I) a Ficoll-Paque gradient, plastic adherence and a nylon wool column; (II) a discontinuous Percoll gradient; or (III) the Dynal NK cell isolation kit. Subsequently, CD16(+) and CD56(+) NK cell subsets were collected using (IV) flow cytometry or (V) magnetic-activated cell sorting (MACS) NK cell isolation kits. The yield, viability, purity and cytotoxicity of the NK cell populations were measured using trypan blue exclusion, flow cytometry using propidium iodide and (51)Cr release assays after enrichments as well as viability and cytotoxicity after a single radiation dose. Results The purity of the preparations, as measured by the CD16(+) and CD56(+) cell content, was equally good between methods I-III (p = 0.323), but the content of CD16(+) and CD56(+) cells using these methods was significantly lower than that using methods IV and V (p = 0.005). The viability of the cell population enriched via flow cytometry (85.5%) was significantly lower than that enriched via other methods (99.4-98.0%, p = 0.003). The cytotoxicity of NK cells enriched using methods I-III was significantly higher than that of NK cells enriched using methods IV and V (p = 0.000). In vitro the NK cells did not recover cytotoxic activity following irradiation. In addition, we detected considerable inter-individual variation in yield, cytotoxicity and radiation sensitivity between the NK cells collected from different human donors. Conclusions The selection of the appropriate NK cell enrichment method is very important for NK cell irradiation studies. According to our results, the Dynal and MACS NK isolation kits best retained the killing capacity and the viability of irradiated NK cells. PMID:26634866

  10. Tracking of [18F]FDG-labeled natural killer cells to HER2/neu-positive tumors

    International Nuclear Information System (INIS)

    Introduction: The objective of this study was to label the human natural killer (NK) cell line NK-92 with [18F]fluoro-deoxy-glucose (FDG) for subsequent in vivo tracking to HER2/neu-positive tumors. Methods: NK-92 cells were genetically modified to NK-92-scFv(FRP5)-zeta cells, which express a chimeric antigen receptor that is specific to the tumor-associated ErbB2 (HER2/neu) antigen. NK-92 and NK-92-scFv(FRP5)-zeta cells were labeled with [18F]FDG by simple incubation at different settings. Labeling efficiency was evaluated by a gamma counter. Subsequently, [18F]FDG-labeled parental NK-92 or NK-92-scFv(FRP5)-zeta cells were intravenously injected into mice with implanted HER2/neu-positive NIH/3T3 tumors. Radioactivity in tumors was quantified by digital autoradiography and correlated with histopathology. Results: The NK-92 and NK-92-scFv(FRP5)-zeta cells could be efficiently labeled with [18F]FDG by simple incubation. Optimal labeling efficiencies (80%) were achieved using an incubation period of 60 min and additional insulin (10 IU/ml). After injection of 5x106 [18F]FDG-labeled NK-92-scFv(FRP5)-zeta cells into tumor-bearing mice, digital autoradiography showed an increased uptake of radioactivity in HER2/neu-positive tumors at 60 min postinjection. Conversely, injection of 5x106 NK-92 cells not directed against HER2/neu receptors did not result in increased uptake of radioactivity in the tumors. Histopathology confirmed an accumulation of the NK-92-scFv(FRP5)-zeta cells, but not the parental NK cells, in tumor tissues. Conclusion: The human NK cell line NK-92 can be directed against HER2/neu antigens by genetic modification. The genetically modified NK cells can be efficiently labeled with [18F]FDG, and the accumulation of these labeled NK cells in HER2/neu-positive tumors can be monitored with autoradiography

  11. Enhanced natural killer cell activation by exopolysaccharides derived from yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1.

    Science.gov (United States)

    Makino, Seiya; Sato, Asako; Goto, Ayako; Nakamura, Marie; Ogawa, Miho; Chiba, Yoshika; Hemmi, Jun; Kano, Hiroshi; Takeda, Kazuyoshi; Okumura, Ko; Asami, Yukio

    2016-02-01

    Yogurt is generally recognized as a beneficial food for our health, but research into its physiological effects has focused mainly on intestinal dysfunctions such as constipation and diarrhea. We previously found yogurt fermented with Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 (hereafter OLL1073R-1) could reduce risks of catching the common cold and flu in human trials. It was assumed that immunostimulatory exopolysaccharide (EPS) produced from OLL1073R-1 play an important role in this context. However, few studies have examined the immunostimulatory effects of traditional Bulgarian yogurts fermented with different strains of lactobacilli and their metabolites. Therefore, we screened 139 L. delbrueckii ssp. bulgaricus strains and identified OLL1073R-1 as the most robust producer of EPS. This strain was also the only strain that induced the production of IFN-γ in vitro. Oral administration of the EPS or yogurt fermented with OLL1073R-1 and Streptococcus thermophilus OLS3059 (OLL1073R-1 yogurt) augmented natural killer (NK) cell activity and induced IFN-γ production in spleen cells in mice, whereas 2 other yogurts fermented with other strains had no effect on NK cell activity. Cellular preparations of the OLL1073R-1 strain also slightly augmented NK cell activity, but were less effective than EPS itself. The EPS-dependent stimulation of NK cell activity was abrogated in IFN-γ knockout mice and in myeloid differentiation factor 88 knockout mice. Furthermore, IFN-γ production from spleen cells stimulated with EPS was completely blocked with both anti-IL-12 and anti-IL-18 antibodies in vitro. These findings suggest that NK cell activation by OLL1073R-1 yogurt is EPS-dependent, occurs via IL-12- and IL-18-mediated IFN-γ production, and requires myeloid differentiation factor 88. We showed that traditional Bulgarian yogurt could exert immunostimulatory effects by selecting starter strains and part of the mechanisms depend on IFN-γ inducible EPS produced

  12. Interleukin-2 enhances the natural killer cell response to Herceptin-coated Her2/neu-positive breast cancer cells.

    Science.gov (United States)

    Carson, W E; Parihar, R; Lindemann, M J; Personeni, N; Dierksheide, J; Meropol, N J; Baselga, J; Caligiuri, M A

    2001-10-01

    The Her2/neu (c-erbB-2) oncogene encodes a 185-kDa protein tyrosine kinase which is overexpressed in 20% of breast adenocarcinomas and is recognized by a humanized anti-Her2/neu monoclonal antibody (mAb) (rhu4D5 or Herceptin). Natural killer (NK) cells are capable of mediating antibody-dependent cell cytotoxicity (ADCC) against antibody-coated targets via their expression of a low-affinity receptor for IgG (FcgammaRIII or CD16). NK cells can be expanded in cancer patients via the administration of low-dose interleukin-2 (IL-2) and become potent cytotoxic effectors following exposure to high doses of IL-2. We tested IL-2-activated NK cells against Her2/neu+ (MCF-7Her2/neu) and Her2/neu- (MDA-468) breast cancer cell lines in a 4-h 51Cr-release cytotoxicity assay in the presence or absence of rhu4D5 mAb (effector : target ratio = 10 : 1). Specific lysis of rhu4D5-coated MCF-7Her2/neu and MDA-468 target cells by IL-2-activated NK cells was 35% and 3%, respectively (p cells was inhibited by 80 % when NK cells were pre-treated with an anti-Fc receptor antibody prior to use in the cytotoxicity assay. Enhanced ADCC of MCF-7Her2/neu target cells was seen when the effector cells consisted of mononuclear cells obtained from a patient demonstrating significant expansion of NK cells secondary to therapy with low-dose IL-2. Serum from patients receiving infusions of rhu4D5 mAb could substitute for exogenous antibody in the ADCC assay. NK cells activated by rhu4D5-coated tumor cells in the presence of IL-2 also produced large amounts of IFN-gamma with concomitant up-regulation of cell-surface activation markers CD25 and CD69. These results lend support to the concurrent use of rhu4D5 mAb and IL-2 therapy in patients with cancers that express the Her2/neu oncogene. PMID:11592078

  13. Analysis on Non-Uniform Flow in Steam Generator During Steady State Natural Circulation Cooling

    OpenAIRE

    Susyadi; T. Yonomoto

    2007-01-01

    Investigation on non uniform flow behavior among U-tube in steam generator during natural circulation cooling has been conducted using RELAP5. The investigation is performed by modeling the steam generator into multi channel models, i.e. 9-tubes model. Two situations are implemented, high pressure and low pressure cases. Using partial model, the calculation simulates situation similar to the natural circulation test performed in LSTF. The imposed boundary conditions are flow rate, quality, pr...

  14. The study and analysis of the capacity on natural circulation in pressurized water reactor

    International Nuclear Information System (INIS)

    The mathematical and physical model of the steady natural circulation in Pressurized Water Reactor (PWR) is presented in this paper. The program MISARS was completed which is used to calculate the heat removed capacity of natural steady circulation and the corresponding parameters in PWR. The calculating results from MISARS are in good agreement with the theoretical analysis. The works performed in this paper are of the significant references for the design and operation of the advanced PWR

  15. Single Phase Natural Circulation Behaviors of the Integral Type Marine Reactor Simulator under Rolling Motion Condition

    OpenAIRE

    Hou-jun Gong; Xing-tuan Yang; Yan-ping Huang; Sheng-yao Jiang

    2015-01-01

    During operation in the sea the reactor natural circulation behaviors are affected by ship rolling motion. The development of an analysis code and the natural circulation behaviors of a reactor simulator under rolling motion are described in this paper. In the case of rolling motion, the primary coolant flow rates in the hot legs and heating channels oscillated periodically, and the amplitude of flow rate oscillation was in direct proportion to rolling amplitude, but in inverse proportion to ...

  16. Evaluation of the natural circulation capability test results for Ulchin nuclear power plant unit 3

    Energy Technology Data Exchange (ETDEWEB)

    Sung, Kang Sik; Jeong, Weon Sang; Lee, Ju Han; Seo, Jong Tae; Lee, Sang Keun [Korea Power Engineering Company, Inc., Taejon (Korea, Republic of); Mo, Yong Won; Ryuk, Keun Su; Shin, Bong Chul; Kim, Byung Ho; Oh, Chul Sung [KEPCO, Ulchin (Korea, Republic of)

    1998-10-01

    During the Power Ascension Test (PAT) period, the transient tests related to the natural circulation capability were successfully completed for Ulchin Nuclear Power Plant Unit 3 (UCN 3). The tests were successfully completed by meeting all acceptance criteria. The post-trip PCS shows good performance as designed and the measured natural circulation capacity was demonstrated to be adequate for the core decay heat removal for UCN 3.

  17. Evaluation of the natural circulation capability test results for Ulchin nuclear power plant unit 3

    International Nuclear Information System (INIS)

    During the Power Ascension Test (PAT) period, the transient tests related to the natural circulation capability were successfully completed for Ulchin Nuclear Power Plant Unit 3 (UCN 3). The tests were successfully completed by meeting all acceptance criteria. The post-trip PCS shows good performance as designed and the measured natural circulation capacity was demonstrated to be adequate for the core decay heat removal for UCN 3

  18. Improvement of the analytical model of Monju air cooler for natural circulation

    International Nuclear Information System (INIS)

    Monju is a sodium-cooled, loop-type prototype fast breeder reactor with three primary cooling loops which can supply 280 MW of electricity. If Station blackout occurs in Monju, the decay heat removal by natural circulation is required, because the power was lost for operating circulation pumps and blowers. The pressure losses of air flow path are very important factors for evaluating of the cooling ability by natural circulation because the air cooler is the ultimate heat sink and the pressure loss characteristic of air side in air cooler affects the temperature of cooling loop greatly. Therefore, the analytical model of the pressure loss characteristic of air side in the plant dynamic analysis code Super-COPD was improved for accurate simulation of natural circulation flow in this study. (author)

  19. Transient behavior of natural circulation for boiling two-phase flow - experimental results

    International Nuclear Information System (INIS)

    The safety of current light water reactors (LWRs) is too dependent on active engineered safety features to enhance their reliability greatly. Many concepts have been proposed for the next generation of LWRs in which passive safety functions are pursued. A natural-circulation boiling water reactor (BWR), such as the simplified BWR SBWR, is one such proposal. From the viewpoint of core stability, the power density of natural-circulation BWRs is lower than that of current BWRs and their fuel pin length is shorter, so that reactor diameter is larger. Moreover, the size of a reactor vessel is limited by the ability of the present machine, and its output power may be lower than 600 MW(electric). As Japan is a relatively small country, it is difficult to find reactor sites, and Japanese electric power companies are not inclined to introduce small or medium-sized reactors. If the merits of eliminating circulation pumps are truly understood, however, it seems that a series of power generators will be supported by industry and natural-circulation BWRs may thus be introduced in Japan. The purpose of this paper is to introduce a discussion on the merits and drawbacks of natural-circulation BWRs. The thermohydraulic behavior of developing processes of natural circulation in boiling two-phase flow has been investigated experimentally by simulating normal and abnormal start-up conditions

  20. Five-year analysis from phase 2 trial of "sandwich" chemoradiotherapy in newly diagnosed, stage IE to IIE, nasal type, extranodal natural killer/T-cell lymphoma.

    Science.gov (United States)

    Zhang, Li; Jiang, Ming; Xie, Li; Zhang, Hong; Jiang, Yu; Yang, Qun-pei; Liu, Wei-ping; Zhang, Wen-yan; Zhuo, Hong-yu; Li, Ping; Chen, Nian-yong; Zhao, Sha; Wang, Feng; Zou, Li-qun

    2016-01-01

    The "sandwich" protocol, was first proposed by us and comprised of l-asparaginase, vincristine, and prednisone chemotherapy with radiotherapy, results in 2-year overall survival and progression-free survival rates that surpass traditional therapies for patients with newly diagnosed, stage IE-IIE, nasal type, extranodal natural killer/T-cell lymphoma. The results had been published by cancer. These patients were followed up over a median period of 67 months, for which updates and the results of prognostic factors analyses are presented. The 5-year overall survival and progress-free survival rates were both 64%. The highest rates of death occurred during the first 6 months, and between the second and third year after enrollment. The initial therapeutic response (odds ratio = 5.83; P = 0.001) and B symptoms (odds ratio = 6.13; P = 0.043) were significant prognostic factors for overall survival. However, the international prognostic index was not significant for progress-free survival and overall survival. There were no severe long-term side effects. These results indicate that the "sandwich" protocol may benefit the long-term survival of patients with newly diagnosed stage IE-IIE, nasal type, extranodal natural killer/T-cell lymphoma. However, additional studies with larger samples are required to confirm these results. This study is registered at www.Chictr.org (ChicTR-TNC-09000394). PMID:26633585

  1. Protective effects of adrenochrome monoaminoguanidine methanesulfonate (AMM) and cytochrome C (CCC) on natural killer cells in the peripheral blood of cancer patients during radiotherapy

    International Nuclear Information System (INIS)

    The purpose of this study was to examine radioprotective effects of adrenochrome monoaminoguanidine methanesulfonate (AMM) and cytochrome C (CCC) on lymphocyte subset during radiotherapy (RT). Sixty five patients received irradiation of 50 Gy or more to the chest field of 100 cm2 or larger. The patients were classified into four groups: those treated with RT alone (Group I, n=15), combined RT and OK-432 (Group II, n=15), combined RT and AMMM + CCC (Group III, n=17), and combined RT and AMM + CCC + OK-432 (Group IV, n=18). Lymphocytes decreased by 64% after RT in Group I and by 50% in Group III. AMM and CCC prevented a decrease in the absolute number of potent natural killer cells and activated T cells, with statistically significant differences. In Group III, the absolute number of activated T cells tended to increase even after RT. Cytotoxic T cells decreased by only 11% after RT in Group III, as compared with 58% in Group I. As found in Groups II and IV, the combination of OK-432 did not have so protective effects on lymphocytes associated with RT as AMM + CCC combined with RT in Groups III. In view of the selective protection for potent natural killer cells and activated T cells, AMM + CCC seemed to serve as biological response modifiers, as well as radioprotective agents. (N.K.)

  2. An experimental study on the flow instabilities and critical heat flux under natural circulation

    International Nuclear Information System (INIS)

    This study has been carried out to investigate the hydrodynamic stabilities of natural circulation and to analyze Critical Heat Flux (CHF) characteristics for the natural and forced circulation. A low pressure experimental loop was constructed, and experiments under various conditions have been performed. In the experiments of the natural circulation, flow oscillations and the average mass flux have been observed. Several parameters such as heat flux, the inlet temperature of test section, friction valve opening and riser length have been varied in order to investigate their effects on the flow stability of the natural circulation system. The results show that the flow instability has strongly dependent on geometric conditions and operating parameters, the inlet temperature and the heat flux of test section. It was found that unstable region for the heat flux and the inlet temperature exists between the single-phase stable region of low heat and low inlet temperature and the two-phase stable region of very high heat flux and high inlet temperature. The CHF data from the natural and forced circulation experiments have been compared each other to identify the effects of the flow instabilities on the CHF for the natural circulation mode. The test conditions were low flow less than 70 kg/m2s of water in vertical round tube with diameter of 0.008m at near atmospheric pressure. In this study, no difference in CHF values is observed between natural and fored circulation. Since low flow usually has the oscillation characteristic of relatively low amplitude and high frequency, the effect of the flow instabilities on the CHF seems to be negligible

  3. Self-organizing maps applied to two-phase flow on natural circulation loop studies

    International Nuclear Information System (INIS)

    Two-phase flow of liquid and gas is found in many closed circuits using natural circulation for cooling purposes. Natural circulation phenomenon is important on recent nuclear power plant projects for heat removal on 'loss of pump power' or 'plant shutdown' accidents. The accuracy of heat transfer estimation has been improved based on models that require precise prediction of pattern transitions of flow. Self-Organizing Maps are trained to digital images acquired on natural circulation flow instabilities. This technique will allow the selection of the more important characteristics associated with each flow pattern, enabling a better comprehension of each observed instability. This periodic flow oscillation behavior can be observed thoroughly in this facility due its glass-made tubes transparency. The Natural Circulation Facility (Circuito de Circulacao Natural - CCN) installed at Instituto de Pesquisas Energeticas e Nucleares, IPEN/CNEN, is an experimental circuit designed to provide thermal hydraulic data related to one and two phase flow under natural circulation conditions. (author)

  4. The impact on vessel level measurement due to natural circulation

    International Nuclear Information System (INIS)

    Background: The Core Cooling and Monitoring System (CCMS) of CPR1000 nuclear power station supplies monitoring means for two primary state functions defined in State Oriented Procedure (SOP). Purpose: We aim to deal with the errors caused by L VSL measurement and discuss the influence on SOP accident treatment. Methods: The calculation formula of natural recirculation flow rate was estimated. The maximum flow rates of single phase natural recirculation (at the time of reactor trip) and two phase natural recirculation (the void fraction in hot leg was 0.2) were calculated. The impact on SOP due to the measurement error of L VSL was analyzed. Results: Firstly, in the condition of single phase recirculation, the estimated error of L VSL measurement induced by the natural recirculation was less than 1.6%. Secondly, in the condition of two phase natural recirculation, the natural recirculation induced an over-estimated error' about 3.6% to L VSL measurement when the void fraction in hot leg was 0.2. Conclusion: As multi-parameters are adopted for SOP to diagnose the core cooling state, the implementation of the safety related operations is guaranteed. (authors)

  5. Structural Basis for Phototoxicity of the Genetically Encoded Photosensitizer KillerRed

    Energy Technology Data Exchange (ETDEWEB)

    Pletnev, Sergei; Gurskaya, Nadya G.; Pletneva, Nadya V.; Lukyanov, Konstantin A.; Chudakov, Dmitri M.; Martynov, Vladimir I.; Popov, Vladimir O.; Kovalchuk, Mikhail V.; Wlodawer, Alexander; Dauter, Zbigniew; Pletnev, Vladimir; (SOIBC); (Russ. Acad. Sci.); (NCI)

    2009-11-23

    KillerRed is the only known fluorescent protein that demonstrates notable phototoxicity, exceeding that of the other green and red fluorescent proteins by at least 1,000-fold. KillerRed could serve as an instrument to inactivate target proteins or to kill cell populations in photodynamic therapy. However, the nature of KillerRed phototoxicity has remained unclear, impeding the development of more phototoxic variants. Here we present the results of a high resolution crystallographic study of KillerRed in the active fluorescent and in the photobleached non-fluorescent states. A unique and striking feature of the structure is a water-filled channel reaching the chromophore area from the end cap of the {beta}-barrel that is probably one of the key structural features responsible for phototoxicity. A study of the structure-function relationship of KillerRed, supported by structure-based, site-directed mutagenesis, has also revealed the key residues most likely responsible for the phototoxic effect. In particular, Glu68 and Ser119, located adjacent to the chromophore, have been assigned as the primary trigger of the reaction chain.

  6. Human lymphokine-activated killer cell system. V. Purified recombinant interleukin 2 activates cytotoxic lymphocytes which lyse both natural killer-resistant autologous and allogeneic tumors and trinitrophenyl-modified autologous peripheral blood lymphocytes

    International Nuclear Information System (INIS)

    Culture of human peripheral blood lymphocytes (PBL) in purified natural or recombinant interleukin 2 in the absence of exogenous antigen or mitogen causes the differentiation of nonlytic precursor cells into lymphokine-activated killers (LAK). A titration of purified Jurkat IL-2 (BRMP, FCRC, NIH) IL-2 showed that the relatively low concentration of 5 U/ml was optimal for LAK activation. When the responding PBL were pretreated with either mitomycin C or gamma irradiation, LAK activation did not occur, indicating that proliferation, in addition to differentiation, is required. The spectrum of target cells susceptible to LAK lysis in a 4-hr chromium-51-release assay includes fresh NK-resistant tumor cells and trinitrophenyl (TNP)-modified autologous PBL. Unmodified PBL are not lysed. Cold target inhibition studies indicated that LAK lysis of autologous TNP-PBL is totally inhibited by fresh tumors cells, and that tumor lysis is inhibited by TNP-PBL. Additionally, allogeneic tumors totally inhibit lysis of autologous tumor cells in other cold target studies. These results demonstrate that the lytic activity expressed by LAK is not HLA restricted, is not limited to tumor cells, and is polyspecific as indicated by the cross-reactive recognition of multiple target cell types in these cold target inhibition studies

  7. Natural circulation and stability limits in advanced plants: The Galilean law

    International Nuclear Information System (INIS)

    In our previous papers natural circulation instability problem have been examined. In particular, we analytically demonstrated the link between critical heart flux (CHF) and instability, and the limitations of the present CHF data. We derived an analytical solution for the static instability in natural circulation. We proceed in this paper to build on these novel ideas and physical principles. We focus on the role of gravity in the analysis and prediction of instability. We derive the non-dimensional correlation of natural circulation flowrate, and link this with our physical analysis of instability in parallel-channel systems. We derive the exact form of the unstable limit, and discuss the important effect of zero gravity on the solution. For static instability, the result is a cubic equation for the quality. We solve for the limiting cases to obtain a new explicit result. The effect of gravity on upflow and downflow is shown to be significant for high subcoolings. By combining the natural-circulation and stability results, we demonstrate a new result which analytically describes the limits on natural-circulation operation. This result is relevant to small breaks and transients, as well as to defining the design envelope for safe operation

  8. Stability of flashing-driven natural circulation in a passive moderator cooling system for Canadian SCWR

    International Nuclear Information System (INIS)

    Highlights: • The stability in a passive moderator cooling system of a unique system in the Canadian SCWR. • Identify and analyze unstable oscillations using flashing-driven natural circulation test results. • The flashing-driven oscillations categorized as a flashing-driven Type-I density wave instability including a geysering-like feature. • A stability map on the dimensionless plane with the Subcooling number and Phase Change number. - Abstract: This paper presents an examination of the instability mechanisms in a Passive Moderator Cooling System for the Canadian SCWR (Supercritical Water-cooled Reactor). The passive system is being developed at AECL using a flashing-driven natural circulation loop. Unstable intermittent and sinusoidal oscillations were identified from experimental data of the flashing-driven natural circulation passive moderator cooling system. The oscillation periods were correlated with the boiling delay time. A stability map for a flashing-driven two-phase natural circulation loop was established on the dimensionless plane with Subcooling number and Phase Change number. It was observed that there is thermal non-equilibrium in the single-phase and two-phase oscillation stages of the flashing-driven natural circulation

  9. The development of natural circulation operation support program for ship nuclear power machinery

    International Nuclear Information System (INIS)

    Highlights: ► The natural circulation under various ocean and ship motion conditions is studied. ► A natural circulation operation support computer program (NCOSP) is developed with Simulink. ► The NCOSP program has the merit of easy input preparation, fast and accurate simulation. ► The NCOSP is suitable for the fast parameter simulation of ship nuclear power machinery. -- Abstract: The existing simulation program of ship nuclear power machinery (SNPM) cannot adequately deal with the natural circulation (NC) operation and the effects of various ocean conditions and ship motion. Aiming at the problem, the natural circulation operation support computer program for SNPM is developed, in which the momentum conservation equation of the primary loop, some heat transfer and flow resistance models and equations are modified for the various ocean conditions and ship motion. The additional pressure loss model and effective height model for the control volume in the gyration movement, simple harmonic rolling and pitching movements are also discussed in the paper. Furthermore, the transient response to load change under NC conditions is analyzed by the developed program. The results are compared with those predicted by the modified RELAP5/mod3.2 code. It is shown that the natural circulation operation support program (NCOSP) is simple in the input preparation, runs fast and has a satisfactory precision, and is therefore very suitable for the operating field support of SNPM under the conditions of NC.

  10. Simplified thermal-hydraulic analysis of single phase natural circulation circuit with two heat exchangers

    Energy Technology Data Exchange (ETDEWEB)

    Pinheiro, Larissa Cunha; Su, Jian, E-mail: larissa@lasme.coppe.ufrj.br, E-mail: sujian@lasme.coppe.ufrj.br [Coordenacao dos Programas de Pos-Graduacao em Engenharia (COPPE/UFRJ), Rio de Janeiro, RJ (Brazil). Programa de Engenhraria Nuclear; Cotta, Renato Machado, E-mail: cotta@mecanica.coppe.ufrj.br [Coordenacao dos Programas de Pos-Graduacao em Engenharia (POLI/COPPE/UFRJ), Rio de Janeiro, RJ (Brazil). Dept. de Engenharia Mecanica

    2015-07-01

    Single phase natural circulation circuits composed of two convective heat exchangers and connecting tubes are important for the passive heat removal from spent fuel pools (SFP). To keep the structural integrity of the stored spent fuel assemblies, continuously cooling has to be provided in order to avoid increase at the pool temperature and subsequent uncovering of the fuel and enhanced reaction between water and metal releasing hydrogen. Decay heat can achieve considerably high amounts of energy e.g. in the AP1000, considering the emergency fuel assemblies, the maximum heat decay will reach 13 MW in the 15th day (Westinghouse Electric Company, 2010). A highly efficient alternative to do so is by means of natural circulation, which is cost-effective compared to active cooling systems and is inherently safer since presents less associated devices and no external work is required. Many researchers have investigated safety and stability aspects of natural circulation loops (NCL). However, there is a lack of literature concerning the improvement of NCL through a standard unified methodology, especially for natural circulation circuits with two heat exchangers. In the present study, a simplified thermal-hydraulic analysis of single phase natural circulation circuit with two heat exchanges is presented. Relevant dimensionless key groups were proposed to for the design and safety analysis of a scaled NCL for the cooling of spent fuel storage pool with convective cooling and heating. (author)

  11. An experimental study on the flow instabilities and critical heat flux under natural circulation

    International Nuclear Information System (INIS)

    This study has been carried out to investigate the hydrodynamic stabilities and Critical Heat Flux (CHF) characteristics for the natural and forced circulation. A low pressure experimental loop was constructed, and experiments under various conditions have been performed. In the experiments of the natural circulation, flow oscillations has been observed and the average mass flux under flow oscillation have been measured. Several parameters such as heat flux, the inlet temperature of test section, friction valve opening and riser length have been varied in order to investigate their effects on the flow stability of the natural circulation system. And the CHF data from low flow experiments, namely the natural and forced circulation, have been compared with each other to identify the effects of the flow instabilities on the CHF for the natural circulation mode. The test conditions for the CHF experiments were a low flow of less than 70 kg/m2s of water in a vertical round tube with diameter of 0.008 m at near atmospheric pressure. (author)

  12. Mechanism of ONB based on nonequilibrium thermodynamics of natural circulation in narrow channels

    International Nuclear Information System (INIS)

    Based on the experiment of onset of nucleate boiling (ONB) in natural circulation and the nonequilibrium thermodynamics dissipative theory, the mechanism of ONB in narrow rectangle channels of natural circulation is proposed. It points out that the onset of nucleate boiling is influenced by the degree of superheat and the special conditions of narrow channels. Under the conditions of both density difference in natural circulation and narrow rectangle channels, the prediction model of ONB in natural circulation of narrow channels based on fluctuating is established. The experimental results show that the present model can be used to predict the heat flux of ONB in narrow rectangle channels. Features of ONB in natural circulation narrow rectangle channels are as follows: heating power is the incentive of the happen of ONB; the higher the heating power is, the higher the degree of superheat is, and the earlier the ONB will appear. With the pressurizing, the appearance of ONB will be delayed. The higher the degree of supercooling is, the later the ONB appears. The ONB will happen easier when there are noncondensable gases and roughness in the channels. (authors)

  13. Natural circulating passive cooling system for nuclear reactor containment structure

    Science.gov (United States)

    Gou, Perng-Fei; Wade, Gentry E.

    1990-01-01

    A passive cooling system for the contaminant structure of a nuclear reactor plant providing protection against overpressure within the containment attributable to inadvertent leakage or rupture of the system components. The cooling system utilizes natural convection for transferring heat imbalances and enables the discharge of irradiation free thermal energy to the atmosphere for heat disposal from the system.

  14. Suppressing the killer instinct.

    Science.gov (United States)

    Campbell, Kerry S

    2016-01-01

    Natural killer (NK) cells are innate lymphoid cells that have adopted activating and inhibitory signaling mechanisms enabling them to be tolerant of normal cells but to distinguish and eliminate tumor cells and virus-infected cells. In this issue of Science Signaling, Matalon et al show how inhibitory receptors disrupt NK cell activation by stimulating dephosphorylation of the adaptor protein LAT (linker of activated T cells) and phospholipase C-γ by the phosphatase SHP-1 [Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1], as well as ubiquitylation of LAT by Cbl family E3 ubiquitin ligases. PMID:27221707

  15. Two-phase natural circulation experiments in a pressurized water loop with CANDU geometry

    International Nuclear Information System (INIS)

    To provide information on two-phase natural circulation in a CANDU-type coolant circuit a series of tests has been performed in the RD-12 loop at the Whiteshell Nuclear Research Establishment. RD-12 is a 10-MPa pressurized-water loop containing two active boilers, two pumps, and two, or four, heated horizontal channels arranged in a symmetrical figure-of-eight configuration characteristic of the CANDU reactor primary heat-transport system. In the tests, single-phase natural circulation was established in the loop and void was introduced by controlled draining, with the surge tank (pressurizer) valved out of the system. The paper reviews the experimental results obtained and describes the evolution of natural circulation flow in particular cases as voidage is progressively increased. The stability behaviour is discussed briefly with reference to a simple stability model

  16. RELAP5 simulation for one and two-phase natural circulation phenomenon

    Energy Technology Data Exchange (ETDEWEB)

    Sabundjian, Gaiane; Andrade, Delvonei Alves de; Umbehaun, Pedro Ernesto; Torres, Walmir Maximo; Castro, Alfredo Jose Alvim de [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)]. E-mails: gdjian@ipen.br; delvonei@ig.com.br; umbehaun@ipen.br; wmtorres@ipen.br; Braz Filho, Francisco A.; Borges, Eduardo Madeira [Centro Tecnico Aeroespacial (CTA-IEAv), Sao Jose dos Campos, SP (Brazil). Inst. de Estudos Avancados]. E-mails: eduardo@ieav.cta.br; fbraz@ieav.cta.br; Belchior Junior, Antonio; Rocha, Ricardo Takeshi Vieira da [Centro Tecnologico da Marinha em Sao Paulo (CTMSP), Sao Paulo, SP (Brazil)]. E-mails: belchior@bol.com.br; rtvrocha@uol.com.br; Damy, Osvaldo Luiz Almeida; Torres, Eduardo [Universidade de Sao Paulo (USP), SP (Brazil). Escola Politecnica]. E-mails: osvaldo.damy@poli.usp.br; etorres@pac.ind.br

    2007-07-01

    The objective of this paper is to study the natural circulation phenomenon in one and two-phase regime. There has been a crescent interest in the scientific community in the study of the natural circulation. New generation of compact nuclear reactors uses the natural circulation for residual heat removal in case of accident or shutdown. For this study, the modeling and the simulation of the experimental circuit is performed with the RELAP5 code. The experimental circuit is mounted in the Chemical Engineering Department of the University of Sao Paulo. It is presented in this work the theoretical/experimental comparison for one and two-phase flow. These results will be stored in a database to validate RELAP5 calculations. This work was also used to training some users of RELAP5 from IEAv. (author)

  17. RELAP5 simulation for one and two-phase natural circulation phenomenon

    International Nuclear Information System (INIS)

    The objective of this paper is to study the natural circulation phenomenon in one and two-phase regime. There has been a crescent interest in the scientific community in the study of the natural circulation. New generation of compact nuclear reactors uses the natural circulation for residual heat removal in case of accident or shutdown. For this study, the modeling and the simulation of the experimental circuit is performed with the RELAP5 code. The experimental circuit is mounted in the Chemical Engineering Department of the University of Sao Paulo. It is presented in this work the theoretical/experimental comparison for one and two-phase flow. These results will be stored in a database to validate RELAP5 calculations. This work was also used to training some users of RELAP5 from IEAv. (author)

  18. Steady state performance of subcritical and supercritical pressure natural circulation in the same test facility

    International Nuclear Information System (INIS)

    For supercritical pressure natural circulation loops, explicit correlation for steady state flow are not available. While using the subcritical natural circulation flow correlation for supercritical pressure data, it has been observed that subcritical flow correlation is not able to predict the steady state flow accurately near supercritical pressure condition. A generalized correlation has been proposed to estimate the steady state flow in supercritical pressure natural circulation loop based on a relationship between dimensionless density and dimensionless enthalpy reported in literature. This generalized correlation has been tested with the steady state supercritical pressure CO2 data and found to be in good agreement. Subsequently supercritical pressure data for different working fluids reported in literature has also been compared with the proposed correlation. It is observed that the same generalized correlation is applicable for other fluids also. The present paper deals with the details of the test facility, the derivation of the generalized correlation and comparison with experimental data. (author)

  19. CIRCUS and DESIRE: Experimental facilities for research on natural-circulation-cooled boiling water reactors

    International Nuclear Information System (INIS)

    At the Delft University of Technology two thermohydraulic test facilities are being used to study the characteristics of Boiling Water Reactors (BWRs) with natural circulation core cooling. The focus of the research is on the stability characteristics of the system. DESIRE is a test facility with freon-12 as scaling fluid in which one fuel bundle of a natural-circulation BWR is simulated. The neutronic feedback can be simulated artificially. DESIRE is used to study the stability of the system at nominal and beyond nominal conditions. CIRCUS is a full-height facility with water, consisting of four parallel fuel channels and four parallel bypass channels with a common riser or with parallel riser sections. It is used to study the start-up characteristics of a natural-circulation BWR at low pressures and low power. In this paper a description of both facilities is given and the research items are presented. (author)

  20. Characteristics of high volumetric quality flow of natural circulation under rolling motion

    International Nuclear Information System (INIS)

    Theoretical studies on characteristics of high volumetric quality flow of natural circulation under rolling motion were performed. Unlike the fluctuating characteristics of single-phase flow of natural circulation under rolling motion, the high volumetric quality flow doesn't fluctuate and is relatively stable. A mathematical model was developed to calculate the flow rate of both the single-phase flow and the high volumetric quality flow under rolling motion. The calculated results are in reasonably good agreement with experimental data. Analyses were made to various terms of pressure drops and frictional coefficient under such two types of flow conditions, and the analytical results show that the increase in the pressure driving head and frictional coefficient leads to the relative stable flow characteristics of the natural circulation of high volumetric quality flow under rolling motion. (authors)

  1. Nonlinear analysis for a nuclear-coupled two-phase natural circulation loop

    International Nuclear Information System (INIS)

    The objective of this paper is to develop a nonlinear numerical model to investigate the stability and nonlinear dynamics of a nuclear-coupled two-phase natural circulation loop. Some stability maps, parametric effects and transient characteristics of this natural circulation loop have been studied. Results indicate that the system indeed has two instability regions, the type-I and type-II instabilities, as is well known for a natural circulation loop. Parameters may induce different effects on the system stability in type-I and type-II unstable regions. In particular, the void-reactivity feedback destabilizes the system in both regions of low and high operating powers. Moreover, by strengthening nuclear feedback effect, period-doubled bifurcation may prevail in the system at relatively high inlet subcoolings and eventually a chaotic attractor appears with a fractal dimension of 1.79 ± 0.01 and an embedding dimension of 5

  2. Natural circulation and stratification in the various passive safety systems of the SWR 1000

    International Nuclear Information System (INIS)

    In some of the passive safety systems of Siemens' SWR 1000 boiling water reactor (i.e. the emergency condensers and containment cooling condensers), natural circulation is the main effect on both the primary and secondary sides by which optimum system efficiency is achieved. Other passive safety systems of the SWR 1000 require natural circulation on the secondary side only (condensation of steam discharged by the safety and relief valves; cooling of the Reactor Pressure Vessel (RPV) by flooding from the outside in case of core melt), while still other systems require stratification to be effective (i.e. the passive pressure pulse transmitters and steam-driven scram tanks). Complex natural circulation and stratification can take place simultaneously if fluids with different densities are enclosed in a single volume (in a core melt accident, for example, the nitrogen, steam and hydrogen in the containment). Related problems and the solutions thereto planned for the SWR 1000 are reported from the designer's viewpoint. (author)

  3. Two-phase flow patterns recognition and parameters estimation through natural circulation test loop image analysis

    International Nuclear Information System (INIS)

    Visualization of natural circulation test loop cycles is used to study two-phase flow patterns associated with phase transients and static instabilities of flow. Experimental studies on natural circulation flow were originally related to accidents and transient simulations relative to nuclear reactor systems with light water refrigeration. In this regime, fluid circulation is mainly caused by a driving force ('thermal head') which arises from density differences due to temperature gradient. Natural circulation phenomenon has been important to provide residual heat removal in cases of 'loss of pump power' or plant shutdown in nuclear power plant accidents. The new generation of compact nuclear reactors includes natural circulation of their refrigerant fluid as a security mechanism in their projects. Two-phase flow patterns have been studied for many decades, and the related instabilities have been object of special attention recently. Experimental facility is an all glass-made cylindrical tubes loop which contains about twelve demineralized water liters, a heat source by an electrical resistor immersion heater controlled by a Variac, and a helicoidal heat exchanger working as cold source. Data is obtained through thermo-pairs distributed over the loop and CCD cameras. Artificial intelligence based algorithms are used to improve (bubble) border detection and patterns recognition, in order to estimate and characterize, phase transitions patterns and correlate them with the periodic static instability (chugging) cycle observed in this circuit. Most of initial results show good agreement with previous numerical studies in this same facility. (author)

  4. Experimental and Analytical Modeling of Natural Circulation and Forced Circulation BWRs : Thermal-Hydraulic, Core-Wide, and Regional Stability Phenomena

    NARCIS (Netherlands)

    Furuya, M.

    2006-01-01

    Currently, 434 nuclear power plants are in operation worldwide. 21% of them are known as Boiling Water Reactors (BWRs). These BWRs have pumps that cool their reactor cores (the forced circulation BWRs). In the design of new BWRs, ways to cool the core by a natural circulation flow, without pumps, al

  5. Reliability Analysis of a Boiling Two-phase Natural Circulation System using the APSRA methodology

    International Nuclear Information System (INIS)

    In this paper, we present a methodology known as APSRA (Assessment of Passive System ReliAbility) for evaluation of reliability of passive systems. The methodology has been applied to the boiling natural circulation system in the Main Heat Transport System of the Indian AHWR (Advanced Heavy Water Reactor) concept. In the APSRA methodology, the passive system reliability is evaluated from the evaluation of the failure probability of the system to carry out the desired function. The methodology first determines the operational characteristics of the system and the failure conditions by assigning a predetermined failure criterion. The failure surface is predicted using a best estimate code considering deviations of the operating parameters from their nominal states, which affect the natural circulation performance. Since applicability of the best estimate codes to passive systems are neither proven nor understood enough, APSRA relies more on experimental data for various aspects of natural circulation such as steady state natural circulation, flow instabilities, CHF (critical heat flux) under oscillatory condition, etc. APSRA proposes to compare the code predictions with the test data to generate the uncertainties on the failure parameter prediction, which is later considered in the code for accurate prediction of failure surface of the system. Once the failure surface of the system is predicted, the cause of failure is examined through root diagnosis, which occurs mainly due to failure of mechanical components. The failure probabilities of these components are evaluated through a classical PSA (Probabilistic Safety Assessment) treatment using the generic data. Reliability of the natural circulation system is evaluated from the probability of availability of the components for the success of natural circulation in the system. (author)

  6. Analytical Evaluation of Two-Phase Natural Circulation Flow Under ERVC condition

    International Nuclear Information System (INIS)

    The process of two-phase natural circulation flow induced in the annular gap between the reactor vessel and the insulation under external reactor vessel cooling conditions was investigated analytically. HERMES-HALF experiments were performed to observe and quantify the induced two-phase natural circulation flow in the annular gap. A half-scaled non-heating experimental facility was designed by utilizing the results of a scaling analysis to simulate the APR1400 reactor and its insulation system. The behavior of the boiling-induced two-phase natural circulation flow in the annular gap was observed, and the liquid mass flow rates driven by the natural circulation loop and the void fraction distribution were measured. To complement the HERMES-HALF experimental effort, an analytical study of the dependence of the induced natural circulation mass flow rate on the inlet area and the volumetric air injection rate was performed using a loop integration of the momentum equation. The loop-integrated momentum equation was formulated in terms of the dimensionless mass flow rate and the area ratio. Asymptotic solutions were obtained for two limiting cases for which the dimensionless mass flow rate was either very large or very small. First-order approximate solution was also obtained and was found to agree with the experimental data within 20% in most situations. The natural circulation mass flow rate was found to increase as the water inlet area and the volumetric air injection rate were increased. For large inlet areas, the mass flow rate was found to depend almost linearly on the inlet area

  7. Soy Isoflavone Supplementation Does Not Alter Distribution of Circulating Lymphocytes or Natural Killer Cell Activity in Postmenopausal Women

    OpenAIRE

    Girmes-Grieco, Nicolin Katleen

    2001-01-01

    A growing body of evidence has demonstrated that soy isoflavone consumption may protect against the development of various chronic diseases. This defense could be linked to isoflavone-induced alterations in immune function. However, to date, no study has examined the effect of soy isoflavone supplementation on human immunity in vivo. Establishing whether isoflavones affect immunity in aging adults is particularly relevant since compromised immune function has been observed in this population....

  8. Analysis of the natural circulation by the computer code RELAP-5

    International Nuclear Information System (INIS)

    The analysis of the natural circulation is one of the first analysis that was done at IJS with the computer code RELAP 5/MOS 1/CY 018. Specific model of the system was made for the natural circulation. The first 400 s of the transient were analyzed. At that time pumps are rotating only by coolant flow. First results show quite realistic picture of the transient although some changes should be made, especially on the steam generator model due to the unrealistic oscillations of the coolant flow on the secondary side. (author)

  9. Experiments on natural circulation during PWR severe accidents and their analysis

    International Nuclear Information System (INIS)

    Buoyancy-induced natural circulation flows will occur during the early-part of PWR high pressure accident scenarios. These flows affect several key parameters; in particular, the course of such accidents will most probably change due to local failures occurring in the primary coolant system (CS) before substantial core degradation. Natural circulation flow patterns were measured in a one-seventh scale PWR PCS facility at Westinghouse RandD laboratories. The measured flow and temperature distributions are report in this paper. The experiments were analyzed with the COMMIX code and good agreement was obtained between data and calculations. 10 refs., 8 figs., 2 tabs

  10. Modeling the flow characteristics during start-up of natural circulation systems from rest state

    International Nuclear Information System (INIS)

    Most of the advanced reactor designs propose to use natural circulation for core heat removal either during normal operational states and/or during off-normal operational states because of simplicity and higher reliability of natural circulation. However, these systems do have their own set of challenges with respect to assessment of their reliability. Simulation of start-up from rest and performance evaluation using conventional models are the key issues in assessing their reliability. In view of their wide importance to nuclear safety, the performance of these systems during start-up from rest is addressed in the present study. (author)

  11. A potential of boiling water power reactors with a natural circulation of a coolant

    International Nuclear Information System (INIS)

    The use of the natural circulation of coolant in the boiling water reactors simplifies a reactor control and facilities the service of the equipment components. The moderated core power loads allows the long fuel burnup, good control ability and large water stock set up the enhancement of safety level. That is considered to be very important for isolated regions or small countries. In the paper a high safety level and effectiveness of BWRs with natural circulation are reviewed. The limitations of flow stability and protection measures are being discussed. Some recent efforts in designing of such reactors are described.(author)

  12. Assessment of RELAP5/MOD2 against a natural circulation experiment in Nuclear Power Plant Borssele

    International Nuclear Information System (INIS)

    As part of the ICAP (International Code Assessment and Applications Program) agreement between ECN (Netherlands Energy Research Foundation) and USNRC, ECN has performed a number of assessment calculations for the thermohydraulic system analysis code RELAP5/MOD2/36.05. This document describes the assessment of this computer program versus a natural circulation experiment as conducted at the Borssele Nuclear Power Plant. The results of this comparison show that the code RELAP5/MOD2 predicts well the natural circulation behaviour of Nuclear Power Plant Borssele

  13. Influence of local natural circulation on the passive residual heat removal in nuclear reactor

    International Nuclear Information System (INIS)

    The primary system of reactor and passive residual heat removal system are modeled using the code RELAP5/ MOD3.2. In order to model the heterogeneous flow in the U-tubes of steam generator under natural circulation, the U -tubes are classified according to their lengths, then each class is divided into different nodes and flow lines. The new method can simulate the reverse flow characteristics in the inverted U-tubes. This paper provides the distribution of forward flow and reverse flow in the inverted U-tubes of the steam generator (SG) under residual heat removal conditions in the natural circulation case. (authors)

  14. Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase inhibitors due to glycogen synthase kinase-3-dependent expression of MHC class I-related chain A and B

    DEFF Research Database (Denmark)

    Skov, Søren; Pedersen, Marianne Terndrup; Andresen, Lars; Straten, Per Thor; Woetmann, Anders; Odum, Niels

    2005-01-01

    We show that histone deacetylase (HDAC) inhibitors lead to functional expression of MHC class I-related chain A and B (MICA/B) on cancer cells, making them potent targets for natural killer (NK) cell-mediated killing through a NK group 2, member D (NKG2D) restricted mechanism. Blocking either...

  15. Interleukin-15-activated natural killer cells kill autologous osteoclasts via LFA-1, DNAM-1 and TRAIL, and inhibit osteoclast-mediated bone erosion in vitro

    DEFF Research Database (Denmark)

    Feng, Shan; Madsen, Suzi H; Viller, Natasja N;

    2015-01-01

    Osteoclasts reside on bone and are the main bone resorbing cells playing an important role in bone homeostasis, while natural killer (NK) cells are bone-marrow-derived cells known to play a crucial role in immune defence against viral infections. Although mature NK cells traffic through bone marrow...

  16. Modeling of Natural Self-Pressurized Circulation Circuits

    International Nuclear Information System (INIS)

    In this work, HUARPE code models for self-pressurized two-phase natural convection systems are improved.A drift-flux model is included, allowing the modeling of the relative velocity between phases.The model of steam dome structures is improved, with a thermal resistance scheme, in order to model the material thermal conductivity.This allows improving thermal losses modeling and structures dynamic.'Shape functions' are implemented based on analytic solutions for pressure derivative and density in each node, which allows less diffusive solving schemes, more appropriate for analyzing cases involving density waves phenomena.Finally, pressure evolutions during a pressurization transient are analyzed, comparing the new models and the previous version results.These results are also checked against RELAP code ones, obtained with different dome nodalizations. Moreover, modeling problems are analyzed for each case

  17. Improvement of ATHLET modelling capability for asymmetric natural circulation phenomenon using uncertainty and sensitivity measures

    International Nuclear Information System (INIS)

    Highlights: • Overprediction of mass flow during asymmetric natural circulation of PKL facility is observed by ATHLET code. • Uncertainty and sensitivity measures are used to evaluate the influence of various input and model parameters. • Bypass heating location, values, and heat loss coefficient of isolated steam generator are identified. • The mass flow reduction phenomenon in the isolated loop can be captured by the improved modelling. - Abstract: Natural circulation is one of the most important phenomena relating to nuclear reactor safety. In the last years of 20th century, lots of test facilities were set up to conduct natural circulation experiments. At the same time, some system codes, such as RELAP5 and CATHARE, have been validated by the experimental data carried out by these facilities. The calculation results show that these codes can capture most of the characters during the natural circulation transient, except some special processes. One of the examples is PKL IIIB3.1 test, an asymmetric natural circulation transient in the primary loop with an isolated steam generator. The cooled down process using the intact steam generators by reducing the secondary side pressure is the driving force of the natural circulation in primary loop. In this paper, a post-test calculation is performed by best-estimate thermal-hydraulic code ATHLET to simulate PKL IIIB3.1 test. Due to the effect of isolated steam generator on the whole primary cooling system, the results show that the mass flow in the isolated loop is overpredicted significantly comparing to the experimental data. Many measures have been tried to improve the simulation results, but an effective method is still missing. Based on the post-test calculation results, an uncertainty and sensitivity analysis is carried out to find out the main reason causing this higher circulation mass flow. Lots of factors are considered in this study, e.g. the boundary conditions, thermal-hydraulic correlations, and

  18. Modeling strategies to compute natural circulation using CFD in a VHTR after a LOFA

    International Nuclear Information System (INIS)

    Highlights: • CFD analysis was performed of natural circulation in a block VHTR after a loss of flow accident. • Multiple strategies were investigated to perform CFD analysis to estimate strength of natural circulation. • Symmetry considerations allowed fine mesh application of CFD to reactor core. • Results extrapolated to whole core to estimate heat loss due to natural circulation. • CFD shows promise for use in nuclear reactor design and analysis. - Abstract: A prismatic gas-cooled very high temperature reactor (VHTR) is being developed under the next generation nuclear plant program (NGNP) of the U.S. Department of Energy, Office of Nuclear Energy. In the design of the prismatic VHTR, hexagonal shaped graphite blocks are drilled to allow insertion of fuel pins, made of compacted tristructural-isotropic (TRISO) fuel particles, and coolant channels for the helium coolant. One of the concerns for the reactor design is the effects of a loss of flow accident (LOFA) where the coolant circulators are lost for some reason, causing a loss of forced coolant flow through the core. In such an event, it is desired to know what happens to the (reduced) heat still being generated in the core and if it represents a problem for the fuel compacts, the graphite core or the reactor vessel (RV) walls. One of the mechanisms for the transport of heat out of the core is by the natural circulation of the coolant, which is still present. It is desired to know how much heat may be transported by natural circulation through the core and upwards to the top of the upper plenum. It is beyond current capability for a computational fluid dynamics (CFD) analysis to perform a calculation on the whole RV with a sufficiently refined mesh to examine the full potential of natural circulation in the vessel. The present paper reports the investigation of several strategies to model the flow and heat transfer in the RV. It is found that it is necessary to employ representative geometries of

  19. Characterization of a novel maitake (Grifola frondosa) protein that activates natural killer and dendritic cells and enhances antitumor immunity in mice.

    Science.gov (United States)

    Tsao, Yao-Wei; Kuan, Yen-Chou; Wang, Jia-Lin; Sheu, Fuu

    2013-10-16

    Grifola frondosa, also known as maitake, is a culinary mushroom with immune-enhancing and antitumor effects. Numerous studies have investigated the activity of maitake polysaccharide extracts, but studies of maitake proteins are scarce. In this study, we purified and characterized a new G. frondosa protein, GFP, from maitake fruiting bodies. GFP is a nonglucan heterodimeric 83 kDa protein that consists of two 41 kDa subunits. GFP induced interferon-γ secretion by murine splenocytes and natural killer cells and activated the maturation of bone marrow-derived dendritic cells (BMDCs) via a TLR4-dependent mechanism. GFP-treated BMDCs promoted a Th1 response and exhibited significant antitumor activity when transferred into tumor-bearing mice. In conclusion, we are the first to reveal the critical role of GFP in modulating the immune response and to link the immune-enhancing effects of maitake to its antitumor activities. PMID:24020458

  20. Vitamin D3 and Monomethyl Fumarate Enhance Natural Killer Cell Lysis of Dendritic Cells and Ameliorate the Clinical Score in Mice Suffering from Experimental Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Zaidoon Al-Jaderi

    2015-11-01

    Full Text Available Experimental autoimmune encephalomyelitis (EAE is a CD4+ T cell mediated inflammatory demyelinating disease that is induced in mice by administration of peptides derived from myelin proteins. We developed EAE in SJL mice by administration of PLP139–151 peptide. The effect of treating these mice with 1α,25-Dihydroxyvitamin D3 (vitamin D3, or with monomethyl fumarate (MMF was then examined. We observed that both vitamin D3 and MMF inhibited and/or prevented EAE in these mice. These findings were corroborated with isolating natural killer (NK cells from vitamin D3-treated or MMF-treated EAE mice that lysed immature or mature dendritic cells. The results support and extend other findings indicating that an important mechanism of action for drugs used to treat multiple sclerosis (MS is to enhance NK cell lysis of dendritic cells.

  1. Vitamin D₃ and monomethyl fumarate enhance natural killer cell lysis of dendritic cells and ameliorate the clinical score in mice suffering from experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Al-Jaderi, Zaidoon; Maghazachi, Azzam A

    2015-11-01

    Experimental autoimmune encephalomyelitis (EAE) is a CD4⁺ T cell mediated inflammatory demyelinating disease that is induced in mice by administration of peptides derived from myelin proteins. We developed EAE in SJL mice by administration of PLP139-151 peptide. The effect of treating these mice with 1α,25-Dihydroxyvitamin D₃ (vitamin D₃), or with monomethyl fumarate (MMF) was then examined. We observed that both vitamin D₃ and MMF inhibited and/or prevented EAE in these mice. These findings were corroborated with isolating natural killer (NK) cells from vitamin D₃-treated or MMF-treated EAE mice that lysed immature or mature dendritic cells. The results support and extend other findings indicating that an important mechanism of action for drugs used to treat multiple sclerosis (MS) is to enhance NK cell lysis of dendritic cells. PMID:26580651

  2. Interferon-¿ production by human T cells and natural killer cells in vitro in response to antigens from the two intracellular pathogens Mycobacterium tuberculosis and Leishmania major

    DEFF Research Database (Denmark)

    Kemp, K; Hviid, L; Kharazmi, A;

    1997-01-01

    Acquired resistance to both mycobacteria and Leishmania is primarily mediated by interferon-gamma (IFN-gamma), which triggers mechanisms leading to the death of the microorganism in macrophages. In this study, cell activation and IFN-gamma production was investigated in human peripheral blood...... mononuclear cells (PBMC) from individuals previously sensitized to tuberculin and without known exposure to Leishmania parasites. Immune staining for intracellular IFN-gamma and surface markers allowed flow cytometric identification of the cellular sources of IFN-gamma in cell cultures incubated with purified...... protein derivative of tuberculin (PPD) and Leishmania antigens. It was found that IFN-gamma was produced in response to both PPD and Leishmania stimulant by T cells in the cultures. Activation of IFN-gamma producing natural killer (NK) cells was demonstrated only in some cultures, and only...

  3. Fucoidan from Sargassum sp. and Fucus vesiculosus reduces cell viability of lung carcinoma and melanoma cells in vitro and activates natural killer cells in mice in vivo

    DEFF Research Database (Denmark)

    Ale, Marcel Tutor; Maruyama, Hiroko; Tamauchi, Hidekazu;

    2011-01-01

    performed using cell viability analysis and showed that SIG and MTA fucoidans significantly decreased the viable number of LCC and MC cells in a dose–response fashion. Histochemical staining showed morphological changes of melanoma B16 cells after exposure to fucoidan. The observed changes were indicative......Fucoidan is known to exhibit crucial biological activities, including anti-tumor activity. In this study, we examined the influence of crude fucoidan extracted from Sargassum sp. (MTA) and Fucus vesiculosus (SIG) on Lewis lung carcinoma cells (LCC) and melanoma B16 cells (MC). In vitro studies were...... of crude fucoidan induced apoptosis. Male C57BL/6JJCL mice were subjected to daily i.p. injections over 4 days with either SIG or MTA fucoidan (50 mg/kg body wt.). The cytolytic activity of natural killer (NK) cells was enhanced by crude fucoidan in a dose-dependent manner as indicated by 51Cr...

  4. Method for increasing the stability of a boiling water cooled reactor with natural coolant circulation and a boiling water cooled reactor with natural coolant circulation (its versions)

    International Nuclear Information System (INIS)

    The invention is aimed at improving the safety of a boiling water reactor with natural coolant circulation and increasing the reactor core power density by increasing the coolant flowrate and neutron flux stability as well as by reducing the medium compressibility effectiveness in pressure compensator in dynamic modes. The reactor vessel includes the core, draught section, heat exchangers and a pressure compensator. A part of the pressure compensator is separated by a barrier with calibrated openings possessing a limited capacity and hydrolocks. The calibrated openings in the barrier are located below the coolant level and a part of space separated by a barrier is filled with gas from external system. The part of the barrier projecting above the coolant level is adjacent to heat exchangers. In transitional regimes with the change of pressure in the circulation circuit a hydrolock facilitates to reactor vessel projection against repressing and keeps the barrier from excessive power load

  5. Near-infrared emitting fluorescent nanocrystals-labeled natural killer cells as a platform technology for the optical imaging of immunotherapeutic cells-based cancer therapy

    International Nuclear Information System (INIS)

    This study describes the development of near-infrared optical imaging technology for the monitoring of immunotherapeutic cell-based cancer therapy using natural killer (NK) cells labeled with fluorescent nanocrystals. Although NK cell-based immunotherapeutic strategies have drawn interest as potent preclinical or clinical methods of cancer therapy, there are few reports documenting the molecular imaging of NK cell-based cancer therapy, primarily due to the difficulty of labeling of NK cells with imaging probes. Human natural killer cells (NK92MI) were labeled with anti-human CD56 antibody-coated quantum dots (QD705) for fluorescence imaging. FACS analysis showed that the NK92MI cells labeled with anti-human CD56 antibody-coated QD705 have no effect on the cell viability. The effect of anti-human CD56 antibody-coated QD705 labeling on the NK92MI cell function was investigated by measuring interferon gamma (IFN- γ) production and cytolytic activity. Finally, the NK92MI cells labeled with anti-human CD56 antibody-coated QD705 showed a therapeutic effect similar to that of unlabeled NK92MI cells. Images of intratumorally injected NK92MI cells labeled with anti-human CD56 antibody-coated could be acquired using near-infrared optical imaging both in vivo and in vitro. This result demonstrates that the immunotherapeutic cells labeled with fluorescent nanocrystals can be a versatile platform for the effective tracking of injected therapeutic cells using optical imaging technology, which is very important in cell-based cancer therapies.

  6. A generalized flow correlation for two-phase natural circulation loops

    International Nuclear Information System (INIS)

    In the present generation of nuclear reactors the two-phase natural circulation core power removal capabilities is extensively exploited for accident situations, basically to demonstrate the inherent safety features of the plants. Scaling is particularly important in research application where full scale testing or experiments are prohibitively expensive or have significant safety implications such as in Light Water Reactor (LWR) or Heavy Water Reactor (HWR) safety research. The general objective of a scaling analysis is to obtain the physical dimension and operating condition of a reduced scale facility capable of simulating the important flow and heat transfer behavior of the system under investigation. Scaling laws also make possible the comparison of the performance of different natural circulation systems and to extrapolate the data from small scale to prototype systems. The scaling criterion for a natural circulation loop under two-phase condition has been derived. The scaling law proposed has been tested with experimental data from five different two-phase natural circulation loops. The experimental results are found to be in reasonable agreement with the proposed correlation. (author)

  7. The natural circulation solar water heater model with linear temperature distribution

    Energy Technology Data Exchange (ETDEWEB)

    Zerrouki, A. [CDER B.P., Algiers (Algeria); Boumedien, A.; Bouhadef, K. [USTHB, Faculte des Sciences de l' Ingenieur, Algiers (Algeria)

    2002-08-01

    This paper presents an analysis of natural circulation of a compact thermosyphon solar domestic hot water (SDHW) system produced and commercialised locally in Algeria. Calculations and measurements were performed on the mass flow rate, temperature rise fluid and absorber temperatures inside the thermosyphon of parallel tube design. Comparison between experimental and theoretical results is presented. (Author)

  8. Analysis of flow excursion in a natural circulation system with low pressure and low steam quality

    International Nuclear Information System (INIS)

    A series of experiments were performed on the test loop (HRTL-5), which simulates the geometry and system design of the 5 MW nuclear heating reactor. The flow excursion accompanied with flow oscillation was observed under certain conditions. Some experimental results have been summarized in the natural circulation with low pressure and low steam quality. The mechanism of subcooled boiling and flashing is analyzed, and an entire process of flow excursion is described too. The analysis shows: 1) Sub-cooled boiling and flashing play an important role on the flow instabilities in a natural circulation system. 2) The static flow excursion in the natural circulation is a rather long thermo-hydraulic process, which can be accompanied by the dynamic flow oscillation. 3) In the course of the flow excursion's beginning, developing and gradually converting to the flow oscillation, the flow instability is first dominate by sub-cooled boiling, then is dominated by void flashing, last is mainly the density wave oscillation. The investigation on flow excursion in the natural circulation is important for the design and accident analysis and upgrading development of the 5 MW nuclear heating reactor

  9. A RELAP5 study to identify flow regime in natural circulation phenomenon

    Energy Technology Data Exchange (ETDEWEB)

    Sabundjian, Gaiane; Torres, Walmir M.; Macedo, Luiz A.; Mesquita, Roberto N.; Andrade, Delvonei A.; Umbehaun, Pedro E.; Conti, Thadeu N.; Masotti, Paulo H.F.; Belchior Junior, Antonio; Angelo, Gabriel, E-mail: gdjian@ipen.b, E-mail: umbehaun@ipen.b, E-mail: wmtorres@ipen.b, E-mail: tnconti@ipen.b, E-mail: rnavarro@ipen.b, E-mail: lamacedo@ipen.b, E-mail: pmasotti@ipen.b, E-mail: abelchior@ipen.b [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2011-07-01

    There has been a crescent interest in the scientific community in the study of natural circulation phenomenon. New generation of compact nuclear reactors uses the natural circulation of the fluid as a system of cooling and of residual heat removal in case of accident or shutdown. The objective of this paper is to compare the flow patterns of experimental data and numerical simulation for the natural circulation phenomenon in two-phase flow regime. An experimental circuit built with glass tubes is used for the experiments. Thus, it allows the thermal hydraulic phenomena visualization. There is an electric heater as the heat source, a heat exchanger as the heat sink and an expansion tank to accommodate fluid density excursions. The circuit instrumentation consists of thermocouples and pressure meters to better keep track of the flow and heat transfer phenomena. Data acquisition is performed through a computer interface developed with LABVIEW. The characteristic of the regime is identified using photography techniques. Numerical modeling and simulation is done with the thermal hydraulic code RELAP5, which is widely used for this purpose. This numerical simulation is capable to reproduce some of the flow regimes which are present in the circuit for the natural circulation phenomenon. Comparison between experimental and numerical simulation is presented in this work. (author)

  10. Experimental investigations on steady state natural circulation behavior of multiple parallel boiling channel system

    International Nuclear Information System (INIS)

    In some industrial applications, including nuclear power plants, natural circulation flow is often employed as a reliable heat transport method. A common characteristic of many industrial two-phase natural circulation systems is the presence of a large number of parallel boiling channels. Sensitivity of the steady state behavior of such a two-phase natural circulation system to different system parameters has many implications vis-a-vis performance of the system as per the design intent under various operating conditions. This article reports the results of experimental studies carried out on the characteristics of a low pressure two-phase natural circulation system with parallel boiling channels having their individual heat sources. The work covers the study of dependence of system behavior on operational history, down-comer resistance and channel power. In view of its particular significance in nuclear industry, a special system condition with zero power in one of the parallel channels was also studied. An experimental setup consisting of 10 transparent parallel channels was designed and constructed for conducting these experimental investigations.

  11. Experimental investigations on steady state natural circulation behavior of multiple parallel boiling channel system

    Energy Technology Data Exchange (ETDEWEB)

    Vyas, H.P., E-mail: harshad.p.vyas@gmail.co [Reactor Engineering Division, Bhabha Atomic Research Centre, Mumbai 400085, Maharashtra (India); Venkat Raj, V. [Department of Mechanical Engineering, Bharati Vidyapeeth College of Engineering, Sector 7, CBD, Navi Mumbai 400614 (India); Nayak, A.K. [Reactor Engineering Division, Bhabha Atomic Research Centre, Mumbai 400085, Maharashtra (India)

    2010-11-15

    In some industrial applications, including nuclear power plants, natural circulation flow is often employed as a reliable heat transport method. A common characteristic of many industrial two-phase natural circulation systems is the presence of a large number of parallel boiling channels. Sensitivity of the steady state behavior of such a two-phase natural circulation system to different system parameters has many implications vis-a-vis performance of the system as per the design intent under various operating conditions. This article reports the results of experimental studies carried out on the characteristics of a low pressure two-phase natural circulation system with parallel boiling channels having their individual heat sources. The work covers the study of dependence of system behavior on operational history, down-comer resistance and channel power. In view of its particular significance in nuclear industry, a special system condition with zero power in one of the parallel channels was also studied. An experimental setup consisting of 10 transparent parallel channels was designed and constructed for conducting these experimental investigations.

  12. Single Phase Natural Circulation Behaviors of the Integral Type Marine Reactor Simulator under Rolling Motion Condition

    Directory of Open Access Journals (Sweden)

    Hou-jun Gong

    2015-01-01

    Full Text Available During operation in the sea the reactor natural circulation behaviors are affected by ship rolling motion. The development of an analysis code and the natural circulation behaviors of a reactor simulator under rolling motion are described in this paper. In the case of rolling motion, the primary coolant flow rates in the hot legs and heating channels oscillated periodically, and the amplitude of flow rate oscillation was in direct proportion to rolling amplitude, but in inverse proportion to rolling period. The total mass flow rate also oscillated with half the rolling period, and the average total mass flow rate was less than that in steady state. In the natural circulation under a rolling motion, the flow rate oscillations in the hot legs were controlled by the tangential force; however, the mass flow rate oscillations in the total natural circulation and the heating channels were a result of the combined action of the change of inclination angle, flow resistance, and the extra force arising from the rolling motion. The extra tangential force brought about intense flow rate oscillations in the hot legs, which resulted in increasing total flow resistance; however the extra centrifugal force played a role in increasing thermal driving head.

  13. Linear and nonlinear analysis of the dynamic behaviour of natural circulation with internally heated fluids

    International Nuclear Information System (INIS)

    In this paper, the study of the dynamic behaviour of single-phase natural circulation with internal heat generation for a rectangular loop is presented. In order to predict natural circulation stability, two different methods of analysis are developed and compared. The first approach is a linear analysis in which the Navier-Stokes equation is linearized around a steady-state solution of the system. This strategy is adopted to calculate transient evolutions and dimensionless stability maps for several system configurations in case of small perturbations, outlining the geometrical parameters that mainly affect the natural circulation behaviour when internal heat generation is also considered. The second approach consists in directly solving the nonlinear governing equations and it is used to confirm the results of the linear analysis. In this case, the hypothesis that the perturbations on the stationary state variables are negligible is removed. Stability maps and time-dependent simulations represent very useful tools of investigation not only from a theoretical point of view but also in practice. As a matter of fact, stability maps may be used to optimize the configuration of natural circulation loops, while time-dependent simulations allow to completely evaluate the system dynamics showing mass flow and temperature transients. (author)

  14. Experimental and numerical stability investigations on natural circulation boiling water reactors

    NARCIS (Netherlands)

    Marcel, C.P.

    2007-01-01

    The stability of natural circulation boiling water reactors is investigated with a strong emphasis on experiments. Two different facilities are used for such a task: the GENESIS facility (to which a void reactivity feedback system is artificially added) and the CIRCUS facility. In addition, numerica

  15. Experimental and numerical stability investigations on natural circulation boiling water reactors

    CERN Document Server

    Marcel, CP

    2007-01-01

    In the design of novel nuclear reactors active systems are replaced by passive ones in order to reduce the risk of failure. For that reason natural circulation is being considered as the primary cooling mechanism in next generation nuclear reactor designs

  16. Calculation capability of NETFLOW++ code for natural circulation in sodium cooled fast reactor

    International Nuclear Information System (INIS)

    The present paper describes the simulation of the natural circulation in the secondary heat transport system (HTS) after an intentional plant trip of the experimental fast reactor 'Joyo' with the 140 MWt irradiation core using the plant dynamics analysis code NETFLOW++. This code is an integrated network code to calculate the nuclear steam supply system (NSSS) and the balance of the plant (BOP), i.e., turbine/feedwater system. Up to now, the code has been validated using transient data of the experimental sodium facility PLANDTL, experimental fast reactor 'Joyo' and the prototype fast breeder reactor 'Monju'. These validations are steps to evaluate the natural circulation transient of a large-scale fast breeder reactor. Therefore, the former validation results are introduced to show the degree of agreement. In order to consolidate the applicability of the code to the evaluation of the natural circulation, the present test was selected and simulated using the NETFLOW++ code. Major plant parameters are simulated with good agreement such a similar accuracy as the Mimir-N2 exclusive code for 'Joyo'. As a result, it is concluded that the NETFLOW++ is applicable to the natural circulation analysis of sodium-cooled fast reactors with the similar scale of the prototype reactor 'Monju'. (author)

  17. Integral test facilities for validation of the performance of passive safety systems and natural circulation

    International Nuclear Information System (INIS)

    Passive safety systems are becoming an important component in advanced reactor designs. This has led to an international interest in examining natural circulation phenomena as this may play an important role in the operation of these passive safety systems. Understanding reactor system behaviour is a challenging process due to the complex interactions between components and associated phenomena. Properly scaled integral test facilities can be used to explore these complex interactions. In addition, system analysis computer codes can be used as predictive tools in understanding the complex reactor system behaviour. However, before the application of system analysis computer codes for reactor design, it is capability in making predictions needs to be validated against the experimental data from a properly scaled integral test facility. The IAEA has organized a coordinated research project (CRP) on natural circulation phenomena, modeling and reliability of passive systems that utilize natural circulation. This paper is a part of research results from this CRP and describes representative international integral test facilities that can be used for data collection for reactor types in which natural circulation may play an important role. Example experiments were described along with the analyses of these example cases in order to examine the ability of system codes to model the phenomena that are occurring in the test facilities. (Author)

  18. Efficient global solution of residual heat removal system with natural circulation

    International Nuclear Information System (INIS)

    The mathematical model of the residual heat removal system with multiple coupled natural circulation loops has distinct nonlinear characteristics. The global solution method with high efficiency was developed, implemented and tested. Compared with the original method which uses the nested point iteration procedure, one magnitude of calculation speed improvement is achieved. (authors)

  19. Preliminary Analysis of Natural Circulation Characteristics of China Lead-based Research Reactor (CLEAR-I)

    International Nuclear Information System (INIS)

    A large science project named “Advanced Nuclear Fission Energy-ADS Transmutation System” has been launched by Chinese Academy of Sciences. China LEAd-based Research Reactor (CLEAR-I) as a verification facility reactor will be developed in the first phase of the ADS program. In CLEAR-I, the liquid Lead-Bismuth eutectic (PbBi) was chosen as coolant in primary cooling system and driven by natural circulation since the power at a low level about 10MWt. The natural circulation of primary coolant system is a coupling of thermal-hydraulic problems of the core, upper and lower plenums of the reactor, reactor internal parts. Therefore, understanding the natural circulation flow capability and characteristics of CLEAR-I is very important, which can significantly improve the security features of the reactor. In this work, natural circulation characteristics and flow distribution at steady state in primary system of CLEAR-I were preliminary evaluated and discussed. A numerical simulation was conducted by using CFD code. The flow characteristics was illustrated and discussed. The temperature and pressure distribution were evaluated. (author)

  20. CFD analysis of molten fluoride salt natural circulation in a rectangular loop

    International Nuclear Information System (INIS)

    Indian Molten Salt Breeder Reactor (IMSBR) is being designed and developed in BARC with main objective of utilizing thorium abundance in India. In order to design the reactor, it is necessary to study the thermal hydraulic behavior of various molten salts. Moreover, considering the importance of natural circulation in high temperature systems, experimental studies on natural circulation of molten salts are required. This paper deals with the fabrication of loop with molten salt, LiF+ThF4 (22.5-77.5 wt%), which is proposed as blanket salt for Indian MSBR program. Loop is fabricated with 15NB Sch 40 pipe made of Hastelloy-N material having height of 400 mm and width of 300 mm. CFD analysis for natural circulation of the same loop is also carried out. CFD simulation is performed for steady state and transient cases at different heater powers. Various transients such as: step power change, heater trip and start-up of natural circulation etc. are also carried out. Comparison of CFD results with standard correlation for steady state flow has been done. (author)

  1. Experiment research and calculation method of natural circulation flow for AC600/1000

    International Nuclear Information System (INIS)

    Passive safety concept is extensively used in the design for next generation advanced PWR nuclear power plant. The decay heat of reactor core can be removed through natural circulation flow of coolant following an accident. This not only increases reliability of engineered safety systems and reduces core melt frequency, but also simplifies systems and increases plant economy. Nuclear Power Institute of China (NPIC) has performed preliminary experiment research and relative theoretical analysis for passive characteristics of advanced PWR nuclear power plant AC600/1000. Three tests about natural circulation flow have finished as the following: residual heat removal through SG secondary side, core makeup tank behavior and wind flow of containment. The above mentioned three mechanism tests have verified natural circulation flow concept of AC600/1000. By the end of this year NPIC will finish other two single tests in order to research the following key technology of the passive safety systems: The natural circulation characteristics of tandem system of SG secondary side loop and air flow loop for emergency residual heat removal system (ERHRS) after station blackout accident; The water flow behavior in primary coolant system contained by core makeup tank, pressurizer, accumulator and reactor pressure vessel after small break accident; Computer code development and verification. Meanwhile, NPIC will cooperate with Karlsruhe Technology Center of Germany to research natural circulation characteristics of air in the annular channel between the steel shell and the concrete shell of containment. NPIC plans to build two large integral test facilities. One of which is used to research natural circulation flow and residual heat removal through primary loop, secondary loop and air flow loop from reactor core to ultimate sink - atmosphere after station blackout accident. It is also used to research the passive safety injection features for emergency core cooling system. The second

  2. Analysis of two phase natural circulation flow in the reactor cavity under external reactor vessel cooling

    International Nuclear Information System (INIS)

    As part of a study on a two-phase natural circulation flow between the outer reactor vessel and the insulation material in the reactor cavity under an external reactor vessel cooling of APR (Advanced Power Reactor) 1400, a K-HERMES-HALF (Hydraulic Evaluation of Reactor cooling Mechanism by External Self-induced flow-HALF scale) experiment was performed at KAERI (Korea Atomic Energy Research Institute) using an air injection method. This experiment was analyzed to verify and evaluate the experimental results using the RELAP5/MOD3 computer code. In addition, the geometry scaling on full height & full sector, and a material scaling between air-water and steam-water two phase natural circulation flow, have been performed for an application of the experimental results to an actual APR1400. The RELAP5/MOD3 results on the water circulation mass flow rate are very similar to the experimental results, in general. The water circulation mass flow rate of the full height & full sector case is approximately 7.6-times higher than that of the K-HERMEL-HALF case. The water circulation mass flow rate of the air injection case is 20-50 % higher than that of the steam injection case at 20 % of the injection rate. (author)

  3. Study of core flow distribution for small modular natural circulation lead or lead-alloy cooled fast reactors

    International Nuclear Information System (INIS)

    Highlights: • A core flow distribution calculation code for natural circulation LFRs was developed. • The comparison study between the channel method and the CFD method was conducted. • The core flow distribution analysis and optimization design for a 10MW natural circulation LFR was conducted. - Abstract: Small modular natural circulation lead or lead-alloy cooled fast reactor (LFR) is a potential candidate for LFR development. It has many attractive advantages such as reduced capital costs and inherent safety. The core flow distribution calculation is an important issue for nuclear reactor design, which will provide important input parameters to thermal-hydraulic analysis and safety analysis. The core flow distribution calculation of a natural circulation LFR is different from that of a forced circulation reactor. In a forced circulation reactor, the core flow distribution can be controlled and adjusted by the pump power and the flow distributor, while in a natural circulation reactor, the core flow distribution is automatically adjusted according to the relationship between the local power and the local resistance feature. In this paper, a non-uniform heated parallel channel flow distribution calculation code was developed and the comparison study between the channel method and the CFD method was carried out to assess the exactness of the developed code. The core flow distribution analysis and optimization design for a 10MW natural circulation LFR was conducted using the developed code. A core flow distribution optimization design scheme for a 10MW natural circulation LFR was proposed according to the optimization analysis results

  4. Heat transfer to water from a vertical tube bundle under natural-circulation conditions

    International Nuclear Information System (INIS)

    The natural circulation heat transfer data for longitudinal flow of water outside a vertical rod bundle are needed for developing correlations which can be used in best estimate computer codes to model thermal-hydraulic behavior of nuclear reactor cores under accident or shutdown conditions. The heat transfer coefficient between the fuel rod surface and the coolant is the key parameter required to predict the fuel temperature. Because of the absence of the required heat transfer coefficient data base under natural circulation conditions, experiments have been performed in a natural circulation loop. A seven-tube bundle having a pitch-to-diameter ratio of 1.25 was used as a test heat exchanger. A circulating flow was established in the loop, because of buoyancy differences between its two vertical legs. Steady-state and transient heat transfer measurements have been made over as wide a range of thermal conditions as possible with the system. Steady state heat transfer data were correlated in terms of relevant dimensionless parameters. Empirical correlations for the average Nusselt number, in terms of Reynolds number, Rayleigh number and the ratio of Grashof to Reynolds number are given

  5. Study on decay heat removal characteristics by natural circulation for top entry loop-type FBR

    International Nuclear Information System (INIS)

    The thermal-hydraulic circulation characteristics of a top entry loop-type FBR are studied experimentally with a 1/8 scaled three-loop model using water as the working fluid. The model is designed to simulate reactor decay heat removal operations including natural circulation mode as well as three types of decay heat removal systems, a direct reactor auxiliary cooling system (DRACS) with a direct heat exchangers immersed in a hot plenum of a reactor vessel (Immersed type DRACS), a DRACS with DHXs penetrating from a hot plenum to a cold plenum of a reactor vessel (Penetrating type DRACS) and a primary reactor auxiliary cooling system (PRACS). The feasibility of reactor decay heat removal operations including natural circulation mode of a top entry loop-type FBR is confirmed based on the experimental results. The natural circulation performance of the Immersed type DRACS is compared with that of the PRACS for the water test results. The results are used to evaluate the accuracy of the one-dimensional flow-network analysis codes and the multi-dimensional thermal-hydraulic analysis code. The analytical results are generally in good agreement with the measurements. (author)

  6. Heavy liquid metal natural circulation in a one-dimensional loop

    Energy Technology Data Exchange (ETDEWEB)

    Coccoluto, G.; Gaggini, P.; Labanti, V. [ENEA Brasimone, 40032 Camugnano (Italy); Tarantino, M., E-mail: mariano.tarantino@enea.i [ENEA Brasimone, 40032 Camugnano (Italy); Ambrosini, W.; Forgione, N.; Napoli, A.; Oriolo, F. [Universita degli Studi di Pisa, Dipartimento di Ingegneria Meccanica, Nucleare e della Produzione Via Diotisalvi, 2 - 56126 Pisa (Italy)

    2011-05-15

    The ENEA Brasimone Research Centre since 1999 is strongly involved in the national and European research programmes performed in the field of heavy liquid metal technology aiming at the development of critical (LFR) and subcritical (ADS) nuclear systems. In particular, in the frame of the IP-EUROTRANS, (6th Framework Program EU), ENEA assumed the commitment to perform an integral experiment with the aim to reproduce the primary flow path of a HLM pool-type nuclear reactor, cooled by lead bismuth eutectics (LBE). This new experimental activity, named ICE 'Integral Circulation Experiment', will be performed by an appropriate test section designed to be installed in the CIRCE facility. In order to support the ICE activity, as well as characterize the natural and gas enhanced circulation flow regimes in a HLM loop, qualify test procedures and components which are nuclear relevant, a new facility was designed and built-up by Brasimone Research Centre, named NACIE 'NAtural CIrculation Experiment'. The paper reports a detailed description of the loop and the main experimental results carried out from the natural circulation tests already performed on the NACIE loop. Numerical simulations have been performed in collaboration with the University of Pisa, adopting the RELAP5/Mod3.3 system code modified to allow for LBE as a cooling fluid. The aim of the performed post-test calculations is to compare the code response with the experimental results under the natural circulation flow regime, allowing to qualify the adopted nodalization as well as the performance of the code when employed on HLM loop.

  7. Effects of inclination angle and operation parameters on supercritical CO2 natural circulation loop

    International Nuclear Information System (INIS)

    Highlights: • Supercritical natural circulation experimental loop system is established and tested. • Stability evolutes from unstable to stable condition with the increase of heat input near-critical NCL. • Horizontal loop is found to have highest thermal resistance while vertical loop is preferred for heat transfer. • Effect of inclination on the flow state is not significant when the inclination angle is greater than 60°. - Abstract: Supercritical fluid based natural circulation flow has been proposed in many energy conversion systems such as solar collector, waste heat recovery, nuclear cooling, etc. The current study is focused on the effect of inclination angle and operation parameters on supercritical CO2 based natural circulation loops. In this study, two-dimensional numerical simulation has been carried out with turbulent model incorporated. Then, a supercritical natural circulation loop system has been established, experimented and also compared with previous studies. In the numerical simulation, the flow condition is found closely related to the heat influx and inclination angle: Under high heat flux conditions the system show stable flow, while relative low heat flux conditions show complex unstable behaviors. Also it is found that when the inclination angle is greater than 60°, the effect of inclination on the flow state is not significant. In the experiments, supercritical cases are found stable under the current operation range. The steady operation pressure inside the NCL changes greatly due to the sensitive fluid properties and the effect of inclination on real systems show similar rend with numerical results. Judging from both the numerical and experimental results, larger inclination angles will have higher circulation rate and better heat transfer performance. New correlation for supercritical CO2 NCL flows is also experimentally proposed in this study

  8. Passive safety systems and natural circulation in water cooled nuclear power plants

    International Nuclear Information System (INIS)

    Nuclear power produces 15% of the world's electricity. Many countries are planning to either introduce nuclear energy or expand their nuclear generating capacity. Design organizations are incorporating both proven means and new approaches for reducing the capital costs of their advanced designs. In the future most new nuclear plants will be of evolutionary design, often pursuing economies of scale. In the longer term, innovative designs could help to promote a new era of nuclear power. Since the mid-1980s it has been recognized that the application of passive safety systems (i.e. those whose operation takes advantage of natural forces such as convection and gravity), can contribute to simplification and potentially improve economics of new nuclear power plant designs. The IAEA Conference on The Safety of Nuclear Power: Strategy for the Future, which was convened in 1991, noted that for new plants 'the use of passive safety features is a desirable method of achieving simplification and increasing the reliability of the performance of essential safety functions, and should be used wherever appropriate'. Some new designs also utilize natural circulation as a means to remove core power during normal operation. The use of passive systems can eliminate the costs associated with the installation, maintenance, and operation of active systems that require multiple pumps with independent and redundant electric power supplies. However, considering the weak driving forces of passive systems based on natural circulation, careful design and analysis methods must be employed to ensure that the systems perform their intended functions. To support the development of advanced water cooled reactor designs with passive systems, investigations of natural circulation are conducted in several IAEA Member States with advanced reactor development programmes. To foster international collaboration on the enabling technology of passive systems that utilize natural circulation, the IAEA

  9. A study of natural circulation in the evaporator of a horizontal-tube heat recovery steam generator

    Science.gov (United States)

    Roslyakov, P. V.; Pleshanov, K. A.; Sterkhov, K. V.

    2014-07-01

    Results obtained from investigations of stable natural circulation in an intricate circulation circuit with a horizontal layout of the tubes of evaporating surface having a negative useful head are presented. The possibility of making a shift from using multiple forced circulation organized by means of a circulation pump to natural circulation in vertical heat recovery steam generator is estimated. Criteria for characterizing the performance reliability and efficiency of a horizontal evaporator with negative useful head are proposed. The influence of various design solutions on circulation robustness is considered. With due regard of the optimal parameters, the most efficient and least costly methods are proposed for achieving more stable circulation in a vertical heat recovery steam generator when a shift is made from multiple forced to natural circulation. A procedure for calculating the circulation parameters and an algorithm for checking evaporator performance reliability are developed, and recommendations for the design of heat recovery steam generator, nonheated parts of natural circulation circuit, and evaporating surface are suggested.

  10. Theoretical investigation on the steady-state natural circulation characteristics of a new type of pressurized water reactor

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    This article presents a theoretical investigation on the steady-state natural circulation characteristics of a new type of pressurized water reactor. Through numerically solving the one-dimensional steady-state single-phase conservative equations for the primary circuit and the steady-state two-phase drift-flux conservative equations for the secondary side of the steam generator, the natural circulation characteristics were studied. On the basis of the preliminary calculation analysis, it was found that natural circulation mass flow rate was proportional to the exponential function of the power and that the value of the exponent is related to the operating conditions of the secondary side of the steam generator. The higher the outlet pressure of the secondary side of the steam generator, the higher the primary natural circulation mass flow rate. The larger height difference between the core center and the steam generator center is favorable for the heat removal capacity of the natural circulation.

  11. Analysis of the multi-application small light-water reactor (MASLWR) design natural circulation phenomena

    International Nuclear Information System (INIS)

    Today the use of advanced nuclear power plants, have an important role in the environment and economic sustainability of country energy strategy considering the capacity of a nuclear reactor of producing energy in safe and stable way contributing in cutting the CO2 emissions. In the last 20 years, in fact, the international community, taking into account the excellent operational experience of the nuclear reactors, starts the development of new advanced reactor designs, by including also the use of the natural circulation for the cooling of the core in normal and transient conditions. In this international framework, Oregon State University has constructed, under a U.S. Department of Energy grant, a system level test facility to examine natural circulation phenomena of importance to Multi-Application Small Light-Water Reactor (MASLWR) design. The MASLWR is a small modular integral pressurized water reactor relying on natural circulation during both steady state and transient operation, including an integrated helical coil steam generator. Starting from an experimental campaign in support of the MASLWR concept design verification, the planned work, related to the OSU-MASLWR test facility, will be not only to specifically investigate the MASLWR concept design further but also advance the broad understanding of integral natural circulation reactor plants and accompanying passive safety features as well. Four tests have been performed at this facility in order to assess the thermal hydraulic behavior of the MASLWR design in normal and transient operation and to assess the passive safety system under transient condition. This paper illustrates a preliminary analyses, performed by TRACE code, aiming at the evaluation of the code capability in predicting natural circulation, heat exchange from primary to secondary side by helical steam generator in superheated condition and primary/containment coupling phenomena typical of the MASLWR design. The tests take into account

  12. Redistribution, Hyperproliferation, Activation of Natural Killer Cells and CD8 T Cells, and Cytokine Production During First-in-Human Clinical Trial of Recombinant Human Interleukin-15 in Patients With Cancer

    Science.gov (United States)

    Conlon, Kevin C.; Lugli, Enrico; Welles, Hugh C.; Rosenberg, Steven A.; Fojo, Antonio Tito; Morris, John C.; Fleisher, Thomas A.; Dubois, Sigrid P.; Perera, Liyanage P.; Stewart, Donn M.; Goldman, Carolyn K.; Bryant, Bonita R.; Decker, Jean M.; Chen, Jing; Worthy, Tat'Yana A.; Figg, William D.; Peer, Cody J.; Sneller, Michael C.; Lane, H. Clifford; Yovandich, Jason L.; Creekmore, Stephen P.; Roederer, Mario; Waldmann, Thomas A.

    2015-01-01

    Purpose Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy. Patients and Methods We performed a first in-human trial of Escherichia coli–produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer. Results Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients. Conclusion IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration. PMID:25403209

  13. Therapeutic envelope vaccination in combination with antiretroviral therapy temporarily rescues SIV-specific CD4⁺ T-cell-dependent natural killer cell effector responses in chronically infected rhesus macaques.

    Science.gov (United States)

    Vargas-Inchaustegui, Diego A; Xiao, Peng; Demberg, Thorsten; Pal, Ranajit; Robert-Guroff, Marjorie

    2015-06-01

    Natural killer (NK) cells are essential components of the immune system, and due to their rapid response potential, can have a great impact during early anti-viral immune responses. We have previously shown that interleukin-2-dependent NK and CD4(+) T-cell co-operative immune responses exist in long-term simian immunodeficiency virus (SIV) -infected controlling macaques and can be rescued in SIV-infected non-controlling macaques by a short course of antiretroviral therapy (ART). Given that co-operative responses may play an important role in disease prevention and therapeutic treatment, in the present study we sought to determine if these responses can be enhanced in chronically SIV-infected macaques by vaccination with a single-dose of envelope protein given during ART. To this end, we treated 14 chronically SIV-infected macaques with ART for 11 weeks and gave 10 of these macaques a single intramuscular dose of SIV gp120 at week 9 of treatment. ART significantly decreased plasma and mucosal viral loads, increased the numbers of circulating CD4(+) T cells in all macaques, and increased T-cell-dependent envelope- and gag-specific interferon-γ and tumour necrosis factor-α production by circulatory CD56(+) NK cells. The therapeutic envelope immunization resulted in higher envelope-specific responses compared with those in macaques that received ART only. Functional T-cell responses restored by ART and therapeutic Env immunization were correlated with transiently reduced plasma viraemia levels following ART release. Collectively our results indicate that SIV-specific T-cell-dependent NK cell responses can be efficiently rescued by ART in chronically SIV-infected macaques and that therapeutic immunization may be beneficial in previously vaccinated individuals. PMID:25626488

  14. Experimental investigations in high-pressure natural circulation loop: progress report for the period January-June, 1999

    International Nuclear Information System (INIS)

    The Advanced Heavy Water Reactor employs natural circulation as the normal mode of coolant circulation. This is expected to enhance safety and reliability as it eliminates all safety issues associated with the pump failure. Two-phase natural circulation, however, is susceptible to several types of instabilities. In addition, the flow rate in a natural circulation loop is a dependent quantity and is not known a priori. Reliable calculations of the flow rate and stability behaviour are essential to ensure the success of AHWR design. Hence computer codes developed to predict the steady state flow rate and stability behaviour require validation against test data under natural circulation. For this purpose a high-pressure natural circulation loop has been designed, constructed and commissioned. Steady state experiments have been carried out in this loop to study the effect of pressure on natural circulation flow rate. The experimental results for this case are presented in this report. More experiments are planned in future to study the various aspects of two-phase natural circulation. (author)

  15. Calculation analysis on the natural circulation of a passive residual heat removal system for IPWR

    International Nuclear Information System (INIS)

    Highlights: • The PRHRS is designed to increase the inherent safety features of the IPWR. • We study the single-phase and two-phase natural circulation characteristics of PRHRS system. • Once-through steam generator still produce superheated steam under accident conditions. • PRHRS parameters study under natural convection condition. - Abstract: The passive residual heat removal system (PRHRS) is designed to increase the inherent safety features of the integrated pressurized water reactor (IPWR). The PRHRS consists of once though steam generator (OTSG) secondary side, a heat exchanger (HX), a cooling water tank (CWT), and corresponding pipes and valves. On the accident conditions, residual heat is transferred to the CWT by the single-phase natural circulation in primary loop and two-phase natural circulation in PRHRS loop, and then the water in CWT is heated and finally evaporates into the air. The calculate results using RELAP5 code show that the PRHRS is sufficient enough to take heat away from primary coolant system. The effect of main parameters on the PRHRS was studied. The results indicate that the effective height between OTSG and HX, the HX areas, the volume of CWT, and the isolation valve actuation time are important parameters which are worth being considered seriously in the design of the PRHRS

  16. Velocity Fields Measurement of Natural Circulation Flow inside a Pool Using PIV Technique

    International Nuclear Information System (INIS)

    Thermal stratification is encountered in large pool of water increasingly being used as heat sink in new generation of advanced reactors. These large pools at near atmospheric pressure provide a heat sink for heat removal from the reactor or steam generator, and the containment by natural circulation as well as a source of water for core cooling. For examples, the PAFS (passive auxiliary feedwater system) is one of the advanced safety features adopted in the APR+ (Advanced Power Reactor Plus), which is intended to completely replace the conventional active auxiliary feedwater system. The PAFS cools down the steam generator secondary side and eventually removes the decay heat from the reactor core by adopting a natural convection mechanism. In a pool, the heat transfer from the PCHX (passive condensation heat exchanger) contributed to increase the pool temperature up to the saturation condition and induce the natural circulation flow of the PCCT (passive condensate cooling tank) pool water. When a heat rod is placed horizontally in a pool of water, the fluid adjacent to the heat rod gets heated up. In the process, its density reduces and by virtue of the buoyancy force, the fluid in this region moves up. After reaching the top free surface, the heated water moves towards the other side wall of the pool along the free surface. Since this heated water is cooling, it goes downward along the wall at the other side wall. Above heater rod, a natural circulation flow is formed. However, there is no flow below heater rod until pool water temperature increases to saturation temperature. In this study, velocity measurement was conducted to reveal a natural circulation flow structure in a small pool using PIV (particle image velocimetry) measurement technique

  17. Development and validation of natural circulation based systems for new WWER designs

    International Nuclear Information System (INIS)

    Elaboration and introduction of NPP designs with improved technical and economic parameters are defined as an important element of the National Program of nuclear power development approved by the Russian Federation Government in 1998. This Program considers the designs of WWER-1000/V-392 and WWER-640/ V-407 power units as the priority projects of the new generation NPPs with increased safety. A number of passive systems based on natural circulation phenomena are used in V-392 and V-407 designs to prevent or mitigate severe accidents. Design basis, configuration and effect of some naturally driven systems of V-392 design sited at Novovoronezh are mainly reflected in the present paper. One of the most important mean for severe accident prevention in V-392 design is so called SPOT - passive heat removal system designed to remove core decay heat in case of station blackout (including failure of all diesel generators). This system extracts the steam from the steam generator, condenses it and returns water to steam generator by natural circulation. The SPOT heat exchangers are cooled by atmospheric air coming by natural circulation through a special direct action control gates which operate passively as well. Extensive experimental investigation of the different aspects of this system operation has been carried out to validate its functioning under real plant conditions. In particular, full-scale section of air heat exchanger-condenser has been tested with natural circulation steam, condensate and air paths modeled. The environment air temperature and steam pressure condensing were varied in the wide range, and the relevant experimental results are being discussed in this paper. The effect of wind velocity and direction to the containment is also checked by the experiments. (author)

  18. Accumulation and mother-to-calf transfer of anthropogenic and natural organohalogens in killer whales (Orcinus orca) stranded on the Pacific coast of Japan.

    Science.gov (United States)

    Haraguchi, Koichi; Hisamichi, Yohsuke; Endo, Tetsuya

    2009-04-01

    Blubber samples were analyzed for anthropogenic and natural persistent organohalogens in nine killer whales (Orcinus orca) stranded on the northern coast of Japan in 2005. Anthropogenic organohalogens were dominated by DDTs (40-240 microg/g lipid weight (lw)), PCBs (19-68 microg/g lw), and chlordanes (trans-nonachlor, 15-80 microg/g lw). Polybrominated diphenyl ethers (PBDEs) were detected at a range of 0.22-0.64 microg/g lw (BDE-47, 42-74% of SigmaPBDE). For natural organohalogens, mixed halogenated dimethylbipyrroles (Br4Cl2-DBP, 6.4-26 microg/g lw), heptachlorinated methylbipyrrole (Cl7-MBP, 0.5-1.9 microg/g lw), two methoxylated tetrabromodiphenyl ethers (6-MeO-BDE47, 0.11-0.58 microg/g lw; 2'-MeO-BDE68, 0.02-0.06 microg/g lw), and dimethoxylated tetrabromobiphenyl (2,2'-diMeO-BB80, 0.06-0.20 microg/g lw) were present. These concentrations in the blubber were higher in calves than in lactating females, indicating that large quantities of the persistent organohalogens transferred from the mother to the calf through lactation. The mother-to-calf transfer ratios of PCBs and PBDEs were significantly decreased with increasing number of halogen substituents, suggesting that higher halogenated congeners are less transferable. PMID:19201449

  19. Study of startup transients and power ramping of natural circulation boiling systems

    Energy Technology Data Exchange (ETDEWEB)

    Lakshmanan, S.P. [Department of Mechanical Engineering, Indian Institute of Technology Guwahati, Guwahati 781039 (India); Pandey, Manmohan [Department of Mechanical Engineering, Indian Institute of Technology Guwahati, Guwahati 781039 (India)], E-mail: manmohan@iitg.ac.in; Pradeep Kumar, P.; Iyer, Kannan N. [Department of Mechanical Engineering, Indian Institute of Technology Bombay, Mumbai 400076 (India)

    2009-06-15

    Numerical models of a natural circulation test facility and its prototype have been developed with RELAP5/MOD3.4 code and verified for their grid independence by nodal sensitivity studies. The model of the test facility has been validated for its steady state as well as transient predictions with the help of experimental observations. The transient predictions and parametric trends obtained by the numerical model of the prototype have been compared with those of the numerical model of the test facility. Thus, the ability of RELAP5 code to predict the transients during startup of a natural circulation boiling water reactor is verified. A powering procedure for the test facility has been conceptualized with the help of its RELAP5 model and demonstrated experimentally. Based on this, a similar powering procedure for the prototype has been proposed and simulated numerically with its RELAP5 model.

  20. Power generation costs and ultimate thermal hydraulic power limits in hypothetical advanced designs with natural circulation

    International Nuclear Information System (INIS)

    Maximum power limits for hypothetical designs of natural circulation plants can be described analytically. The thermal hydraulic design parameters are those which limit the flow, being the elevations, flow areas, and loss coefficients. WE have found some simple ''design'' equations for natural circulation flow to power ratio, and for the stability limit. The analysis of historical and available data for maximum capacity factor estimation shows 80% to be reasonable and achievable. The least cost is obtained by optimizing both hypothetical plant performance for a given output,a nd the plant layout and design. There is also scope to increase output and reduce cost by considering design variations of primary and secondary pressure, and by optimizing component elevations and loss coefficients. The design limits for each are set by stability and maximum flow considerations, which deserve close and careful evaluation