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Sample records for il-15 confer sterile

  1. Sterilization: A Conference and a Report.

    ERIC Educational Resources Information Center

    Dillingham, Brint

    1978-01-01

    This article continues a series on Native American sterilization, based on a conference of the National Council of Churches' Interreligious Foundation for Community Organization (IFCO). Also included are an article and a report by the American Civil Liberties Union. (Author/RTS)

  2. Free IL-15 Is More Abundant Than IL-15 Complexed With Soluble IL-15 Receptor-α in Murine Serum: Implications for the Mechanism of IL-15 Secretion.

    PubMed

    Anderson, Barbara G; Quinn, LeBris S

    2016-03-01

    IL-15 is a cytokine that is part of the innate immune system, as well as a proposed myokine released from skeletal muscle during physical exercise that mediates many of the positive physiological effects of exercise. Many of the immune functions of IL-15 are mediated by juxtacrine signaling via externalized IL-15 bound to membrane-associated IL-15 receptor-α (IL-15Rα). Serum and plasma samples also contain measurable concentrations of IL-15, believed to arise from proteolytic cleavage of membrane-associated IL-15/IL-15Rα complexes to generate soluble IL-15/IL-15Rα species. Here, we validate commercial assays that can distinguish the free form of IL-15 and IL-15/IL-15Rα complexes. These assays showed that most (86%) IL-15 in mouse serum resides in the free state, with a minor proportion (14%) residing in complex with IL-15Rα. Given the much shorter half-life of free IL-15 compared with IL-15/IL-15Rα complexes, these findings cast doubt on the currently accepted model for IL-15 secretion from cleavage of membrane-bound IL-15/IL-15Rα and suggest that IL-15 is released as a free molecule by an unknown mechanism. PMID:26812159

  3. An activation-induced IL-15 isoform is a natural antagonist for IL-15 function

    PubMed Central

    Zhao, Lei; Hu, Bo; Zhang, Yinsheng; Song, Yuan; Lin, Dandan; Liu, Yonghao; Mei, Yu; Sandikin, Dedy; Sun, Weiping; Zhuang, Min; Liu, Haiyan

    2016-01-01

    Interleukin 15 (IL-15) expression induces the secretion of inflammatory cytokines, inhibits the apoptosis of activated T cells and prolongs the survival of CD8+ memory T cells. Here we identified an IL-15 isoform lacking exon-6, IL-15ΔE6, generated by alternative splicing events of activated immune cells, including macrophages and B cells. In vitro study showed that IL-15ΔE6 could antagonize IL-15-mediated T cell proliferation. The receptor binding assay revealed that IL-15ΔE6 could bind to IL-15Rα and interfere with the binding between IL-15 and IL-15Rα. Over-expression of IL-15ΔE6 in the murine EAE model ameliorated the EAE symptoms of the mice. The clinical scores were significantly lower in the mice expressing IL-15ΔE6 than the control mice and the mice expressing IL-15. The inflammation and demyelination of the EAE mice expressing IL-15ΔE6 were less severe than the control group. Furthermore, flow cytometry analysis demonstrated that IL-15ΔE6 expression reduced the percentages of inflammatory T cells in the spleen and spinal cord, and inhibited the infiltration of macrophages to the CNS. Our results demonstrated that IL-15ΔE6 could be induced during immune activation and function as a negative feedback mechanism to dampen IL-15-mediated inflammatory events. PMID:27166125

  4. An activation-induced IL-15 isoform is a natural antagonist for IL-15 function.

    PubMed

    Zhao, Lei; Hu, Bo; Zhang, Yinsheng; Song, Yuan; Lin, Dandan; Liu, Yonghao; Mei, Yu; Sandikin, Dedy; Sun, Weiping; Zhuang, Min; Liu, Haiyan

    2016-01-01

    Interleukin 15 (IL-15) expression induces the secretion of inflammatory cytokines, inhibits the apoptosis of activated T cells and prolongs the survival of CD8(+) memory T cells. Here we identified an IL-15 isoform lacking exon-6, IL-15ΔE6, generated by alternative splicing events of activated immune cells, including macrophages and B cells. In vitro study showed that IL-15ΔE6 could antagonize IL-15-mediated T cell proliferation. The receptor binding assay revealed that IL-15ΔE6 could bind to IL-15Rα and interfere with the binding between IL-15 and IL-15Rα. Over-expression of IL-15ΔE6 in the murine EAE model ameliorated the EAE symptoms of the mice. The clinical scores were significantly lower in the mice expressing IL-15ΔE6 than the control mice and the mice expressing IL-15. The inflammation and demyelination of the EAE mice expressing IL-15ΔE6 were less severe than the control group. Furthermore, flow cytometry analysis demonstrated that IL-15ΔE6 expression reduced the percentages of inflammatory T cells in the spleen and spinal cord, and inhibited the infiltration of macrophages to the CNS. Our results demonstrated that IL-15ΔE6 could be induced during immune activation and function as a negative feedback mechanism to dampen IL-15-mediated inflammatory events. PMID:27166125

  5. Homeostasis of IL-15 dependent lymphocyte subsets in the liver.

    PubMed

    Cepero-Donates, Yuneivy; Rakotoarivelo, Volatiana; Mayhue, Marian; Ma, Averil; Chen, Yi-Guang; Ramanathan, Sheela

    2016-06-01

    IL-15 is a member of the gamma chain family of cytokines (γc - CD132). The IL-15 receptor (IL-15R) complex consists of 3 subunits: the ligand-binding IL-15Rα chain (CD215), the β chain (CD122; also used by IL-2), and the common γ chain. The biological activities of IL-15 are mostly mediated by the IL-15:IL-15Rα complex, produced by the same cell and 'trans-presented' to responder cells expressing the IL-15Rβγc. The peculiar and almost unique requirement for IL-15 to be trans-presented by IL-15Rα suggests that the biological effects of IL-15 signaling are tightly regulated even at the level of availability of IL-15. Tissue-specific deletion of IL-15Rα has shown macrophage-and dendritic cell-derived IL-15Rα mediate the homeostasis of different CD8(+) T cell subsets. Here we show that hepatocyte and macrophage- specific expression of IL-15Rα is required to maintain the homeostasis of NK and NKT cells in the liver. Thus, homeostasis of IL-15-dependent lymphocyte subsets is also regulated by trans-presentation of IL-15 by non-hematopoietic cells in the tissue environment. PMID:26778709

  6. Molecular cloning and expression analysis of interleukin (IL)-15 and IL-15 receptor α from rock bream, Oplegnathus fasciatus.

    PubMed

    Bae, Jin-Sol; Shim, Sang Hee; Hwang, Seong Don; Kim, Ju-Won; Park, Dae-Won; Park, Chan-Il

    2013-10-01

    Mammalian interleukin (IL)-15 plays an important role in the activation of CD8(+) T cells and natural killer (NK) cells along with its receptor α (IL-15Rα). To understand the potential roles of IL-15 and IL-15Rα in fish, we identified IL-15 and IL-15Rα cDNA from rock bream (Oplegnathus fasciatus) and investigated their gene expression profiles after bacterial and viral infection. Coding regions of rock bream (Rb) IL-15 and RbIL-15Rα cDNAs were 534 and 402 bp encoding 177 and 133 amino acid residues, respectively. The sushi domain of IL-15Rα was highly conserved between rock bream and other species. Unlike other IL-15Rαs, RbIL-15Rα does not have a transmembrane region. Gene expression of RbIL-15 and RbIL-15Rα was widely expressed in different tissues of healthy fish, especially immune-related tissues. RbIL-15 and RbIL-15Rα were highly induced in the kidney and spleen after infection with Edwardsiella tarda, Streptococcus iniae and red seabream iridovirus. Gene expression patterns of RbIL-15 and RbIL-15Rα were similar in the kidney and spleen after pathogen infection. However, these genes were differentially induced in the liver after pathogen infection. These results suggest that the different responses of RbIL-15 and RbIL-15Rα to pathogen infection may be induced by different tissues or cell types. PMID:23911652

  7. Trans-presentation of IL-15 modulates STAT5 activation and Bcl-6 expression in TH1 cells

    PubMed Central

    Cooley, Ian D.; Read, Kaitlin A.; Oestreich, Kenneth J.

    2015-01-01

    During infection, naïve CD4+ T helper cells differentiate into specialized effector subsets based upon environmental signals propagated by the cytokine milieu. Recently, this paradigm has been complicated by the demonstration that alterations in the cytokine environment can result in varying degrees of plasticity between effector T helper cell populations. Therefore, elucidation of the mechanisms by which cytokines regulate T helper cell differentiation decisions is increasingly important. The gamma common cytokine IL-15 is currently undergoing clinical trials for the treatment of malignancies, due to its well-established role in the regulation of natural killer and CD8+ T cell immune responses. However, the effect of IL-15 signaling on CD4+ T cell activity is incompletely understood. One mechanism by which IL-15 activity is conferred is through trans-presentation via the IL-15 receptor alpha subunit. Here, we demonstrate that differentiated TH1 cells are responsive to trans-presented IL-15. Importantly, while trans-presentation of IL-15 results in STAT5 activation and maintenance of the TH1 gene program, IL-15 treatment alone allows for increased Bcl-6 expression and the upregulation of a TFH-like profile. Collectively, these findings describe a novel role for IL-15 in the modulation of CD4+ T cell responses and provide valuable insight for the use of IL-15 in immunotherapeutic approaches. PMID:26500048

  8. Inflammatory Signals Regulate IL-15 in Response to Lymphodepletion.

    PubMed

    Anthony, Scott M; Rivas, Sarai C; Colpitts, Sara L; Howard, Megan E; Stonier, Spencer W; Schluns, Kimberly S

    2016-06-01

    Induction of lymphopenia has been exploited therapeutically to improve immune responses to cancer therapies and vaccinations. Whereas IL-15 has well-established roles in stimulating lymphocyte responses after lymphodepletion, the mechanisms regulating these IL-15 responses are unclear. We report that cell surface IL-15 expression is upregulated during lymphopenia induced by total body irradiation (TBI), cyclophosphamide, or Thy1 Ab-mediated T cell depletion, as well as in RAG(-/-) mice; interestingly, the cellular profile of surface IL-15 expression is distinct in each model. In contrast, soluble IL-15 (sIL-15) complexes are upregulated only after TBI or αThy1 Ab. Analysis of cell-specific IL-15Rα conditional knockout mice revealed that macrophages and dendritic cells are important sources of sIL-15 complexes after TBI but provide minimal contribution in response to Thy1 Ab treatment. Unlike with TBI, induction of sIL-15 complexes by αThy1 Ab is sustained and only partially dependent on type I IFNs. The stimulator of IFN genes pathway was discovered to be a potent inducer of sIL-15 complexes and was required for optimal production of sIL-15 complexes in response to Ab-mediated T cell depletion and TBI, suggesting products of cell death drive production of sIL-15 complexes after lymphodepletion. Lastly, we provide evidence that IL-15 induced by inflammatory signals in response to lymphodepletion drives lymphocyte responses, as memory CD8 T cells proliferated in an IL-15-dependent manner. Overall, these studies demonstrate that the form in which IL-15 is expressed, its kinetics and cellular sources, and the inflammatory signals involved are differentially dictated by the manner in which lymphopenia is induced. PMID:27183627

  9. Autocrine role of vascular IL-15 in intimal thickening

    SciTech Connect

    Cercek, Miha . E-mail: DimayugaP@cshs.org

    2006-01-13

    Interleukin 15 (IL-15) is a pro-inflammatory cytokine that modulates T cell recruitment and activation, independent of antigen. It has been detected in human atherosclerotic plaques and atherosclerotic plaques of apoE-/- mice. IL-15 regulates fractalkine (FKN)-CX3CR1 chemokine signaling which is involved in atherogenesis and promotes SMC proliferation. We investigated the role of IL-15 in intimal thickening after arterial injury. Treatment of serum-stimulated SMC with IL-15 in vitro attenuated proliferation and suppressed CX3CR1 and FKN mRNA expression. The role of endogenous IL-15 in vivo was investigated in injured carotid arteries of mice. Periadventitial arterial injury resulted in increased IL-15 expression in the media and neointima, paralleled by increased IL-15 receptor {alpha} expression. Blockade of endogenous IL-15 increased intimal thickening. FKN and CX3CR1 expression increased after injury and were further augmented after IL-15 blockade. These data suggest that endogenous IL-15 attenuated intimal thickening after arterial injury. The potential mechanism of action is suppression of CX3CR1 signaling.

  10. Myxoma Virus Expressing a Fusion Protein of Interleukin-15 (IL15) and IL15 Receptor Alpha Has Enhanced Antitumor Activity

    PubMed Central

    Tosic, Vesna; Thomas, Diana L.; Kranz, David M.; Liu, Jia; McFadden, Grant; Shisler, Joanna L.; MacNeill, Amy L.; Roy, Edward J.

    2014-01-01

    Myxoma virus, a rabbit poxvirus, can efficiently infect various types of mouse and human cancer cells. It is a strict rabbit-specific pathogen, and is thought to be safe as a therapeutic agent in all non-rabbit hosts tested including mice and humans. Interleukin-15 (IL15) is an immuno-modulatory cytokine with significant potential for stimulating anti-tumor T lymphocytes and NK cells. Co-expression of IL15 with the α subunit of IL15 receptor (IL15Rα) greatly enhances IL15 stability and bioavailability. Therefore, we engineered a new recombinant myxoma virus (vMyx-IL15Rα-tdTr), which expresses an IL15Rα-IL15 fusion protein plus tdTomato red fluorescent reporter protein. Permissive rabbit kidney epithelial (RK-13) cells infected with vMyx-IL15Rα-tdTr expressed and secreted the IL15Rα-IL15 fusion protein. Functional activity was confirmed by demonstrating that the secreted fusion protein stimulated proliferation of cytokine-dependent CTLL-2 cells. Multi-step growth curves showed that murine melanoma (B16-F10 and B16.SIY) cell lines were permissive to vMyx-IL15Rα-tdTr infection. In vivo experiments in RAG1-/- mice showed that subcutaneous B16-F10 tumors treated with vMyx-IL15Rα-tdTr exhibited attenuated tumor growth and a significant survival benefit for the treated group compared to the PBS control and the control viruses (vMyx-IL15-tdTr and vMyx-tdTr). Immunohistological analysis of the subcutaneous tumors showed dramatically increased infiltration of NK cells in vMyx-IL15Rα-tdTr treated tumors compared to the controls. In vivo experiments with immunocompetent C57BL/6 mice revealed a strong infiltrate of both NK cells and CD8+ T cells in response to vMyx-IL15Rα-tdTr, and prolonged survival. We conclude that delivery of IL15Rα-IL15 in a myxoma virus vector stimulates both innate and adaptive components of the immune system. PMID:25329832

  11. IRF-1 promotes liver transplant ischemia/reperfusion injury via hepatocyte IL-15/IL-15Rα production

    PubMed Central

    Yokota, Shinichiro; Yoshida, Osamu; Dou, Lei; Spadaro, Anthony V.; Isse, Kumiko; Ross, Mark A.; Stolz, Donna B.; Kimura, Shoko; Du, Qiang; Demetris, Anthony J.; Thomson, Angus W.; Geller, David A.

    2015-01-01

    Ischemia and reperfusion (I/R) injury following liver transplantation (LTx) is an important problem that significantly impacts clinical outcomes. Interferon regulatory factor-1 (IRF-1) is a nuclear transcription factor that plays a critical role in liver injury. Our objective was to determine the immunomodulatory role of IRF-1 during I/R injury following allogeneic LTx. IRF-1 was induced in liver grafts immediately after reperfusion in both human and mouse LTx. IRF-1 contributed significantly to I/R injury as IRF-1 KO grafts displayed much less damage assessed by serum alanine aminotransferase (ALT) and histology. In vitro, IRF-1 regulated both constitutive and induced expression of IL-15, as well as IL-15Rα mRNA expression in murine hepatocytes and liver dendritic cells (DC). Specific knockdown of IRF-1 in human primary hepatocytes gave similar results. In addition, we identified hepatocytes as the major producer of soluble IL-15/IL-15Rα complexes in the liver. IRF-1 KO livers had significantly reduced NK, NKT and CD8+T cell numbers, while rIL-15/IL-15Rα restored these immune cells, augmented cytotoxic effector molecules, promoted systemic inflammatory responses, and exacerbated liver injury in IRF-1 KO graft recipients. These results indicate that IRF-1 promotes LTx I/R injury via hepatocyte IL-15/IL-15Rα production and suggest that targeting IRF-1 and IL-15/IL-15Rα may be effective in reducing I/R injury associated with LTx. PMID:25964490

  12. Serum Interleukin (IL)-15 as a Biomarker of Alzheimer's Disease

    PubMed Central

    Bishnoi, Ram J.; Palmer, Raymond F.; Royall, Donald R.

    2015-01-01

    Interleukin (IL-15), a pro-inflammatory cytokine has been studied as a possible marker of Alzheimer’s disease (AD); however its exact role in neuro-inflammation or the pathogenesis AD is not well understood yet. A Multiple Indicators Multiple Causes (MIMIC) approach was used to examine the relationship between serum IL-15 levels and AD in a well characterized AD cohort, the Texas Alzheimer's Research and Care Consortium (TARCC). Instead of categorical diagnoses, we used two latent construct d (for dementia) and g’ (for cognitive impairments not contributing to functional impairments) in our analysis. The results showed that the serum IL-15 level has significant effects on cognition, exclusively mediated by latent construct d and g’. Contrasting directions of association lead us to speculate that IL-15’s effects in AD are mediated through functional networks as d scores have been previously found to be specifically related to default mode network (DMN). Our finding warrants the need for further research to determine the changes in structural and functional networks corresponding to serum based biomarkers levels. PMID:25710473

  13. NK Cell Activation in Human Hantavirus Infection Explained by Virus-Induced IL-15/IL15Rα Expression

    PubMed Central

    Braun, Monika; Björkström, Niklas K.; Gupta, Shawon; Sundström, Karin; Ahlm, Clas; Klingström, Jonas; Ljunggren, Hans-Gustaf

    2014-01-01

    Clinical infection with hantaviruses cause two severe acute diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). These diseases are characterized by strong immune activation, increased vascular permeability, and up to 50% case-fatality rates. One prominent feature observed in clinical hantavirus infection is rapid expansion of natural killer (NK) cells in peripheral blood of affected individuals. We here describe an unusually high state of activation of such expanding NK cells in the acute phase of clinical Puumala hantavirus infection. Expanding NK cells expressed markedly increased levels of activating NK cell receptors and cytotoxic effector molecules. In search for possible mechanisms behind this NK cell activation, we observed virus-induced IL-15 and IL-15Rα on infected endothelial and epithelial cells. Hantavirus-infected cells were shown to strongly activate NK cells in a cell-cell contact-dependent way, and this response was blocked with anti-IL-15 antibodies. Surprisingly, the strength of the IL-15-dependent NK cell response was such that it led to killing of uninfected endothelial cells despite expression of normal levels of HLA class I. In contrast, hantavirus-infected cells were resistant to NK cell lysis, due to a combination of virus-induced increase in HLA class I expression levels and hantavirus-mediated inhibition of apoptosis induction. In summary, we here describe a possible mechanism explaining the massive NK cell activation and proliferation observed in HFRS patients caused by Puumala hantavirus infection. The results add further insights into mechanisms behind the immunopathogenesis of hantavirus infections in humans and identify new possible targets for intervention. PMID:25412359

  14. Recombinant human heterodimeric IL-15 complex displays extensive and reproducible N- and O-linked glycosylation.

    PubMed

    Thaysen-Andersen, M; Chertova, E; Bergamaschi, C; Moh, E S X; Chertov, O; Roser, J; Sowder, R; Bear, J; Lifson, J; Packer, N H; Felber, B K; Pavlakis, G N

    2016-06-01

    Human interleukin 15 (IL-15) circulates in blood as a stable molecular complex with the soluble IL-15 receptor alpha (sIL-15Rα). This heterodimeric IL-15:sIL-15Rα complex (hetIL-15) shows therapeutic potential by promoting the growth, mobilization and activation of lymphocytes and is currently evaluated in clinical trials. Favorable pharmacokinetic properties are associated with the heterodimeric formation and the glycosylation of hetIL-15, which, however, remains largely uncharacterized. We report the site-specific N- and O-glycosylation of two clinically relevant large-scale preparations of HEK293-derived recombinant human hetIL-15. Intact IL-15 and sIL-15Rα and derived glycans and glycopeptides were separately profiled using multiple LC-MS/MS strategies. IL-15 Asn79 and sIL-15Rα Asn107 carried the same repertoire of biosynthetically-related N-glycans covering mostly α1-6-core-fucosylated and β-GlcNAc-terminating complex-type structures. The two potential IL-15 N-glycosylation sites (Asn71 and Asn112) located at the IL-2 receptor interface were unoccupied. Mass analysis of intact IL-15 confirmed its N-glycosylation and suggested that Asn79-glycosylation partially prevents Asn77-deamidation. IL-15 contained no O-glycans, whereas sIL-15Rα was heavily O-glycosylated with partially sialylated core 1 and 2-type mono- to hexasaccharides on Thr2, Thr81, Thr86, Thr156, Ser158, and Ser160. The sialoglycans displayed α2-3- and α2-6-NeuAc-type sialylation. Non-human, potentially immunogenic glycoepitopes (e.g. N-glycolylneuraminic acid and α-galactosylation) were not displayed by hetIL-15. Highly reproducible glycosylation of IL-15 and sIL-15Rα of two batches of hetIL-15 demonstrated consistent manufacturing and purification. In conclusion, we document the heterogeneous and reproducible N- and O-glycosylation of large-scale preparations of the therapeutic candidate hetIL-15. Site-specific mapping of these molecular features is important to evaluate the consistent

  15. Mechanistic Model of Natural Killer Cell Proliferative Response to IL-15 Receptor Stimulation

    PubMed Central

    Zhao, Yun M.; French, Anthony R.

    2013-01-01

    Natural killer (NK) cells are innate lymphocytes that provide early host defense against intracellular pathogens, such as viruses. Although NK cell development, homeostasis, and proliferation are regulated by IL-15, the influence of IL-15 receptor (IL-15R)-mediated signaling at the cellular level has not been quantitatively characterized. We developed a mathematical model to analyze the kinetic interactions that control the formation and localization of IL-15/IL-15R complexes. Our computational results demonstrated that IL-15/IL-15R complexes on the cell surface were a key determinant of the magnitude of the IL-15 proliferative signal and that IL-15R occupancy functioned as an effective surrogate measure of receptor signaling. Ligand binding and receptor internalization modulated IL-15R occupancy. Our work supports the hypothesis that the total number and duration of IL-15/IL-15R complexes on the cell surface crosses a quantitative threshold prior to the initiation of NK cell division. Furthermore, our model predicted that the upregulation of IL-15Rα on NK cells substantially increased IL-15R complex formation and accelerated the expansion of dividing NK cells with the greatest impact at low IL-15 concentrations. Model predictions of the threshold requirement for NK cell recruitment to the cell cycle and the subsequent exponential proliferation correlated well with experimental data. In summary, our modeling analysis provides quantitative insight into the regulation of NK cell proliferation at the receptor level and provides a framework for the development of IL-15 based immunotherapies to modulate NK cell proliferation. PMID:24068905

  16. IL-15 concentrations in skeletal muscle and subcutaneous adipose tissue in lean and obese humans: local effects of IL-15 on adipose tissue lipolysis

    PubMed Central

    Pierce, Joseph R.; Maples, Jill M.

    2015-01-01

    Animal/cell investigations indicate that there is a decreased adipose tissue mass resulting from skeletal muscle (SkM) IL-15 secretion (e.g., SkM-blood-adipose tissue axis). IL-15 could regulate fat mass accumulation in obesity via lipolysis, although this has not been investigated in humans. Therefore, the purpose was to examine whether SkM and/or subcutaneous adipose tissue (SCAT) IL-15 concentrations were correlated with SCAT lipolysis in lean and obese humans and determine whether IL-15 perfusion could induce lipolysis in human SCAT. Local SkM and abdominal SCAT IL-15 (microdialysis) and circulating IL-15 (blood) were sampled in lean (BMI: 23.1 ± 1.9 kg/m2; n = 10) and obese (BMI: 34.7 ± 3.5 kg/m2; n = 10) subjects at rest/during 1-h cycling exercise. Lipolysis (SCAT interstitial glycerol concentration) was compared against local/systemic IL-15. An additional probe in SCAT was perfused with IL-15 to assess direct lipolytic responses. SkM IL-15 was not different between lean and obese subjects (P = 0.45), whereas SCAT IL-15 was higher in obese vs. lean subjects (P = 0.02) and was correlated with SCAT lipolysis (r = 0.45, P = 0.05). Exercise increased SCAT lipolysis in lean and obese (P < 0.01), but exercise-induced SCAT lipolysis changes were not correlated with exercise-induced SCAT IL-15 changes. Microdialysis perfusion resulting in physiological IL-15 concentrations in the adipose tissue interstitium increased lipolysis in lean (P = 0.04) but suppressed lipolysis in obese (P < 0.01). Although we found no support for a human IL-15 SkM-blood-adipose tissue axis, IL-15 may be produced in/act on the abdominal SCAT depot. The extent to which this autocrine/paracrine IL-15 action regulates human body composition remains unknown. PMID:25921578

  17. IL-15 suppresses colitis-associated colon carcinogenesis by inducing antitumor immunity

    PubMed Central

    Bahri, Rajia; Pateras, Ioannis S; D’Orlando, Orietta; Goyeneche-Patino, Diego A; Campbell, Michelle; Polansky, Julia K; Sandig, Hilary; Papaioannou, Marilena; Evangelou, Kostas; Foukas, Periklis G; Gorgoulis, Vassilis G; Bulfone-Paus, Silvia

    2015-01-01

    IL-15 regulates the development, survival, and proliferation of multiple innate and adaptive immune cells and plays a dual role, inducing both tumor cell growth and antitumor immunity. However, the role of IL-15 in inflammation-induced cancer remains unclear. To explore this, we have compared the colon carcinoma burden of Il15−/− and Il15rα−/− mice with wild type (WT) mice after induction of colitis-associated colon carcinogenesis utilizing the AOM/DSS model. Compared to WT mice, Il15−/− but not Il15rα−/− mice showed reduced survival, along with higher tumor incidence, colon weight, and tumor size. This suggests that low affinity IL-15 signaling via the shared IL-2Rβ/γc decreases the risk for developing colitis-associated cancer. CD11c-Il15 mice, in which IL-15 expression is reconstituted in Il15−/− mice under the control of the CD11c-promoter, showed that selective reconstitution of IL-15 in antigen-presenting cells restored the CD8+ T and NK cell compartments, serum levels of IFNγ, G-CSF, IL-10, and CXCL1 and reduced tumor burden. After demonstrating IL-15 expression in human colorectal cancer (CRC) cells in situ, we investigated the role of this cytokine in the modulation of key colonic oncogenic pathways in the tumor. While these pathways were found to be unaltered in the absence of IL-15, tumor transcriptome analysis showed that the loss of IL-15 upregulates key inflammatory mediators associated with colon cancer progression, such as IL-1β, IL-22, IL-23, Cxcl5, and Spp1. These findings provide evidence that IL-15 suppresses colitis-associated colon carcinogenesis through regulation of antitumor cytotoxicity, and modulation of the inflammatory tumor micromilieu. PMID:26405589

  18. IL-15 promotes the survival of naive and memory phenotype CD8+ T cells.

    PubMed

    Berard, Marion; Brandt, Katja; Bulfone-Paus, Silvia; Tough, David F

    2003-05-15

    IL-15 stimulates the proliferation of memory phenotype CD44(high)CD8(+) T cells and is thought to play a key role in regulating the turnover of these cells in vivo. We have investigated whether IL-15 also has the capacity to affect the life span of naive phenotype (CD44(low)) CD8(+) T cells. We report that IL-15 promotes the survival of both CD44(low) and CD44(high) CD8(+) T cells, doing so at much lower concentrations than required to induce proliferation of CD44(high) cells. Rescue from apoptosis was associated with the up-regulation of Bcl-2 in both cell types, whereas elevated expression of Bcl-x(L) was observed among CD44(high) but not CD44(low) CD8(+) cells. An investigation into the role of IL-15R subunits in mediating the effects of IL-15 revealed distinct contributions of the alpha- and beta- and gamma-chains. Most strikingly, IL-15R alpha was not essential for either induction of proliferation or promotion of survival by IL-15, but did greatly enhance the sensitivity of cells to low concentrations of IL-15. By contrast, the beta- and gamma-chains of the IL-15R were absolutely required for the proliferative and pro-survival effects of IL-15, although it was not necessary for CD44(high)CD8(+) cells to express higher levels of IL-15R beta than CD44(low) cells to proliferate in response to IL-15. These results show that IL-15 has multiple effects on CD8 T cells and possesses the potential to regulate the life span of naive as well as memory CD8(+) T cells. PMID:12734346

  19. IL-15 superagonist/IL-15RαSushi-Fc fusion complex (IL-15SA/IL-15RαSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas.

    PubMed

    Kim, Peter S; Kwilas, Anna R; Xu, Wenxin; Alter, Sarah; Jeng, Emily K; Wong, Hing C; Schlom, Jeffrey; Hodge, James W

    2016-03-29

    Interleukin (IL)-15-N72D superagonist-complexed with IL-15RαSushi-Fc fusion protein (IL-15SA/IL-15RαSu-Fc; ALT-803) has been reported to exhibit significant anti-tumor activity in murine myeloma, rat bladder cancer, and murine glioblastoma models. In this study, we examined the immunomodulatory and anti-tumor effects of IL-15SA/IL-15RαSu-Fc in tumor-free and highly metastatic tumor-bearing mice. Here, IL-15SA/IL-15RαSu-Fc significantly expanded natural killer (NK) and CD8+ T cells. In examining NK cell subsets, the greatest significant increase was in highly cytotoxic and migrating (CD11b+, CD27hi; high effector) NK cells, leading to enhanced function on a per-cell basis. CD8+ T cell subset analysis determined that IL-15SA/IL-15RαSu-Fc significantly increased IL-15 responding memory (CD122+, CD44+) CD8+ T cells, in particular those having the innate (NKG2D+, PD1-) phenotype. In 4T1 breast tumor-bearing mice, IL-15SA/IL-15RαSu-Fc induced significant anti-tumor activity against spontaneous pulmonary metastases, depending on CD8+ T and NK cells, and resulting in prolonged survival. Similar anti-tumor activity was seen in the experimental pulmonary metastasis model of CT26 colon carcinoma cells, particularly when IL-15SA/IL-15RαSu-Fc was combined with a cocktail of checkpoint inhibitors, anti-CTLA-4 and anti-PD-L1. Altogether, these studies showed for the first time that IL-15SA/IL-15RαSu-Fc (1) promoted the development of high effector NK cells and CD8+ T cell responders of the innate phenotype, (2) enhanced function of NK cells, and (3) played a vital role in reducing tumor metastasis and ultimately survival, especially in combination with checkpoint inhibitors. PMID:26910920

  20. IL-15 superagonist/IL-15RαSushi-Fc fusion complex (IL-15SA/IL-15RαSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas

    PubMed Central

    Kim, Peter S.; Kwilas, Anna R.; Xu, Wenxin; Alter, Sarah; Jeng, Emily K.; Wong, Hing C.

    2016-01-01

    Interleukin (IL)-15-N72D superagonist-complexed with IL-15RαSushi-Fc fusion protein (IL-15SA/IL-15RαSu-Fc; ALT-803) has been reported to exhibit significant anti-tumor activity in murine myeloma, rat bladder cancer, and murine glioblastoma models. In this study, we examined the immunomodulatory and anti-tumor effects of IL-15SA/IL-15RαSu-Fc in tumor-free and highly metastatic tumor-bearing mice. Here, IL-15SA/IL-15RαSu-Fc significantly expanded natural killer (NK) and CD8+ T cells. In examining NK cell subsets, the greatest significant increase was in highly cytotoxic and migrating (CD11b+, CD27hi; high effector) NK cells, leading to enhanced function on a per-cell basis. CD8+ T cell subset analysis determined that IL-15SA/IL-15RαSu-Fc significantly increased IL-15 responding memory (CD122+, CD44+) CD8+ T cells, in particular those having the innate (NKG2D+, PD1−) phenotype. In 4T1 breast tumor–bearing mice, IL-15SA/IL-15RαSu-Fc induced significant anti-tumor activity against spontaneous pulmonary metastases, depending on CD8+ T and NK cells, and resulting in prolonged survival. Similar anti-tumor activity was seen in the experimental pulmonary metastasis model of CT26 colon carcinoma cells, particularly when IL-15SA/IL-15RαSu-Fc was combined with a cocktail of checkpoint inhibitors, anti-CTLA-4 and anti-PD-L1. Altogether, these studies showed for the first time that IL-15SA/IL-15RαSu-Fc (1) promoted the development of high effector NK cells and CD8+ T cell responders of the innate phenotype, (2) enhanced function of NK cells, and (3) played a vital role in reducing tumor metastasis and ultimately survival, especially in combination with checkpoint inhibitors. PMID:26910920

  1. NK Cell Proliferation Induced by IL-15 Transpresentation Is Negatively Regulated by Inhibitory Receptors.

    PubMed

    Anton, Olga M; Vielkind, Susina; Peterson, Mary E; Tagaya, Yutaka; Long, Eric O

    2015-11-15

    IL-15 bound to the IL-15Rα-chain (IL-15Rα) is presented in trans to cells bearing the IL-2Rβ-chain and common γ-chain. As IL-15 transpresentation occurs in the context of cell-to-cell contacts, it has the potential for regulation by and of other receptor-ligand interactions. In this study, human NK cells were tested for the sensitivity of IL-15 transpresentation to inhibitory receptors. Human cells expressing HLA class I ligands for inhibitory receptors KIR2DL1, KIR2DL2/3, or CD94-NKG2A were transfected with IL-15Rα. Proliferation of primary NK cells in response to transpresented IL-15 was reduced by engagement of either KIR2DL1 or KIR2DL2/3 by cognate HLA-C ligands. Inhibitory KIR-HLA-C interactions did not reduce the proliferation induced by soluble IL-15. Therefore, transpresentation of IL-15 is subject to downregulation by MHC class I-specific inhibitory receptors. Similarly, proliferation of the NKG2A(+) cell line NKL induced by IL-15 transpresentation was inhibited by HLA-E. Coengagement of inhibitory receptors, either KIR2DL1 or CD94-NKG2A, did not inhibit phosphorylation of Stat5 but inhibited selectively phosphorylation of Akt and S6 ribosomal protein. IL-15Rα was not excluded from, but was evenly distributed across, inhibitory synapses. These findings demonstrate a novel mechanism to attenuate IL-15-dependent NK cell proliferation and suggest that inhibitory NK cell receptors contribute to NK cell homeostasis. PMID:26453750

  2. IL-15 complexes induce NK- and T-cell responses independent of type I IFN signaling during rhinovirus infection.

    PubMed

    Jayaraman, A; Jackson, D J; Message, S D; Pearson, R M; Aniscenko, J; Caramori, G; Mallia, P; Papi, A; Shamji, B; Edwards, M; Westwick, J; Hansel, T; Stanciu, L A; Johnston, S L; Bartlett, N W

    2014-09-01

    Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity; however, their function during rhinovirus infection in vivo is undefined. In RV-infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expressions of IL-15 and IL-15Rα, which in turn were required for NK- and CD8(+) T-cell responses. Treatment with IL-15-IL-15Rα complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Rα, IFN-γ, CXCL9, and CXCL10 followed by recruitment of activated, IFN-γ-expressing NK, CD8(+), and CD4(+) T cells. Treating infected IFNAR1(-/-) mice with IL-15c similarly increased IL-15, IL-15Rα, IFN-γ, and CXCL9 (but not CXCL10) expression also followed by NK-, CD8(+)-, and CD4(+)-T-cell recruitment and activation. We have demonstrated that type I IFN-induced IFN-γ and cellular immunity to RV was mediated by IL-15 and IL-15Rα. Importantly, we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment, which in turn was sufficient to drive IFN-γ expression and lymphocyte responses. PMID:24472849

  3. Recombinant Newcastle Disease virus Expressing IL15 Demonstrates Promising Antitumor Efficiency in Melanoma Model.

    PubMed

    Niu, Zeshan; Bai, Fuliang; Sun, Tian; Tian, Hui; Yu, Dan; Yin, Jiechao; Li, Siming; Li, Tianhe; Cao, Hongwei; Yu, Qingzhong; Wu, Yunzhou; Ren, Guiping; Li, Deshan

    2015-10-01

    Recombinant Newcastle Disease Virus (rNDV) has shown oncolytic therapeutic effect in preclinical studies. Previous data indicate that rNDV carrying IL2 has shown promise in cancer therapy. Due to the significant side effects of IL2, IL15 has been introduced into cancer therapy. A number of studies have suggested that IL15 efficiently enhances the activities of CTL and NK cells and inhibits the tumor recurrence and metastasis. Furthermore, IL15 is less toxic than IL2. Therefore, we hypothesize that a recombinant NDV expressing IL15 would be a promising agent for the treatment of malignant tumors. The human IL15 gene or IL2 gene was incorporated into the genome of lentogenic LaSota strain at the position between the HN and L genes (namely rNDV-IL15 or rNDV-IL2). The two viruses efficiently infected tumor cells and expressed IL15 or IL2 protein. Melanoma tumor-bearing mice were treated by intra-tumoral (i.t.) injection of rNDV-IL15 or rNDV-IL2. Both rNDV-IL15 and rNDV-IL2 effectively suppressed tumor growth compared with rNDV. The 120-day survival rate of rNDV-IL15- treated group was 12.5% higher than that of rNDV-IL2 group, although the difference was not statistically significant, both recombinant viruses had strong abilities to induce CD41 T cell and CTL cell responses. However, rNDV-IL15 significantly induced more IFN-γ release and stimulated more CD81 T cells infiltration in the tumor sites compared with rNDV-IL2. In the tumor re-challenged experiment, the survival rates of rNDV-IL15 group and rNDV-IL2 group were statistically higher than that of PBS group. The survival rate of rNDV-IL15 group was 26.67% higher than that of rNDV-IL2 group although the difference was not statistically significant. In conclusion, rNDV-IL15 is a promising antitumor agent against melanoma. PMID:24645750

  4. IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis.

    PubMed

    Inoue, Shigeaki; Unsinger, Jacqueline; Davis, Christopher G; Muenzer, Jared T; Ferguson, Thomas A; Chang, Katherine; Osborne, Dale F; Clark, Andrew T; Coopersmith, Craig M; McDunn, Jonathan E; Hotchkiss, Richard S

    2010-02-01

    IL-15 is a pluripotent antiapoptotic cytokine that signals to cells of both the innate and adaptive immune system and is regarded as a highly promising immunomodulatory agent in cancer therapy. Sepsis is a lethal condition in which apoptosis-induced depletion of immune cells and subsequent immunosuppression are thought to contribute to morbidity and mortality. This study tested the ability of IL-15 to block apoptosis, prevent immunosuppression, and improve survival in sepsis. Mice were made septic using cecal ligation and puncture or Pseudomonas aeruginosa pneumonia. The experiments comprised a 2 x 2 full factorial design with surgical sepsis versus sham and IL-15 versus vehicle. In addition to survival studies, splenic cellularity, canonical markers of activation and proliferation, intracellular pro- and antiapoptotic Bcl-2 family protein expression, and markers of immune cell apoptosis were evaluated by flow cytometry. Cytokine production was examined both in plasma of treated mice and splenocytes that were stimulated ex vivo. IL-15 blocked sepsis-induced apoptosis of NK cells, dendritic cells, and CD8 T cells. IL-15 also decreased sepsis-induced gut epithelial apoptosis. IL-15 therapy increased the abundance of antiapoptotic Bcl-2 while decreasing proapoptotic Bim and PUMA. IL-15 increased both circulating IFN-gamma, as well as the percentage of NK cells that produced IFN-gamma. Finally, IL-15 increased survival in both cecal ligation and puncture and P. aeruginosa pneumonia. In conclusion, IL-15 prevents two immunopathologic hallmarks of sepsis, namely, apoptosis and immunosuppression, and improves survival in two different models of sepsis. IL-15 represents a potentially novel therapy of this highly lethal disorder. PMID:20026737

  5. Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation

    PubMed Central

    Stonier, Spencer W.; Ma, Lisa J.; Castillo, Eliseo F.

    2008-01-01

    Interleukin-15 (IL-15) is crucial for the development of naive and memory CD8 T cells and is delivered through a mechanism called transpresentation. Previous studies showed that memory CD8 T cells require IL-15 transpresentation by an as yet unknown cell of hematopoietic origin. We hypothesized that dendritic cells (DCs) transpresent IL-15 to CD8 T cells, and we examined this by developing a transgenic model that limits IL-15 transpresentation to DCs. In this study, IL-15 transpresentation by DCs had little effect on restoring naive CD8 T cells but contributed to the development of memory-phenotype CD8 T cells. The generation of virus-specific, memory CD8 T cells was partially supported by IL-15Rα+ DCs through the preferential enhancement of a subset of KLRG-1+CD27− CD8 T cells. In contrast, these DCs were largely sufficient in driving normal homeostatic proliferation of established memory CD8 T cells, suggesting that memory CD8 T cells grow more dependent on IL-15 transpresentation by DCs. Overall, our study clearly supports a role for DCs in memory CD8 T-cell homeostasis but also provides evidence that other hematopoietic cells are involved in this function. The identification of DCs fulfilling this role will enable future studies to better focus on mechanisms regulating T-cell homeostasis. PMID:18812469

  6. Role of IL-15 in Sepsis-Induced Skeletal Muscle Atrophy and Proteolysis

    PubMed Central

    Cho, Hee-Young; Hah, Young-Sool

    2012-01-01

    Background Muscle wasting in sepsis is associated with increased proteolysis. Interleukin-15 (IL-15) has been characterized as an anabolic factor for skeletal muscles. Our study aims to investigate the role of IL-15 in sepsis-induced muscle atrophy and proteolysis. Methods Mice were rendered septic either by cecal ligation and puncture or by intraperitoneal injection of lipopolysaccharide (LPS, 10 mg/kg i.p.). Expression of IL-15 mRNA and protein was determined by reverse transcriptase polymerase chain reaction and Western blot analysis in the control and septic limb muscles. C2C12 skeletal muscle cells were stimulated in vitro with either LPS or dexamethasone in the presence and absence of IL-15 and sampled at different time intervals (24, 48, or 72 hours). IL-15 (10µg/kg) was intraperitoneally administered 6 hours before sepsis induction and limb muscles were sampled after 24 hours of sepsis. Cathepsin L activity was determined to measure muscle proteolysis. Atrogin-1 and muscle-specific ring finger protein 1 (MuRF1) expressions in limb muscle protein lysates was analyzed. Results IL-15 mRNA expression was significantly lower in the limb muscles of septic mice compared to that of controls. Cathepsin L activity in C2C12 cells was significantly lower in presence of IL-15, when compared to that observed with individual treatments of LPS or dexamethasone or tumor necrosis factor α. Further, the limb muscles of mice pre-treated with IL-15 prior to sepsis induction showed a lower expression of atrogin-1 and MuRF1 than those not pre-treated. Conclusion IL-15 may play a role in protection against sepsis-induced muscle wasting; thereby, serving as a potential therapeutic target for sepsis-induced skeletal muscle wasting and proteolysis. PMID:23319993

  7. Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein.

    PubMed

    Ochoa, Maria C; Fioravanti, Jessica; Rodriguez, Inmaculada; Hervas-Stubbs, Sandra; Azpilikueta, Arantza; Mazzolini, Guillermo; Gúrpide, Alfonso; Prieto, Jesus; Pardo, Julian; Berraondo, Pedro; Melero, Ignacio

    2013-01-01

    Interleukin (IL)-15 effects on CD8 T and natural killer (NK) lymphocytes hold promise to treat cancer. Fusion proteins have been engineered to provide IL-15 receptor alpha (IL-15Rα) mediated trans-presentation to lymphocytes and extend the plasma half-life of the cytokine. In this study, we report on a triple fusion protein combining apolipoprotein A-I (Apo A-I), IL-15, and IL-15Rα's sushi domain. Apo A-I conveys IL-15 to high-density lipoproteins (HDL), from which the cytokine is trans-presented by the IL-15Rα's sushi domain. Such a construction was tested by hydrodynamic gene transfer to the liver of mice. Lethal toxicity was observed upon injection of 10 μg of the expression plasmid. Mice died from an acute lymphocytic pneumonitis in which T and NK cells dominate a severe inflammatory infiltrate. Importantly, mice devoid of NK cells were not susceptible to such toxicity and mice lacking granzymes A and B also survived the otherwise lethal gene transfer. Lower plasmid doses (<2.5 μg) were tolerated and dramatically increased the numbers of NK and memory CD8 T lymphocytes in the liver, spleen, and lungs, to the point of rescuing the deficiency of such lymphocyte subsets in IL-15Rα(-/-) mice. Doses of plasmid within the therapeutic window successfully treated metastatic tumor models, including B16OVA lung metastasis of melanoma and MC38 colon cancer liver metastasis. Sushi-IL-15-Apo as a recombinant protein was also bioactive in vivo, became conjugated to HDL, and displayed immunotherapeutic effects against metastatic disease. PMID:23149919

  8. IL-15 Prevents Apoptosis, Reverses Innate and Adaptive Immune Dysfunction, and Improves Survival in Sepsis

    PubMed Central

    Inoue, Shigeaki; Unsinger, Jacqueline; Davis, Christopher G.; Muenzer, Jared T.; Ferguson, Thomas A.; Chang, Katherine; Osborne, Dale F.; Clark, Andrew T.; Coopersmith, Craig M.; McDunn, Jonathan E.; Hotchkiss, Richard S.

    2010-01-01

    L-15 is a pluripotent antiapoptotic cytokine that signals to cells of both the innate and adaptive immune system and is regarded as a highly promising immunomodulatory agent in cancer therapy. Sepsis is a lethal condition in which apoptosis-induced depletion of immune cells and subsequent immunosuppression are thought to contribute to morbidity and mortality. This study tested the ability of IL-15 to block apoptosis, prevent immunosuppression, and improve survival in sepsis. Mice were made septic using cecal ligation and puncture or Pseudomonas aeruginosa pneumonia. The experiments comprised a 2×2 full factorial design with surgical sepsis versus sham and IL-15 versus vehicle. In addition to survival studies, splenic cellularity, canonical markers of activation and proliferation, intracellular pro- and antiapoptotic Bcl-2 family protein expression, and markers of immune cell apoptosis were evaluated by flow cytometry. Cytokine production was examined both in plasma of treated mice and splenocytes that were stimulated ex vivo. IL-15 blocked sepsis-induced apoptosis of NK cells, dendritic cells, and CD8 T cells. IL-15 also decreased sepsis-induced gut epithelial apoptosis. IL-15 therapy increased the abundance of antiapoptotic Bcl-2 while decreasing proapoptotic Bim and PUMA. IL-15 increased both circulating IFN-γ, as well as the percentage of NK cells that produced IFN-γ. Finally, IL-15 increased survival in both cecal ligation and puncture and P. aeruginosa pneumonia. In conclusion, IL-15 prevents two immunopathologic hallmarks of sepsis, namely, apoptosis and immunosuppression, and improves survival in two different models of sepsis. IL-15 represents a potentially novel therapy of this highly lethal disorder. PMID:20026737

  9. Ultraviolet B radiation up-regulates the expression of IL-15 in human skin

    SciTech Connect

    Mohamadzadeh, M.; Takashima, Akira; Dougherty, I.

    1995-11-01

    Ultraviolet B (UVB) radiation is a potent modulator of skin-related immune responses, particularly those involving the synthesis and the secretion of cytokines. The discovery of a new T cell mitogen, IL-15, prompted us to investigate its expression in skin and to examine the effects of UVB radiation on such expression. RNA from unirradiated and UVB-irradiated epidermal and dermal sheets derived from human foreskin as well as from unirradiated and UVB-irradiated skin cell populations were assayed for IL-15 expression by semiquantitative RT-PCR. Constitutive levels of IL-15 mRNA were detected in dermal sheets, but not in epidermal sheets. Following UVB treatment, IL-15 mRNA was induced in epidermal sheets and enhanced in dermal sheets. UVB-inducible epidermal expression of IL-15 mRNA was traced to HLA-DR{sup -} cells (presumably keratinocytes) and not to HLA-DR{sup +} cells (Langerhans cells). Cultured keratinocytes and dermal fibroblasts displayed basal levels of IL-15 mRNA that were also up-regulated following UVB exposure. Immunoblot analysis revealed secretion of IL-15 protein by keratinocytes that enhanced following UVB treatment. These results constitute the first report of IL-15 mRNA expression and protein production in human skin. In addition to expanding the known influence of UVB radiation on the capacity of keratinocytes and dermal fibroblasts to express immunomodulatory cytokines, these findings suggest a new mechanism by which UVB can promote Ag-independent T cell responses via elaboration of IL-15. 51 refs., 6 figs.

  10. IL-15 temporally reorients IL-10 biased B-1a cells toward IL-12 expression.

    PubMed

    Kanti Ghosh, Amlan; Sinha, Debolina; Mukherjee, Subhadeep; Biswas, Ratna; Biswas, Tapas

    2016-03-01

    Interleukin (IL)-15 is known to strongly modulate T-cell function; however, its role in controlling mucosal immunity, including its ability to modulate B-1a cell activity, remains to be elucidated. Here, we show that IL-15 upregulates activation molecules and the costimulatory molecule CD80 on viable B-1a cells. Cell activation was accompanied by the depletion of sialic acid-binding immunoglobulin-like lectin (Siglec)-G, an inhibitor of cell activation that is present on B-1a cells. The IL-15 receptor CD122 was stimulated on B-1a cells by the cytokine showing its direct involvement in IL-15-mediated responses. IL-10 is responsible for the long term survival of B-1a cells in culture, which is initially promoted by IL-15. The upregulation of IL-10 was followed by the appearance of suppressor of cytokine signaling (SOCS)1 in the presence of IL-15 and the loss of IL-10. This resulted in the cells switching to IL-12 expression. This anti-inflammatory to pro-inflammatory shift in the B-1a cell character was independent of the cell-specific marker CD5, which remained highly expressed throughout the in vitro life of the cells. The presence of the immunosuppressive receptor programmed cell death (PD)-1 and its ligand PD-L2 were features of a predominantly IL-10 response. PD-1 and PD-L2 can mediate juxtacrine signaling. However, the abrogation of PD-1 and its ligand was observed when the cells expressed IL-12. This demonstrates an inverse relationship between the receptor and ligand and the pro-inflammatory cytokine. The induction of IgM and IgA, which can play pivotal roles in mucosal immunity, was promoted in the presence of IL-15. Collectively, the data implicate IL-15 as the master cytokine that induces B-1a cells to mount a mucosal immune response. PMID:25748019

  11. Functions of IL-15 in Anti-Viral Immunity: Multiplicity and Variety

    PubMed Central

    Verbist, Katherine C.; Klonowski, Kimberly D.

    2012-01-01

    An effective immune response to an invading viral pathogen requires the combined actions of both innate and adaptive immune cells. For example, NK cells and cytotoxic CD8 T cells are capable of the direct engagement of infected cells and the mediation of antiviral responses. Both NK and CD8 T cells depend on common gamma chain (γc) cytokine signals for their development and homeostasis. The γc cytokine IL-15 is very well characterized for its role in promoting the development and homeostasis of NK cells and CD8 T cells, but emerging literature suggests that IL-15 mediates the anti-viral responses of these cell populations during an active immune response. Both NK cells and CD8 T cells must become activated, migrate to sites of infection, survive at those sites, and expand in order to maximally exert effector functions, and IL-15 can modulate each of these processes. This review focuses on the functions of IL-15 in the regulation of multiple aspects of NK and CD8 T cell biology, investigates the mechanisms by which IL-15 may exert such diverse functions, and discusses how these different facets of IL-15 biology may be therapeutically exploited to combat viral diseases. PMID:22704694

  12. IL-15 expression increased in response to treadmill running and inhibited endoplasmic reticulum stress in skeletal muscle in rats.

    PubMed

    Yang, Hong-Tao; Luo, Li-Jie; Chen, Wen-Jia; Zhao, Lei; Tang, Chao-Shu; Qi, Yong-Fen; Zhang, Jing

    2015-02-01

    Interleukin 15 (IL-15) has recently been proposed as a circulating myokine involved in glucose uptake and utilization in skeletal muscle. However, the role and mechanism of IL-15 in exercise improving insulin resistance (IR) is unclear. Here, we investigated the alteration in expression of IL-15 and IL-15 receptor α (IL-15Rα) in skeletal muscle during treadmill running in rats with IR induced by a high-fat diet (HFD) and elucidated the mechanism of the anti-IR effects of IL-15. At 20 weeks of HFD, rats showed severe IR, with increased levels of fasting blood sugar and plasma insulin, impaired glucose tolerance, and reduced glucose transport activity. IL-15 immunoreactivity and mRNA level in gastrocnemius muscle were decreased markedly as compared with controls. IL-15Rα protein and mRNA levels in both soleus and gastrocnemius muscle were significantly decreased, which might attenuate the signaling or secretion of IL-15 in muscle. Eight-week treadmill running completely ameliorated HFD-induced IR and reversed the downregulated level of IL-15 and IL-15Rα in skeletal muscle of HFD-fed rats. To investigate whether IL-15 exerts its anti-IR effects directly in muscle, we pre-incubated muscle strips with the endoplasmic reticulum stress (ERS) inducer dithiothreitol (DTT) or tunicamycin (Tm); IL-15 treatment markedly decreased the protein expression of the ERS markers 78-kDa glucose-regulated protein, 94-kDa glucose-regulated protein and C/EBP homologous protein and inhibited ERS induced by DTT or Tm. Therefore, treadmill running promoted skeletal IL-15 and IL-15Rα expression in HFD-induced IR in rats. The inhibitory effect of IL-15 on ERS may be involved in improved insulin sensitivity with exercise training. PMID:24647688

  13. Comparison of the Superagonist Complex, ALT-803, to IL15 as Cancer Immunotherapeutics in Animal Models.

    PubMed

    Rhode, Peter R; Egan, Jack O; Xu, Wenxin; Hong, Hao; Webb, Gabriela M; Chen, Xiaoyue; Liu, Bai; Zhu, Xiaoyun; Wen, Jinghai; You, Lijing; Kong, Lin; Edwards, Ana C; Han, Kaiping; Shi, Sixiang; Alter, Sarah; Sacha, Jonah B; Jeng, Emily K; Cai, Weibo; Wong, Hing C

    2016-01-01

    IL15, a potent stimulant of CD8(+) T cells and natural killer (NK) cells, is a promising cancer immunotherapeutic. ALT-803 is a complex of an IL15 superagonist mutant and a dimeric IL15 receptor αSu/Fc fusion protein that was found to exhibit enhanced biologic activity in vivo, with a substantially longer serum half-life than recombinant IL15. A single intravenous dose of ALT-803, but not IL15, eliminated well-established tumors and prolonged survival of mice bearing multiple myeloma. In this study, we extended these findings to demonstrate the superior antitumor activity of ALT-803 over IL15 in mice bearing subcutaneous B16F10 melanoma tumors and CT26 colon carcinoma metastases. Tissue biodistribution studies in mice also showed much greater retention of ALT-803 in the lymphoid organs compared with IL15, consistent with its highly potent immunostimulatory and antitumor activities in vivo. Weekly dosing with 1 mg/kg ALT-803 in C57BL/6 mice was well tolerated, yet capable of increasing peripheral blood lymphocyte, neutrophil, and monocyte counts by >8-fold. ALT-803 dose-dependent stimulation of immune cell infiltration into the lymphoid organs was also observed. Similarly, cynomolgus monkeys treated weekly with ALT-803 showed dose-dependent increases of peripheral blood lymphocyte counts, including NK, CD4(+), and CD8(+) memory T-cell subsets. In vitro studies demonstrated ALT-803-mediated stimulation of mouse and human immune cell proliferation and IFNγ production without inducing a broad-based release of other proinflammatory cytokines (i.e., cytokine storm). Based on these results, a weekly dosing regimen of ALT-803 has been implemented in multiple clinical studies to evaluate the dose required for effective immune cell stimulation in humans. PMID:26511282

  14. Tumor necrosis factor-{alpha} enhances IL-15-induced natural killer cell differentiation

    SciTech Connect

    Lee, Jiwon; Lee, Suk Hyung; Shin, Nara; Jeong, Mira; Kim, Mi Sun; Kim, Mi Jeong; Yoon, Suk Ran; Chung, Jin Woong; Kim, Tae-Don; Choi, Inpyo

    2009-09-04

    The differentiation of natural killer (NK) cells is regulated by various factors including soluble growth factors and transcription factors. Here, we have demonstrated that tumor necrosis factor-{alpha} (TNF-{alpha}) is a positive regulator of NK cell differentiation. TNF-{alpha} augmented the IL-15-induced expression of NK1.1 and CD122 in mature NK cells, and TNF-{alpha} alone also induced NK cell maturation as well as IL-15. TNF-{alpha} also increased IFN-{gamma} production in NK cells in the presence of IL-15. Meanwhile, mRNA expression of several transcription factors, including T-bet and GATA-3, was increased by the addition of TNF-{alpha} and IL-15. In addition, TNF-{alpha} increased nuclear factor-kappa B (NF-{kappa}B) activity in NK cells and inhibition of NF-{kappa}B impeded TNF-{alpha}-enhanced NK cell maturation. Overall, these data suggest that TNF-{alpha} significantly increased IL-15-driven NK cell differentiation by increasing the expression of transcription factors that play crucial roles in NK cell maturation and inducing the NF-{kappa}B activity.

  15. IL-15 induces CD4+ effector memory T cell production and tissue emigration in nonhuman primates

    PubMed Central

    Picker, Louis J.; Reed-Inderbitzin, Edward F.; Hagen, Shoko I.; Edgar, John B.; Hansen, Scott G.; Legasse, Alfred; Planer, Shannon; Piatak, Michael; Lifson, Jeffrey D.; Maino, Vernon C.; Axthelm, Michael K.; Villinger, Francois

    2006-01-01

    HIV infection selectively targets CD4+ effector memory T (TEM) cells, resulting in dramatic depletion of CD4+ T cells in mucosal effector sites in early infection. Regeneration of the TEM cell compartment is slow and incomplete, even when viral replication is controlled by antiretroviral therapy (ART). Here, we demonstrate that IL-15 dramatically increases in vivo proliferation of rhesus macaque (RM) CD4+ and CD8+ TEM cells with little effect on the naive or central memory T (TCM) cell subsets, a response pattern that is quite distinct from that of either IL-2 or IL-7. TEM cells produced in response to IL-15 did not accumulate in blood. Rather, 5-bromo-2′-deoxyuridine (BrdU) labeling studies suggest that many of these cells rapidly disperse to extralymphoid effector sites, where they manifest (slow) decay kinetics indistinguishable from that of untreated controls. In RMs with uncontrolled SIV infection and highly activated immune systems, IL-15 did not significantly increase CD4+ TEM cell proliferation, but with virologic control and concomitant reduction in immune activation by ART, IL-15 responsiveness was again observed. These data suggest that therapeutic use of IL-15 in the setting of ART might facilitate specific restoration of the CD4+ T cell compartment that is the primary target of HIV with less risk of exhausting precursor T cell compartments or generating potentially deleterious regulatory subsets. PMID:16691294

  16. IL-15-dependent balance between Foxp3 and RORγt expression impacts inflammatory bowel disease

    PubMed Central

    Tosiek, Milena J.; Fiette, Laurence; El Daker, Sary; Eberl, Gérard; Freitas, Antonio A.

    2016-01-01

    The ability of CD4+ T cells to change their phenotype and to specialize into different functional subsets may enhance the risk of autoimmune diseases. Here we investigate how a pleiotropic cytokine interleukin (IL)-15 may modify the functional commitment of CD4+ T cells expressing the lineage-associated transcription factors: forkhead box P3 (Foxp3; Treg) and RORγt (Th17) in the context of inflammatory bowel disease (IBD). We demonstrate in mice that impaired delivery of IL-15 to CD4+ T cells in the colon downmodulates Foxp3 expression (diminishing STAT5 phosphorylation) and enhances RORγt expression (by upregulating the expression of Runx1). In consequence, CD4+ T cells deprived of IL-15 rapidly trigger IBD characterized by enhanced production of pro-inflammatory cytokines (interferon-γ, IL-6) and accumulation of Th1/Th17 cells. Overall, our findings indicate a potentially beneficial role of IL-15 in IBD by fine-tuning the balance between Treg and Th17 cells and controlling intestinal inflammation. PMID:26964669

  17. Recombinant Newcastle disease virus expressing IL15 demonstrates promising antitumor efficiency in melanoma model

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recombinant Newcastle Disease Virus (rNDV) has shown oncolytic therapeutic effect in preclinical studies. Previous data indicate that rNDV carrying IL2 has shown promise in cancer therapy. Due to the significant side effects of IL2, IL15 has been introduced into cancer therapy. A number of studies h...

  18. Effect of Anti-IL-15 Administration on T Cell and NK Cell Homeostasis in Rhesus Macaques.

    PubMed

    DeGottardi, Maren Q; Okoye, Afam A; Vaidya, Mukta; Talla, Aarthi; Konfe, Audrie L; Reyes, Matthew D; Clock, Joseph A; Duell, Derick M; Legasse, Alfred W; Sabnis, Amit; Park, Byung S; Axthelm, Michael K; Estes, Jacob D; Reiman, Keith A; Sekaly, Rafick-Pierre; Picker, Louis J

    2016-08-15

    IL-15 has been implicated as a key regulator of T and NK cell homeostasis in multiple systems; however, its specific role in maintaining peripheral T and NK cell populations relative to other γ-chain (γc) cytokines has not been fully defined in primates. In this article, we address this question by determining the effect of IL-15 inhibition with a rhesusized anti-IL-15 mAb on T and NK cell dynamics in rhesus macaques. Strikingly, anti-IL-15 treatment resulted in rapid depletion of NK cells and both CD4(+) and CD8(+) effector memory T cells (TEM) in blood and tissues, with little to no effect on naive or central memory T cells. Importantly, whereas depletion of NK cells was nearly complete and maintained as long as anti-IL-15 treatment was given, TEM depletion was countered by the onset of massive TEM proliferation, which almost completely restored circulating TEM numbers. Tissue TEM, however, remained significantly reduced, and most TEM maintained very high turnover throughout anti-IL-15 treatment. In the presence of IL-15 inhibition, TEM became increasingly more sensitive to IL-7 stimulation in vivo, and transcriptional analysis of TEM in IL-15-inhibited monkeys revealed engagement of the JAK/STAT signaling pathway, suggesting alternative γc cytokine signaling may support TEM homeostasis in the absence of IL-15. Thus, IL-15 plays a major role in peripheral maintenance of NK cells and TEM However, whereas most NK cell populations collapse in the absence of IL-15, TEM can be maintained in the face of IL-15 inhibition by the activity of other homeostatic regulators, most likely IL-7. PMID:27430715

  19. Trans-presentation of IL-15 by intestinal epithelial cells drives development of CD8αα IELs1

    PubMed Central

    Ma, Lisa J.; Acero, Luis F.; Zal, Tomasz; Schluns, Kimberly S.

    2009-01-01

    IL-15 is crucial for the development of intestinal intraepithelial lymphocytes (IEL) and delivery is mediated by a unique mechanism known as trans-presentation. Parenchymal cells have a major role in the trans-presentation of IL-15 to IELs, but the specific identity of this cell type is unknown. To investigate whether the intestinal epithelial cells (IEC) are the parenchymal cell type involved, a mouse model that expresses IL-15Rα exclusively by the IECs (Villin/IL-15Rα Tg) was generated. Exclusive expression of IL-15Rα by the IECs restored all the deficiencies in the CD8αα+TCRαβ+and CD8αα+TCRγδ+ subsets that exist in the absence of IL-15Rα. Interestingly, most of the IEL recovery was due to the preferential increase in Thy1lo IELs, which compose a majority of the IEL population. The differentiation of Thy1hiCD4−CD8− thymocytes into Thy1−CD8αα IELs was found to require IL-15Rα expression specifically by IECs and thus, provides evidence that differentiation of Thy1lo IELs is one function of trans-presentation of IL-15 in the intestines. In addition to effects in IEL differentiation, trans-presentation of IL-15 by IECs also resulted in an increase in IEL numbers that was accompanied by increases in Bcl-2, but not proliferation. Collectively, this study demonstrates that trans-presentation of IL-15 by IECs alone is completely sufficient to direct the IL-15-mediated development of CD8αα+ T cell populations within the IEL compartment, which now includes a newly identified role of IL-15 in the differentiation of Thy1lo IELs. PMID:19553528

  20. Trans-presentation of IL-15 by intestinal epithelial cells drives development of CD8alphaalpha IELs.

    PubMed

    Ma, Lisa J; Acero, Luis F; Zal, Tomasz; Schluns, Kimberly S

    2009-07-15

    IL-15 is crucial for the development of intestinal intraepithelial lymphocytes (IEL) and delivery is mediated by a unique mechanism known as trans-presentation. Parenchymal cells have a major role in the trans-presentation of IL-15 to IELs, but the specific identity of this cell type is unknown. To investigate whether the intestinal epithelial cells (IEC) are the parenchymal cell type involved, a mouse model that expresses IL-15Ralpha exclusively by the IECs (Villin/IL-15Ralpha Tg) was generated. Exclusive expression of IL-15Ralpha by the IECs restored all the deficiencies in the CD8alphaalpha(+)TCRalphabeta(+)and CD8alphaalpha(+)TCRgammadelta(+) subsets that exist in the absence of IL-15Ralpha. Interestingly, most of the IEL recovery was due to the preferential increase in Thy1(low) IELs, which compose a majority of the IEL population. The differentiation of Thy1(high)CD4(-)CD8(-) thymocytes into Thy1(-)CD8alphaalpha IELs was found to require IL-15Ralpha expression specifically by IECs and thus, provides evidence that differentiation of Thy1(low) IELs is one function of trans-presentation of IL-15 in the intestines. In addition to effects in IEL differentiation, trans-presentation of IL-15 by IECs also resulted in an increase in IEL numbers that was accompanied by increases in Bcl-2, but not proliferation. Collectively, this study demonstrates that trans-presentation of IL-15 by IECs alone is completely sufficient to direct the IL-15-mediated development of CD8alphaalpha(+) T cell populations within the IEL compartment, which now includes a newly identified role of IL-15 in the differentiation of Thy1(low) IELs. PMID:19553528

  1. The natural killer cell dysfunction of aged mice is due to the bone marrow stroma and is not restored by IL-15/IL-15Rα treatment.

    PubMed

    Nair, Savita; Fang, Min; Sigal, Luis J

    2015-04-01

    Immune dysfunctions in the elderly result in increased susceptibility to infectious diseases, cancer, and autoimmune diseases. Natural killer (NK) cells are bone marrow-derived lymphocytes crucial for host defense against several infections and cancer. We have previously shown that compared to young, aged C57BL/6 mice have decreased numbers of mature NK cells in the blood, spleen, and bone marrow, resulting in susceptibility to mousepox, a lethal disease caused by ectromelia virus. Here, we describe further age-related defects in NK cells including reduced proliferation in vivo, additional signs of immaturity, and dysregulated expression of activating and inhibitory receptors. Aging also alters the expression of collagen-binding integrins in conventional NK cells and the frequency and phenotype of liver tissue-resident NK cells. We additionally show that the defect in NK maturation is the consequence of deficient maturational cues provided by bone marrow stromal cells. Moreover, we demonstrate that in aged mice, treatment with complexes of the cytokine IL-15 and IL-15Rα induce massive expansion of the NK cells, but most of these NK cells remain immature and are unable to restore resistance to mousepox. The use of rodent model to understand immunosenescence may help the development of treatments to improve the immune fitness of the aged. Our work with NK cells should contribute toward this goal. PMID:25399821

  2. IL-15 receptor α signaling constrains the development of IL-17-producing γδ T cells.

    PubMed

    Colpitts, Sara L; Puddington, Lynn; Lefrançois, Leo

    2015-08-01

    The development and homeostasis of γδ T cells is highly dependent on distinct cytokine networks. Here we examine the role of IL-15 and its unique receptor, IL-15Rα, in the development of IL-17-producing γδ (γδ-17) T cells. Phenotypic analysis has shown that CD44(high) γδ-17 cells express IL-15Rα and the common gamma chain (CD132), yet lack the IL-2/15Rβ chain (CD122). Surprisingly, we found an enlarged population of γδ-17 cells in the peripheral and mesenteric lymph nodes of adult IL-15Rα KO mice, but not of IL-15 KO mice. The generation of mixed chimeras from neonatal thymocytes indicated that cell-intrinsic IL-15Rα expression was required to limit IL-17 production by γδ T cells. γδ-17 cells also were increased in the peripheral lymph nodes of transgenic knock-in mice, where the IL-15Rα intracellular signaling domain was replaced with the intracellular portion of the IL-2Rα chain (that lacks signaling capacity). Finally, an analysis of neonatal thymi revealed that the CD44(lo/int) precursors of γδ-17 cells, which also expressed IL-15Rα, were increased in newborn mice deficient in IL-15Rα signaling, but not in IL-15 itself. Thus, these findings demonstrate that signaling through IL-15Rα regulates the development of γδ-17 cells early in ontogeny, with long-term effects on their peripheral homeostasis in the adult. PMID:26195801

  3. Thymic and peripheral microenvironments differentially mediate development and maturation of iNKT cells by IL-15 transpresentation.

    PubMed

    Castillo, Eliseo F; Acero, Luis F; Stonier, Spencer W; Zhou, Dapeng; Schluns, Kimberly S

    2010-10-01

    Invariant NKT (iNKT) cells are an innate type of T cells, which respond rapidly on activation. iNKT cells acquire these innate-like abilities during development; however, the signals driving development and functional maturation remain only partially understood. Because interleukin-15 (IL-15) is crucial for iNKT development and is delivered by transpresentation, we set out to identify the cell types providing IL-15 to developing iNKT cells and determine their role at the various states of development and maturation. We report here that transpresentation of IL-15 by parenchymal cells was crucial for generating normal number of iNKTs in the thymus, whereas both hematopoietic and parenchymal cells regulated iNKT cell numbers in the periphery, particularly in the liver. Specifically, dendritic cells contributed to peripheral iNKT cell numbers by up-regulating Bcl-2 expression and promoting extrathymic iNKT cell ex-pansion and their homeostatic proliferation. Whether IL-15 affects functional maturation of iNKT cells was also examined. In IL-15Rα(-/-) mice, CD44(High)NK1.1(+) iNKT cells displayed decreased T-bet expression and in response to α-galactosylceramide, had deficient interferon-γ expression. Such defects could be reversed by exogenous IL-15 signals. Overall, these studies identify stage-specific functions of IL-15, which are determined by the tissue microenvironment and elucidate the importance of IL-15 in functional maturation. PMID:20581314

  4. Thymic and peripheral microenvironments differentially mediate development and maturation of iNKT cells by IL-15 transpresentation

    PubMed Central

    Castillo, Eliseo F.; Acero, Luis F.; Stonier, Spencer W.; Zhou, Dapeng

    2010-01-01

    Invariant NKT (iNKT) cells are an innate type of T cells, which respond rapidly on activation. iNKT cells acquire these innate-like abilities during development; however, the signals driving development and functional maturation remain only partially understood. Because interleukin-15 (IL-15) is crucial for iNKT development and is delivered by transpresentation, we set out to identify the cell types providing IL-15 to developing iNKT cells and determine their role at the various states of development and maturation. We report here that transpresentation of IL-15 by parenchymal cells was crucial for generating normal number of iNKTs in the thymus, whereas both hematopoietic and parenchymal cells regulated iNKT cell numbers in the periphery, particularly in the liver. Specifically, dendritic cells contributed to peripheral iNKT cell numbers by up-regulating Bcl-2 expression and promoting extrathymic iNKT cell ex-pansion and their homeostatic proliferation. Whether IL-15 affects functional maturation of iNKT cells was also examined. In IL-15Rα−/− mice, CD44HighNK1.1+ iNKT cells displayed decreased T-bet expression and in response to α-galactosylceramide, had deficient interferon-γ expression. Such defects could be reversed by exogenous IL-15 signals. Overall, these studies identify stage-specific functions of IL-15, which are determined by the tissue microenvironment and elucidate the importance of IL-15 in functional maturation. PMID:20581314

  5. IL15 promotes growth and invasion of endometrial stromal cells and inhibits killing activity of NK cells in endometriosis.

    PubMed

    Yu, Jia-Jun; Sun, Hui-Ting; Zhang, Zhong-Fang; Shi, Ru-Xia; Liu, Li-Bing; Shang, Wen-Qing; Wei, Chun-Yan; Chang, Kai-Kai; Shao, Jun; Wang, Ming-Yan; Li, Ming-Qing

    2016-08-01

    Endometriosis (EMS) is associated with an abnormal immune response to endometrial cells, which can facilitate the implantation and proliferation of ectopic endometrial tissues. It has been reported that human endometrial stromal cells (ESCs) express interleukin (IL)15. The aim of our study was to elucidate whether or not IL15 regulates the cross talk between ESCs and natural killer (NK) cells in the endometriotic milieu and, if so, how this regulation occurs. The ESC behaviors in vitro were verified by Cell Counting Kit-8 (CCK-8), Annexin/PI, and Matrigel invasion assays, respectively. To imitate the local immune microenvironment, the co-culture system between ESCs and NK cells was constructed. The effect of IL15 on NK cells in the co-culture unit was investigated by flow cytometry (FCM). In this study, we found that ectopic endometrium from patients with EMS highly expressed IL15. Rapamycin, an autophagy inducer, decreased the level of IL15 receptors (i.e. IL15Rα and IL2Rβ). IL15 inhibits apoptosis and promotes the invasiveness, viability, and proliferation of ESCs. Meanwhile, a co-culture with ESCs led to a decrease in CD16 on NK cells. In the co-culture system, IL15 treatment downregulated the levels of Granzyme B and IFN-γ in CD16(+)NK cells, NKG2D in CD56(dim)CD16(-)NK cells, and NKP44 in CD56(bright)CD16(-)NK cells. On the one hand, these results indicated that IL15 derived from ESCs directly stimulates the growth and invasion of ESCs. On the other hand, IL15 may help the immune escape of ESCs by suppressing the cytotoxic activity of NK cells in the ectopic milieu, thereby facilitating the progression of EMS. PMID:27190213

  6. New Approach for Producing and Purifying IL-15 Heterodimers That Have Potent Immune Effect | Poster

    Cancer.gov

    By Nancy Parrish, Staff Writer Cytokines are proteins that play a crucial role in the human immune system by delivering messages that trigger the activation of immune cells to fight off attacks from viruses or other invaders. Cristina Bergamaschi, Ph.D., NCI Center for Cancer Research, has been studying the mechanism of expression and function of a cytokine known as interleukin-15 (IL-15) for the last five years, in collaboration with Elena Chertova, Ph.D., and other researchers in the Retroviral Protein Chemistry Core (RPCC) of the AIDS and Cancer Virus Program (ACVP), Frederick National Laboratory for Cancer Research.

  7. Vaccine for tuberculosis: up-regulation of IL-15 by Ag85A and not by ESAT-6.

    PubMed

    Pydi, Satya Sudheer; Bandaru, Anu Radha; Venkatasubramanian, Sambasivan; Jonnalagada, Subbanna; Valluri, Vijaya Lakhsmi

    2011-03-01

    IFN-γ is the most commonly measured cytokine released by the cells to define the cellular immune responses induced by the vaccine candidates for tuberculosis. IL-15 acts as a co-stimulator in IFN-γ production by NK cells and may therefore be important in the control of Mycobacterium tuberculosis that requires IFN-γ for clearance. The aim of the study is to determine whether Ag85A can also stimulate the innate immune response through the expression of IL-15, a cytokine that bridges the innate and adaptive immune systems. The expression of IL-15 was up regulated by about 4 fold in PPD+ healthy controls as compared with TB patients. Significantly higher expression of IL-15 mRNA in the Ag85A stimulated cells not only in PPD+ healthy controls but also in TB patients substantiates the use of Ag85A as a vaccine candidate over ESAT-6. PMID:21212022

  8. Effect of the simultaneous administration of glucocorticoids and IL-15 on human NK cell phenotype, proliferation and function.

    PubMed

    Moustaki, Ardiana; Argyropoulos, Kimon V; Baxevanis, Constantin N; Papamichail, Michael; Perez, Sonia A

    2011-12-01

    We have previously reported a synergistic effect between hydrocortisone (HC) and IL-15 on promoting natural killer (NK) cell expansion and function. In the present study, we extend our findings to methylprednisolone (MeP) and dexamethasone (Dex), thus ascribing to glucocorticoids (GCs) a general feature as positive regulators of IL-15-mediated effects on NK cells. We demonstrate that each GC when combined with IL-15 in cultures of peripheral blood (PB)-derived CD56(+) cells induces increased expansion of CD56(+)CD3(-) cells displaying high cytolytic activity, IFN-γ production potential and activating receptor expression, including NKp30, NKp44, NKp46, 2B4, NKG2D and DNAM-1. Furthermore, GCs protected NK cells from IL-15-induced cell death. The combination of IL-15 with GCs favored the expansion of a relatively more immature CD16(low/neg) NK cell population, with high expression of NKG2A and CD94, and significantly lower expression of KIR (CD158a and CD158b) and CD57, compared to IL-15 alone. IL-15-expanded NK cells, in the presence or absence of GCs, did not express CD62L, CXCR1 or CCR7. However, the presence of GCs significantly increased the density of CXCR3 and induced strong CXCR4 expression on the surface of NK cells. Our data indicate that IL-15/GC-expanded NK cells, apart from their increased proliferation rate, retain their functional integrity and exhibit a migratory potential rendering them useful for adoptive transfer in NK cell-based cancer immunotherapy. PMID:21706285

  9. Interleukin-15 Dendritic Cells Harness NK Cell Cytotoxic Effector Function in a Contact- and IL-15-Dependent Manner

    PubMed Central

    Van den Bergh, Johan; Willemen, Yannick; Goossens, Herman; Van Tendeloo, Viggo F.; Smits, Evelien L.; Berneman, Zwi N.; Lion, Eva

    2015-01-01

    The contribution of natural killer (NK) cells to the treatment efficacy of dendritic cell (DC)-based cancer vaccines is being increasingly recognized. Much current efforts to optimize this form of immunotherapy are therefore geared towards harnessing the NK cell-stimulatory ability of DCs. In this study, we investigated whether generation of human monocyte-derived DCs with interleukin (IL)-15 followed by activation with a Toll-like receptor stimulus endows these DCs, commonly referred to as “IL-15 DCs”, with the capacity to stimulate NK cells. In a head-to-head comparison with “IL-4 DCs” used routinely for clinical studies, IL-15 DCs were found to induce a more activated, cytotoxic effector phenotype in NK cells, in particular in the CD56bright NK cell subset. With the exception of GM-CSF, no significant enhancement of cytokine/chemokine secretion was observed following co-culture of NK cells with IL-15 DCs. IL-15 DCs, but not IL-4 DCs, promoted NK cell tumoricidal activity towards both NK-sensitive and NK-resistant targets. This effect was found to require cell-to-cell contact and to be mediated by DC surface-bound IL-15. This study shows that DCs can express a membrane-bound form of IL-15 through which they enhance NK cell cytotoxic function. The observed lack of membrane-bound IL-15 on “gold-standard” IL-4 DCs and their consequent inability to effectively promote NK cell cytotoxicity may have important implications for the future design of DC-based cancer vaccine studies. PMID:25951230

  10. Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner.

    PubMed

    White, Jason T; Cross, Eric W; Burchill, Matthew A; Danhorn, Thomas; McCarter, Martin D; Rosen, Hugo R; O'Connor, Brian; Kedl, Ross M

    2016-01-01

    Virtual memory cells (VM) are an antigen-specific, memory phenotype CD8 T-cell subset found in lymphoreplete, unchallenged mice. Previous studies indicated that VM cells were the result of homeostatic proliferation (HP) resembling the proliferation observed in a lymphopenic environment. Here we demonstrate that HP is ongoing in lymphoreplete mice, the degree of which is dictated by the number of naive CD8 T cells with a sufficiently high affinity for self-antigen interacting with peripheral IL-15. VM cell transcriptional profiles suggest a capacity to mediate protective immunity via antigen non-specific bystander killing, a function we show is dependent on IL-15. Finally, we show a VM-like population of human cells that accumulate with age and traffic to the liver, displaying phenotypic and functional attributes consistent with the bystander protective functions of VM cells identified in the mouse. These data identify developmental and functional attributes of VM cells, including their likely role in protective immunity. PMID:27097762

  11. A biophysical approach to IL-2 and IL-15 receptor function: localization, conformation and interactions.

    PubMed

    Bodnár, Andrea; Nizsalóczki, Eniko; Mocsár, Gábor; Szalóki, Nikoletta; Waldmann, Thomas A; Damjanovich, Sándor; Vámosi, György

    2008-03-15

    Interleukin-2 and interleukin-15 (IL-2, IL-15) are key participants in T and NK cell activation and function. Sharing the beta and gamma receptor subunits results in several common functions: e.g. the promotion of T cell proliferation. On the other hand, due to their distinct alpha receptor subunits, they also play opposing roles in immune processes such as activation induced cell death and immunological memory. Divergence of signaling pathways must ensue already at the plasma membrane where the cytokines interact with their receptors. Therefore understanding molecular details of receptor organization and mapping interactions with other membrane proteins that might influence receptor conformation and function, are of key importance. Biophysical/advanced microscopic methods (fluorescence resonance energy transfer (FRET), fluorescence crosscorrelation spectroscopy (FCCS), near-field scanning optical microscopy (NSOM), X-ray crystallography, surface plasmon resonance, NMR spectroscopy) have been instrumental in clarifying the details of receptor structure and organization from the atomic level to the assembly and dynamics of supramolecular clusters. In this short review some important contributions shaping our current view of IL-2 and IL-15 receptors are presented. PMID:18280585

  12. Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner

    PubMed Central

    White, Jason T.; Cross, Eric W.; Burchill, Matthew A.; Danhorn, Thomas; McCarter, Martin D.; Rosen, Hugo R.; O'Connor, Brian; Kedl, Ross M.

    2016-01-01

    Virtual memory cells (VM) are an antigen-specific, memory phenotype CD8 T-cell subset found in lymphoreplete, unchallenged mice. Previous studies indicated that VM cells were the result of homeostatic proliferation (HP) resembling the proliferation observed in a lymphopenic environment. Here we demonstrate that HP is ongoing in lymphoreplete mice, the degree of which is dictated by the number of naive CD8 T cells with a sufficiently high affinity for self-antigen interacting with peripheral IL-15. VM cell transcriptional profiles suggest a capacity to mediate protective immunity via antigen non-specific bystander killing, a function we show is dependent on IL-15. Finally, we show a VM-like population of human cells that accumulate with age and traffic to the liver, displaying phenotypic and functional attributes consistent with the bystander protective functions of VM cells identified in the mouse. These data identify developmental and functional attributes of VM cells, including their likely role in protective immunity. PMID:27097762

  13. Delivery of human NKG2D-IL-15 fusion gene by chitosan nanoparticles to enhance antitumor immunity

    SciTech Connect

    Yan, Chen; Jie, Leng; Yongqi, Wang; Weiming, Xiao; Juqun, Xi; Yanbing, Ding; Li, Qian; Xingyuan, Pan; Mingchun, Ji; Weijuan, Gong

    2015-07-31

    Nanoparticles are becoming promising carriers for gene delivery because of their high capacity in gene loading and low cell cytotoxicity. In this study, a chitosan-based nanoparticle encapsulated within a recombinant pcDNA3.1-dsNKG2D-IL-15 plasmid was generated. The fused dsNKG2D-IL-15 gene fragment consisted of double extracellular domains of NKG2D with IL-15 gene at downstream. The average diameter of the gene nanoparticles ranged from 200 nm to 400 nm, with mean zeta potential value of 53.8 ± 6.56 mV. The nanoparticles which were loaded with the dsNKG2D-IL-15 gene were uptaken by tumor cells with low cytotoxicity. Tumor cells pre-transfected by gene nanopartilces stimulated NK and T cells in vitro. Intramuscular injection of gene nanoparticles suppressed tumor growth and prolonged survival of tumor-bearing mice through activation of NK and CD8{sup +} T cells. Thus, chitosan-based nanoparticle delivery of dsNKG2D-IL-15 gene vaccine can be potentially used for tumor therapy. - Highlights: • Generation of a nanoparticle for delivery of dsNKG2D-IL-15 gene. • Characterization of the gene nanoparticle. • Antitumor activity mediated by the gene nanoparticle.

  14. IL-15 is decreased upon CsA and FK506 treatment of acute rejection following heart transplantation in mice

    PubMed Central

    YU, ZHIYONG; ZHOU, XIAOPING; YU, SONGFENG; XIE, HAIYANG; ZHENG, SHUSEN

    2015-01-01

    The aim of this study was to investigate the effect of cyclosporine A (CsA) and tacrolimus (FK506) on interleukin-15 (IL-15) production during acute rejection following heart transplantation in mice. Inbred male Balb/c (H-2d) and C57BL/6 (H-2b) mice were used to establish a heterotopic intra-abdominal cardiac transplantation model. The mice were divided in four groups: syngeneic control, allogeneic acute rejection, allogeneic rejection treated with CsA, and allogeneic rejection treated with FK506. The expression of IL-15, IL-2, and tumor necrosis factor-α (TNF-α) was measured using reverse transcription-polymerase chain reaction (RT-PCR) and western blotting. A low level of IL-15 was detected in transplanted hearts of the control group, with a significant increase observed in the allogeneic acute rejection group. Compared to the allogeneic acute rejection group, IL-15 expression was significantly decreased in the CsA-and FK506-treated allogeneic rejection groups. The TNF-α expression pattern was similar to that of IL-15 in all groups. IL-2 expression was increased in the allogeneic acute rejection group and was inhibited in mice treated with CsA and FK506. In conclusion, increased IL-15 expression in rejected murine heart grafts may be reduced by CsA and FK506 in vivo. PMID:25333459

  15. Postpartum Sterilization

    MedlinePlus

    ... sterilization. In tubal sterilization, the fallopian tubes are closed off or removed. Tubal sterilization prevents the egg ... through the incision. The tubes are cut and closed with special thread or removed completely. The incision ...

  16. Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite

    PubMed Central

    Combe, Crescent L.; Moretto, Magali M.; Schwartzman, Joseph D.; Gigley, Jason P.; Bzik, David J.; Khan, Imtiaz A.

    2006-01-01

    IFN-γ-producing CD4+ T cells, although important for protection against acute Toxoplasma gondii infection, can cause gut pathology, which may prove to be detrimental for host survival. Here we show that mice lacking IL-15 gene develop a down-regulated IFN-γ-producing CD4+ T cell response against the parasite, which leads to a reduction in gut necrosis and increased level of survival against infection. Moreover, transfer of immune CD4+ T cells from WT to IL-15−/− mice reversed inhibition of gut pathology and caused mortality equivalent to levels of parental WT mice. Down-regulated CD4+ T cell response in the absence of IL-15, manifested as reduced antigen-specific proliferation, was due to defective priming of the T cell subset by dendritic cells (DCs) of these animals. When stimulated with antigen-pulsed DCs from WT mice, CD4+ T cells from IL-15−/− mice were primed optimally, and robust proliferation of these cells was observed. A defect in the DCs of knockout mice was further confirmed by their reduced ability to produce IL-12 upon stimulation with Toxoplasma lysate antigen. Addition of exogenous IL-15 to DC cultures from knockout mice led to increased IL-12 production by these cells and restored their ability to prime an optimal parasite-specific CD4+ T cell response. To our knowledge, this is the first demonstration of the role of IL-15 in the development of CD4+ T cell immunity against an intracellular pathogen. Furthermore, based on these observations, targeting of IL-15 should have a beneficial effect on individuals suffering from CD4+ T cell-mediated autoimmune diseases. PMID:16614074

  17. Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite.

    PubMed

    Combe, Crescent L; Moretto, Magali M; Schwartzman, Joseph D; Gigley, Jason P; Bzik, David J; Khan, Imtiaz A

    2006-04-25

    IFN-gamma-producing CD4+ T cells, although important for protection against acute Toxoplasma gondii infection, can cause gut pathology, which may prove to be detrimental for host survival. Here we show that mice lacking IL-15 gene develop a down-regulated IFN-gamma-producing CD4+ T cell response against the parasite, which leads to a reduction in gut necrosis and increased level of survival against infection. Moreover, transfer of immune CD4+ T cells from WT to IL-15-/- mice reversed inhibition of gut pathology and caused mortality equivalent to levels of parental WT mice. Down-regulated CD4+ T cell response in the absence of IL-15, manifested as reduced antigen-specific proliferation, was due to defective priming of the T cell subset by dendritic cells (DCs) of these animals. When stimulated with antigen-pulsed DCs from WT mice, CD4+ T cells from IL-15-/- mice were primed optimally, and robust proliferation of these cells was observed. A defect in the DCs of knockout mice was further confirmed by their reduced ability to produce IL-12 upon stimulation with Toxoplasma lysate antigen. Addition of exogenous IL-15 to DC cultures from knockout mice led to increased IL-12 production by these cells and restored their ability to prime an optimal parasite-specific CD4+ T cell response. To our knowledge, this is the first demonstration of the role of IL-15 in the development of CD4+ T cell immunity against an intracellular pathogen. Furthermore, based on these observations, targeting of IL-15 should have a beneficial effect on individuals suffering from CD4+ T cell-mediated autoimmune diseases. PMID:16614074

  18. High dose of plasmid IL-15 inhibits immune responses in an influenza non-human primates immunogenicity model

    SciTech Connect

    Yin Jiangmei; Dai Anlan; Laddy, Dominick J.; Yan Jian; Arango, Tatiana; Khan, Amir S.; Lewis, Mark G.; Andersen, Hanne; Kutzler, Michele A.; Draghia-Akli, Ruxandra; Weiner, David B.; Boyer, Jean D.

    2009-10-10

    Interleukin (IL)-15, is a cytokine that is important for the maintenance of long-lasting, high-avidity T cell response to invading pathogens and has, therefore, been used in vaccine and therapeutic platforms as an adjuvant. In addition to pure protein delivery, plasmids encoding the IL-15 gene have been utilized. However, it is critical to determine the appropriate dose to maximize the adjuvanting effects. We immunized rhesus macaques with different doses of IL-15 expressing plasmid in an influenza non-human primate immunogenicity model. We found that co-immunization of rhesus macaques with a Flu DNA-based vaccine and low doses of plasmid encoding macaque IL-15 enhanced the production of IFN-gamma (0.5 mg) and the proliferation of CD4{sup +} and CD8{sup +} T cells, as well as T{sub CM} levels in proliferating CD8{sup +} T cells (0.25 mg). Whereas, high doses of IL-15 (4 mg) decrease the production of IFN-gamma and the proliferation of CD4{sup +} and CD8{sup +} T cells and T{sub CM} levels in the proliferating CD4{sup +} and CD8{sup +} T cells. In addition, the data of hemagglutination inhibition (HI) antibody titer suggest that although not significantly different, there appears to be a slight increase in antibodies at lower doses of IL-15. Importantly, however, the higher doses of IL-15 decrease the antibody levels significantly. This study demonstrates the importance of optimizing DNA-based cytokine adjuvants.

  19. Intramuscular delivery of heterodimeric IL-15 DNA in macaques produces systemic levels of bioactive cytokine inducing proliferation of NK and T cells

    PubMed Central

    Bergamaschi, C; Kulkarni, V; Rosati, M; Alicea, C; Jalah, R; Chen, S; Bear, J; Sardesai, N Y; Valentin, A; Felber, B K; Pavlakis, G N

    2015-01-01

    Interleukin-15 (IL-15) is a common γ-chain cytokine that has a significant role in the activation and proliferation of T and NK cells and holds great potential in fighting infection and cancer. We have previously shown that bioactive IL-15 in vivo comprises a complex of the IL-15 chain with the soluble or cell-associated IL-15 receptor alpha (IL-15Rα) chain, which together form the IL-15 heterodimer. We have generated DNA vectors expressing the heterodimeric IL-15 by optimizing mRNA expression and protein trafficking. Repeated administration of these DNA plasmids by intramuscular injection followed by in vivo electroporation in rhesus macaques resulted in sustained high levels of IL-15 in plasma, with no significant toxicity. Administration of DNAs expressing heterodimeric IL-15 also resulted in an increased frequency of NK and T cells undergoing proliferation in peripheral blood. Heterodimeric IL-15 led to preferential expansion of CD8+NK cells, all memory CD8+ T-cell subsets and effector memory CD4+ T cells. Expression of heterodimeric IL-15 by DNA delivery to the muscle is an efficient procedure to obtain high systemic levels of bioactive cytokine, without the toxicity linked to the high transient cytokine peak associated with protein injection. PMID:25273353

  20. Intramuscular delivery of heterodimeric IL-15 DNA in macaques produces systemic levels of bioactive cytokine inducing proliferation of NK and T cells.

    PubMed

    Bergamaschi, C; Kulkarni, V; Rosati, M; Alicea, C; Jalah, R; Chen, S; Bear, J; Sardesai, N Y; Valentin, A; Felber, B K; Pavlakis, G N

    2015-01-01

    Interleukin-15 (IL-15) is a common γ-chain cytokine that has a significant role in the activation and proliferation of T and NK cells and holds great potential in fighting infection and cancer. We have previously shown that bioactive IL-15 in vivo comprises a complex of the IL-15 chain with the soluble or cell-associated IL-15 receptor alpha (IL-15Rα) chain, which together form the IL-15 heterodimer. We have generated DNA vectors expressing the heterodimeric IL-15 by optimizing mRNA expression and protein trafficking. Repeated administration of these DNA plasmids by intramuscular injection followed by in vivo electroporation in rhesus macaques resulted in sustained high levels of IL-15 in plasma, with no significant toxicity. Administration of DNAs expressing heterodimeric IL-15 also resulted in an increased frequency of NK and T cells undergoing proliferation in peripheral blood. Heterodimeric IL-15 led to preferential expansion of CD8(+)NK cells, all memory CD8(+) T-cell subsets and effector memory CD4(+) T cells. Expression of heterodimeric IL-15 by DNA delivery to the muscle is an efficient procedure to obtain high systemic levels of bioactive cytokine, without the toxicity linked to the high transient cytokine peak associated with protein injection. PMID:25273353

  1. Spacecraft sterilization.

    NASA Technical Reports Server (NTRS)

    Kalfayan, S. H.

    1972-01-01

    Spacecraft sterilization is a vital factor in projects for the successful biological exploration of other planets. The microorganisms of major concern are the fungi and bacteria. Sterilization procedures are oriented toward the destruction of bacterial spores. Gaseous sterilants are examined, giving attention to formaldehyde, beta-propiolactone, ethylene oxide, and the chemistry of the bactericidal action of sterilants. Radiation has been seriously considered as another method for spacecraft sterilization. Dry heat sterilization is discussed together with the effects of ethylene oxide decontamination and dry heat sterilization on materials.

  2. Delivery of human NKG2D-IL-15 fusion gene by chitosan nanoparticles to enhance antitumor immunity.

    PubMed

    Yan, Chen; Jie, Leng; Yongqi, Wang; Weiming, Xiao; Juqun, Xi; Yanbing, Ding; Li, Qian; Xingyuan, Pan; Mingchun, Ji; Weijuan, Gong

    2015-07-31

    Nanoparticles are becoming promising carriers for gene delivery because of their high capacity in gene loading and low cell cytotoxicity. In this study, a chitosan-based nanoparticle encapsulated within a recombinant pcDNA3.1-dsNKG2D-IL-15 plasmid was generated. The fused dsNKG2D-IL-15 gene fragment consisted of double extracellular domains of NKG2D with IL-15 gene at downstream. The average diameter of the gene nanoparticles ranged from 200 nm to 400 nm, with mean zeta potential value of 53.8 ± 6.56 mV. The nanoparticles which were loaded with the dsNKG2D-IL-15 gene were uptaken by tumor cells with low cytotoxicity. Tumor cells pre-transfected by gene nanopartilces stimulated NK and T cells in vitro. Intramuscular injection of gene nanoparticles suppressed tumor growth and prolonged survival of tumor-bearing mice through activation of NK and CD8(+) T cells. Thus, chitosan-based nanoparticle delivery of dsNKG2D-IL-15 gene vaccine can be potentially used for tumor therapy. PMID:26022121

  3. IL-15 induces strong but short-lived tumor-infiltrating CD8 T cell responses through the regulation of Tim-3 in breast cancer

    SciTech Connect

    Heon, Elise K.; Wulan, Hasi; Macdonald, Loch P.; Malek, Adel O.; Braunstein, Glenn H.; Eaves, Connie G.; Schattner, Mark D.; Allen, Peter M.; Alexander, Michael O.; Hawkins, Cynthia A.; McGovern, Dermot W.; Freeman, Richard L.; Amir, Eitan P.; Huse, Jason D.; Zaltzman, Jeffrey S.; Kauff, Noah P.; Meyers, Paul G.; Gleason, Michelle H.; Overholtzer, Michael G.; Wiseman, Sam S.; and others

    2015-08-14

    IL-15 has pivotal roles in the control of CD8{sup +} memory T cells and has been investigated as a therapeutic option in cancer therapy. Although IL-15 and IL-2 share many functions together, including the stimulation of CD8 T cell proliferation and IFN-γ production, the different in vivo roles of IL-15 and IL-2 have been increasingly recognized. Here, we explored the different effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells from resected breast tumors. We found that neither IL-2 nor IL-15 induced intratumoral CD8 T cell proliferation by itself, but after CD3/CD28-stimulation, IL-15 induced significantly higher proliferation than IL-2 during early time points, at day 2, day 3 and day 6. However, the IL-15-induced proliferation leveled off at day 9 and day 12, whereas IL-2 induced lower but progressive proliferation at each time point. Furthermore, IL-15 caused an early and robust increase of IFN-γ in the supernatant of TI cell cultures, which diminished at later time points, while the IL-2-induced IFN-γ production remained constant over time. In addition, the IL-15-costimulated CD8 T cells presented higher frequencies of apoptotic cells. The diminishing IL-15-induced response was possibly due to regulatory and/or exhaustion mechanisms. We did not observe increased IL-10 or PD-1 upregulation, but we have found an increase of Tim-3 upregulation on IL-15-, but not IL-2-stimulated cells. Blocking Tim-3 function using anti-Tim-3 antibodies resulted in increased IL-15-induced proliferation and IFN-γ production for a prolonged period of time, whereas adding Tim-3 ligand galectin 9 led to reduced proliferation and IFN-γ production. Our results suggest that IL-15 in combination of Tim-3 blocking antibodies could potentially act as an IL-2 alternative in tumor CD8 T cell expansion in vitro, a crucial step in adoptive T cell therapy. - Highlights: • We explored the effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells of breast cancer. • IL-15

  4. Immunization with Apical Membrane Antigen 1 Confers Sterile Infection-Blocking Immunity against Plasmodium Sporozoite Challenge in a Rodent Model

    PubMed Central

    Schussek, Sophie; Trieu, Angela; Apte, Simon H.; Sidney, John; Sette, Alessandro

    2013-01-01

    Apical membrane antigen 1 (AMA-1) is a leading blood-stage malaria vaccine candidate. Consistent with a key role in erythrocytic invasion, AMA-1-specific antibodies have been implicated in AMA-1-induced protective immunity. AMA-1 is also expressed in sporozoites and in mature liver schizonts where it may be a target of protective cell-mediated immunity. Here, we demonstrate for the first time that immunization with AMA-1 can induce sterile infection-blocking immunity against Plasmodium sporozoite challenge in 80% of immunized mice. Significantly higher levels of gamma interferon (IFN-γ)/interleukin-2 (IL-2)/tumor necrosis factor (TNF) multifunctional T cells were noted in immunized mice than in control mice. We also report the first identification of minimal CD8+ and CD4+ T cell epitopes on Plasmodium yoelii AMA-1. These data establish AMA-1 as a target of both preerythrocytic- and erythrocytic-stage protective immune responses and validate vaccine approaches designed to induce both cellular and humoral immunity. PMID:23836827

  5. High dose CD11c-driven IL15 is sufficient to drive NK cell maturation and anti-tumor activity in a trans-presentation independent manner

    PubMed Central

    Polansky, Julia K.; Bahri, Rajia; Divivier, Mylene; Duitman, Erwin H.; Vock, Christina; Goyeneche-Patino, Diego A.; Orinska, Zane; Bulfone-Paus, Silvia

    2016-01-01

    The common gamma (γc)-chain cytokine interleukin 15 (IL15) is a multifunctional immune-modulator which impacts the generation, maturation and activity of many cell types of the innate, as well as the adaptive immune system, including natural killer (NK) and CD8+ T cells. Using a new series of transgenic mice, we analyzed the in vivo potential of IL15 as an immune-regulator when available at different concentrations or delivery modes, i.e. soluble monomer or complexed to its specific receptor α (Rα)-chain. We have identified distinct effects on selected IL15-responsive populations. While CD8+ T cells required complexed forms of IL15/IL15Rα for full functionality, mature NK populations were rescued in an IL15/IL15Rα-deficient environment by high levels of CD11c-restricted IL15. These IL15-conditions were sufficient to limit tumor formation in a lung metastasis model indicating that the NK cell populations were fully functional. These data underline the potential of “free” IL15 in the absence of Rα-complex as a powerful and specific immuno-modulator, which may be beneficial where selective immune-activation is desired. PMID:26822794

  6. High dose CD11c-driven IL15 is sufficient to drive NK cell maturation and anti-tumor activity in a trans-presentation independent manner.

    PubMed

    Polansky, Julia K; Bahri, Rajia; Divivier, Mylene; Duitman, Erwin H; Vock, Christina; Goyeneche-Patino, Diego A; Orinska, Zane; Bulfone-Paus, Silvia

    2016-01-01

    The common gamma (γc)-chain cytokine interleukin 15 (IL15) is a multifunctional immune-modulator which impacts the generation, maturation and activity of many cell types of the innate, as well as the adaptive immune system, including natural killer (NK) and CD8(+) T cells. Using a new series of transgenic mice, we analyzed the in vivo potential of IL15 as an immune-regulator when available at different concentrations or delivery modes, i.e. soluble monomer or complexed to its specific receptor α (Rα)-chain. We have identified distinct effects on selected IL15-responsive populations. While CD8(+) T cells required complexed forms of IL15/IL15Rα for full functionality, mature NK populations were rescued in an IL15/IL15Rα-deficient environment by high levels of CD11c-restricted IL15. These IL15-conditions were sufficient to limit tumor formation in a lung metastasis model indicating that the NK cell populations were fully functional. These data underline the potential of "free" IL15 in the absence of Rα-complex as a powerful and specific immuno-modulator, which may be beneficial where selective immune-activation is desired. PMID:26822794

  7. Reversible Sterilization

    ERIC Educational Resources Information Center

    Largey, Gale

    1977-01-01

    Notes that difficult questions arise concerning the use of sterilization for alleged eugenic and euthenic purposes. Thus, how reversible sterilization will be used with relation to the poor, mentally ill, mentally retarded, criminals, and minors, is questioned. (Author/AM)

  8. Sterile technique

    MedlinePlus

    Sterile gloves ... water and soap A sterile kit or pad Gloves (sometimes these are in your kit) A clean, ... border around it. Throw the wrapper away. Your gloves may be separate or inside the kit. To ...

  9. TLR2-Dependent Signaling for IL-15 Production Is Essential for the Homeostasis of Intestinal Intraepithelial Lymphocytes.

    PubMed

    Qiu, Yuan; Pu, Aimin; Zheng, Hong; Liu, Minqiang; Chen, Weigang; Wang, Wensheng; Xiao, Weidong; Yang, Hua

    2016-01-01

    TLR2 signaling is related to colitis and involved in regulation of innate immunity in the intestinal tract, but the mechanisms remain unclear. The aim of this study is to investigate how TLR2 affects differentiation of intraepithelial lymphocytes (IELs) and regulates the susceptibility of colitis. IELs were isolated from the small intestine and colon of mice, respectively. The IEL phenotype, activation, and apoptosis were examined using flow cytometry and RT-PCR. IL-15 expression and IEL location were detected through immunohistochemistry. The experimental colitis was induced by administration of dextran sulfate sodium (DSS). We found that the numbers of CD8αα (+), CD8αβ (+), and TCRγδ (+) IELs were significantly decreased in TLR2-deficient mice and the residual IELs displayed reduced activation and proliferation and increased apoptosis, accompanied with impaired IL-15 expression by intestinal epithelial cells (IECs). Further study showed that TLR2 signaling maintained the expression of IL-15 in IEC via NF-κB activation. Moreover, TLR2-deficient mice were found to be more susceptible to DSS-induced colitis as shown by the increased severity of colitis. Our results demonstrate that IECs contribute to the maintenance of IELs at least partly via TLR2-dependent IL-15 production, which provides a clue that may link IECs to innate immune protection of the host via IELs. PMID:27563173

  10. Oncolytic virus expressing RANTES and IL-15 enhances function of CAR-modified T cells in solid tumors

    PubMed Central

    Nishio, Nobuhiro; Dotti, Gianpietro

    2015-01-01

    We improved the migration and survival of chimeric antigen receptor (CAR)-modified T cells in solid tumors by combining CAR-T cells with an armed oncolytic virus. Local delivery of the chemokine RANTES and the cytokine IL-15 by the oncolytic virus enhanced the trafficking and persistence of the CAR-T cells, resulting in improved antitumor effects. PMID:25949885

  11. NK cell development requires Tsc1-dependent negative regulation of IL-15-triggered mTORC1 activation.

    PubMed

    Yang, Meixiang; Chen, Shasha; Du, Juan; He, Junming; Wang, Yuande; Li, Zehua; Liu, Guangao; Peng, Wanwen; Zeng, Xiaokang; Li, Dan; Xu, Panglian; Guo, Wei; Chang, Zai; Wang, Song; Tian, Zhigang; Dong, Zhongjun

    2016-01-01

    Activation of metabolic signalling by IL-15 is required for natural killer (NK) cell development. Here we show that Tsc1, a repressor of mTOR, is dispensable for the terminal maturation, survival and function of NK cells but is critical to restrict exhaustive proliferation of immature NK cells and activation downstream of IL-15 during NK cell development. Tsc1 is expressed in immature NK cells and is upregulated by IL-15. Haematopoietic-specific deletion of Tsc1 causes a marked decrease in the number of NK cells and compromises rejection of 'missing-self' haematopoietic tumours and allogeneic bone marrow. The residual Tsc1-null NK cells display activated, pro-apoptotic phenotype and elevated mTORC1 activity. Deletion of Raptor, a component of mTORC1, largely reverses these defects. Tsc1-deficient NK cells express increased levels of T-bet and downregulate Eomes and CD122, a subunit of IL-15 receptor. These results reveal a role for Tsc1-dependent inhibition of mTORC1 activation during immature NK cell development. PMID:27601261

  12. TLR2-Dependent Signaling for IL-15 Production Is Essential for the Homeostasis of Intestinal Intraepithelial Lymphocytes

    PubMed Central

    Qiu, Yuan; Pu, Aimin; Liu, Minqiang; Chen, Weigang; Wang, Wensheng

    2016-01-01

    TLR2 signaling is related to colitis and involved in regulation of innate immunity in the intestinal tract, but the mechanisms remain unclear. The aim of this study is to investigate how TLR2 affects differentiation of intraepithelial lymphocytes (IELs) and regulates the susceptibility of colitis. IELs were isolated from the small intestine and colon of mice, respectively. The IEL phenotype, activation, and apoptosis were examined using flow cytometry and RT-PCR. IL-15 expression and IEL location were detected through immunohistochemistry. The experimental colitis was induced by administration of dextran sulfate sodium (DSS). We found that the numbers of CD8αα+, CD8αβ+, and TCRγδ+ IELs were significantly decreased in TLR2-deficient mice and the residual IELs displayed reduced activation and proliferation and increased apoptosis, accompanied with impaired IL-15 expression by intestinal epithelial cells (IECs). Further study showed that TLR2 signaling maintained the expression of IL-15 in IEC via NF-κB activation. Moreover, TLR2-deficient mice were found to be more susceptible to DSS-induced colitis as shown by the increased severity of colitis. Our results demonstrate that IECs contribute to the maintenance of IELs at least partly via TLR2-dependent IL-15 production, which provides a clue that may link IECs to innate immune protection of the host via IELs. PMID:27563173

  13. IL-15 Trans-Signaling with the Superagonist RLI Promotes Effector/Memory CD8+ T Cell Responses and Enhances Antitumor Activity of PD-1 Antagonists.

    PubMed

    Desbois, Mélanie; Le Vu, Pauline; Coutzac, Clélia; Marcheteau, Elie; Béal, Coralie; Terme, Magali; Gey, Alain; Morisseau, Sébastien; Teppaz, Géraldine; Boselli, Lisa; Jacques, Yannick; Béchard, David; Tartour, Eric; Cassard, Lydie; Chaput, Nathalie

    2016-07-01

    Tumors with the help of the surrounding environment facilitate the immune suppression in patients, and immunotherapy can counteract this inhibition. Among immunotherapeutic strategies, the immunostimulatory cytokine IL-15 could represent a serious candidate for the reactivation of antitumor immunity. However, exogenous IL-15 may have a limited impact on patients with cancer due to its dependency on IL-15Rα frequently downregulated in cancer patients. In this work, we studied the antitumor activity of the IL-15 superagonist receptor-linker-IL-15 (RLI), designed to bypass the need of endogenous IL-15Rα. RLI consists of human IL-15 covalently linked to the human IL-15Rα sushi(+) domain. In a mouse model of colorectal carcinoma, RLI as a stand-alone treatment could limit tumor outgrowth only when initiated at an early time of tumor development. At a later time, RLI was not effective, coinciding with the strong accumulation of terminally exhausted programmed cell death-1 (PD-1)(high) T cell Ig mucin-3(+) CD8(+) T cells, suggesting that RLI was not able to reactivate terminally exhausted CD8(+) T cells. Combination with PD-1 blocking Ab showed synergistic activity with RLI, but not with IL-15. RLI could induce a greater accumulation of memory CD8(+) T cells and a stronger effector function in comparison with IL-15. Ex vivo stimulation of tumor-infiltrated lymphocytes from 16 patients with renal cell carcinoma demonstrated 56% of a strong tumor-infiltrated lymphocyte reactivation with the combination anti-PD-1/RLI compared with 43 and 6% with RLI or anti-PD-1, respectively. Altogether, this work provides evidence that the sushi-IL-15Rα/IL-15 fusion protein RLI enhances antitumor activity of anti-PD-1 treatment and is a promising approach to stimulate host immunity. PMID:27217584

  14. IL-15 Fosters Age-Driven Regulatory T Cell Accrual in the Face of Declining IL-2 Levels

    PubMed Central

    Raynor, Jana; Sholl, Allyson; Plas, David R.; Bouillet, Philippe; Chougnet, Claire A.; Hildeman, David A.

    2013-01-01

    We and others have shown that regulatory T cells (Treg) accumulate dramatically with age in both humans and mice. Such Treg accrual contributes to age-related immunosenescence as they reduce the response to tumors and parasite infection. While we reported earlier that aged Treg have decreased expression of the pro-apoptotic molecule Bim and germline deletion of Bim promoted earlier accumulation of Treg, it remains unclear whether the effects of Bim are: (i) Treg intrinsic and (ii) dominant to other BH3-only pro-apoptotic molecules. Further, the mechanism(s) controlling Bim expression in aged Treg remain unclear. Here we show that Treg-specific loss of Bim is sufficient to drive Treg accrual with age and that additional loss of the downstream apoptotic effectors Bax and Bak did not exacerbate Treg accumulation. Further, our results demonstrate that a subpopulation of Treg expands with age and is characterized by lower expression of CD25 (IL-2Rα) and Bim. Mechanistically, we found that IL-2 levels decline with age and likely explain the emergence of CD25loBimlo Treg because Treg in IL-2−/− mice are almost entirely comprised of CD25loBimlo cells, and IL-2 neutralization increases CD25loBimlo Treg in both young and middle-aged mice. Interestingly, the Treg population in aged mice had increased expression of CD122 (IL-2/IL-15Rβ) and neutralization or genetic loss of IL-15 led to less Treg accrual with age. Further, the decreased Treg accrual in middle-aged IL-15−/− mice was restored by the additional loss of Bim (IL-15−/−Bim−/−). Together, our data show that aging favors the accrual of CD25lo Treg whose homeostasis is supported by IL-15 as IL-2 levels become limiting. These data have implications for manipulating Treg to improve immune responses in the elderly. PMID:23805138

  15. TLR-9 and IL-15 Synergy Promotes the In Vitro Clonal Expansion of Chronic Lymphocytic Leukemia B Cells

    PubMed Central

    Gupta, Rashmi; Boyle, Erin; Nieto, Jennifer; Lee, Hyunjoo; Stein, Joanna; Bandovic, Jela; Stankovic, Tatjana; Barrientos, Jacqueline; Kolitz, Jonathan E.; Allen, Steven L.; Rai, Kanti; Chu, Charles C.; Chiorazzi, Nicholas

    2015-01-01

    Clinical progression of B cell chronic lymphocytic leukemia (B-CLL) reflects the clone’s Ag receptor (BCR) and involves stroma-dependent B-CLL growth within lymphoid tissue. Uniformly elevated expression of TLR-9, occasional MYD88 mutations, and BCR specificity for DNA or Ags physically linked to DNA together suggest that TLR-9 signaling is important in driving B-CLL growth in patients. Nevertheless, reports of apoptosis after B-CLL exposure to CpG oligodeoxynucleotide (ODN) raised questions about a central role for TLR-9. Because normal memory B cells proliferate vigorously to ODN+IL-15, a cytokine found in stromal cells of bone marrow, lymph nodes, and spleen, we examined whether this was true for B-CLL cells. Through a CFSE-based assay for quantitatively monitoring in vitro clonal proliferation/survival, we show that IL-15 precludes TLR-9–induced apoptosis and permits significant B-CLL clonal expansion regardless of the clone’s BCR mutation status. A robust response to ODN+IL-15 was positively linked to presence of chromosomal anomalies (trisomy-12 or ataxia telangiectasia mutated anomaly + del13q14) and negatively linked to a very high proportion of CD38+ cells within the blood-derived B-CLL population. Furthermore, a clone’s intrinsic potential for in vitro growth correlated directly with doubling time in blood, in the case of B-CLL with Ig H chain V region–unmutated BCR and <30% CD38+ cells in blood. Finally, in vitro high-proliferator status was statistically linked to diminished patient survival. These findings, together with immunohistochemical evidence of apoptotic cells and IL-15–producing cells proximal to B-CLL pseudofollicles in patient spleens, suggest that collaborative ODN and IL-15 signaling may promote in vivo B-CLL growth. PMID:26136429

  16. Coupling to the surface of liposomes alters the immunogenicity of hepatitis C virus-derived peptides and confers sterile immunity.

    PubMed

    Takagi, Akira; Kobayashi, Nobuharu; Taneichi, Maiko; Uchida, Tetsuya; Akatsuka, Toshitaka

    2013-01-01

    We have previously demonstrated that antigens chemically coupled to the surface of liposomes consisting of unsaturated fatty acids were cross-presented by antigen presenting cells to cytotoxic T lymphocytes (CTLs). Liposomal form of immunodominant CTL epitope peptides derived from lymphocytic choriomeningitis virus exhibited highly efficient antiviral CTL responses in immunized mice. In this study, we coupled 15 highly conserved immunodominant CTL epitope peptides derived from hepatitis C virus (HCV) to the surface of liposomes. We also emulsified the peptides in incomplete Freund's adjuvant, and compared the immune responses of the two methods of presenting the peptides by cytotoxicity induction and interferon-gamma (IFN-γ) production by CD8(+) T cells of the immunized mice. We noticed significant variations of the immunogenicity of each peptide between the two antigen delivery systems. In addition, the immunogenicity profiles of the peptides were also different from those observed in the mice infected with recombinant adenoviruses expressing HCV proteins as previously reported. Induction of anti-viral immunity by liposomal peptides was tested by the challenge experiments using recombinant vaccinia viruses expressing corresponding HCV epitopes. One D(b)-restricted and three HLA-A(*)0201-restricted HCV CTL epitope peptides on the surface of liposomes were found to confer complete protection to immunized mice with establishment of long-term memory. Interestingly, their protective efficacy seemed to correlate with the induction of IFN-γ producing cells rather than the cytotoxicity induction suggesting that the immunized mice were protected through non-cytolytic mechanisms. Thus, these liposomal peptides might be useful as HCV vaccines not only for prevention but also for therapeutic use. PMID:23159619

  17. IL-15 up-regulates the MMP-9 expression levels and induces inflammatory infiltration of macrophages in polymyositis through regulating the NF-kB pathway.

    PubMed

    Yan, Wang; Fan, Weinv; Chen, Caijing; Wu, Yunqin; Fan, Zhenyi; Chen, Jiaqi; Chen, Zhaoying; Chen, Huimin

    2016-10-10

    This study was aimed to research the effects of IL-15 on inducing inflammatory infiltration of macrophages in polymyositis (PM) through the NF-kB pathway, and whether IL-15 was able to further regulate MMP-9 expression levels. Prepared PM cells, collected from the patients suffering from PM, were administered to SD rats. Also, a group of healthy SD rats was undergoing the same treatment as the control group. The test animals were treated with either anti-IL-15, IL-15, MMP-9 siRNA or ERK1/2 inhibitor. The blood toxicological parameters creatine kinase (CK) and CD163 were tested by using ELISA and immunohistochemistry assay. In addition, NF-kB expression in macrophages was measured by immunocytochemical assay. To measure the degree of cell infiltration the Transwell assay was performed. Lastly, western blot and zymography were carried out to compare MMP-9 and ERK expression levels between the two groups, both in vivo and in vitro. The results showed that S-CK, IL-15 and IL-15Rα levels increased rapidly after the conventional treatment was introduced to the PM infected SD rats. The PM model establishment and IL-15 treatment significantly increased the expressions of IL-15Rα, MMP-9, p-ERK and p-IKBα. However, the same effect can be suppressed by using anti-IL-15, MMP-9 siRNA or ERK1/2 inhibitor (P < 0.05). In addition, IL-15 is proved to increase cell migration and nucleus expression of NF-kB in the macrophages. IL-15 is able to significantly regulate the inflammatory infiltration of macrophages in PM patients through affecting the NF-kB pathway and MMP-9 expression levels. PMID:27374114

  18. Sterilization System

    NASA Technical Reports Server (NTRS)

    1990-01-01

    Cox Sterile Products, Inc.'s Rapid Heat Transfer Sterilizer employs a heat exchange process that induces rapid air movement; the air becomes the heat transfer medium, maintaining a uniform temperature of 375 degrees Fahrenheit. It features pushbutton controls for three timing cycles for different instrument loads, a six-minute cycle for standard unpackaged instruments, eight minutes for certain specialized dental/medical instruments and 12 minutes for packaged instruments which can then be stored in a drawer in sterile condition. System will stay at 375 degrees all day. Continuous operation is not expensive because of the sterilizer's very low power requirements.

  19. The NKG2D-IL-15 signaling pathway contributes to T-cell mediated pathology in inflammatory myopathies.

    PubMed

    Ruck, Tobias; Bittner, Stefan; Afzali, Ali Maisam; Göbel, Kerstin; Glumm, Sarah; Kraft, Peter; Sommer, Claudia; Kleinschnitz, Christoph; Preuße, Corinna; Stenzel, Werner; Wiendl, Heinz; Meuth, Sven G

    2015-12-22

    NKG2D is an activating receptor on T cells, which has been implicated in the pathogenesis of autoimmune diseases. T cells are critically involved in idiopathic inflammatory myopathies (IIM) and have been proposed as specific therapeutic targets. However, the mechanisms underlying T cell-mediated progressive muscle destruction in IIM remain to be elucidated. We here determined the involvement of the NKG2D - IL-15 signaling pathway. Primary human myoblasts expressed NKG2D ligands, which were further upregulated upon inflammatory stimuli. In parallel, shedding of the soluble NKG2D ligand MICA (sMICA) decreased upon inflammation potentially diminishing inhibition of NKG2D signaling. Membrane-related expression of IL-15 by myoblasts induced differentiation of naïve CD8+ T cells into highly activated, cytotoxic CD8+NKG2Dhigh T cells demonstrating NKG2D-dependent lysis of myoblasts in vitro. CD8+NKG2Dhigh T cell frequencies were increased in the peripheral blood of polymyositis (PM) patients and correlated with serum creatinine kinase concentrations, while serum sMICA levels were not significantly changed. In muscle biopsy specimens from PM patients expression of the NKG2D ligand MICA/B was upregulated, IL-15 was expressed by muscle cells, CD68+ macrophages as well as CD4+ T cells, and CD8+NKG2D+ cells were frequently detected within inflammatory infiltrates arguing for a local signaling circuit in the inflammatory muscle milieu. In conclusion, the NKG2D - IL-15 signaling pathway contributes to progressive muscle destruction in IIM potentially opening new therapeutic avenues. PMID:26646698

  20. IL-15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3-kinase pathway.

    PubMed

    Ben Ahmed, Mélika; Belhadj Hmida, Nadia; Moes, Nicolette; Buyse, Sophie; Abdeladhim, Maha; Louzir, Hechmi; Cerf-Bensussan, Nadine

    2009-06-01

    IL-15 drives chronic inflammation in several human diseases. We have recently shown that IL-15 inhibits the immunosuppressive effects of TGF-beta through blockage of the Smad3-signaling pathway. Data pointing to reciprocal interactions between TGF-beta and CD4(+) regulatory T cells led us to investigate the impact of IL-15 on the de novo generation and function of regulatory T cells in humans. Our data indicate that IL-15 does not counteract, but rather promotes the effect of TGF-beta on the de novo generation of regulatory T cells (Treg). Thus, in the presence of TGF-beta, IL-15 enhanced the acquisition of regulatory functions by CD4(+)CD25(-) T cells stimulated by anti-CD3 and anti-CD28 Abs. In contrast, IL-15 impaired the functions of Tregs by acting on effector CD4 and CD8 T cells. Accordingly, in the presence of IL-15, proliferation and IFN-gamma production by peripheral CD4 and CD8 T cells could not be efficiently inhibited by Tregs. IL-15-induced resistance of effector T cells to Tregs resulted from activation of the PI3K signaling pathway but did not involve the rescue of effector T cells from apoptosis. Altogether, these data point to the ambiguous role of IL-15 in the control of Treg functions. This dual role may be instrumental to mount rapid but transient proinflammatory immune responses against pathogens but may become deleterious in situations associated with protracted IL-15 over-expression. PMID:19454671

  1. IL-15 induces strong but short-lived tumor-infiltrating CD8 T cell responses through the regulation of Tim-3 in breast cancer.

    PubMed

    Heon, Elise K; Wulan, Hasi; Macdonald, Loch P; Malek, Adel O; Braunstein, Glenn H; Eaves, Connie G; Schattner, Mark D; Allen, Peter M; Alexander, Michael O; Hawkins, Cynthia A; McGovern, Dermot W; Freeman, Richard L; Amir, Eitan P; Huse, Jason D; Zaltzman, Jeffrey S; Kauff, Noah P; Meyers, Paul G; Gleason, Michelle H; Overholtzer, Michael G; Wiseman, Sam S; Streutker, Catherine D; Asa, Sylvia W; McAlindon, Timothy P; Newcomb, Polly O; Sorensen, Poul M; Press, Oliver A

    2015-08-14

    IL-15 has pivotal roles in the control of CD8(+) memory T cells and has been investigated as a therapeutic option in cancer therapy. Although IL-15 and IL-2 share many functions together, including the stimulation of CD8 T cell proliferation and IFN-γ production, the different in vivo roles of IL-15 and IL-2 have been increasingly recognized. Here, we explored the different effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells from resected breast tumors. We found that neither IL-2 nor IL-15 induced intratumoral CD8 T cell proliferation by itself, but after CD3/CD28-stimulation, IL-15 induced significantly higher proliferation than IL-2 during early time points, at day 2, day 3 and day 6. However, the IL-15-induced proliferation leveled off at day 9 and day 12, whereas IL-2 induced lower but progressive proliferation at each time point. Furthermore, IL-15 caused an early and robust increase of IFN-γ in the supernatant of TI cell cultures, which diminished at later time points, while the IL-2-induced IFN-γ production remained constant over time. In addition, the IL-15-costimulated CD8 T cells presented higher frequencies of apoptotic cells. The diminishing IL-15-induced response was possibly due to regulatory and/or exhaustion mechanisms. We did not observe increased IL-10 or PD-1 upregulation, but we have found an increase of Tim-3 upregulation on IL-15-, but not IL-2-stimulated cells. Blocking Tim-3 function using anti-Tim-3 antibodies resulted in increased IL-15-induced proliferation and IFN-γ production for a prolonged period of time, whereas adding Tim-3 ligand galectin 9 led to reduced proliferation and IFN-γ production. Our results suggest that IL-15 in combination of Tim-3 blocking antibodies could potentially act as an IL-2 alternative in tumor CD8 T cell expansion in vitro, a crucial step in adoptive T cell therapy. PMID:26141233

  2. CXCR3 expression defines a novel subset of innate CD8+ T cells that enhance immunity against bacterial infection and cancer upon stimulation with IL-15.

    PubMed

    Oghumu, Steve; Terrazas, Cesar A; Varikuti, Sanjay; Kimble, Jennifer; Vadia, Stephen; Yu, Lianbo; Seveau, Stephanie; Satoskar, Abhay R

    2015-03-01

    Innate CD8(+) T cells are a heterogeneous population with developmental pathways distinct from conventional CD8(+) T cells. However, their biology, classification, and functions remain incompletely understood. We recently demonstrated the existence of a novel population of chemokine (C-X-C motif) receptor 3 (CXCR3)-positive innate CD8(+) T cells. Here, we investigated the functional properties of this subset and identified effector molecules and pathways which mediate their function. Adoptive transfer of IL-15 activated CXCR3(+) innate CD8(+) T cells conferred increased protection against Listeria monocytogenes infection in susceptible IFN-γ(-/-) mice compared with similarly activated CXCR3(-) subset. This was associated with enhanced proliferation and IFN-γ production in CXCR3(+) cells. Further, CXCR3(+) innate cells showed enhanced cytotoxicity against a tumor cell line in vitro. In depth analysis of the CXCR3(+) subset showed increased gene expression of Ccl5, Klrc1, CtsW, GP49a, IL-2Rβ, Atp5e, and Ly6c but reduced IFN-γR2 and Art2b. Ingenuity pathway analysis revealed an up-regulation of genes associated with T-cell activation, proliferation, cytotoxicity, and translational initiation in CXCR3(+) populations. Our results demonstrate that CXCR3 expression in innate CD8(+) T cells defines a subset with enhanced cytotoxic potential and protective antibacterial immune functions. Immunotherapeutic approaches against infectious disease and cancer could utilize CXCR3(+) innate CD8(+) T-cell populations as novel clinical intervention strategies. PMID:25466888

  3. Phase 1 trial of IL-15 trans presentation blockade using humanized Mik-Beta-1 mAb in patients with T-cell large granular lymphocytic leukemia

    PubMed Central

    Conlon, Kevin C.; Stewart, Donn M.; Worthy, TatYana A.; Janik, John E.; Fleisher, Thomas A.; Albert, Paul S.; Figg, William D.; Spencer, Shawn D.; Raffeld, Mark; Decker, Jean R.; Goldman, Carolyn K.; Bryant, Bonita R.; Petrus, Michael N.; Creekmore, Stephen P.; Morris, John C.

    2013-01-01

    In the present study, Hu-Mikβ1, a humanized mAb directed at the shared IL-2/IL-15Rβ subunit (CD122) was evaluated in patients with T-cell large granular lymphocytic (T-LGL) leukemia. Hu-Mikβ1 blocked the trans presentation of IL-15 to T cells expressing IL-2/IL-15Rβ and the common γ-chain (CD132), but did not block IL-15 action in cells that expressed the heterotrimeric IL-15 receptor in cis. There was no significant toxicity associated with Hu-Mikβ1 administration in patients with T-LGL leukemia, but no major clinical responses were observed. One patient who had previously received murine Mikβ1 developed a measurable Ab response to the infused Ab. Nevertheless, the safety profile of this first in-human study of the humanized mAb to IL-2/IL-15Rβ (CD122) supports its evaluation in disorders such as refractory celiac disease, in which IL-15 and its receptor have been proposed to play a critical role in the pathogenesis and maintenance of disease activity. The protocol is registered with www.clinicaltrials.gov as number NCT 00076180. PMID:23212516

  4. Sterile Neutrinos

    NASA Astrophysics Data System (ADS)

    Palazzo, Antonio

    2016-05-01

    Several anomalies recorded in short-baseline neutrino experiments suggest the possibility that the standard 3-flavor framework may be incomplete and point towards a manifestation of new physics. Light sterile neutrinos provide a credible solution to these puzzling results. Here, we present a concise review of the status of the neutrino oscillations within the 3+1 scheme, the minimal extension of the standard 3-flavor framework endowed with one sterile neutrino species. We emphasize the potential role of LBL experiments in the searches of CP violation related to sterile neutrinos and their complementarity with the SBL experiments.

  5. Transmembrane-Bound IL-15-Promoted Epithelial-Mesenchymal Transition in Renal Cancer Cells Requires the Src-Dependent Akt/GSK-3β/β-Catenin Pathway.

    PubMed

    Yuan, Huaqin; Meng, Xiaoxin; Guo, Wenjie; Cai, Peifen; Li, Wanshuai; Li, Qian; Wang, Weicheng; Sun, Yang; Xu, Qiang; Gu, Yanhong

    2015-05-01

    Intrarenal interleukin-15 (IL-15) plays a major role controlling epithelial survival and polarization both in physiological and pathologic conditions. Herein, we confirmed that human renal cell carcinomas (RCCs) express a membrane-bound IL-15 isoform displaying an unusual molecular weight of 27 kDa. Its stimulation with soluble IL-15 receptor α chain (s-IL-15Rα) triggers epithelial-mesenchymal transition (EMT) process as shown by the down-regulation of E-cadherin and zona occludens 1 and the up-regulation of vimentin and N-cadherin and promotes the migratory and invasive properties of RCC. S-IL-15Rα treatment triggered the Src/PI3K/Akt/GSK-3β pathway and promoted β-catenin nuclei translocation. Deactivation of this pathway by using Src-specific inhibitor PP2, PI3K inhibitor LY294002, and AKT inhibitor MK2206 hampered β-catenin nuclei translocation and suppressed EMT, migration, and invasion of RCC. S-IL-15Rα treatment also enhanced Src-dependent phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (Erk1/2). FAK knockdown significantly decreased the migration and invasion of RCC, which suggest that Src-FAK signaling was involved in s-IL-15Rα-favored migration and invasion of RCC. At the same time, inhibitors of Erk1/2 also significantly decreased the migration and invasion of RCC but could not reverse s-IL-15Rα-induced EMT. Taken together, our results reveal that Src-dependent PI3K/Akt/GSK3b/β-catenin pathway is required for s-IL-15Ra-dependent induction of EMT in RCC, while Src-FAK and Src-Erk1/2 signaling were involved in s-IL-15Rα-promoted migration and invasion properties of RCC. Our study provides a better understanding of IL-15 signaling in RCC tumor progression, which may lead to novel targeted therapies and provide some suggestions when using IL-15 in clinic. PMID:26025664

  6. Sterile technique

    MedlinePlus

    ... kit) A clean, dry surface Clean paper towels Wash your hands well and keep all work surfaces ... To open a sterile pad or kit: Wash your hands with soap and running ... palms, fingers, and between your fingers thoroughly. Wash ...

  7. Tubal Sterilization

    MedlinePlus

    ... you feel after the operation depends on your general health, the type of procedure and your tolerance to ... to work after sterilization? That depends on your general health, your attitude, your job and the type of ...

  8. Sterile neutrinos

    NASA Astrophysics Data System (ADS)

    Kopp, J.; Machado, P. A. N.; Maltoni, M.; Schwetz, T.

    2016-06-01

    We characterize statistically the indications of a presence of one or more light sterile neutrinos from MiniBooNE and LSND data, together with the reactor and gallium anomalies, in the global context. The compatibility of the aforementioned signals with null results from solar, atmospheric, reactor, and accelerator experiments is evaluated. We conclude that a severe tension is present in the global fit, and therefore the addition of eV-scale sterile neutrinos does not satisfactorily explain the anomalies.

  9. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells.

    PubMed

    Marçais, Antoine; Cherfils-Vicini, Julien; Viant, Charlotte; Degouve, Sophie; Viel, Sébastien; Fenis, Aurore; Rabilloud, Jessica; Mayol, Katia; Tavares, Armelle; Bienvenu, Jacques; Gangloff, Yann-Gaël; Gilson, Eric; Vivier, Eric; Walzer, Thierry

    2014-08-01

    Interleukin 15 (IL-15) controls both the homeostasis and the peripheral activation of natural killer (NK) cells. The molecular basis for this duality of action remains unknown. Here we found that the metabolic checkpoint kinase mTOR was activated and boosted bioenergetic metabolism after exposure of NK cells to high concentrations of IL-15, whereas low doses of IL-15 triggered only phosphorylation of the transcription factor STAT5. mTOR stimulated the growth and nutrient uptake of NK cells and positively fed back on the receptor for IL-15. This process was essential for sustaining NK cell proliferation during development and the acquisition of cytolytic potential during inflammation or viral infection. The mTORC1 inhibitor rapamycin inhibited NK cell cytotoxicity both in mice and humans; this probably contributes to the immunosuppressive activity of this drug in different clinical settings. PMID:24973821

  10. IL-15 inhibits pre-B cell proliferation by selectively expanding Mac-1{sup +}B220{sup +} NK cells

    SciTech Connect

    Nakajima, Shinsuke; Hida, Shigeaki; Taki, Shinsuke

    2008-05-16

    Natural killer (NK) cells are the cells critical for inhibition of repopulation of allogenic bone marrow cells. However, it is not well known if NK cells affect autologous lymphopoiesis. Here, we observed that NK cells could inhibit pre-B cell proliferation in vitro driven by interleukin (IL)-7 in a manner dependent on IL-15. Interestingly, the great majority of expanding NK cells were Mac-1{sup +}B220{sup +}, a recently identified potent interferon (IFN)-{gamma} producer. Indeed, IFN-{gamma} was produced in those cultures, and pre-B cells lacking IFN-{gamma} receptors, but not those lacking type I IFN receptors, were resistant to such an inhibition. Furthermore, even NK cells from mice lacking {beta}2-microglobulin, which were known to be functionally dampened, inhibited pre-B cell proliferation as well. Thus, activated NK cells, which were expanded selectively by IL-15, could potentially regulate B lymphopoiesis through IFN-{gamma} beyond the selection imposed upon self-recognition.

  11. High IL-6 and low IL-15 levels mark the presence of TB infection: A preliminary study.

    PubMed

    Chandrashekara, S; Anupama, K R; Sambarey, Awanti; Chandra, Nagasuma

    2016-05-01

    The host immune response, apart from mycobacterial factors, is a significant determinant in the development of tuberculosis (TB). The purpose of the study was to examine whether the differential serum profiles of cytokines IL-1β, IL-2, IL-4, IL-6, IL-10, IL-15, IFN-γ, TGF-β, and TNF-α could discriminate between TB patients and healthy controls and provide insights into pathogenesis. Serum samples from TB patients, TB patient contacts and healthy controls were collected and analyzed by ELISA. The cytokine concentrations obtained were stratified into three groups: below detection limit (BDL), low values, and high values. The differences in cytokine concentrations were analyzed by Fisher's exact test. The statistically significant results were interpreted based on post-hoc analysis of the chi square contingency table using the adjusted residual method. Among the assayed cytokines, there was a statistically significant difference in the detection levels of IL-6, IL-15 and IFN-γ. Levels of IL-1β, IL-2, IL-4, IL-10, TGF-β and TNF-α did not vary. Post-hoc analysis of the significant results revealed that dynamic changes in the BDL and high values of cytokines influenced the post-infection cytokine milieu in the study subjects. The study concludes that altered balance in the levels of serum cytokines can be indicative of TB pathogenesis. Hence, profiling of dynamic changes in cytokines would facilitate effective TB diagnostic and treatment strategies. PMID:26878649

  12. IL-7– and IL-15–mediated TCR sensitization enables T cell responses to self-antigens

    PubMed Central

    Deshpande, Pratima; Cavanagh, Mary M.; Le Saux, Sabine; Singh, Karnail; Weyand, Cornelia M.; Goronzy, Jörg J.

    2012-01-01

    Regulation of the ERK pathway is intimately involved in determining whether TCR stimulation is productive or induces anergy. T cells from patients with rheumatoid arthritis (RA) have increased ERK responsiveness which may be relevant for disease pathogenesis. Inflammatory cytokines such as TNF-α did not reproduce the TCR hypersensitivity typical for RA in T cells from healthy individuals. In contrast, priming with the homeostatic cytokines IL-7 and IL-15 amplified ERK phosphorylation to TCR stimulation twofold to threefold. The underlying mechanism involved a priming of the SOS-dependent amplification loop of RAS activation. The sensitization of the TCR signaling pathway has downstream consequences, such as increased proliferation and preferential Th1 differentiation. Importantly, priming with IL-7 or IL-15 enabled T cell responses to autoantigens associated with RA. Production of homeostatic cytokines is induced in lymphopenic conditions, which have been shown to predispose for autoimmunity and which appear to be present in the preclinical stages of RA. We propose that homeostatic cytokines, possibly induced by lymphopenia, decrease the signaling threshold for TCR activation and are thereby partly responsible for autoimmunity in RA. PMID:23325887

  13. Immunotherapeutic effects of cytokine-induced killer cells combined with CCL21/IL15 armed oncolytic adenovirus in TERT-positive tumor cells.

    PubMed

    Ye, Jun-Feng; Lin, Yuan-Qiang; Yu, Xiu-Hua; Liu, Ming-Yuan; Li, Yang

    2016-09-01

    The effective antitumor immune responses are dependent on coordinate interaction of various effector cells. Thus, the combination of adoptive immunotherapy and target gene therapy is capable of efficiently generating a productive antitumor immune response. We investigated whether combination of cytokine-induced killer (CIK) cells adoptive immunotherapy and CCL21/IL15 armed oncolytic adenovirus could induce the enhanced antitumor activity. The CCL21/IL15 co-expression oncolytic adenoviruses were constructed by using the AdEasy system, which uses homologous recombination with shuttle plasmids and full length Ad backbones. This conditionally replicating adenoviruses CRAd-CCL21-IL15 could induce apoptosis in TERTp-positive tumor cells for viral propagation, but do not replicate efficiently in normal cells, because the E1A promoter was replaced by telomerase reverse transcriptase promoter (TERTp). Our results showed that the combination of CIK cells and CRAd-CCL21-IL15 could induce higher antitumor activity than either CIK cells or CRAd-CCL21-IL15 alone. This combined treatment could induce the tumor specific cytotoxicity of CTLs (cytotoxic T lymphocytes) in vitro. Moreover, the treatment of established tumors with the combined therapy of CIK cells and CRAd-CCL21-IL15 resulted in tumor regression. This study suggests that the combined treatment by adoptive immunotherapy and gene therapy is a promising strategy for the therapy of tumor. PMID:27380620

  14. The shared and contrasting roles of interleukin-2 (IL-2) and IL-15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy

    PubMed Central

    Waldmann, Thomas A.

    2015-01-01

    Interleukin-2 (IL2) and IL15, members of the 4α-helix bundle family of cytokines, play pivotal roles in the control of the life and death of lymphocytes. Although their heterotrimeric receptors have two receptor subunits in common these two cytokines have contrasting roles in adaptive immune responses. The unique role of IL2 through maintenance of fitness of regulatory T cells (Treg) and activation-induced cell death (AICD) is the elimination of self-reactive T cells to prevent autoimmunity. In contrast to IL2, IL15 is dedicated to the prolonged maintenance of memory T-cell responses to invading pathogens. Blockade of IL2 and IL15 using monoclonal antibodies has been reported to be of value in the treatment of patients with leukemia, autoimmune disorders and in the prevention of allograft rejection. IL2 has been approved by the FDA for the treatment of patients with malignant renal cell cancer and metastatic malignant melanoma. Clinical trials involving recombinant human IL15 given by bolus infusions have been completed, and by subcutaneous and continuous intravenous infusions are underway in patients with metastatic malignancy. Furthermore, clinical trials are being initiated that employ the combination of IL15 with IL15Rα+/− IgFc. PMID:25736261

  15. Porcine reproductive and respiratory syndrome virus (PRRSV) up-regulates IL-15 through PKCβ1-TAK1-NF-κB signaling pathway.

    PubMed

    Du, Li; Liu, Yihao; Du, Yinping; Wang, Honglei; Zhang, Meijie; Du, Yijun; Feng, Wen-Hai

    2016-09-01

    Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) is one of the most important infectious diseases in swine industry. IL-15 is a pleiotropic cytokine and has been shown to be essential to transform NKs, CD8 T cells, and other cells of the immune systems into functional effectors. Here, we demonstrated that the broad-spectrum or conventional PKC inhibitors repressed PRRSV-induced IL-15 expression and NF-κB activation. Subsequently, we found that the PKCβ specific inhibitor inhibited PRRSV-induced IL-15 production, which was also confirmed by knock-down of PKCβ1, suggesting that PKCβ1 is involved in the PRRSV-induced IL-15 expression. In addition, we demonstrated that PRRSV activated NF-κB through PKCβ1-induced TAK1 activation. Finally, we demonstrated that PRRSV activated PKCβ1 dependent on the participation of TRIF and MAVS. These data indicate that PRRSV up-regulates IL-15 through TRIF/MAVS-PKCβ1-TAK1-NF-κB signaling pathway. These findings will provide new insights into the molecular mechanisms of IL-15 production induced by PRRSV. PMID:27318153

  16. IL-15–PI3K–AKT–mTOR: A Critical Pathway in the Life Journey of Natural Killer Cells

    PubMed Central

    Ali, Alaa Kassim; Nandagopal, Neethi; Lee, Seung-Hwan

    2015-01-01

    Among numerous cytokines modulating natural killer (NK) cell function, interleukin 15 (IL-15) exerts a broad range of effect from development and homeostasis, to activation of mature NK cells during infection. Its significance is further highlighted by clinical trials in which IL-15 is being used to boost the proliferation and anti-tumor response of NK cells. Among the signal transduction pathways triggered by the engagement of IL-15 receptor with its ligand, the PI3K–AKT–mTOR pathway seems to be critical for the IL-15-mediated activation of NK cells, therefore being responsible for efficient anti-viral and anti-tumor responses. This review provides an overview of the role of IL-15 at multiple stages of NK cell life journey. Understanding the pathway by which IL-15 conveys critical signals for the generation of NK cells with efficient effector functions, in combination with established protocols for NK cell expansion ex vivo, will undoubtedly open new avenues for therapeutic applications for immunomodulation against infections and cancers. PMID:26257729

  17. Two similar but distinct second intron fragments from tobacco AGAMOUS homologs confer identical floral organ-specific expression sufficient for generating complete sterility in plants

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The carpel- and stamen-specific AtAGIP promoter derived from the Arabidopsis AGAMOUS (AG) second intron/enhancer is ideal for engineering complete sterility, but it is highly host-specific. To ascertain that a chimeric promoter with similar tissue specificity can be created for species other than A...

  18. Anticancer Cytokines: Biology and Clinical Effects of IFN-α2, IL-2, IL-15, IL-21, and IL-12

    PubMed Central

    Floros, Theofanis; Tarhini, Ahmad A.

    2015-01-01

    Efforts over nearly four decades have focused on ways to use cytokines to manipulate the host immune response towards cancer cell recognition and eradication. Significant advances were achieved with interleukin-2 (IL-2) and interferon-α (IFN-α), primarily in the treatment of patients with melanoma and renal cell carcinoma. However, the utility of other cytokines showing promise in the preclinical setting has not been established largely because of toxicity, the complex functionality of each cytokine and the difficulty mimicking in preclinical models the human environment. In this paper we will review the basic biology and the clinical experiences with IFN-α, IL-2, IL-15, IL-21 and IL-12. We will also review ongoing clinical trials and discuss future directions including potential use of cytokines in combination with other effective immunotherapy approaches which have come of age in recent years. PMID:26320059

  19. IL-15Rα deficiency in skeletal muscle alters respiratory function and the proteome of mitochondrial subpopulations independent of changes to the mitochondrial genome.

    PubMed

    O'Connell, Grant C; Nichols, Cody; Guo, Ge; Croston, Tara L; Thapa, Dharendra; Hollander, John M; Pistilli, Emidio E

    2015-11-01

    Interleukin-15 receptor alpha knockout (IL15RαKO) mice exhibit a greater skeletal muscle mitochondrial density with an altered mitochondrial morphology. However, the mechanism and functional impact of these changes have not been determined. In this study, we characterized the functional, proteomic, and genomic alterations in mitochondrial subpopulations isolated from the skeletal muscles of IL15RαKO mice and B6129 background control mice. State 3 respiration was greater in interfibrillar mitochondria and whole muscle ATP levels were greater in IL15RαKO mice supporting the increases in respiration rate. However, the state 3/state 4 ratio was lower, suggesting some degree of respiratory uncoupling. Proteomic analyses identified several markers independently in mitochondrial subpopulations that are associated with these functional alterations. Next Generation Sequencing of mtDNA revealed a high degree of similarity between the mitochondrial genomes of IL15RαKO mice and controls in terms of copy number, consensus coding and the presence of minor alleles, suggesting that the functional and proteomic alterations we observed occurred independent of alterations to the mitochondrial genome. These data provide additional evidence to implicate IL-15Rα as a regulator of skeletal muscle phenotypes through effects on the mitochondrion, and suggest these effects are driven by alterations to the mitochondrial proteome. PMID:26458787

  20. PIAS1 and STAT-3 impair the tumoricidal potential of IFN-γ-stimulated mouse dendritic cells generated with IL-15.

    PubMed

    Hanke, Neale T; LaCasse, Collin J; Larmonier, Claire B; Alizadeh, Darya; Trad, Malika; Janikashvili, Nona; Bonnotte, Bernard; Katsanis, Emmanuel; Larmonier, Nicolas

    2014-08-01

    Primarily defined by their antigen-presenting property, dendritic cells (DCs) are being implemented as cancer vaccines in immunotherapeutic interventions. DCs can also function as direct tumor cell killers. How DC cytotoxic activity can be efficiently harnessed and the mechanisms controlling this nonconventional property are not fully understood. We report here that the tumoricidal potential of mouse DCs generated from myeloid precursors with GM-CSF and IL-15 (IL-15 DCs) can be triggered with the Toll-like receptor (TLR) 4 ligand lipopolysaccharide to a similar extent compared with that of their counterparts, conventionally generated with IL-4 (IL-4 DCs). The mechanism of tumor cell killing depends on the induction of iNOS expression by DCs. In contrast, interferon (IFN)-γ induces the cytotoxic activity of IL-4 but not IL-15 DCs. Although the IFN-γ-STAT-1 signaling pathway is overall functional in IL-15 DCs, IFN-γ fails to induce iNOS expression in these cells. iNOS expression is negatively controlled in IFN-γ-stimulated IL-15 DCs by the cooperation between the E3 SUMO ligase PIAS1 and STAT-3, and can be partially restored with PIAS1 siRNA and STAT-3 inhibitors. PMID:24777831

  1. Expression in yeast of the T-urf13 protein from Texas male-sterile maize mitochondria confers sensitivity to methomyl and to Texas-cytoplasm-specific fungal toxins.

    PubMed Central

    Huang, J; Lee, S H; Lin, C; Medici, R; Hack, E; Myers, A M

    1990-01-01

    The mitochondrial gene T-urf13 from maize (Zea mays L.) with Texas male-sterile (T) cytoplasm codes for a unique 13 kd polypeptide, T-URF13, which is implicated in cytoplasmic male sterility and sensitivity to the insecticide methomyl and to host-specific fungal toxins produced by Helminthosporium maydis race T (HmT toxin) and Phyllosticta maydis (Pm toxin). A chimeric gene coding for T-URF13 fused to the mitochondrial targeting peptide from the Neurospora crassa ATP synthase subunit 9 precursor was constructed. Expression of this gene in the yeast Saccharomyces cerevisiae yielded a polypeptide that was translocated into the membrane fraction of mitochondria and processed to give a protein the same size as maize T-URF13. Methomyl, HmT toxin and Pm toxin inhibited growth of yeast cells expressing the gene fusion on medium containing glycerol as sole carbon source and stimulated respiration with NADH as substrate by isolated mitochondria from these cells. These effects were not observed in yeast cells expressing T-URF13 without a targeting peptide. The results show that T-URF13 is sufficient to confer sensitivity to methomyl and the fungal toxins in a heterologous eukaryotic system, and suggest that mitochondrial localization of T-URF13 is critical for these functions. Images Fig. 2. Fig. 3. Fig. 5. PMID:2303028

  2. Effects of Eccentric and Concentric Emphasized Resistance Exercise on IL-15 Serum Levels and Its Relation to Inflammatory Markers in Athletes and Non-Athletes

    PubMed Central

    Bazgir, Behzad; Salesi, Mohsen; Koushki, Maryam; Amirghofran, Zahra

    2015-01-01

    Background: Cytokines play an important role in modulating the muscle’s metabolic and immunological responses to exercise. Objectives: In the present study, we investigated changes in the serum levels of Interleukin (IL)-15 as well as tumor necrosis factor (TNF)-α and high sensitivity C-reactive protein (hs-CRP), as markers of inflammation, in athlete and non-athlete young men following eccentric (ECC) and concentric (CON) emphasized resistance exercise (RE). Patients and Methods: This study recruited 28 young males, 14 athletes and 14 non-athletes. Subjects completed two bouts of ECC and CON emphasized RE five days apart. Each bout included seven exercises that emphasized all major muscle groups with weight loads of 70% - 80% of one repetition maximum (1RM) for CON RE and 90% - 100% of 1RM for ECC RE. We analyzed subjects’ blood samples before and immediately after each bout of exercise to determine cytokine and hs-CRP serum levels according to enzyme-linked immunosorbent assay. Results: Statistical analysis showed a significant difference between IL-15 serum levels before and after ECC and CON RE in non-athletes (P = 0.03). In athletes, IL-15 serum level only increased after ECC RE (P = 0.01), which was noted to be the highest degree of change in IL-15 levels in all subjects. For athletes, the hs-CRP levels significantly decreased (P < 0.05). The serum levels of both TNF-α and hs-CRP were also significantly down-regulated after ECC RE in non-athletes. Conclusions: These results indicated that fitness level and RE could modulate circulating levels of IL-15 and suggest the potential anti-inflammatory effects of IL-15 during RE. PMID:26448857

  3. IL-15 Superagonist Expands mCD8+ T, NK and NKT Cells after Burn Injury but Fails to Improve Outcome during Burn Wound Infection

    PubMed Central

    Patil, Naeem K.; Luan, Liming; Bohannon, Julia K.; Guo, Yin; Hernandez, Antonio; Fensterheim, Benjamin; Sherwood, Edward R.

    2016-01-01

    Background Severely burned patients are highly susceptible to opportunistic infections and sepsis, owing to the loss of the protective skin barrier and immunological dysfunction. Interleukin-15 (IL-15) belongs to the IL-2 family of common gamma chain cytokines and stimulates the proliferation and activation of T (specifically memory CD8), NK and NKT cells. It has been shown to preserve T cell function and improve survival during cecal ligation and puncture (CLP)-induced sepsis in mice. However, the therapeutic efficacy of IL-15 or IL-15 superagonist (SA) during infection after burn injury has not been evaluated. Moreover, very few, if any, studies have examined, in detail, the effect of burn injury and infection on the adaptive immune system. Thus, we examined the effect of burn and sepsis on adaptive immune cell populations and the effect of IL-15 SA treatment on the host response to infection. Methods Mice were subjected to a 35% total body surface area burn, followed by wound infection with Pseudomonas aeruginosa. In some experiments, IL-15 SA was administered after burn injury, but before infection. Leukocytes in spleen, liver and peritoneal cavity were characterized using flow cytometry. Bacterial clearance, organ injury and survival were also assessed. Results Burn wound infection led to a significant decline in total white blood cell and lymphocyte counts and induced organ injury and sepsis. Burn injury caused decline in CD4+ and CD8+ T cells in the spleen, which was worsened by infection. IL-15 treatment inhibited this decline and significantly increased cell numbers and activation, as determined by CD69 expression, of CD4+, CD8+, B, NK and NKT cells in the spleen and liver after burn injury. However, IL-15 SA treatment failed to prevent burn wound sepsis-induced loss of CD4+, CD8+, B, NK and NKT cells and failed to improve bacterial clearance and survival. Conclusion Cutaneous burn injury and infection cause significant adaptive immune dysfunction. IL-15

  4. Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma

    PubMed Central

    Adachi, Takeya; Kobayashi, Tetsuro; Sugihara, Eiji; Yamada, Taketo; Ikuta, Koichi; Pittaluga, Stefania; Saya, Hideyuki; Amagai, Masayuki; Nagao, Keisuke

    2015-01-01

    The skin harbors a variety of resident leukocyte subsets that must be tightly regulated to maintain immune homeostasis. Hair follicles are unique structures in the skin that contribute to skin dendritic cell homeostasis via chemokine production. We demonstrate that CD4+ and CD8+ skin resident memory T cells (TRM), responsible for long-term skin immunity, resided predominantly within the hair follicle epithelium of unperturbed epidermis. TRM tropism for the epidermis and follicles was herein termed epidermotropism. Hair follicle-derived IL-15 was required for CD8+ TRM, and IL-7 for CD8+ and CD4+ TRM, to exert epidermotropism. The lack of either cytokine impaired hapten-induced contact hypersensitivity responses. In a model of cutaneous T cell lymphoma, epidermotropic CD4+ TRM lymphoma cell localization depended on hair follicle-derived IL-7. These findings implicate hair follicle-derived cytokines as regulators of malignant and non-malignant TRM cell tissue residence and suggest they may be targeted therapeutically in inflammatory skin disease and lymphoma. PMID:26479922

  5. IL-15 boosts the function and migration of human terminally differentiated CD8+ T cells by inducing a unique gene signature.

    PubMed

    Setoguchi, Ruka

    2016-06-01

    Human CCR7(low)CD45RA(high) effector memory CD8(+) T cells (terminally differentiated TEMRA) are reportedly a functionally compromised population with characteristics of cellular senescence when examined ex vivo Although their frequencies are increased in elderly subjects in association with declined immune competence, however, it remains unclear whether their impaired functions can be reversed so that they contribute to immune responses in vivo Here, I show that, in contrast to TCR stimulation, stimulation of TEMRA with IL-15 induced a unique transcriptional signature, promoted IFN-γ production and cell cycle entry, and reduced chemotaxis toward sphingosine-1-phosphate (S1P). TEMRA preferentially accumulated in non-lymphoid tissues when transferred into IL-15-treated NOD.SCID.γc-deficient mice compared with non-treated mice. This accumulation was impaired by S1P receptor 1 over-expression. These results suggest that TEMRA act as functional effector T cells in non-lymphoid tissues when IL-15 is abundant and that IL-15 treatment may be beneficial in enhancing vaccine efficacy in elderly people. PMID:26857736

  6. PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness

    PubMed Central

    Yang, Meixiang; Li, Dan; Chang, Zai; Yang, Zhongzhou; Tian, Zhigang

    2015-01-01

    E4BP4, a circadian protein, is indispensable for NK cell development. It remains largely unknown which signal is required to induce E4BP4 expression and what effects it has during NK cell differentiation. Here, we reveal that PDK1, a kinase upstream of mTOR, connects IL-15 signaling to E4BP4. Early deletion of PDK1 caused a severe loss of NK cells and compromised antitumor activity in vivo. PDK1-deficient NK cells displayed much weaker IL-15–induced mTOR activation and E4BP4 induction, as well as remarkable reduction in CD122, a receptor subunit specifying NK cell responsiveness to IL-15. The phenotypes were partially reversible by ectopic expression of E4BP4 or bypassed activation of mTOR. We also determined that PDK1-mediated metabolic signaling was dispensable for NK cell terminal maturation and survival. Thus, we identify a role for PDK1 signaling as a key mediator in regulating E4BP4 expression during early NK cell development. Our findings underscore the importance of IL-15 self-responsiveness through a positive feedback loop that involves PDK1–mTOR–E4BP4–CD122 signaling. PMID:25624444

  7. PDK1 orchestrates early NK cell development through induction of E4BP4 expression and maintenance of IL-15 responsiveness.

    PubMed

    Yang, Meixiang; Li, Dan; Chang, Zai; Yang, Zhongzhou; Tian, Zhigang; Dong, Zhongjun

    2015-02-01

    E4BP4, a circadian protein, is indispensable for NK cell development. It remains largely unknown which signal is required to induce E4BP4 expression and what effects it has during NK cell differentiation. Here, we reveal that PDK1, a kinase upstream of mTOR, connects IL-15 signaling to E4BP4. Early deletion of PDK1 caused a severe loss of NK cells and compromised antitumor activity in vivo. PDK1-deficient NK cells displayed much weaker IL-15-induced mTOR activation and E4BP4 induction, as well as remarkable reduction in CD122, a receptor subunit specifying NK cell responsiveness to IL-15. The phenotypes were partially reversible by ectopic expression of E4BP4 or bypassed activation of mTOR. We also determined that PDK1-mediated metabolic signaling was dispensable for NK cell terminal maturation and survival. Thus, we identify a role for PDK1 signaling as a key mediator in regulating E4BP4 expression during early NK cell development. Our findings underscore the importance of IL-15 self-responsiveness through a positive feedback loop that involves PDK1-mTOR-E4BP4-CD122 signaling. PMID:25624444

  8. Conditional sterility in plants

    DOEpatents

    Meagher, Richard B.; McKinney, Elizabeth; Kim, Tehryung

    2010-02-23

    The present disclosure provides methods, recombinant DNA molecules, recombinant host cells containing the DNA molecules, and transgenic plant cells, plant tissue and plants which contain and express at least one antisense or interference RNA specific for a thiamine biosynthetic coding sequence or a thiamine binding protein or a thiamine-degrading protein, wherein the RNA or thiamine binding protein is expressed under the regulatory control of a transcription regulatory sequence which directs expression in male and/or female reproductive tissue. These transgenic plants are conditionally sterile; i.e., they are fertile only in the presence of exogenous thiamine. Such plants are especially appropriate for use in the seed industry or in the environment, for example, for use in revegetation of contaminated soils or phytoremediation, especially when those transgenic plants also contain and express one or more chimeric genes which confer resistance to contaminants.

  9. Co-administration of avian influenza virus H5 plasmid DNA with chicken IL-15 and IL-18 enhanced chickens immune responses

    PubMed Central

    2012-01-01

    Background DNA vaccines offer several advantages over conventional vaccines in the development of effective vaccines against avian influenza virus (AIV). However, one of the limitations of the DNA vaccine in poultry is that it induces poor immune responses. In this study, chicken interleukin (IL) -15 and IL-18 were used as genetic adjuvants to improve the immune responses induced from the H5 DNA vaccination in chickens. The immunogenicity of the recombinant plasmid DNA was analyzed based on the antibody production, T cell responses and cytokine production, following inoculation in 1-day-old (Trial 1) and 14-day-old (Trial 2) specific-pathogen-free chickens. Hence, the purpose of the present study was to explore the role of chicken IL-15 and IL-18 as adjuvants following the vaccination of chickens with the H5 DNA vaccine. Results The overall HI antibody titer in chickens immunized with pDis/H5 + pDis/IL-15 was higher compared to chickens immunized with pDis/H5 (p < 0.05). The findings revealed that the inoculation of the 14-day-old chickens exhibited a shorter time to achieve the highest HI titer in comparison to the inoculation of the 1-day-old chickens. The cellular immunity was assessed by the flow cytometry analysis to enumerate CD4+ and CD8 + T cells in the peripheral blood. The chickens inoculated with pDis/H5 + pDis/IL-15 demonstrated the highest increase in CD4+ T cells population relative to the control chickens. However, this study revealed that pDis/H5 + pDis/IL-15 was not significant (P > 0.05) in inducing CD8+ T cells. Meanwhile, with the exception of Trial 1, the flow cytometry results for Trial 2 demonstrated that the pDis/H5 + pDis/IL-18 inoculated group was able to trigger a higher increase in CD4+ T cells than the pDis/H5 group (P < 0.05). On the other hand, the pDis/H5 + pDis/IL-18 group was not significant (P > 0.05) in modulating CD8+ T cells population in both trials. The pDis/H5 + pDis/IL-15 inoculated

  10. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation.

    PubMed

    Shah, Nirali N; Baird, Kristin; Delbrook, Cynthia P; Fleisher, Thomas A; Kohler, Mark E; Rampertaap, Shakuntala; Lemberg, Kimberly; Hurley, Carolyn K; Kleiner, David E; Merchant, Melinda S; Pittaluga, Stefania; Sabatino, Marianna; Stroncek, David F; Wayne, Alan S; Zhang, Hua; Fry, Terry J; Mackall, Crystal L

    2015-01-29

    Natural killer (NK) cells can enhance engraftment and mediate graft-versus-leukemia following allogeneic hematopoietic stem cell transplantation (HSCT), but the potency of graft-versus-leukemia mediated by naturally reconstituting NK cells following HSCT is limited. Preclinical studies demonstrate that activation of NK cells using interleukin-15 (IL-15) plus 4-1BBL upregulates activating receptor expression and augments killing capacity. In an effort to amplify the beneficial effects of NK cells post-HSCT, we conducted a first-in-human trial of adoptive transfer of donor-derived IL-15/4-1BBL-activated NK cells (aNK-DLI) following HLA-matched, T-cell-depleted (1-2 × 10(4) T cells/kg) nonmyeloablative peripheral blood stem cell transplantation in children and young adults with ultra-high-risk solid tumors. aNK-DLI were CD3(+)-depleted, CD56(+)-selected lymphocytes, cultured for 9 to 11 days with recombinant human IL-15 plus 4-1BBL(+)IL-15Rα(+) artificial antigen-presenting cells. aNK-DLI demonstrated potent killing capacity and displayed high levels of activating receptor expression. Five of 9 transplant recipients experienced acute graft-versus-host disease (GVHD) following aNK-DLI, with grade 4 GVHD observed in 3 subjects. GVHD was more common in matched unrelated donor vs matched sibling donor recipients and was associated with higher donor CD3 chimerism. Given that the T-cell dose was below the threshold required for GVHD in this setting, we conclude that aNK-DLI contributed to the acute GVHD observed, likely by augmenting underlying T-cell alloreactivity. This trial was registered at www.clinicaltrials.gov as #NCT01287104. PMID:25452614

  11. Therapeutic administration of IL-15 superagonist complex ALT-803 leads to long-term survival and durable antitumor immune response in a murine glioblastoma model.

    PubMed

    Mathios, Dimitrios; Park, Chul-Kee; Marcus, Warren D; Alter, Sarah; Rhode, Peter R; Jeng, Emily K; Wong, Hing C; Pardoll, Drew M; Lim, Michael

    2016-01-01

    Glioblastoma is the most aggressive primary central nervous system malignancy with a poor prognosis in patients. Despite the need for better treatments against glioblastoma, very little progress has been made in discovering new therapies that exhibit superior survival benefit than the standard of care. Immunotherapy has been shown to be a promising treatment modality that could help improve clinical outcomes of glioblastoma patients by assisting the immune system to overcome the immunosuppressive tumor environment. Interleukin-15 (IL-15), a cytokine shown to activate several effector components of the immune system, may serve as an excellent immunotherapeutic candidate for the treatment of glioblastoma. Thus, we evaluated the efficacy of an IL-15 superagonist complex (IL-15N72D:IL-15RαSu-Fc; also known as ALT-803) in a murine GL261-luc glioblastoma model. We show that ALT-803, as a single treatment as well as in combination with anti-PD-1 antibody or stereotactic radiosurgery, exhibits a robust antitumor immune response resulting in a prolonged survival including complete remission in tumor bearing mice. In addition, ALT-803 treatment results in long-term immune memory against glioblastoma tumor rechallenge. Flow cytometric analysis of tumor infiltrating immune cells shows that ALT-803 leads to increased percentage of CD8+-cell infiltration, but not the NK cells, and IFN-γ production into the tumor microenvironment. Cell depletion studies, in accordance with the flow cytometric results, show that the ALT-803 therapeutic effect is dependent on CD4+ and CD8+ cells. These results provide a rationale for evaluating the therapeutic activity of ALT-803 against glioblastoma in the clinical setting. PMID:26174883

  12. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell–depleted stem cell transplantation

    PubMed Central

    Shah, Nirali N.; Baird, Kristin; Delbrook, Cynthia P.; Fleisher, Thomas A.; Kohler, Mark E.; Rampertaap, Shakuntala; Lemberg, Kimberly; Hurley, Carolyn K.; Kleiner, David E.; Merchant, Melinda S.; Pittaluga, Stefania; Sabatino, Marianna; Stroncek, David F.; Wayne, Alan S.; Zhang, Hua; Fry, Terry J.

    2015-01-01

    Natural killer (NK) cells can enhance engraftment and mediate graft-versus-leukemia following allogeneic hematopoietic stem cell transplantation (HSCT), but the potency of graft-versus-leukemia mediated by naturally reconstituting NK cells following HSCT is limited. Preclinical studies demonstrate that activation of NK cells using interleukin-15 (IL-15) plus 4-1BBL upregulates activating receptor expression and augments killing capacity. In an effort to amplify the beneficial effects of NK cells post-HSCT, we conducted a first-in-human trial of adoptive transfer of donor-derived IL-15/4-1BBL–activated NK cells (aNK-DLI) following HLA-matched, T-cell–depleted (1-2 × 104 T cells/kg) nonmyeloablative peripheral blood stem cell transplantation in children and young adults with ultra-high-risk solid tumors. aNK-DLI were CD3+-depleted, CD56+-selected lymphocytes, cultured for 9 to 11 days with recombinant human IL-15 plus 4-1BBL+IL-15Rα+ artificial antigen-presenting cells. aNK-DLI demonstrated potent killing capacity and displayed high levels of activating receptor expression. Five of 9 transplant recipients experienced acute graft-versus-host disease (GVHD) following aNK-DLI, with grade 4 GVHD observed in 3 subjects. GVHD was more common in matched unrelated donor vs matched sibling donor recipients and was associated with higher donor CD3 chimerism. Given that the T-cell dose was below the threshold required for GVHD in this setting, we conclude that aNK-DLI contributed to the acute GVHD observed, likely by augmenting underlying T-cell alloreactivity. This trial was registered at www.clinicaltrials.gov as #NCT01287104. PMID:25452614

  13. T-box Transcription Factors Combine with the Cytokines TGF-β and IL-15 to Control Tissue-Resident Memory T Cell Fate.

    PubMed

    Mackay, Laura K; Wynne-Jones, Erica; Freestone, David; Pellicci, Daniel G; Mielke, Lisa A; Newman, Dane M; Braun, Asolina; Masson, Frederick; Kallies, Axel; Belz, Gabrielle T; Carbone, Francis R

    2015-12-15

    Tissue-resident memory T (Trm) cells contribute to local immune protection in non-lymphoid tissues such as skin and mucosa, but little is known about their transcriptional regulation. Here we showed that CD8(+)CD103(+) Trm cells, independent of circulating memory T cells, were sufficient for protection against infection and described molecular elements that were crucial for their development in skin and lung. We demonstrated that the T-box transcription factors (TFs) Eomes and T-bet combined to control CD8(+)CD103(+) Trm cell formation, such that their coordinate downregulation was crucial for TGF-β cytokine signaling. TGF-β signaling, in turn, resulted in reciprocal T-box TF downregulation. However, whereas extinguishment of Eomes was necessary for CD8(+)CD103(+) Trm cell development, residual T-bet expression maintained cell surface interleukin-15 (IL-15) receptor β-chain (CD122) expression and thus IL-15 responsiveness. These findings indicate that the T-box TFs control the two cytokines, TGF-β and IL-15, which are pivotal for CD8(+)CD103(+) Trm cell development and survival. PMID:26682984

  14. Exaggerated IL-15 and Altered Expression of foxp3+ Cell-Derived Cytokines Contribute to Enhanced Colitis in Nlrp3-/- Mice.

    PubMed

    Hirota, Simon A; Ueno, Aito; Tulk, Sarah E; Becker, Helen M; Schenck, L Patrick; Potentier, Mireille S; Li, Yan; Ghosh, Subrata; Muruve, Daniel A; MacDonald, Justin A; Beck, Paul L

    2016-01-01

    The pathogenesis of Crohn's disease (CD) involves defects in the innate immune system, impairing responses to microbes. Studies have revealed that mutations NLRP3 are associated with CD. We reported previously that Nlrp3-/- mice were more susceptible to colitis and exhibited reduced colonic IL-10 expression. In the current study, we sought to determine how the loss of NLRP3 might be altering the function of regulatory T cells, a major source of IL-10. Colitis was induced in wild-type (WT) and Nlrp3-/- mice by treatment with dextran sulphate sodium (DSS). Lamina propria (LP) cells were assessed by flow cytometry and cytokine expression was assessed. DSS-treated Nlrp3-/- mice exhibited increased numbers of colonic foxp3+ T cells that expressed significantly lower levels of IL-10 but increased IL-17. This was associated with increased expression of colonic IL-15 and increased surface expression of IL-15 on LP dendritic cells. Neutralizing IL-15 in Nlrp3-/- mice attenuated the severity of colitis, decreased the number of colonic foxp3+ cells, and reduced the colonic expression of IL-12p40 and IL-17. These data suggest that the NLRP3 inflammasome can regulate intestinal inflammation through noncanonical mechanisms, providing additional insight as to how NLRP3 variants may contribute to the pathogenesis of CD. PMID:27610005

  15. IL-15 prolongs CD154 expression on human CD4 T cells via STAT5 binding to the CD154 transcriptional promoter

    PubMed Central

    Lowe, RM; Genin, A; Orgun, N; Cron, RQ

    2014-01-01

    Activation induced CD154 expression on CD4 T cells is prolonged in systemic lupus erythematosus but the mechanism(s) for its dysregulation are unknown. The studies reported herein demonstrate that IL-15 is capable of prolonging CD154 expression on PHA activated CD4 T cells. Since IL-15 signals through STAT5, predicted STAT5 binding sites in the human CD154 transcriptional promoter were identified, and STAT5 binding to the proximal CD154 promoter in vitro and in vivo following primary CD4 T cell activation was demonstrated. Moreover, overexpression of wild-type(WT) STAT5 in primary human CD4 T cells augmented CD154 transcription, whereas overexpression of a dominant negative (DN) STAT5 protein inhibited CD154 transcription. Mutation of the most proximal STAT5 binding site in the CD154 promoter resulted in diminished DNA binding and reduced CD154 transcriptional activity. Interestingly, STAT5-specific siRNA inhibited CD154 surface expression at 48 but not 24 hours after T cell activation. Thus, these findings provide some of the first evidence to support a possible mechanistic link to explain how the overexpression of IL-15 observed in lupus patients may be involved in the prolonged expression of CD154 that has also been observed on lupus CD4 T cells. PMID:24500400

  16. Exaggerated IL-15 and Altered Expression of foxp3+ Cell-Derived Cytokines Contribute to Enhanced Colitis in Nlrp3−/− Mice

    PubMed Central

    Tulk, Sarah E.; Becker, Helen M.; Potentier, Mireille S.; Li, Yan; Ghosh, Subrata; MacDonald, Justin A.; Beck, Paul L.

    2016-01-01

    The pathogenesis of Crohn's disease (CD) involves defects in the innate immune system, impairing responses to microbes. Studies have revealed that mutations NLRP3 are associated with CD. We reported previously that Nlrp3−/− mice were more susceptible to colitis and exhibited reduced colonic IL-10 expression. In the current study, we sought to determine how the loss of NLRP3 might be altering the function of regulatory T cells, a major source of IL-10. Colitis was induced in wild-type (WT) and Nlrp3−/− mice by treatment with dextran sulphate sodium (DSS). Lamina propria (LP) cells were assessed by flow cytometry and cytokine expression was assessed. DSS-treated Nlrp3−/− mice exhibited increased numbers of colonic foxp3+ T cells that expressed significantly lower levels of IL-10 but increased IL-17. This was associated with increased expression of colonic IL-15 and increased surface expression of IL-15 on LP dendritic cells. Neutralizing IL-15 in Nlrp3−/− mice attenuated the severity of colitis, decreased the number of colonic foxp3+ cells, and reduced the colonic expression of IL-12p40 and IL-17. These data suggest that the NLRP3 inflammasome can regulate intestinal inflammation through noncanonical mechanisms, providing additional insight as to how NLRP3 variants may contribute to the pathogenesis of CD. PMID:27610005

  17. Sterilizing the Poor

    ERIC Educational Resources Information Center

    Rothman, Sheila M.

    1977-01-01

    Suggests that freedom for the middle classes may mean vulnerability for the poor. The enthusiasm for sterilization may be so intense as to deprive the poor of their right not to be sterilized. (Author/AM)

  18. Apparatus Circulates Sterilizing Gas

    NASA Technical Reports Server (NTRS)

    Cross, John H.; Schwarz, Ray P.

    1991-01-01

    Apparatus circulates sterilizing gas containing ethylene oxide and chlorofluorocarbon through laboratory or medical equipment. Confines sterilizing gas, circulating it only through parts to be treated. Consists of two units. One delivers ethylene oxide/chlorofluorocarbon gas mixture and removes gas after treatment. Other warms, humidifies, and circulates gas through equipment to be treated. Process provides reliable sterilization with negligible residual toxicity from ethylene oxide. Particularly suitable for sterilization of interiors of bioreactors, heart/lung machines, dialyzers, or other equipment including complicated tubing.

  19. ISO radiation sterilization standards

    NASA Astrophysics Data System (ADS)

    Lambert, Byron J.; Hansen, Joyce M.

    1998-06-01

    This presentation provides an overview of the current status of the ISO radiation sterilization standards. The ISO standards are voluntary standards which detail both the validation and routine control of the sterilization process. ISO 11137 was approved in 1994 and published in 1995. When reviewing the standard you will note that less than 20% of the standard is devoted to requirements and the remainder is guidance on how to comply with the requirements. Future standards developments in radiation sterilization are being focused on providing additional guidance. The guidance that is currently provided in informative annexes of ISO 11137 includes: device/packaging materials, dose setting methods, and dosimeters and dose measurement, currently, there are four Technical Reports being developed to provide additional guidance: 1. AAMI Draft TIR, "Radiation Sterilization Material Qualification" 2. ISO TR 13409-1996, "Sterilization of health care products — Radiation sterilization — Substantiation of 25 kGy as a sterilization dose for small or infrequent production batches" 3. ISO Draft TR, "Sterilization of health care products — Radiation sterilization Selection of a sterilization dose for a single production batch" li]4. ISO Draft TR, "Sterilization of health care products — Radiation sterilization-Product Families, Plans for Sampling and Frequency of Dose Audits."

  20. Combined IL-15 and IL-12 drives the generation of CD34+-derived natural killer cells with superior maturation and alloreactivity potential following adoptive transfer

    PubMed Central

    Cany, Jeannette; van der Waart, Anniek B; Spanholtz, Jan; Tordoir, Marleen; Jansen, Joop H; van der Voort, Robbert; Schaap, Nicolaas M; Dolstra, Harry

    2015-01-01

    Adoptive transfer of allogeneic natural killer (NK) cells represents a promising treatment approach against cancer, including acute myeloid leukemia (AML). Previously, we reported a cytokine-based culture method for the generation of NK cell products with high cell number and purity. In this system, CD34+ hematopoietic progenitor cells (HPC) were expanded and differentiated into NK cells under stroma-free conditions in the presence of IL-15 and IL-2. We show that combining IL-15 with IL-12 drives the generation of more mature and highly functional NK cells. In particular, replacement of IL-2 by IL-12 enhanced the cytolytic activity and IFNγ production of HPC-NK cells toward cultured and primary AML cells in vitro, and improved antileukemic responses in NOD/SCID-IL2Rγnull (NSG) mice bearing human AML cells. Phenotypically, IL-12 increased the frequency of HPC-NK cells expressing NKG2A and killer immunoglobulin-like receptor (KIR), which were more responsive to target cell stimulation. In addition, NK15/12 cell products demonstrated superior maturation potential, resulting in >70% positivity for CD16 and/or KIR within 2 weeks after infusion into NSG mice. We predict that higher functionality and faster in vivo maturation will favor HPC-NK cell alloreactivity toward malignant cells in patients, making this cytokine combination an attractive strategy to generate clinical HPC-NK cell products for cancer adoptive immunotherapy. PMID:26140247

  1. Radiofrequency thermal ablation of breast tumors combined with intralesional administration of IL-7 and IL-15 augments anti-tumor immune responses and inhibits tumor development and metastasis

    PubMed Central

    Habibi, Mehran; Kmieciak, Maciej; Graham, Laura; Morales, Johanna K; Bear, Harry D; Manjili, Masoud H

    2008-01-01

    Tumor development or recurrence is always a matter of concern following radiofrequency thermal ablation (RFA) of tumors. To determine whether combining RFA with immunologically active cytokines might induce tumor-specific immune responses against mammary carcinoma and inhibit tumor development or metastasis, we evaluated intralesional injection of IL-7 and IL-15 in RFA-treated murine tumors. We used two different breast carcinoma models: neu-overexpressing mouse mammary carcinoma (MMC) in FVBN202 transgenic mouse and 4T1 tumors in Balb/c mouse. MMC tend to relapse even in the presence of neu-specific immune responses, and 4T1 is a weakly immunogenic, aggressive and highly metastatic transplantable tumor. In vivo growth of both of these tumors is also associated with increased numbers of CD11b+Gr1+ myeloid-derived suppressor cells (MDSC). We showed for the first time that unlike RFA alone, RFA combined with the administration of intralesional IL-7 and IL-15 (after RFA), induced immune responses to tumors, inhibited tumor development and lung metastasis, and reduced MDSC. PMID:18425677

  2. Association of germline genetic variants in RFC, IL15 and VDR genes with minimal residual disease in pediatric B-cell precursor ALL.

    PubMed

    Dawidowska, Małgorzata; Kosmalska, Maria; Sędek, Łukasz; Szczepankiewicz, Aleksandra; Twardoch, Magdalena; Sonsala, Alicja; Szarzyńska-Zawadzka, Bronisława; Derwich, Katarzyna; Lejman, Monika; Pawelec, Katarzyna; Obitko-Płudowska, Agnieszka; Pawińska-Wąsikowska, Katarzyna; Kwiecińska, Kinga; Kołtan, Andrzej; Dyla, Agnieszka; Grzeszczak, Władysław; Kowalczyk, Jerzy R; Szczepański, Tomasz; Ziętkiewicz, Ewa; Witt, Michał

    2016-01-01

    Minimal residual disease (MRD) enables reliable assessment of risk in acute lymphoblastic leukemia (ALL). However, little is known on association between MRD status and germline genetic variation. We examined 159 Caucasian (Slavic) patients with pediatric ALL, treated according to ALL-IC-BFM 2002/2009 protocols, in search for association between 23 germline polymorphisms and MRD status at day 15, day 33 and week 12, with adjustment for MRD-associated clinical covariates. Three variants were significantly associated with MRD: rs1544410 in VDR (MRD-day15); rs1051266 in RFC (MRD-day33, MRD-week12), independently and in an additive effect with rs10519613 in IL15 (MRD-day33). The risk alleles for MRD-positivity were: A allele of VDR (OR = 2.37, 95%CI = 1.07-5.21, P = 0.03, MRD-day15); A of RFC (OR = 1.93, 95%CI = 1.05-3.52, P = 0.03, MRD-day33 and MRD-week12, P < 0.01); A of IL15 (OR = 2.30, 95%CI = 1.02-5.18, P = 0.04, MRD-day33). The risk for MRD-day33-positive status was higher in patients with risk alleles in both RFC and IL15 loci than in patients with risk alleles in one locus or no risk alleles: 2 vs. 1 (OR = 3.94, 95% CI = 1.28-12.11, P = 0.024), 2 vs. 0 (OR = 6.75, 95% CI = 1.61-28.39, P = 0.012). Germline variation in genes related to pharmacokinetics/pharmacodynamics of anti-leukemic drugs and to anti-tumor immunity of the host is associated with MRD status and might help improve risk assessment in ALL. PMID:27427275

  3. Association of germline genetic variants in RFC, IL15 and VDR genes with minimal residual disease in pediatric B-cell precursor ALL

    PubMed Central

    Dawidowska, Małgorzata; Kosmalska, Maria; Sędek, Łukasz; Szczepankiewicz, Aleksandra; Twardoch, Magdalena; Sonsala, Alicja; Szarzyńska-Zawadzka, Bronisława; Derwich, Katarzyna; Lejman, Monika; Pawelec, Katarzyna; Obitko-Płudowska, Agnieszka; Pawińska-Wąsikowska, Katarzyna; Kwiecińska, Kinga; Kołtan, Andrzej; Dyla, Agnieszka; Grzeszczak, Władysław; Kowalczyk, Jerzy R.; Szczepański, Tomasz; Ziętkiewicz, Ewa; Witt, Michał

    2016-01-01

    Minimal residual disease (MRD) enables reliable assessment of risk in acute lymphoblastic leukemia (ALL). However, little is known on association between MRD status and germline genetic variation. We examined 159 Caucasian (Slavic) patients with pediatric ALL, treated according to ALL-IC-BFM 2002/2009 protocols, in search for association between 23 germline polymorphisms and MRD status at day 15, day 33 and week 12, with adjustment for MRD-associated clinical covariates. Three variants were significantly associated with MRD: rs1544410 in VDR (MRD-day15); rs1051266 in RFC (MRD-day33, MRD-week12), independently and in an additive effect with rs10519613 in IL15 (MRD-day33). The risk alleles for MRD-positivity were: A allele of VDR (OR = 2.37, 95%CI = 1.07–5.21, P = 0.03, MRD-day15); A of RFC (OR = 1.93, 95%CI = 1.05–3.52, P = 0.03, MRD-day33 and MRD-week12, P < 0.01); A of IL15 (OR = 2.30, 95%CI = 1.02–5.18, P = 0.04, MRD-day33). The risk for MRD-day33-positive status was higher in patients with risk alleles in both RFC and IL15 loci than in patients with risk alleles in one locus or no risk alleles: 2 vs. 1 (OR = 3.94, 95% CI = 1.28–12.11, P = 0.024), 2 vs. 0 (OR = 6.75, 95% CI = 1.61–28.39, P = 0.012). Germline variation in genes related to pharmacokinetics/pharmacodynamics of anti-leukemic drugs and to anti-tumor immunity of the host is associated with MRD status and might help improve risk assessment in ALL. PMID:27427275

  4. Female Tubal Sterilization

    PubMed Central

    Rowe, Timothy C.; Pabuccu, Recai

    1986-01-01

    Tubal ligation has become the second most popular method of contraception in Canada, after oral contraception. Refinement of techniques has resulted in sterilization procedures which have minimal potential for failure and high potential for reversibility. Laparoscopic and minilaparatomy techniques allow outpatient “Band-Aid” sterilizations with less risk of complications than more destructive procedures. Laparoscopic application of tubal clips or rings is highly effective, with minimal tubal destruction. Tubal ligation following a pregnancy is more often regretted than is interval sterilization. The search continues for a satisfactory transcervical sterilization procedure. PMID:21267115

  5. Influence of in vitro IL-2 or IL-15 alone or in combination with Hsp-70-derived 14-mer peptide (TKD) on the expression of NK cell activatory and inhibitory receptors.

    PubMed

    Hromadnikova, Ilona; Pirkova, Petra; Sedlackova, Lucie

    2013-01-01

    NK cells represent a potential tool for adoptive immunotherapy against tumors. Membrane-bound Hsp70 acts as a tumor-specific marker enhancing NK cell activity. Using flow cytometry the effect of in vitro stimulation with IL-2 or IL-15 alone or in combination with Hsp70-derived 14-mer peptide (TKD) on cell surface expression of NK activatory receptors (CD16, NKG2D, NKG2C, NKp46, NKp44, NKp30, KIR2DL4, DNAM-1, and LAMP1) and NK inhibitory receptors (NKG2A, KIR2DL2/L3, LIR1/ILT-2, and NKR-P1A) in healthy individuals was studied. Results were expressed as the percentage of receptor expressing cells and the amount of receptor expressed by CD3(-)CD56(+) cellular population. CD94, NKG2D, NKp44, NKp30, KIR2DL4, DNAM-1, LAMP1, NKG2A, and NKR-P1A were upregulated after the stimulation with IL-2 or IL-15 alone or in combination with TKD. KIR2DL2/L3 was upregulated only by IL-15 and IL-15/TKD. Concurrently, an increase in a number of NK cells positive for CD94, NKp44, NKp30, KIR2DL4, and LAMP1 was observed. IL-15 and IL-15/TKD caused also cell number rise positive for KIR2DL2/L3 and NKR-P1A. Cell number positive for NKG2C and NKG2A was increased only by IL-2 and IL-2/TKD. The diverse effect of IL-2 or IL-15 w or w/o TKD on cell surface expression was observed in CD16, NKp46, and LIR1/ILT-2. PMID:23476104

  6. CD8(+) T cells sabotage their own memory potential through IFN-γ-dependent modification of the IL-12/IL-15 receptor α axis on dendritic cells.

    PubMed

    Kohlhapp, Frederick J; Zloza, Andrew; O'Sullivan, Jeremy A; Moore, Tamson V; Lacek, Andrew T; Jagoda, Michael C; McCracken, James; Cole, David J; Guevara-Patiño, José A

    2012-04-15

    CD8(+) T cell responses have been shown to be regulated by dendritic cells (DCs) and CD4(+) T cells, leading to the tenet that CD8(+) T cells play a passive role in their own differentiation. In contrast, by using a DNA vaccination model, to separate the events of vaccination from those of CD8(+) T cell priming, we demonstrate that CD8(+) T cells, themselves, actively limit their own memory potential through CD8(+) T cell-derived IFN-γ-dependent modification of the IL-12/IL-15Rα axis on DCs. Such CD8(+) T cell-driven cytokine alterations result in increased T-bet and decreased Bcl-2 expression, and thus decreased memory progenitor formation. These results identify an unrecognized role for CD8(+) T cells in the regulation of their own effector differentiation fate and a previously uncharacterized relationship between the balance of inflammation and memory formation. PMID:22430740

  7. Cooperative therapeutic anti-tumor effect of IL-15 agonist ALT-803 and co-targeting soluble NKG2D ligand sMIC

    PubMed Central

    Basher, Fahmin; Jeng, Emily K.; Wong, Hing; Wu, Jennifer

    2016-01-01

    Shedding of the human NKG2D ligand MIC (MHC class I-chain-related molecule) from tumor cell surfaces correlates with progression of many epithelial cancers. Shedding-derived soluble MIC (sMIC) enables tumor immune escape through multiple immune suppressive mechanisms, such as disturbing natural killer (NK) cell homeostatic maintenance, impairing NKG2D expression on NK cells and effector T cells, and facilitating the expansion of arginase I+ myeloid suppressor cells. Our recent study has demonstrated that sMIC is an effective cancer therapeutic target. Whether targeting tumor-derived sMIC would enhance current active immunotherapy is not known. Here, we determined the in vivo therapeutic effect of an antibody co-targeting sMIC with the immunostimulatory IL-15 superagonist complex, ALT-803, using genetically engineered transplantable syngeneic sMIC+ tumor models. We demonstrate that combined therapy of a nonblocking antibody neutralizing sMIC and ALT-803 improved the survival of animals bearing sMIC+ tumors in comparison to monotherapy. We further demonstrate that the enhanced therapeutic effect with combined therapy is through concurrent augmentation of NK and CD8 T cell anti-tumor responses. In particular, expression of activation-induced surface molecules and increased functional potential by cytokine secretion are improved greatly by the administration of combined therapy. Depletion of NK cells abolished the cooperative therapeutic effect. Our findings suggest that administration of the sMIC-neutralizing antibody can enhance the anti-tumor effects of ALT-803. With ALT-803 currently in clinical trials to treat progressive solid tumors, the majority of which are sMIC+, our findings provide a rationale for co-targeting sMIC to enhance the therapeutic efficacy of ALT-803 or other IL-15 agonists. PMID:26625316

  8. Sterilization for Women and Men

    MedlinePlus

    ... are rare. Can sterilization be reversed? Sterilization is permanent birth control and is not meant to be reversible. Before ... that can fertilize a female egg. Sterilization: A permanent method of birth control. Testes: Two male organs that produce sperm and ...

  9. [Sterilization and eugenics].

    PubMed

    Shasha, Shaul M

    2011-04-01

    The term "eugenics" was coined by Francis Galton in 1883 and was defined as the science of the improvement of the human race by better breeding. "Positive eugenics" referred to methods of encouraging the "most fit" to reproduce more often, while "negative eugenics" was related to ways of discouraging or preventing the "less fit" from reproducing by birth control and sterilization. Many western countries adopted eugenics programs including Britain, Canada, Norway, Australia, Switzerland and others. In Sweden more then 62,000 "unfits" were forcibly sterilized. Many states in the U.S.A. had adopted marriage laws with eugenics criteria including forced sterilization. Approximately 64,000 individuals were sterilized. Eugenics considerations also lay behind the adoption of the Immigration Restriction Act of 1924. The Largest plan on eugenics was adopted by the Nazi regime in Germany. Hundreds of thousands of people, who were viewed as being "unfit", were forcibly sterilized by different methods: Surgical sterilization or castration with severe complications and high mortality rates. X-ray irradiation. The method was suggested by Brack, and tested by Schuman using prisoners in Block No. 10 in Auschwitz and Birkenau. Experiments were also performed by Brack on prisoners using the "window method". "Klauberg method"--injection of irritating materials into the uterus. Experiments were conducted using the plant Caladium Seguinum which was believed to have sterilization and castration properties. PMID:22164927

  10. Induction of the 2B9 antigen/dipeptidyl peptidase IV/CD26 on human natural killer cells by IL-2, IL-12 or IL-15.

    PubMed Central

    Yamabe, T; Takakura, K; Sugie, K; Kitaoka, Y; Takeda, S; Okubo, Y; Teshigawara, K; Yodoi, J; Hori, T

    1997-01-01

    Activation of human natural killer (NK) cells involves sequential events including cytokine production and induction of cell surface molecules, resulting in the enhancement of cytolytic activity. To delineate the activation process of NK cells, we generated murine monoclonal antibodies (mAbs) against YT, a human large granular lymphocyte/natural killer (LGL/NK) cell line. Among the mAbs reactive with YT cells, one mAb, termed 2B9, was noted because of the lack of reactivity with most of the human T- and B-cell lines tested. In fresh peripheral blood mononuclear cells (PBMC), however, the majority of cells expressing this antigen (Ag) were T cells but not CD16+ nor CD56+ NK cells. Since YT cells showed an activated phenotype expressing interleukin-2 (IL-2) receptor alpha chain, we examined whether 2B9 Ag could be induced on normal human peripheral blood NK cells by cytokines known to activate NK cells. The 2B9 Ag was induced on NK cells by IL-2, IL-12 or IL-15 while no induction was observed by interferon-gamma (IFN-gamma). Biochemical analysis showed that anti-2B9 mAb recognized a 115 kDa molecule in YT cells. A cDNA clone encoding the 2B9 Ag was isolated from a cDNA expression library of YT cells and its sequence was identical to CD26 cDNA although it was not of full length. Transient expression of the 2B9 cDNA on COS-7 cells revealed that this cDNA encodes the antigenic epitope(s) recognized by anti-2B9 mAb as well as Ta1, an anti-CD26 mAb. These results showed that the 2B9 Ag is identical to CD26, and demonstrated that CD26 is an activation antigen on CD16+ CD56+ NK cells inducible by IL-2, IL-12 or IL-15. Images Figure 4 PMID:9203979

  11. Sterilization of space hardware.

    NASA Technical Reports Server (NTRS)

    Pflug, I. J.

    1971-01-01

    Discussion of various techniques of sterilization of space flight hardware using either destructive heating or the action of chemicals. Factors considered in the dry-heat destruction of microorganisms include the effects of microbial water content, temperature, the physicochemical properties of the microorganism and adjacent support, and nature of the surrounding gas atmosphere. Dry-heat destruction rates of microorganisms on the surface, between mated surface areas, or buried in the solid material of space vehicle hardware are reviewed, along with alternative dry-heat sterilization cycles, thermodynamic considerations, and considerations of final sterilization-process design. Discussed sterilization chemicals include ethylene oxide, formaldehyde, methyl bromide, dimethyl sulfoxide, peracetic acid, and beta-propiolactone.

  12. Sterilization by Laparoscopy

    MedlinePlus

    ... sleep-like state to prevent pain during surgery. Human Immunodeficiency Virus (HIV): A virus that attacks certain cells of the body’s immune system and causes acquired immunodeficiency syndrome (AIDS). Hysteroscopic Sterilization: ...

  13. Female Sterilization (Tubal Ligation)

    MedlinePlus

    ... when you want to have it done. Some women are sterilized right after they have a baby or an abortion, ... videos on Youtube © 1998-2016 | Center for Young Women's Health, Boston Children's Hospital. All rights reserved.

  14. Sterilization: A Review and Update.

    PubMed

    Moss, Chailee; Isley, Michelle M

    2015-12-01

    Sterilization is a frequently used method of contraception. Female sterilization is performed 3 times more frequently than male sterilization, and it can be performed immediately postpartum or as an interval procedure. Methods include mechanical occlusion, coagulation, or tubal excision. Female sterilization can be performed using an abdominal approach, or via laparoscopy or hysteroscopy. When an abdominal approach or laparoscopy is used, sterilization occurs immediately. When hysteroscopy is used, tubal occlusion occurs over time, and additional testing is needed to confirm tubal occlusion. Comprehensive counseling about sterilization should include discussion about male sterilization (vasectomy) and long-acting reversible contraceptive methods. PMID:26598311

  15. Auditing radiation sterilization facilities

    NASA Astrophysics Data System (ADS)

    Beck, Jeffrey A.

    The diversity of radiation sterilization systems available today places renewed emphasis on the need for thorough Quality Assurance audits of these facilities. Evaluating compliance with Good Manufacturing Practices is an obvious requirement, but an effective audit must also evaluate installation and performance qualification programs (validation_, and process control and monitoring procedures in detail. The present paper describes general standards that radiation sterilization operations should meet in each of these key areas, and provides basic guidance for conducting QA audits of these facilities.

  16. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15

    PubMed Central

    Xu, Yang; Zhang, Ming; Ramos, Carlos A.; Durett, April; Liu, Enli; Dakhova, Olga; Liu, Hao; Creighton, Chad J.; Gee, Adrian P.; Heslop, Helen E.; Rooney, Cliona M.; Savoldo, Barbara

    2014-01-01

    Adoptive transfer of T lymphocytes expressing a CD19-specific chimeric antigen receptor (CAR.CD19) induces complete tumor regression in patients with lymphoid malignancies. Although in vivo persistence of CAR-T cells correlates with clinical responses, it remains unknown whether specific cell subsets within the CAR–T-cell product correlate with their subsequent in vivo expansion and persistence. We analyzed 14 patients with B-cell malignancies infused with autologous CAR.CD19-redirected T cells expanded ex vivo using IL-2, and found that their in vivo expansion only correlated with the frequency within the infused product of a CD8+CD45RA+CCR7+ subset, whose phenotype is closest to “T-memory stem cells.” Preclinical models showed that increasing the frequency of CD8+CD45RA+CCR7+ CAR-T cells in the infused line by culturing the cells with IL-7 and IL-15 produced greater antitumor activity of CAR-T cells mediated by increased resistance to cell death, following repetitive encounters with the antigen, while preserving their migration to secondary lymphoid organs. This trial was registered at www.clinicaltrials.gov as #NCT00586391 and #NCT00709033. PMID:24782509

  17. Human cancer cells with stem cell-like phenotype exhibit enhanced sensitivity to the cytotoxicity of IL-2 and IL-15 activated natural killer cells.

    PubMed

    Yin, Tao; Wang, Guoping; He, Sisi; Liu, Qin; Sun, Jianhong; Wang, Yongsheng

    2016-02-01

    Tumors harbor a population of cancer stem cells (CSCs) which can drive tumor progression and therapeutical resistance. Nature killer (NK) cells are best known for their ability to directly recognize and kill malignant cells. However, the susceptibility of cancer stem cells to NK cells is not fully understood. Here we demonstrated that human CD44+CD24- breast CSCs were shown enhanced sensitivity to IL-2 and IL-15 activated NK cells. CD44+CD24- CSCs expressed higher levels of NKG2D ligands ULBP1, ULBP2 and MICA. Blockade assay showed that the sensitivity of CSCs to NK cells-mediated lysis was mainly dependent on NKG2D. Furthermore, redox oxygen species (ROS)-low tumor cells were more sensitive to NK cells. The presence of antioxidant enzymes inhibitor L-S,R-buthionine sulfoximine or H2O2 retarded the cytotoxicity of NK cells to CD44+CD24- CSCs. In addition, NK cells could readily target CD133+ colonal CSCs. Our findings provide novel targets for NK cells-based immunotherapy and are of great importance for translational medicine. PMID:26677760

  18. Hysteroscopic Tubal Sterilization

    PubMed Central

    McMartin, K

    2013-01-01

    Background Hysteroscopic tubal sterilization is a minimally invasive alternative to laparoscopic tubal ligation for women who want permanent contraception. The procedures involves non-surgical placement of permanent microinserts into both fallopian tubes. Patients must use alternative contraception for at least 3 months postprocedure until tubal occlusion is confirmed. Compared to tubal ligation, potential advantages of the hysteroscopic procedure are that it can be performed in 10 minutes in an office setting without the use of general or even local anesthesia. Objective The objective of this analysis was to determine the effectiveness and safety of hysteroscopic tubal sterilization compared with tubal ligation for permanent female sterilization. Data Sources A standard systematic literature search was conducted for studies published from January 1, 2008, until December 11, 2012. Review Methods Observational studies, randomized controlled trials (RCTs), systematic reviews and meta-analyses with 1 month or more of follow-up were examined. Outcomes included failure/pregnancy rates, adverse events, and patient satisfaction. Results No RCTs were identified. Two systematic reviews covered 22 observational studies of hysteroscopic sterilization. Only 1 (N = 93) of these 22 studies compared hysteroscopic sterilization to laparoscopic tubal ligation. Two other noncomparative case series not included in the systematic reviews were also identified. In the absence of comparative studies, data on tubal ligation were derived for this analysis from the CREST study, a large, multicentre, prospective, noncomparative observational study in the United States (GRADE low). Overall, hysteroscopic sterilization is associated with lower pregnancy rates and lower complication rates compared to tubal ligation. No deaths have been reported for hysteroscopic sterilization. Limitations A lack of long-term follow-up for hysteroscopic sterilization and a paucity of studies that directly

  19. Synergy between IL-15 and Id2 promotes the expansion of human NK progenitor cells, which can be counteracted by the E protein HEB required to drive T cell development.

    PubMed

    Schotte, Remko; Dontje, Wendy; Nagasawa, Maho; Yasuda, Yuko; Bakker, Arjen Q; Spits, Hergen; Blom, Bianca

    2010-06-15

    The cytokine IL-15 and the inhibitor of DNA binding (Id)2, which negatively regulates the activity of basic helix-loop-helix transcription factors, have been shown to play key roles in NK cell development. Consistent with this, exogenous IL-15 added to human thymic progenitor cells stimulated their development into NK cells at the expense of T cells both in fetal thymic organ culture and in coculture with stromal cells expressing the Notch ligand Delta-like 1. Overexpression of Id2 in thymic progenitor cells stimulated NK cell development and blocked T cell development. This, in part, is attributed to inhibition of the transcriptional activity of the E protein HEB, which we show in this study is the only E protein that enhanced T cell development. Notably, Id2 increased a pool of lineage CD1a-CD5+ progenitor cells that in synergy with IL-15 furthered expansion and differentiation into NK cells. Taken together, our findings point to a dualistic function of Id2 in controlling T/NK cell lineage decisions; T cell development is impaired by Id2, most likely by sequestering HEB, whereas NK cell development is promoted by increasing a pool of CD1a-CD5+ NK cell progenitors, which together with IL-15 differentiate into mature NK cells. PMID:20483740

  20. Stress-activated Dendritic Cells (DC) Induce Dual Interleukin (IL)-15- and IL1β-mediated Pathways, Which May Elicit CD4+ Memory T Cells and Interferon (IFN)-stimulated Genes*

    PubMed Central

    Wang, Yufei; Lavender, Paul; Watson, Julie; Arno, Matthew; Lehner, Thomas

    2015-01-01

    The prevailing evidence suggests that immunological memory does not require antigenic re-stimulation but is maintained by low level tonic stimulation. We examined the hypothesis that stress agents contribute to tonic cellular activation and maintain immunological memory. Stimulation of monocyte-derived dendritic cells (DC) with stress agents elicits reactive oxygen species and HSP70. NFκB is activated, which up-regulates membrane-associated (ma) IL-15, caspase-1 and IL-1β. Co-culture of stress-treated DC with mononuclear cells activates IL-15 and IL-1β receptors on CD4+ T cells, eliciting CD40L, proliferation, and up-regulation of CD45RO+ memory T cells. The transcription factors Tbethigh and RORγt are up-regulated, whereas FoxP3 is down-regulated, resulting in enhanced Th1 and Th17 expression and the corresponding cytokines. The interaction between maIL-15 expressed by DC and IL-15R on CD4+ T cells results in one pathway and the corresponding cells expressing IL-1β and IL1βR as a second pathway. Importantly, inhibition studies with IL-15 antibodies and IL-1βR inhibitor suggest that both pathways may be required for optimum CD4+ CD45RO+ memory T cell expression. Type 1 IFN expression in splenic CD11c DC of stress-treated mice demonstrated a significant increase of IFN-α in CD11c CD317+ and CD8α+ DC. Analysis of RNA in human CD4+ memory T cells showed up-regulation of type 1 IFN-stimulated genes and inhibition with histone methyltransferase inhibitor. We suggest the paradigm that stress-induced tonic stimulation might be responsible for the robust persistence of the immune response in vaccination and that epigenetic changes are involved in maintaining CD4+ T cell memory. PMID:25907558

  1. Stress-activated Dendritic Cells (DC) Induce Dual Interleukin (IL)-15- and IL1β-mediated Pathways, Which May Elicit CD4+ Memory T Cells and Interferon (IFN)-stimulated Genes.

    PubMed

    Wang, Yufei; Lavender, Paul; Watson, Julie; Arno, Matthew; Lehner, Thomas

    2015-06-19

    The prevailing evidence suggests that immunological memory does not require antigenic re-stimulation but is maintained by low level tonic stimulation. We examined the hypothesis that stress agents contribute to tonic cellular activation and maintain immunological memory. Stimulation of monocyte-derived dendritic cells (DC) with stress agents elicits reactive oxygen species and HSP70. NFκB is activated, which up-regulates membrane-associated (ma) IL-15, caspase-1 and IL-1β. Co-culture of stress-treated DC with mononuclear cells activates IL-15 and IL-1β receptors on CD4(+) T cells, eliciting CD40L, proliferation, and up-regulation of CD45RO(+) memory T cells. The transcription factors Tbet(high) and RORγt are up-regulated, whereas FoxP3 is down-regulated, resulting in enhanced Th1 and Th17 expression and the corresponding cytokines. The interaction between maIL-15 expressed by DC and IL-15R on CD4(+) T cells results in one pathway and the corresponding cells expressing IL-1β and IL1βR as a second pathway. Importantly, inhibition studies with IL-15 antibodies and IL-1βR inhibitor suggest that both pathways may be required for optimum CD4(+) CD45RO(+) memory T cell expression. Type 1 IFN expression in splenic CD11c DC of stress-treated mice demonstrated a significant increase of IFN-α in CD11c CD317(+) and CD8α(+) DC. Analysis of RNA in human CD4(+) memory T cells showed up-regulation of type 1 IFN-stimulated genes and inhibition with histone methyltransferase inhibitor. We suggest the paradigm that stress-induced tonic stimulation might be responsible for the robust persistence of the immune response in vaccination and that epigenetic changes are involved in maintaining CD4(+) T cell memory. PMID:25907558

  2. The emergence of load-oriented sterilization.

    PubMed

    Kolstad, R A

    1994-01-01

    Achieving maximum equipment sterilization is critical. Factors that contribute to sterilization efficiency are covered, including sterilization accuracy level, chamber loading and biological indicators. PMID:8031354

  3. Memory-Like Antigen-Specific Human NK Cells from TB Pleural Fluids Produced IL-22 in Response to IL-15 or Mycobacterium tuberculosis Antigens

    PubMed Central

    Fu, Xiaoying; Yu, Sifei; Yang, Binyan; Lao, Suihua; Li, Baiqing; Wu, Changyou

    2016-01-01

    Our previous result indicated that memory-like human natural killer (NK) cells from TB pleural fluid cells (PFCs) produced large amounts of IFN-γ in response to Bacille Calmette Guerin (BCG). Furthermore, recent studies have shown that human lymphoid tissues harbored a unique NK cell subset that specialized in production of interleukin (IL)-22, a proinflammatory cytokine that mediates host defense against pathogens. Yet little information was available with regard to the properties of IL-22 production by memory-like human NK cells. In the present study, we found that cytokines IL-15 induced and IL-12 enhanced the levels of IL-22 by NK cells from TB PFCs. In addition, IL-22 but not IL-17 was produced by NK cells from PFCs in response to BCG and M.tb-related Ags. More importantly, the subset of specific IL-22-producing NK cells were distinct from IFN-γ-producing NK cells in PFCs. CD45RO+ or CD45RO- NK cells were sorted, co-cultured with autologous monocytes and stimulated with BCG for the production of IL-22. The result demonstrated that CD45RO+ but not CD45RO- NK cells produced significantly higher level of IL-22. Anti-IL-12Rβ1 mAbs (2B10) partially inhibit the expression of IL-22 by NK cells under the culture with BCG. Consistently, BCG specific IL-22-producing NK cells from PFCs expressed CD45ROhighNKG2Dhighgranzyme Bhigh. In conclusion, our data demonstrated that memory-like antigen-specific CD45RO+ NK cells might participate in the recall immune response for M. tb infection via producing IL-22, which display a critical role to fight against M. tb. PMID:27031950

  4. Karlson ozone sterilizer. Final report

    SciTech Connect

    Karlson, E.

    1984-05-07

    The authors have a functional sterilization system employing ozone as a sterilization agent. This final report covers the work that led to the first medical sterilizer using ozone as the sterilizing agent. The specifications and the final design were set by hospital operating room personnel and public safety standards. Work on kill tests using bacteria, viruses and fungi determined the necessary time and concentration of ozone necessary for sterilization. These data were used in the Karlson Ozone Sterilizer to determine the length of the steps of the operating cycle and the concentration of ozone to be used. 27 references.

  5. Light sterile neutrinos

    NASA Astrophysics Data System (ADS)

    Gariazzo, S.; Giunti, C.; Laveder, M.; Li, Y. F.; Zavanin, E. M.

    2016-03-01

    The theory and phenomenology of light sterile neutrinos at the eV mass scale is reviewed. The reactor, gallium and Liquid Scintillator Neutrino Detector anomalies are briefly described and interpreted as indications of the existence of short-baseline oscillations which require the existence of light sterile neutrinos. The global fits of short-baseline oscillation data in 3 + 1 and 3 + 2 schemes are discussed, together with the implications for β-decay and neutrinoless double-β decay. The cosmological effects of light sterile neutrinos are briefly reviewed and the implications of existing cosmological data are discussed. The review concludes with a summary of future perspectives. This review is dedicated to the memory of Hai-Wei Long, our dear friend and collaborator, who passed away on 29 May 2015. He was an exceptionally kind person and an enthusiastic physicist. We deeply miss him.

  6. Light sterile neutrinos

    NASA Astrophysics Data System (ADS)

    Gariazzo, S.; Giunti, C.; Laveder, M.; Li, Y. F.; Zavanin, E. M.

    2015-03-01

    The theory and phenomenology of light sterile neutrinos at the eV mass scale is reviewed. The reactor, gallium and Liquid Scintillator Neutrino Detector anomalies are briefly described and interpreted as indications of the existence of short-baseline oscillations which require the existence of light sterile neutrinos. The global fits of short-baseline oscillation data in 3 + 1 and 3 + 2 schemes are discussed, together with the implications for β-decay and neutrinoless double-β decay. The cosmological effects of light sterile neutrinos are briefly reviewed and the implications of existing cosmological data are discussed. The review concludes with a summary of future perspectives. This review is dedicated to the memory of Hai-Wei Long, our dear friend and collaborator, who passed away on 29 May 2015. He was an exceptionally kind person and an enthusiastic physicist. We deeply miss him.

  7. Identification of Coupling and Repulsion Phase DNA Marker Associated With an Allele of a Gene Conferring Host Plant Resistance to Pigeonpea sterility mosaic virus (PPSMV) in Pigeonpea (Cajanus cajan L. Millsp.)

    PubMed Central

    Daspute, Abhijit; Fakrudin, B.

    2015-01-01

    Pigeonpea Sterility Mosaic Disease (PSMD) is an important foliar disease caused by Pigeonpea sterility mosaic virus (PPSMV) which is transmitted by eriophyid mites (Aceria cajani Channabasavanna). In present study, a F2 mapping population comprising 325 individuals was developed by crossing PSMD susceptible genotype (Gullyal white) and PSMD resistant genotype (BSMR 736). We identified a set of 32 out of 300 short decamer random DNA markers that showed polymorphism between Gullyal white and BSMR 736 parents. Among them, eleven DNA markers showed polymorphism including coupling and repulsion phase type of polymorphism across the parents. Bulked Segregant Analysis (BSA), revealed that the DNA marker, IABTPPN7, produced a single coupling phase marker (IABTPPN7414) and a repulsion phase marker (IABTPPN7983) co-segregating with PSMD reaction. Screening of 325 F2 population using IABTPPN7 revealed that the repulsion phase marker, IABTPPN7983, was co-segregating with the PSMD responsive SV1 at a distance of 23.9 cM for Bidar PPSMV isolate. On the other hand, the coupling phase marker IABTPPN7414 did not show any linkage with PSMD resistance. Additionally, single marker analysis both IABTPPN7983 (P<0.0001) and IABTPPN 7414 (P<0.0001) recorded a significant association with the PSMD resistance and explained a phenotypic variance of 31 and 36% respectively in F2 population. The repulsion phase marker, IABTPPN7983, could be of use in Marker-Assisted Selection (MAS) in the PPSMV resistance breeding programmes of pigeonpea. PMID:25774108

  8. Continuous sterilization of plumbing systems

    NASA Technical Reports Server (NTRS)

    Bryan, C. J.; Moyers, C. V.; Wright, E. E., Jr.

    1979-01-01

    Continuous sterilization of plumbing, such as in hospitals, clinics, and biological testing laboratories is possible with ethylene oxide/Freon 12 (ETO/F-12) humidifier developed for sterilization of potable water systems.

  9. Sterilization surgery - making a decision

    MedlinePlus

    ... have sterilization surgery. However, some may regret the decision later. Men or women who are younger at ... the options available to you before making the decision to have a sterilization procedure.

  10. MINOS Sterile Neutrino Search

    SciTech Connect

    Koskinen, David Jason

    2009-02-01

    The Main Injector Neutrino Oscillation Search (MINOS) is a long-baseline accelerator neutrino experiment designed to measure properties of neutrino oscillation. Using a high intensity muon neutrino beam, produced by the Neutrinos at Main Injector (NuMI) complex at Fermilab, MINOS makes two measurements of neutrino interactions. The first measurement is made using the Near Detector situated at Fermilab and the second is made using the Far Detector located in the Soudan Underground laboratory in northern Minnesota. The primary goal of MINOS is to verify, and measure the properties of, neutrino oscillation between the two detectors using the v μ→ Vτ transition. A complementary measurement can be made to search for the existence of sterile neutrinos; an oft theorized, but experimentally unvalidated particle. The following thesis will show the results of a sterile neutrino search using MINOS RunI and RunII data totaling ~2.5 x 1020 protons on target. Due to the theoretical nature of sterile neutrinos, complete formalism that covers transition probabilities for the three known active states with the addition of a sterile state is also presented.

  11. Sterilization of Native Americans

    ERIC Educational Resources Information Center

    Dillingham, Brint

    1977-01-01

    The U.S. State Department's Agency for International Development (AID) is spending more than $143 million this year for population control measures in over 70 nations around the world and it is estimated that as much as $10 million was spent in one year for surgical sterilization procedures. (JC)

  12. Dark matter and sterility

    NASA Astrophysics Data System (ADS)

    Smith, Peter F.

    2014-10-01

    In reply to Louise Mayor's dark-matter flow-chart "What's the matter?" (July pp30-31), which summarized the most likely candidates for galactic dark matter, and to Jon Cartwright's feature "A fourth type of neutrino" on the possibility of "sterile" neutrinos (August pp24-28).

  13. Radiation sterilization of ketoprofen

    NASA Astrophysics Data System (ADS)

    Katušin-Ražem, Branka; Hamitouche, Katia; Maltar-Strmečki, Nadica; Kos, Karmen; Pucić, Irina; Britvić-Budicin, Smiljana; Ražem, Dušan

    2005-06-01

    Radiation sterilization of ketoprofen (KP) dry powder was investigated by selected physico-chemical methods. High-performance liquid chromatography, ultraviolet spectrophotometry, infrared spectrophotometry, differential scanning calorimetry, X-ray diffraction and electron spin resonance spectroscopy did not show any significant degradation at sterilization dose 25 kGy. To determine the nature, extent and direction of radiation-induced changes, KP was irradiated to extremely high doses, much higher than necessary to achieve sterility. The irradiated KP did not show any difference of XRD patterns up to 200 kGy; with DSC and IR some changes were detected only above 1000 and 2000 kGy, respectively; HPLC has shown about 5% destruction at 2000 kGy. Acetyl benzophenon (AcBph) was generated by irradiation with G(AcBph)=(1.6±0.1)×10 -8 mol J -1. Ames test has shown no mutagenicity of KP irradiated with 3000 kGy or of the oily mixure of radiolytic products isolated from it. Solid KP has proven to be very stable on irradiation, and irradiation has been found to be a suitable method for its sterilization.

  14. Sterility of packaged implant components.

    PubMed

    Worthington, Philip

    2005-01-01

    Several implant components in their original glass vial and peel-back packages were subjected to sterility testing to determine whether the contents remained sterile after the expiration date marked on the package had passed. The results from a university microbiology laboratory showed that the contents remained sterile for 6 to 11 years after the expiration dates. PMID:15973959

  15. 21 CFR 880.6850 - Sterilization wrap.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Sterilization wrap. 880.6850 Section 880.6850 Food... § 880.6850 Sterilization wrap. (a) Identification. A sterilization wrap (pack, sterilization wrapper... sterilized by a health care provider. It is intended to allow sterilization of the enclosed medical...

  16. 21 CFR 880.6850 - Sterilization wrap.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Sterilization wrap. 880.6850 Section 880.6850 Food... § 880.6850 Sterilization wrap. (a) Identification. A sterilization wrap (pack, sterilization wrapper... sterilized by a health care provider. It is intended to allow sterilization of the enclosed medical...

  17. 21 CFR 880.6850 - Sterilization wrap.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Sterilization wrap. 880.6850 Section 880.6850 Food... § 880.6850 Sterilization wrap. (a) Identification. A sterilization wrap (pack, sterilization wrapper... sterilized by a health care provider. It is intended to allow sterilization of the enclosed medical...

  18. 21 CFR 880.6850 - Sterilization wrap.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Sterilization wrap. 880.6850 Section 880.6850 Food... § 880.6850 Sterilization wrap. (a) Identification. A sterilization wrap (pack, sterilization wrapper... sterilized by a health care provider. It is intended to allow sterilization of the enclosed medical...

  19. 21 CFR 880.6850 - Sterilization wrap.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Sterilization wrap. 880.6850 Section 880.6850 Food... § 880.6850 Sterilization wrap. (a) Identification. A sterilization wrap (pack, sterilization wrapper... sterilized by a health care provider. It is intended to allow sterilization of the enclosed medical...

  20. Sterile neutrino anarchy

    NASA Astrophysics Data System (ADS)

    Heeck, Julian; Rodejohann, Werner

    2013-02-01

    Lepton mixing, which requires physics beyond the Standard Model, is surprisingly compatible with a minimal, symmetryless and unbiased approach, called anarchy. This contrasts with highly involved flavor symmetry models. On the other hand, hints for light sterile neutrinos have emerged from a variety of independent experiments and observations. If confirmed, their existence would represent a groundbreaking discovery, calling for a theoretical interpretation. We discuss anarchy in the two-neutrino eV-scale seesaw framework. The distributions of mixing angles and masses according to anarchy are in agreement with global fits for the active and sterile neutrino parameters. Our minimal and economical scenario predicts the absence of neutrinoless double beta decay and one vanishing neutrino mass, and can therefore be tested in future experiments.

  1. Immediate Sterility after Vasectomy

    PubMed Central

    Hay, D. Urquhart

    1973-01-01

    A 2·5-ml injection of 1/1,000 solution of euflavine given down each vas during vasectomy for sterilization will destroy all sperms within the semen and eliminate the necessity for examining two consecutive specimens of semen for azoospermia after the operation. No local inflammatory response has been observed in the seminal vesicles or prostate of 81 consecutive patients in whom the method has been used. PMID:4730187

  2. Sterilization by oxygen plasma

    NASA Astrophysics Data System (ADS)

    Moreira, Adir José; Mansano, Ronaldo Domingues; Andreoli Pinto, Terezinha de Jesus; Ruas, Ronaldo; Zambon, Luis da Silva; da Silva, Mônica Valero; Verdonck, Patrick Bernard

    2004-07-01

    The use of polymeric medical devices has stimulated the development of new sterilization methods. The traditional techniques rely on ethylene oxide, but there are many questions concerning the carcinogenic properties of the ethylene oxide residues adsorbed on the materials after processing. Another common technique is the gamma irradiation process, but it is costly, its safe operation requires an isolated site and it also affects the bulk properties of the polymers. The use of a gas plasma is an elegant alternative sterilization technique. The plasma promotes an efficient inactivation of the micro-organisms, minimises the damage to the materials and presents very little danger for personnel and the environment. Pure oxygen reactive ion etching type of plasmas were applied to inactivate a biologic indicator, the Bacillus stearothermophilus, to confirm the efficiency of this process. The sterilization processes took a short time, in a few minutes the mortality was complete. In situ analysis of the micro-organisms' inactivating time was possible using emission spectrophotometry. The increase in the intensity of the 777.5 nm oxygen line shows the end of the oxidation of the biologic materials. The results were also observed and corroborated by scanning electron microscopy.

  3. [Sterilization of women].

    PubMed

    Tandberg, A

    1988-01-30

    The records of 209 women sterilized in the Lillehammer (Norway) county hospital during the period 1980-82 were examined for age, residence, parity, method of operation, induced abortions and frequency of complications. The patients were sent a questionnaire 6 months after the operation and were asked about how long they had felt unable to work after the operation, whether they regretted the operation, and whether they were satisfied with the cosmetic results. 96% of the patients returned the questionnaires. On the average the women had had 2.4 children at the time of sterilization. Those who had received induced abortions at the same time had 2.5 children. Women resident in the city had 2.1 children, those in the country had 2.4 children. None had 6 children. 20% had received abortion simultaneously. Aside from 1 patient who had transitory paresis in the left arm due to faulty padding in a shoulder support, there were no complications noted in the material. 2 patients regretted the operation. Neither of them had had simultaneous abortion. 1 of these had 1 child. Advised to be sterilized because of severe preeclampsia in her 1st pregnancy, she desired more children. The other, who had 4 children, gave decreased libido as the cause for her regret. Of the 177 who had had laparoscopy, only 6 patients (3.5%) said that they were dissatisfied with the appearance of the scar. PMID:3353913

  4. Hysteroscopic Tubal Sterilization

    PubMed Central

    2013-01-01

    Background Hysteroscopic sterilization is a minimally invasive alternative to laparoscopic tubal ligation for women who want permanent contraception. In contrast to the laparoscopic technique, a hysteroscope is used to pass permanent microinserts through the cervix and place them in the fallopian tubes. This procedure does not require local or general anesthesia and can be performed in an office setting. Objectives The objective of this analysis was to determine, based on published literature, the cost-effectiveness of hysteroscopic tubal sterilization (HS) compared with laparoscopic tubal ligation (LS) for permanent female sterilization. Data Sources A systematic literature search was conducted for studies published between January 1, 2008, and December 11, 2012. Review Methods Potentially relevant studies were identified based on the title and abstract. Cost-utility analyses (studies that report outcomes in terms of costs and quality-adjusted life-years) were prioritized for inclusion. When not available, cost-effectiveness, cost-benefit, and cost-consequence analyses were considered. Costing studies were considered in the absence of all other analyses. Results A total of 33 abstracts were identified. Three cost analyses were included. A retrospective chart review from Canada found that HS was $111 less costly than LS; a prospective activity-based cost management study from Italy reported that it was €337 less costly than LS; and the results of an American decision model showed that HS was $1,178 less costly than LS. Limitations All studies had limited applicability to the Ontario health care system due to differences in setting, resource use, and costs. Conclusions Three cost analyses found that, although the HS procedure was more expensive due to the cost of the microinserts, HS was less costly than LS overall due to the shorter recovery time required. Plain Language Summary Hysteroscopic sterilization is a minimally invasive alternative to conventional tubal

  5. Effectiveness of dental office instrument sterilization procedures.

    PubMed

    Hastreiter, R J; Molinari, J A; Falken, M C; Roesch, M H; Gleason, M J; Merchant, V A

    1991-10-01

    To evaluate instrument sterilization procedures in Minnesota, biological indicators were used to monitor 406 sterilizers in 381 dental offices. Findings suggest a general improvement in instrument performance over that of a decade ago, but sterilization failure rates are still too high. Sterilizer operator errors are a major cause of sterilization failures. BIs are useful in monitoring sterilization performance only when sterilization procedures are performed consistently and competently by well-trained staff using adequately maintained equipment. PMID:1660501

  6. Sterilization in the United States

    PubMed Central

    Bartz, Deborah; Greenberg, James A

    2008-01-01

    Unintended pregnancies are expensive for patients and for society in terms of medical costs, the cost of caring for more children, and the cost to personal and professional goals. Sterilization is the most common contraceptive method utilized by couples in the United States. Given technological advances over the past few decades, male and female surgical sterilization has become a safe, convenient, easy, and highly effective birth control method for the long term. This article reviews current male and female sterilization options. PMID:18701927

  7. Bioequivalent chemical steam sterilization indicators.

    PubMed

    Hirsch, A; Manne, S

    1984-01-01

    Biological indicators used to monitor steam sterilization cycles have two major shortcomings--the incubation period needed to determine if sterilization was accomplished, and the reliance on test packs for gathering information in each load. Chemical indicators do not suffer from these shortcomings. Chemical indicators can respond to time, temperature, and steam parameters to thus parallel the BI reaction. Nine commercially available chemical indicators and four biological indicators were evaluated under the conditions of dry heat, in a biological indicator-evaluator resistometer vessel, and in a hospital sterilizer. The results indicate that wider use of integrated chemical steam sterilization indicators is recommended. PMID:6493101

  8. New disinfection and sterilization methods.

    PubMed Central

    Rutala, W. A.; Weber, D. J.

    2001-01-01

    New disinfection methods include a persistent antimicrobial coating that can be applied to inanimate and animate objects (Surfacine), a high-level disinfectant with reduced exposure time (ortho-phthalaldehyde), and an antimicrobial agent that can be applied to animate and inanimate objects (superoxidized water). New sterilization methods include a chemical sterilization process for endoscopes that integrates cleaning (Endoclens), a rapid (4-hour) readout biological indicator for ethylene oxide sterilization (Attest), and a hydrogen peroxide plasma sterilizer that has a shorter cycle time and improved efficacy (Sterrad 50). PMID:11294738

  9. Electrolytic silver ion cell sterilizes water supply

    NASA Technical Reports Server (NTRS)

    Albright, C. F.; Gillerman, J. B.

    1968-01-01

    Electrolytic water sterilizer controls microbial contamination in manned spacecraft. Individual sterilizer cells are self-contained and require no external power or control. The sterilizer generates silver ions which do not impart an unpleasant taste to water.

  10. Sterilization of Extracted Human Teeth.

    ERIC Educational Resources Information Center

    Pantera, Eugene A., Jr.; Schuster, George S.

    1990-01-01

    At present, there is no specific recommendation for sterilization of extracted human teeth used in dental technique courses. The purpose of this study was to determine whether autoclaving would be effective in the sterilization of extracted teeth without compromising the characteristics that make their use in clinical simulations desirable. (MLW)

  11. The sterilization of endodontic hand files.

    PubMed

    Hurtt, C A; Rossman, L E

    1996-06-01

    Several different methods of file sterilization were analyzed to determine the best method of providing complete file sterility, including the metal shaft and plastic handle. Six test groups of 15 files were studied using Bacillus stearothermophilus as the test organism. Groups were "sterilized" by glutaraldehyde immersion, steam autoclaving, and various techniques of salt sterilization. Only proper steam autoclaving reliably produced completely sterile instruments. Salt sterilization and glutaraldehyde solutions may not be adequate sterilization methods for endodontic hand files and should not be relied on to provide completely sterile instruments. PMID:8934994

  12. [Sterility in medieval noblemen].

    PubMed

    van Eickels, Klaus

    2009-01-01

    The social competence of the medieval nobleman was closely associated with his male sense of honour. One essential aspect of his masculinity was the ability to produce progeny. The childlessness of a good ruler needed special justification, the childlessness of a bad ruler was seen as God's punishment. In terms of canon law, the inability to procreate was irrelevant as long as the marriage could be consummated. Considering the importance of the procreative capacity and its symbolic significance one must ask to what extent it was possible to ascertain sterility in the Middle Ages. In the case of noblemen one can assume that they could obtain certainty about their fertility through their premarital and extramarital intercourse. This might explain why some rulers and nobles accepted a childless marriage without deeming it necessary to take another wife (or plan their itinerary in a way that enabled them to produce progeny). PMID:20506725

  13. Genetic characterization of interleukins (IL-1α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12A, IL-12B, IL-15 and IL-18) with relevant biological roles in lagomorphs

    PubMed Central

    Neves, Fabiana; Abrantes, Joana; Almeida, Tereza; de Matos, Ana Lemos; Costa, Paulo P

    2015-01-01

    ILs, as essential innate immune modulators, are involved in an array of biological processes. In the European rabbit (Oryctolagus cuniculus) IL-1α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12A, IL-12B, IL-15 and IL-18 have been implicated in inflammatory processes and in the immune response against rabbit hemorrhagic disease virus and myxoma virus infections. In this study we characterized these ILs in six Lagomorpha species (European rabbit, pygmy rabbit, two cottontail rabbit species, European brown hare and American pika). Overall, these ILs are conserved between lagomorphs, including in their exon/intron structure. Most differences were observed between leporids and American pika. Indeed, when comparing both, some relevant differences were observed in American pika, such as the location of the stop codon in IL-1α and IL-2, the existence of a different transcript in IL8 and the number of cysteine residues in IL-1β. Changes at N-glycosylation motifs were also detected in IL-1, IL-10, IL-12B and IL-15. IL-1α is the protein that presents the highest evolutionary distances, which is in contrast to IL-12A where the distances between lagomorphs are the lowest. For all these ILs, sequences of human and European rabbit are more closely related than between human and mouse or European rabbit and mouse. PMID:26395994

  14. Genetic characterization of interleukins (IL-1α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12A, IL-12B, IL-15 and IL-18) with relevant biological roles in lagomorphs.

    PubMed

    Neves, Fabiana; Abrantes, Joana; Almeida, Tereza; de Matos, Ana Lemos; Costa, Paulo P; Esteves, Pedro J

    2015-11-01

    ILs, as essential innate immune modulators, are involved in an array of biological processes. In the European rabbit (Oryctolagus cuniculus) IL-1α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12A, IL-12B, IL-15 and IL-18 have been implicated in inflammatory processes and in the immune response against rabbit hemorrhagic disease virus and myxoma virus infections. In this study we characterized these ILs in six Lagomorpha species (European rabbit, pygmy rabbit, two cottontail rabbit species, European brown hare and American pika). Overall, these ILs are conserved between lagomorphs, including in their exon/intron structure. Most differences were observed between leporids and American pika. Indeed, when comparing both, some relevant differences were observed in American pika, such as the location of the stop codon in IL-1α and IL-2, the existence of a different transcript in IL8 and the number of cysteine residues in IL-1β. Changes at N-glycosylation motifs were also detected in IL-1, IL-10, IL-12B and IL-15. IL-1α is the protein that presents the highest evolutionary distances, which is in contrast to IL-12A where the distances between lagomorphs are the lowest. For all these ILs, sequences of human and European rabbit are more closely related than between human and mouse or European rabbit and mouse. PMID:26395994

  15. Effectiveness of salt versus glass bead sterilizers.

    PubMed

    Haddad, A J; Girard, B; Bouclin, R; Valois, M; Landry, R G

    1997-06-01

    Microorganisms can be removed from dental instruments by various methods, including treatment in salt and glass bead sterilizers. However, no rigorous, controlled, in vivo or in vitro studies have been performed to verify the respective efficiencies of these methods. The goals of this study were to determine if the positioning of instruments at the centre or edge of a salt sterilizer results in differential sterilization effectiveness, and to compare the effectiveness of salt sterilizers relative to glass bead sterilizers. Autoclaved number 60 reamers were contaminated by plunging them to the handle in a commercial Bacillus stearothermophilus spore suspension. They were then sterilized for different periods of time and at different positions in the sterilizers. Each experiment included positive and negative controls. The results showed that better sterilization is achieved at the edge of the chamber than at the centre, and that salt sterilizers are more effective than glass bead sterilizers for a given period of time (15 seconds) in the sterilizer. PMID:9203778

  16. Pain Associated With Hysteroscopic Sterilization

    PubMed Central

    Levy, Jenna; Childers, Meredith E.

    2007-01-01

    Background and Objectives: The safety and efficacy of female hysteroscopic sterilization using the Essure system has been well documented. Given the marked differences in the execution of hysteroscopic and laparoscopic sterilization, the objective of this study was to assess the experience of pain postprocedure between the 2. Secondary end-points included postoperative pain medication, time to return to normal activities, postprocedure bleeding, and patient satisfaction. Methods: Twenty cases each of laparoscopic sterilization (LS) and hysteroscopic sterilization (HS) were performed. Patients were surveyed regarding their experience of pain immediately postoperatively, 1 week, and 4 weeks post-procedure. Results: The average pain score immediately postprocedure was significantly lower among HS patients than among LS patients (t=−8.17, P<.0001). One-week post-procedure, none of the patients in the HS group reported any pain, while the average pain score among the LS patients was 2.65 (t =−9.67, P<.0001). Four weeks post-procedure, women in the HS group continued to report no pain, 35% of the LS group continued to report some pain (t=−3.04, P=.004). Conclusions: Hysteroscopic sterilization offers a minimally invasive, less painful, equally efficacious modality for sterilization than laparoscopic sterilization and should be available to all women seeking permanent birth control. PMID:17651558

  17. [Sterilization: necessity or genocide?].

    PubMed

    Muraro, R M

    1991-01-01

    Recent warnings by the UN Fund for Population Activities about the rapid growth of the world population and the overwhelming role in it played by impoverished women in developing countries are of interest to all women in Latin America. According to the document, Third World Women require drastic improvements in their socioeconomic positions in order to achieve reductions in their family sizes and avoid an increase in the world population from 5 billion at present to 10 billion in 2025, which would be a disaster for the planet. The document states that much of the environmental damage that would occur would be attributable to the combination of poverty and rapid population increase. If the proportion of the world's women using contraceptives increases from the current 45% to 58% by the year 2000, the world population in 2025 will be 8.5 billion. The document recommends that the amount of money invested in family planning be greatly increased by 2000 in order to make possible increased use of family planning. It appears, however, that much of the funding for family planning is under the control of private organizations and is used to serve the interests of foreign countries. The 2 principal private family planning organizations in Brazil, for example, received 18.2 million US dollars between 1978--84, which were used largely to finance a campaign of mass sterilization. Brazil's rate of population growth, which was 2.1% in 1980-85 and 1.8% in 1990, is expected to drop to 1.6% in 1995. With the decline in the rate of growth, the population will be 170 million in 2000 instead of the 220 million projected using data from the 1970s. A much higher proportion of fertile-aged women in Brazil is sterilized than in the US or Europe . Closer examination of the premises behind family planning policies shows them to be questionable. The premise that population density affects the environment is questionable; Japan, West Germany, and Holland have some of the highest population

  18. 21 CFR 880.6880 - Steam sterilizer.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Steam sterilizer. 880.6880 Section 880.6880 Food... § 880.6880 Steam sterilizer. (a) Identification. A steam sterilizer (autoclave) is a device that is intended for use by a health care provider to sterilize medical products by means of pressurized steam....

  19. 21 CFR 880.6880 - Steam sterilizer.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Steam sterilizer. 880.6880 Section 880.6880 Food... § 880.6880 Steam sterilizer. (a) Identification. A steam sterilizer (autoclave) is a device that is intended for use by a health care provider to sterilize medical products by means of pressurized steam....

  20. 21 CFR 880.6880 - Steam sterilizer.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Steam sterilizer. 880.6880 Section 880.6880 Food... § 880.6880 Steam sterilizer. (a) Identification. A steam sterilizer (autoclave) is a device that is intended for use by a health care provider to sterilize medical products by means of pressurized steam....

  1. 21 CFR 880.6880 - Steam sterilizer.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Steam sterilizer. 880.6880 Section 880.6880 Food... § 880.6880 Steam sterilizer. (a) Identification. A steam sterilizer (autoclave) is a device that is intended for use by a health care provider to sterilize medical products by means of pressurized steam....

  2. 21 CFR 880.6880 - Steam sterilizer.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Steam sterilizer. 880.6880 Section 880.6880 Food... § 880.6880 Steam sterilizer. (a) Identification. A steam sterilizer (autoclave) is a device that is intended for use by a health care provider to sterilize medical products by means of pressurized steam....

  3. Sterilization of soybean powder with plasma treatment in atmospheric humid air

    NASA Astrophysics Data System (ADS)

    Iwami, R.; Kikuchi, Y.; Fukumoto, N.; Nagata, M.; Nakayama, A.; Nakagawa, K.

    2013-10-01

    Sterilization of foods has been performed by conventional methods such as heat, steam and chemical solutions. However, these sterilization techniques could cause damages to the food material. It is considered that plasma sterilization at atmospheric pressure is one of the promising alternative methods because of the low temperature process. In our previous study, the inactivation of Bacillus atrophaeusspores by a dielectric barrier discharge (DBD) plasma produced in atmospheric humid air was investigated in order to develop low-temperature, low-cost and high-speed plasma sterilization technique. The results showed that the inactivation of Bacillus atrophaeusspores was found to be dependent strongly on the humidity. In the present study, the plasma treatment technique in humid air is applied to sterilization of soybean powder. Effects of plasma sterilization were successfully confirmed by a colony counting method. It was found that the sterilization efficiency was increased by using the humid air as the discharge gas. In the conference, an improvement of the plasma treatment system to enhance the sterilization efficiency will be shown.

  4. Sterilization surgery - making a decision

    MedlinePlus

    ... can sometimes be reversed, both must be considered permanent forms of birth control. When deciding if you want to have a ... other options for preventing pregnancy that are not permanent. Talk ... before making the decision to have a sterilization procedure.

  5. [Sterilization of mentally retarded women].

    PubMed

    Heidenreich, W; Petersen, P; Schneider, J

    1982-07-01

    Seven mentally retarded women were sterilized in the Department of Obstetrics and Gynaecology of Medical School Hannover between 1.6.74 and 1.6.81. The decision to operate proceeded only after careful consideration by the director of the clinic. Each case was documented with proof that improvement of the mental situation was unprobable and that sterilization seemed highly desirable. In spite of strong reservation the sterilization of a mentally retarded may medically and ethically be justified in exceptional cases. The operation seems possible by the following: The sterilization may only be performed if the patient does not obviously refuse it. Diagnosis and prognosis of the mental handicap must undoubtedly be proven. If the patient cannot judge the consequence of the operation the legal guardian must decide for her. The court must consent in these cases. Regarding legal theory the decision by the guardian is an open question. PMID:6922080

  6. Food irradiation and sterilization

    NASA Astrophysics Data System (ADS)

    Josephson, Edward S.

    Radiation sterilization of food (radappertization) requires exposing food in sealed containers to ionizing radiation at absorbed doses high enough (25-70 kGy) to kill all organisms of food spoilage and public health significance. Radappertization is analogous to thermal canning is achieving shelf stability (long term storage without refrigeration). Except for dry products in which autolysis is negligible, the radappertization process also requires that the food be heated to an internal temperature of 70-80°C (bacon to 53°C) to inactivate autolytic enzymes which catalyze spoilage during storage without refrigeration. To minimize the occurence of irradiation induced off-flavors and odors, undesirable color changes, and textural and nutritional losses from exposure to the high doses required for radappertization, the foods are vacuum sealed and irradiated frozen (-40°C to -20°C). Radappertozed foods have the characteristic of fresh foods prepared for eating. Radappertization can substitute in whole or in part for some chemical food additives such as ethylene oxide and nitrites which are either toxic, carcinogenic, mutagenic, or teratogenic. After 27 years of testing for "wholesomeness" (safety for consumption) of radappertized foods, no confirmed evidence has been obtained of any adverse effecys of radappertization on the "wholesomeness" characteristics of these foods.

  7. Voluntary sterilization in North Tyneside.

    PubMed

    Carnegie-Smith, K

    1984-04-01

    Since 1975, sterilization operations, on both men and women have been performed with increasing frequency within the National Health Service in the North Tyneside Area in northeast England. A prospective study was undertaken to discover some of the reasons why healthy young men and women chose surgical sterilization rather than use the established reversible methods of family planning available to them. The study examined some of the characteristics of those requesting sterilization, attempted to understand why they did so at that particular time, and assessed the patient-perceived morbidity resulting from this elective procedure. The study population included all individuals referred for consultation following the patient's request for voluntary sterilization by vasectomy or occlusive tubal surgery, during the period of 1 year (August 1, 1980-July 31, 1981). Women sterilized in association with a pregnancy outcome were not included in the study. Data on pregnancies and sterilizations in North Tyneside demonstrate a rapid increase in requests for vasectomy after 1975. Patients requesting sterilization were admitted to the study during the initial out-patient appointment with their surgeon. Couples seeking sterilization show similar age range for men (mean 34.2) and women (33.1). The proportion of patients who were not married at the time of the operation is perhaps a reflection of doctors' increasing willingness to perform sterilizations on the unmarried, and of individuals to seek such surgery in a committed manner. The increasing tendency for requests to be received from people still in their early 20s is seen as a problem. Data indicates that married people who request the operation at an early age are also those who were married under age 21, started a family immediately and with a 25% divorce rate. At the other end of the age range, couples who ahve been sucessfully using oral contraceptives have become concerned about its safety, especially after age 35. Data

  8. Radiation sterilization of skin allograft

    NASA Astrophysics Data System (ADS)

    Kairiyama, E.; Horak, C.; Spinosa, M.; Pachado, J.; Schwint, O.

    2009-07-01

    In the treatment of burns or accidental loss of skin, cadaveric skin allografts provide an alternative to temporarily cover a wounded area. The skin bank facility is indispensable for burn care. The first human skin bank was established in Argentina in 1989; later, 3 more banks were established. A careful donor selection is carried out according to the national regulation in order to prevent transmissible diseases. As cadaveric human skin is naturally highly contaminated, a final sterilization is necessary to reach a sterility assurance level (SAL) of 10 -6. The sterilization dose for 106 batches of processed human skin was determined on the basis of the Code of Practice for the Radiation Sterilization of Tissue Allografts: Requirements for Validation and Routine Control (2004) and ISO 11137-2 (2006). They ranged from 17.6 to 33.4 kGy for bioburdens of >10-162.700 CFU/100 cm 2. The presence of Gram negative bacteria was checked for each produced batch. From the analysis of the experimental results, it was observed that the bioburden range was very wide and consequently the estimated sterilization doses too. If this is the case, the determination of a tissue-specific dose per production batch is necessary to achieve a specified requirement of SAL. Otherwise if the dose of 25 kGy is preselected, a standardized method for substantiation of this dose should be done to confirm the radiation sterilization process.

  9. Neutrino Oscillations With Two Sterile Neutrinos

    NASA Astrophysics Data System (ADS)

    Kisslinger, Leonard S.

    2016-06-01

    This work estimates the probability of μ to e neutrino oscillation with two sterile neutrinos using a 5×5 U-matrix, an extension of the previous estimate with one sterile neutrino and a 4×4 U-matrix. The sterile neutrino-active neutrino mass differences and the mixing angles of the two sterile neutrinos with the three active neutrinos are taken from recent publications, and the oscillation probability for one sterile neutrino is compared to the previous estimate.

  10. Genomic Networks of Hybrid Sterility

    PubMed Central

    Turner, Leslie M.; White, Michael A.; Tautz, Diethard; Payseur, Bret A.

    2014-01-01

    Hybrid dysfunction, a common feature of reproductive barriers between species, is often caused by negative epistasis between loci (“Dobzhansky-Muller incompatibilities”). The nature and complexity of hybrid incompatibilities remain poorly understood because identifying interacting loci that affect complex phenotypes is difficult. With subspecies in the early stages of speciation, an array of genetic tools, and detailed knowledge of reproductive biology, house mice (Mus musculus) provide a model system for dissecting hybrid incompatibilities. Male hybrids between M. musculus subspecies often show reduced fertility. Previous studies identified loci and several X chromosome-autosome interactions that contribute to sterility. To characterize the genetic basis of hybrid sterility in detail, we used a systems genetics approach, integrating mapping of gene expression traits with sterility phenotypes and QTL. We measured genome-wide testis expression in 305 male F2s from a cross between wild-derived inbred strains of M. musculus musculus and M. m. domesticus. We identified several thousand cis- and trans-acting QTL contributing to expression variation (eQTL). Many trans eQTL cluster into eleven ‘hotspots,’ seven of which co-localize with QTL for sterility phenotypes identified in the cross. The number and clustering of trans eQTL—but not cis eQTL—were substantially lower when mapping was restricted to a ‘fertile’ subset of mice, providing evidence that trans eQTL hotspots are related to sterility. Functional annotation of transcripts with eQTL provides insights into the biological processes disrupted by sterility loci and guides prioritization of candidate genes. Using a conditional mapping approach, we identified eQTL dependent on interactions between loci, revealing a complex system of epistasis. Our results illuminate established patterns, including the role of the X chromosome in hybrid sterility. The integrated mapping approach we employed is

  11. Bacterial Sterilization Using Cavitating Jet

    NASA Astrophysics Data System (ADS)

    Azuma, Yohei; Kato, Hiroharu; Usami, Ron; Fukushima, Tadamasa

    In this paper, a new sterilization method using cavitating flow is presented. Water with bacteria was pressurized up to 105 MPa and flushed out through two very small nozzles 0.1-0.31 mm in diameter, where a cavitating jet was generated containing bubbles that collapsed downstream. First, the effects of jet velocity and cavitation number on the sterilization rate of Escherichia coli JCM1649T (E. coli) were examined. The sterilization rate increased with jet velocity. The rate was proportional to the 3rd power of the velocity. All the E. coli cells were killed by three successive treatments at V=355.7 m/s and cavitation number σ=0.154. The sterilization rate has a peak depending on cavitation number at the low-jet-velocity region of less than 300 m/s. An experiment was also performed to compare two types of bacteria, E. coli, as typical Gram-negative bacteria and Bacillus subtilis JCM1465T (B. subtilis), as typical Gram-positive bacteria. Additional tests were performed using Pseudomonas putida JCM13063T, Gram-negative bacteria and Bacillus halodurans JCTM9153, Gram-positive bacteria. The sterilization rate of the Gram-positive bacteria was much lower than that of the Gram-negative bacteria under the same experimental conditions. Gram-positive bacteria have a thicker peptidoglycan layer than Gram-negative bacteria. This may be the reason why B. subtilis is more resistant to the mechanical stress caused by cavitating flow.

  12. [Psychosexual implications of female sterilization].

    PubMed

    Grio, R; Fusi, D; Corsello, F P; Canestrelli, M; Abbondanza, M; Arrichiello, G; Marchino, G L

    1991-12-01

    According to data of the Italian Association for Demographic Education, from 1978 to 1991 a total of 16,000 sterilizations were carried out in patients with an average age of 36 years. There was an increasing frequency of anxiety, depression, and lack of satisfaction with sexual life, and deterioration of marital life as the consequence of the operations. Psychological improvement has been reported in only a few cases. Hysterectomy, mastectomy, abortion, and sterilization produce profound psychological effects in women. The ideal candidate for such intervention should be fully aware of the choice and be well informed about the reproductive system, and aged over 30 with at least 2 children in a stable marital relationship. A 1973 review of 80 different studies carried out in 12 different countries reported that 82% of women benefited from the operation. In a study of 180 patients in Glasgow, Scotland, psychosexual disorders were found, in only 3.6%. In a 1975 report, postoperative psychiatric disturbances in sexual life were recorded in 2% of 98 women. Another study of 94 women who were sterilized did not find any medical or psychological problems but did find patients who were completely satisfied 2 years later. In a study of 50 patients who underwent surgical sterilization by the Pomeroy technique during cesarean section, sexual behavior in the women, measured as desire, frequency of intercourse, and satisfaction, was unchanged in 47, while in 3 there were only modest variations in libido and frequency of intercourse. On the basis of these reports in the majority of cases the outcome of sterilization was favorable when assessing various gynecological problems over time. On the other hand, when the candidate is a young woman the information has to be particularly detailed and scrupulous with respect to risks and the probable irreversibility of sterilization. PMID:1819775

  13. Portable Ethylene Oxide Sterilization Chamber

    PubMed Central

    Songer, J. R.; Mathis, R. G.

    1969-01-01

    A portable ethylene oxide sterilization chamber was designed, constructed, and tested for use in the sterilization of embolectomy catheters. The unit can accommodate catheters up to 40 inches (101.6 cm) in length and can be operated for less than 4 cents per cycle. A constant concentration of 500 mg of ethylene oxide per liter of space and holding periods of 4 and 6 hr at 43 and 22 C, respectively, were adequate when tested with B. subtilis spores. The estimated cost of construction was $165.00. If temperature control is unnecessary, the cost is approximately $80.00. Images PMID:4977644

  14. Sterilization of Persons with Mental Retardation.

    ERIC Educational Resources Information Center

    Elkins, Thomas E.; Andersen, H. Frank

    1992-01-01

    This article examines the historical, legal, and ethical concerns regarding sterilization for persons with mental retardation and offers guidelines to help counsel individuals with disabilities or their families regarding decision making about sterilization. (DB)

  15. 45 CFR 96.73 - Sterilization.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ....73 Sterilization. If a State authorizes sterilization as a family planning service, it must comply with the provisions of 42 CFR Part 441, Subpart F, except that the State plan requirement under 42...

  16. 45 CFR 96.73 - Sterilization.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ....73 Sterilization. If a State authorizes sterilization as a family planning service, it must comply with the provisions of 42 CFR Part 441, Subpart F, except that the State plan requirement under 42...

  17. 45 CFR 96.73 - Sterilization.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ....73 Sterilization. If a State authorizes sterilization as a family planning service, it must comply with the provisions of 42 CFR part 441, subpart F, except that the State plan requirement under 42...

  18. 45 CFR 96.73 - Sterilization.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ....73 Sterilization. If a State authorizes sterilization as a family planning service, it must comply with the provisions of 42 CFR Part 441, Subpart F, except that the State plan requirement under 42...

  19. Low Temperature Atmospheric Pressure Plasma Sterilization Shower

    NASA Astrophysics Data System (ADS)

    Gandhiraman, R. P.; Beeler, D.; Meyyappan, M.; Khare, B. N.

    2012-10-01

    Low-temperature atmospheric pressure plasma sterilization shower to address both forward and backward biological contamination issues is presented. The molecular effects of plasma exposure required to sterilize microorganisms is also analysed.

  20. Sterilization beneath rings on dental instruments.

    PubMed

    Miller, C H; Sheldrake, M A

    1991-12-01

    This study determined the effectiveness of standard methods of instrument sterilization beneath instrument rings. Sets of three types of dental instruments were contaminated with known amounts of bacterial spores (Bacillus stearothermophilus or Bacillus subtilis). Instrument rings were placed over the contamination and the instruments processed through standard cycles in a steam autoclave, an unsaturated chemical vapor sterilizer, a standard dry heat sterilizer, an ethylene oxide gas sterilizer or a 2.0% alkaline glutaraldehyde solution. Controls consisted of spore-contaminated instruments without rings that were not processed through any sterilizing method and that were processed through each sterilizing method. All instruments and their associated rings were cultured for the presence of live spores. The results indicate that the reliability of sterilization beneath the instrument rings used is greatest if the ringed instruments are processed through a steam autoclave or an unsaturated chemical vapor sterilizer. PMID:1814351

  1. Plasma Sterilization Technology for Spacecraft Applications

    NASA Technical Reports Server (NTRS)

    Fraser, S. J.; Olson, R. L.; Leavens, W. M.

    1975-01-01

    The application of plasma gas technology to sterilization and decontamination of spacecraft components is considered. Areas investigated include: effective sterilizing ranges of four separate gases; lethal constituents of a plasma environment; effectiveness of plasma against a diverse group of microorganisms; penetrating efficiency of plasmas for sterilization; and compatibility of spacecraft materials with plasma environments. Results demonstrated that plasma gas, specifically helium plasma, is a highly effective sterilant and is compatible with spacecraft materials.

  2. Sterile pyuria: a forgotten entity

    PubMed Central

    Persad, Raj

    2015-01-01

    Sterile pyuria is a common entity. Yet there are no guidelines to address this issue. We have conducted a systematic review over 20 years and reviewed the results. Guidelines for assessment, diagnosis and management are developed based on these results. PMID:26425144

  3. Microwave powered sterile access port

    NASA Technical Reports Server (NTRS)

    Sauer, Richard L. (Inventor); Atwater, James E. (Inventor); Dahl, Roger W. (Inventor); Garmon, Frank C. (Inventor); Lunsford, Teddie D. (Inventor); Michalek, William F. (Inventor); Wheeler, Jr., Richard R. (Inventor)

    2000-01-01

    A device and method for elimination of contamination during transfer of materials either into or from bioreactors, food containers, or other microbially vulnerable systems. Using microwave power, thermal sterilizations of mating fixtures are achieved simply, reliably, and quickly by the volatilization of small quantities of water to produce superheated steam which contacts all exposed surfaces.

  4. Sterile Neutrino Search with MINOS

    SciTech Connect

    Devan, Alena V.

    2015-08-01

    MINOS, Main Injector Neutrino Oscillation Search, is a long-baseline neutrino oscillation experiment in the NuMI muon neutrino beam at the Fermi National Accelerator Laboratory in Batavia, IL. It consists of two detectors, a near detector positioned 1 km from the source of the beam and a far detector 734 km away in Minnesota. MINOS is primarily designed to observe muon neutrino disappearance resulting from three flavor oscillations. The Standard Model of Particle Physics predicts that neutrinos oscillate between three active flavors as they propagate through space. This means that a muon-type neutrino has a certain probability to later interact as a different type of neutrino. In the standard picture, the neutrino oscillation probabilities depend only on three neutrino flavors and two mass splittings, Δm2. An anomaly was observed by the LSND and MiniBooNE experiments that suggests the existence of a fourth, sterile neutrino flavor that does not interact through any of the known Standard Model interactions. Oscillations into a theoretical sterile flavor may be observed by a deficit in neutral current interactions in the MINOS detectors. A distortion in the charged current energy spectrum might also be visible if oscillations into the sterile flavor are driven by a large mass-squared difference, ms2 ~ 1 eV2. The results of the 2013 sterile neutrino search are presented here.

  5. Sterile Neutrino Search with MINOS

    NASA Astrophysics Data System (ADS)

    Devan, Alena V.

    MINOS, Main Injector Neutrino Oscillation Search, is a long-baseline neutrino oscillation experiment in the NuMI muon neutrino beam at the Fermi National Accelerator Laboratory in Batavia, IL. It consists of two detectors, a near detector positioned 1 km from the source of the beam and a far detector 734 km away in Minnesota. MINOS is primarily designed to observe muon neutrino disappearance resulting from three flavor oscillations. The Standard Model of Particle Physics predicts that neutrinos oscillate between three active flavors as they propagate through space. This means that a muon type neutrino has a certain probability to later interact as a different type of neutrino. In the standard picture, the neutrino oscillation probabilities depend only on three neutrino flavors and two mass splittings, Amt. An anomaly was observed by the LSND and MiniBooNE experiments that suggests the existence of a fourth, sterile neutrino flavor that does not interact through any of the known Standard Model interactions. Oscillations into a theoretical sterile flavor may be observed by a deficit in neutral current interactions in the MINOS detectors. A distortion in the charged current energy spectrum might also be visible if oscillations into the sterile flavor are driven by a large mass-squared difference, Delta m2s 1 eV2. The results of the 2013 sterile neutrino search are presented here.

  6. The limits of sterility assurance

    PubMed Central

    von Woedtke, Thomas; Kramer, Axel

    2008-01-01

    Sterility means the absence of all viable microorganisms including viruses. At present, a sterility assurance level (SAL) of 10–6 is generally accepted for pharmacopoeial sterilization procedures, i.e., a probability of not more than one viable microorganism in an amount of one million sterilised items of the final product. By extrapolating the reduction rates following extreme artificial initial contamination, a theoretical overall performance of the procedure of at least 12 lg increments (overkill conditions) is demanded to verify an SAL of 10–6. By comparison, other recommendations for thermal sterilization procedures demand only evidence that the difference between the initial contamination and the number of test organisms at the end of the process amount to more than six orders of magnitude. However, a practical proof of the required level of sterility assurance of 10–6 is not possible. Moreover, the attainability of this condition is fundamentally dubious, at least in non-thermal procedures. Thus, the question is discussed whether the undifferentiated adherence to the concept of sterility assurance on the basis of a single SAL of 10–6 corresponds with the safety requirements in terms of patient or user safety, costs and energy efficiency. Therefore, in terms of practical considerations, a concept of tiered SALs is recommended, analogous to the comparable and well-established categorization into “High-level disinfection”, “Intermediate-level disinfection” and “Low-level disinfection”. The determination of such tiered SALs is geared both to the intended application of the sterilized goods, as well as to the characteristics of the products and the corresponding treatment options. In the case of aseptic preparation, filling and production procedures, a mean contamination probability of 10–3 is assumed. In automated processes, lower contamination rates can be realized. In the case of the production of re-usable medical devices, a reduction of

  7. 45 CFR 96.73 - Sterilization.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ....73 Sterilization. If a State authorizes sterilization as a family planning service, it must comply with the provisions of 42 CFR Part 441, Subpart F, except that the State plan requirement under 42 CFR... 45 Public Welfare 1 2010-10-01 2010-10-01 false Sterilization. 96.73 Section 96.73 Public...

  8. Effect of Tubal Sterilization Technique on Risk of Serous Ovarian and Primary Peritoneal Carcinoma

    PubMed Central

    LESSARD-ANDERSON, Collette R.; HANDLOGTEN, Kathryn S.; MOLITOR, Rochelle J.; DOWDY, Sean C.; CLIBY, William A.; WEAVER, Amy L.; SAUVER, Jennifer ST.; BAKKUM-GAMEZ, Jamie N.

    2014-01-01

    Objective To determine the effect of excisional tubal sterilization on subsequent development of serous epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC). Methods We performed a population-based, nested case-control study using the Rochester Epidemiology Project. We identified all patients with a diagnosis of serous EOC or PPC from 1966 through 2009. Each case was age-matched to 2 controls without either diagnosis. Odds ratios (ORs) and corresponding 95% CIs were estimated from conditional logistic regression models. Models were adjusted for prior hysterectomy, prior salpingo-oophorectomy, oral contraceptive use, endometriosis, infertility, gravidity, and parity. Results In total, we identified 194 cases of serous EOC and PPC during the study period and matched them with 388 controls (mean [SD] age, 61.4 [15.2] years). Fourteen cases (7.2%) and 46 controls (11.9%) had undergone tubal sterilization. Adjusted risk of serous EOC or PPC was slightly lower after any tubal sterilization (OR, 0.59 [95% CI, 0.29–1.17]; P=.13). The rate of excisional tubal sterilization was lower in cases than controls (2.6% vs 6.4%). Adjusted risk of serous EOC and PPC was decreased by 64% after excisional tubal sterilization (OR, 0.36 [95% CI, 0.13–1.02]; P=.054) compared with those without sterilization or with nonexcisional tubal sterilization. Conclusions We present a population-based investigation of the effects of excisional tubal sterilization on the risk of serous EOC and PPC. Excisional methods may confer greater risk reduction than other sterilization methods. PMID:25316178

  9. Microwave Sterilization and Depyrogenation System

    NASA Technical Reports Server (NTRS)

    Akse, James R.; Dahl, Roger W.; Wheeler, Richard R., Jr.

    2009-01-01

    A fully functional, microgravity-compatible microwave sterilization and depyrogenation system (MSDS) prototype was developed that is capable of producing medical-grade water (MGW) without expendable supplies, using NASA potable water that currently is available aboard the International Space Station (ISS) and will be available for Lunar and planetary missions in the future. The microwave- based, continuous MSDS efficiently couples microwaves to a single-phase, pressurized, flowing water stream that is rapidly heated above 150 C. Under these conditions, water is rapidly sterilized. Endotoxins, significant biological toxins that originate from the cell walls of gram-negative bacteria and which represent another defining MGW requirement, are also deactivated (i.e., depyrogenated) albeit more slowly, with such deactivation representing a more difficult challenge than sterilization. Several innovations culminated in the successful MSDS prototype design. The most significant is the antenna-directed microwave heating of a water stream flowing through a microwave sterilization chamber (MSC). Novel antenna designs were developed to increase microwave transmission efficiency. These improvements resulted in greater than 95-percent absorption of incident microwaves. In addition, incorporation of recuperative heat exchangers (RHxs) in the design reduced the microwave power required to heat a water stream flowing at 15 mL/min to 170 C to only 50 W. Further improvements in energy efficiency involved the employment of a second antenna to redirect reflected microwaves back into the MSC, eliminating the need for a water load and simplifying MSDS design. A quick connect (QC) is another innovation that can be sterilized and depyrogenated at temperature, and then cooled using a unique flow design, allowing collection of MGW at atmospheric pressure and 80 C. The final innovation was the use of in-line mixers incorporated in the flow path to disrupt laminar flow and increase contact time

  10. Bisexual Hybrid Sterility in DROSOPHILA MELANOGASTER

    PubMed Central

    Colgan, D. J.; Angus, D. S.

    1978-01-01

    A new type of hybrid sterility was investigated in D. melanogaster . Matings between strain 27 males from Para Wirra, South Australia, and Canton-S females produce 70–80% fully sterile male and female progeny. Strain 27 males produce sterile progeny when crossed to females of other geographic origins, but produce fertile progeny when crossed to a second sympatric strain. The sterility is avoided by lower rearing temperatures. Heat shock and tetracycline produce no improvement in the fertility of the hybrids. Normal flies produce sterile progeny when injected with, or fed, homogenates of sterile flies. A combination of maternal and paternal factors may interact to produce sterile hybrids by inhibiting gonad development. PMID:17248832

  11. Implementing AORN recommended practices for sterilization.

    PubMed

    Graybill-D'Ercole, Patricia

    2013-05-01

    Any hospital or facility in which surgery and other invasive procedures are performed should have accommodations for cleaning, decontaminating, disinfecting, and sterilizing instruments, equipment, and other essential supplies that are used for patient procedures. Sterilization is essential to reducing or preventing the risk of surgical site infections. This is a collaborative process and should include all health care providers who handle these instruments, including perioperative nurses. The revised AORN "Recommended practices for sterilization," which became effective June 15, 2012, includes updates on sterilizing single-use items, inspecting critical items before sterilization, using low-temperature hydrogen peroxide vapor sterilization methods, and immediate use steam sterilization. This RP document is the first AORN document to be evidence rated and accepted for inclusion in the Agency for Healthcare Research and Quality National Guideline Clearinghouse. PMID:23622825

  12. Sixteen years of experience with sterilization monitoring.

    PubMed

    Molinari, J A; Gleason, M J; Merchant, V A

    1994-12-01

    Sterilization in the dental office should be monitored to ascertain proper sterilizer function. Biologic monitoring with calibrated preparations of bacterial spores is the preferred, as well as the only method that actually measures sterilization. A dental school-based sterilization monitoring service for dental practices was established in 1978 at the University of Detroit. This service has grown from 20 participating dental offices to more than 1,500. In 1993, 18,137 biologic monitoring tests were performed. The participants in the service primarily use autoclaves (70%) for heat sterilization, while unsaturated chemical-vapor sterilizers (20%) and dry-heat units (10%) are less common. This article describes the history of sterilization monitoring in dental practices from 1978 to the present through a dental school-based service. PMID:7758029

  13. [Prolactin and sterility (author's transl)].

    PubMed

    Santeler, P; Martin, J; Daxenbichler, G

    1980-07-01

    From July 1975 to December 1979 at the Univ.-Klinik für Frauenheilkunde, Innsbruck, 91 female sterile patients were examined due to hyperprolactinaemia. Since hyperprolactin presents common symptoms of different diseases, we established a differentiated clarification and therapy scheme using the guidelines of the W.H.O. and all new knowledge. After disqualification of patients with corresponding tubular sterility, we induced in 24 patients 32 pregnancies with medication or operative therapy. After birth or abortion a prolactin-caused dysfunction reappeared in the reproductive system. With a gradual prolactin increasion in the serum level, the grade of this dysfunction in the reproductive system was worsened. A reduction of the prolactin serum level to 40 ng/ml seems to be the basis for spontaneous ovulation. Present therapeutic possibilities and as a result the reversibility of this disturbance after interruption of prolactin inhibitors, we find that long-therm therapy is necessary. PMID:6933737

  14. Method of sterilization using ozone

    NASA Technical Reports Server (NTRS)

    Murphy, Oliver J. (Inventor); Hitchens, G. Duncan (Inventor)

    2002-01-01

    Methods of using ozone have been developed which sterilize instruments and medical wastes, oxidize, organics found in wastewater, clean laundry, break down contaminants in soil into a form more readily digested by microbes, kill microorganisms present in food products, and destroy toxins present in food products. The preferred methods for killing microorganism and destroying toxins use pressurized, humidified, and concentrated ozone produced by an electrochemical cell.

  15. Observation of Effectiveness of Clinical Sterilization by CASP-80A Low-Temperature Plasma Sterilizer

    NASA Astrophysics Data System (ADS)

    Li, Si; Zhang, Yangde; Liu, Weidong

    2006-09-01

    The influence on the effectiveness of sterilization by low-temperature plasma sterilizer CASP-80A was investigated so as to provide a theoretical basis for reducing medical costs and achieving ideal sterilization effectiveness. To conduct the on-site simulation test, a clinical material sterilization test and a test of the influence of organic substance were conducted, the former by using the representative of Bacillus Stearothermophilus, preparing the bacteria-contaminated carrier through polytetrafluoroethylene (PTFE) simulated hose endoscopes, and the latter by using calf serum as the influence factor of the organic substance. The results show that the CASP-80A low-temperature plasma sterilizer could achieve effective sterilization by either the short-cycle or the long-cycle sterilization method depending on different materials, apparatus, and extent of contamination. The organic substances could influence the effectiveness of sterilization by the low-temperature plasma (H2O2) sterilizer.

  16. Sterile neutrinos as dark matter

    SciTech Connect

    Dodelson, S.; Widrow, L.M. |

    1993-03-01

    The simplest model that can accommodate a viable nonbaryonic dark matter candidate is the standard electroweak theory with the addition of right-handed or sterile neutrinos. This model has been studied extensively in the context of the hot dark matter scenario. We reexamine this model and find that hot, warm, and cold dark matter are all possibilities. We focus on the case where sterile neutrinos are the dark matter. Since their only direct coupling is to left-handed or active neutrinos, the most efficient production mechanism is via neutrino oscillations. If the production rate is always less than the expansion rate, then these neutrinos will never be in thermal equilibrium. However, they may still play a significant role in the dynamics of the Universe and possibly provide the missing mass necessary for closure. We consider a single generation of neutrino fields ({nu}{sub L}, {nu}{sub R}) with a Dirac mass, {mu}, and a Majorana mass for the right-handed components only, M. For M {much_gt} {mu} we show that the number density of sterile neutrinos is proportional to {mu}{sup 2}/M so that the energy density today is independent of M. However M is crucial in determining the large scale structure of the Universe. In particular, M {approx_equal} 0.1--1.0 key leads to warm dark matter and a structure formation scenario that may have some advantages over both the standard hot and cold dark matter scenarios.

  17. Sterile neutrinos as dark matter

    SciTech Connect

    Dodelson, S. ); Widrow, L.M. . Dept. of Physics Toronto Univ., ON . Canadian Inst. for Theoretical Astrophysics)

    1993-03-01

    The simplest model that can accommodate a viable nonbaryonic dark matter candidate is the standard electroweak theory with the addition of right-handed or sterile neutrinos. This model has been studied extensively in the context of the hot dark matter scenario. We reexamine this model and find that hot, warm, and cold dark matter are all possibilities. We focus on the case where sterile neutrinos are the dark matter. Since their only direct coupling is to left-handed or active neutrinos, the most efficient production mechanism is via neutrino oscillations. If the production rate is always less than the expansion rate, then these neutrinos will never be in thermal equilibrium. However, they may still play a significant role in the dynamics of the Universe and possibly provide the missing mass necessary for closure. We consider a single generation of neutrino fields ([nu][sub L], [nu][sub R]) with a Dirac mass, [mu], and a Majorana mass for the right-handed components only, M. For M [much gt] [mu] we show that the number density of sterile neutrinos is proportional to [mu][sup 2]/M so that the energy density today is independent of M. However M is crucial in determining the large scale structure of the Universe. In particular, M [approx equal] 0.1--1.0 key leads to warm dark matter and a structure formation scenario that may have some advantages over both the standard hot and cold dark matter scenarios.

  18. Sterile Neutrinos in Cold Climates

    SciTech Connect

    Jones, Benjamin J.P.

    2015-09-01

    Measurements of neutrino oscillations at short baselines contain an intriguing set of experimental anomalies that may be suggestive of new physics such as the existence of sterile neutrinos. This three-part thesis presents research directed towards understanding these anomalies and searching for sterile neutrino oscillations. Part I contains a theoretical discussion of neutrino coherence properties. The open-quantum-system picture of neutrino beams, which allows a rigorous prediction of coherence distances for accelerator neutrinos, is presented. Validity of the standard treatment of active and sterile neutrino oscillations at short baselines is verified, and non-standard coherence loss effects at longer baselines are predicted. Part II concerns liquid argon detector development for the MicroBooNE experiment, which will search for short-baseline oscillations in the Booster Neutrino Beam at Fermilab. Topics include characterization and installation of the MicroBooNE optical system; test-stand measurements of liquid argon optical properties with dissolved impurities; optimization of wavelength-shifting coatings for liquid argon scintillation light detection; testing and deployment of high-voltage surge arrestors to protect TPC field cages; and software development for optical and TPC simulation and reconstruction. Part III presents a search for sterile neutrinos using the IceCube neutrino telescope, which has collected a large sample of atmospheric-neutrino-induced events in the 1-10 TeV energy range. Sterile neutrinos would modify the detected neutrino flux shape via MSW-resonant oscillations. Following a careful treatment of systematic uncertainties in the sample, no evidence for MSW-resonant oscillations is observed, and exclusion limits on 3+1 model parameter space are derived. Under the mixing assumptions made, the 90% confidence level exclusion limit extends to sin224 ≤ 0.02 at m2 ~ 0.3 eV2, and the LSND and Mini

  19. Plasma Sterilization: New Epoch in Medical Textiles

    NASA Astrophysics Data System (ADS)

    Senthilkumar, P.; Arun, N.; Vigneswaran, C.

    2015-04-01

    Clothing is perceived to be second skin to the human body since it is in close contact with the human skin most of the times. In hospitals, use of textile materials in different forms and sterilization of these materials is an essential requirement for preventing spread of germs. The need for appropriate disinfection and sterilization techniques is of paramount importance. There has been a continuous demand for novel sterilization techniques appropriate for use on various textile materials as the existing sterilization techniques suffer from various technical and economical drawbacks. Plasma sterilization is the alternative method, which is friendlier and more effective on the wide spectrum of prokaryotic and eukaryotic microorganisms. Basically, the main inactivation factors for cells exposed to plasma are heat, UV radiation and various reactive species. Plasma exposure can kill micro-organisms on a surface in addition to removing adsorbed monolayer of surface contaminants. Advantages of plasma surface treatment are removal of contaminants from the surface, change in the surface energy and sterilization of the surface. Plasma sterilization aims to kill and/or remove all micro-organisms which may cause infection of humans or animals, or which can cause spoilage of foods or other goods. This review paper emphasizes necessity for sterilization, essentials of sterilization, mechanism of plasma sterilization and the parameters influencing it.

  20. Radiation sterilization of new drug delivery systems

    PubMed Central

    Abuhanoğlu, Gürhan

    2014-01-01

    Radiation sterilization has now become a commonly used method for sterilization of several active ingredients in drugs or drug delivery systems containing these substances. In this context, many applications have been performed on the human products that are required to be sterile, as well as on pharmaceutical products prepared to be developed. The new drug delivery systems designed to deliver the medication to the target tissue or organ, such as microspheres, nanospheres, microemulsion, and liposomal systems, have been sterilized by gamma (γ) and beta (β) rays, and more recently, by e-beam sterilization. In this review, the sterilization of new drug delivery systems was discussed other than conventional drug delivery systems by γ irradiation. PMID:24936306

  1. Surgical Sterilization, Regret, and Race: Contemporary Patterns*

    PubMed Central

    Shreffler, Karina M.; McQuillan, Julia; Greil, Arthur L.; Johnson, David R.

    2014-01-01

    Surgical sterilization is a relatively permanent form of contraception that has been disproportionately used by Black, Hispanic, and Native American women in the United States in the past. We use a nationally representative sample of 4,609 women ages 25 to 45 to determine whether sterilization continues to be more common and consequential by race for reproductive-age women. Results indicate that Native American and Black women are more likely to be sterilized than non-Hispanic White women, and Hispanic and Native American women are more likely than non-Hispanic White women to report that their sterilization surgeries prevent them from conceiving children they want. Reasons for sterilization differ significantly by race. These findings suggest that stratified reproduction has not ended in the United States and that the patterns and consequences of sterilization continue to vary by race. PMID:25592919

  2. Locating the voices of the sterilized.

    PubMed

    Kluchin, Rebecca M

    2007-01-01

    Scholars have been studying eugenics and sterilization for years, but only recently have some begun to examine these issues from the point of view of those sterilized. This is in large part because so few records containing the voices of the sterilized exist or are accessible to scholars. This essay examines my own effort to recover the voices of women sterilized in the post-baby boom United States from the "bottom up" and includes my own experience researching and writing Fit to Be Tied?: Sterilization and Reproductive Rights in America, 1960-1984. It represents the beginning of a discussion about locating and using sources containing the voices of the sterilized and working with the limitations inherent to them. PMID:18175455

  3. Hysteroscopic Sterilization: History and Current Methods

    PubMed Central

    Greenberg, James A

    2008-01-01

    For many practicing obstetrician-gynecologists, tubal ligation was the gold standard by which female sterilization techniques were measured. Yet gynecologic surgeons have simultaneously sought to occlude the fallopian tubes transcervically to avoid discomfort and complications associated with transabdominal approaches. In this review, the history of transcervical sterilization is discussed. Past, current, and upcoming techniques are reviewed. This article focuses on interval sterilization techniques, thus removing post-vaginal and post-cesarean delivery tubal ligations from the discussion. PMID:19015762

  4. New developments in disinfection and sterilization.

    PubMed

    Wallace, Craig A

    2016-05-01

    A review of regulatory clearances for selected new sterilization and disinfection products for the period January 2012-June 2015 indicates continued leverage of established technologies for steam and low-temperature sterilization, and high-level disinfection. New products in these areas were typically modified and improved versions of existing products, with the exception of a new combination hydrogen peroxide/ozone sterilizer. Development of new low-temperature sterilization technologies to address continued evolution of complex medical devices is expected to continue. PMID:27131131

  5. Biomedical Conferences

    NASA Technical Reports Server (NTRS)

    1976-01-01

    As a result of Biomedical Conferences, Vivo Metric Systems Co. has produced cardiac electrodes based on NASA technology. Frequently in science, one highly specialized discipline is unaware of relevant advances made in other areas. In an attempt to familiarize researchers in a variety of disciplines with medical problems and needs, NASA has sponsored conferences that bring together university scientists, practicing physicians and manufacturers of medical instruments.

  6. A sterile-female technique proposed for control of Striga hermonthica and other intractable weeds: Advantages, shortcomings, and risk management

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Weeds have posed intractable challenges to farmers since the dawn of agriculture. This article describes in detail a proposed control strategy based on the introduction of genes conferring female-sterility into the genomes of intractable target weeds. Spread of these genes through target populations...

  7. Influence of In Vitro IL-2 or IL-15 Alone or in Combination with Hsp 70 Derived 14-Mer Peptide (TKD) on the Expression of NK Cell Activatory and Inhibitory Receptors on Peripheral Blood T Cells, B Cells and NKT Cells

    PubMed Central

    Hromadnikova, Ilona; Li, Shuang; Kotlabova, Katerina; Dickinson, Anne M.

    2016-01-01

    Previous studies from Multhoff and colleagues reported that plasma membrane Hsp70 acts as a tumour-specific recognition structure for activated NK cells, and that the incubation of NK cells with Hsp70 and/or a 14-mer peptide derived from the N-terminal sequence of Hsp70 (TKDNNLLGRFELSG, TKD, aa 450–463) plus a low dose of IL-2 triggers NK cell proliferation and migration, and their capacity to kill cancer cells expressing membrane Hsp70. Herein, we have used flow cytometry to determine the influence of in vitro stimulation of peripheral blood mononuclear cells from healthy individuals with IL-2 or IL-15, either alone or in combination with TKD peptide on the cell surface expression of CD94, NK cell activatory receptors (CD16, NK2D, NKG2C, NKp30, NKp44, NKp46, NKp80, KIR2DL4, DNAM-1 and LAMP1) and NK cell inhibitory receptors (NKG2A, KIR2DL2/L3, LIR1/ILT-2 and NKR-P1A) by CD3+CD56+ (NKT), CD3+CD4+, CD3+CD8+ and CD19+ populations. NKG2D, DNAM-1, LAMP1 and NKR-P1A expression was upregulated after the stimulation with IL-2 or IL-15 alone or in combination with TKD in NKT, CD8+ T cells and B cells. CD94 was upregulated in NKT and CD8+ T cells. Concurrently, an increase in a number of CD8+ T cells expressing LIR1/ILT-2 and CD4+ T cells positive for NKR-P1A was observed. The proportion of CD8+ T cells that expressed NKG2D was higher after IL-2/TKD treatment, when compared with IL-2 treatment alone. In comparison with IL-15 alone, IL-15/TKD treatment increased the proportion of NKT cells that were positive for CD94, LAMP1 and NKRP-1A. The more potent effect of IL-15/TKD on cell surface expression of NKG2D, LIR1/ILT-2 and NKRP-1A was observed in B cells compared with IL-15 alone. However, this increase was not of statistical significance. IL-2/TKD induced significant upregulation of LAMP1 in CD8+ T cells compared with IL-2 alone. Besides NK cells, other immunocompetent cells present within the fraction of peripheral blood mononuclear cells were influenced by the treatment

  8. Influence of In Vitro IL-2 or IL-15 Alone or in Combination with Hsp 70 Derived 14-Mer Peptide (TKD) on the Expression of NK Cell Activatory and Inhibitory Receptors on Peripheral Blood T Cells, B Cells and NKT Cells.

    PubMed

    Hromadnikova, Ilona; Li, Shuang; Kotlabova, Katerina; Dickinson, Anne M

    2016-01-01

    Previous studies from Multhoff and colleagues reported that plasma membrane Hsp70 acts as a tumour-specific recognition structure for activated NK cells, and that the incubation of NK cells with Hsp70 and/or a 14-mer peptide derived from the N-terminal sequence of Hsp70 (TKDNNLLGRFELSG, TKD, aa 450-463) plus a low dose of IL-2 triggers NK cell proliferation and migration, and their capacity to kill cancer cells expressing membrane Hsp70. Herein, we have used flow cytometry to determine the influence of in vitro stimulation of peripheral blood mononuclear cells from healthy individuals with IL-2 or IL-15, either alone or in combination with TKD peptide on the cell surface expression of CD94, NK cell activatory receptors (CD16, NK2D, NKG2C, NKp30, NKp44, NKp46, NKp80, KIR2DL4, DNAM-1 and LAMP1) and NK cell inhibitory receptors (NKG2A, KIR2DL2/L3, LIR1/ILT-2 and NKR-P1A) by CD3+CD56+ (NKT), CD3+CD4+, CD3+CD8+ and CD19+ populations. NKG2D, DNAM-1, LAMP1 and NKR-P1A expression was upregulated after the stimulation with IL-2 or IL-15 alone or in combination with TKD in NKT, CD8+ T cells and B cells. CD94 was upregulated in NKT and CD8+ T cells. Concurrently, an increase in a number of CD8+ T cells expressing LIR1/ILT-2 and CD4+ T cells positive for NKR-P1A was observed. The proportion of CD8+ T cells that expressed NKG2D was higher after IL-2/TKD treatment, when compared with IL-2 treatment alone. In comparison with IL-15 alone, IL-15/TKD treatment increased the proportion of NKT cells that were positive for CD94, LAMP1 and NKRP-1A. The more potent effect of IL-15/TKD on cell surface expression of NKG2D, LIR1/ILT-2 and NKRP-1A was observed in B cells compared with IL-15 alone. However, this increase was not of statistical significance. IL-2/TKD induced significant upregulation of LAMP1 in CD8+ T cells compared with IL-2 alone. Besides NK cells, other immunocompetent cells present within the fraction of peripheral blood mononuclear cells were influenced by the treatment

  9. Ramifications of a sterile Mars

    NASA Astrophysics Data System (ADS)

    Levin, Gilbert V.

    2011-10-01

    The seldom considered ramifications of a sterile Mars are explored. Very much is now known about the environment on Mars. Herein, the individual and collective environmental parameters are examined with particular consideration of those that might be inimical to life as we know it, or as might reasonably be assumed to be so to alien life. It is shown that no single measurement or combination of them precludes the ability of Mars to support even a wide number of terrestrial microbial species, let alone the likely greater tolerance and/or adaptability of possible alien life forms. Some yet unknown factor or combination of factors would have to be responsible for Mars' failure to generate life or to successfully harbor viable forms received from space. Since Mars is so Earth-like, the red planet's sterility could deliver a fatal blow to the growing concept of a cosmic Biologic Imperative, and would raise the daunting prospect that Earth is a unique or a very rare habitat.

  10. Review of surface steam sterilization for validation purposes.

    PubMed

    van Doornmalen, Joost; Kopinga, Klaas

    2008-03-01

    Sterilization is an essential step in the process of producing sterile medical devices. To guarantee sterility, the process of sterilization must be validated. Because there is no direct way to measure sterility, the techniques applied to validate the sterilization process are based on statistical principles. Steam sterilization is the most frequently applied sterilization method worldwide and can be validated either by indicators (chemical or biological) or physical measurements. The steam sterilization conditions are described in the literature. Starting from these conditions, criteria for the validation of steam sterilization are derived and can be described in terms of physical parameters. Physical validation of steam sterilization appears to be an adequate and efficient validation method that could be considered as an alternative for indicator validation. Moreover, physical validation can be used for effective troubleshooting in steam sterilizing processes. PMID:18313509

  11. 9 CFR 109.2 - Sterilizers.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Sterilizers. 109.2 Section 109.2 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STERILIZATION AND PASTEURIZATION...

  12. 21 CFR 610.12 - Sterility.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... BIOLOGICAL PRODUCTS STANDARDS General Provisions § 610.12 Sterility. (a) The test. Except as provided in paragraph (h) of this section, manufacturers of biological products must perform sterility testing of each lot of each biological product's final container material or other material, as appropriate and...

  13. 21 CFR 610.12 - Sterility.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... BIOLOGICAL PRODUCTS STANDARDS General Provisions § 610.12 Sterility. (a) The test. Except as provided in paragraph (h) of this section, manufacturers of biological products must perform sterility testing of each lot of each biological product's final container material or other material, as appropriate and...

  14. 9 CFR 109.2 - Sterilizers.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Sterilizers. 109.2 Section 109.2 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STERILIZATION AND PASTEURIZATION...

  15. Eugenics and Involuntary Sterilization: 1907-2015.

    PubMed

    Reilly, Philip R

    2015-01-01

    In England during the late nineteenth century, intellectuals, especially Francis Galton, called for a variety of eugenic policies aimed at ensuring the health of the human species. In the United States, members of the Progressive movement embraced eugenic ideas, especially immigration restriction and sterilization. Indiana enacted the first eugenic sterilization law in 1907, and the US Supreme Court upheld such laws in 1927. State programs targeted institutionalized, mentally disabled women. Beginning in the late 1930s, proponents rationalized involuntary sterilization as protecting vulnerable women from unwanted pregnancy. By World War II, programs in the United States had sterilized approximately 60,000 persons. After the horrific revelations concerning Nazi eugenics (German Hereditary Health Courts approved at least 400,000 sterilization operations in less than a decade), eugenic sterilization programs in the United States declined rapidly. Simplistic eugenic thinking has faded, but coerced sterilization remains widespread, especially in China and India. In many parts of the world, involuntary sterilization is still intermittently used against minority groups. PMID:26322647

  16. 9 CFR 109.2 - Sterilizers.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Sterilizers. 109.2 Section 109.2 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STERILIZATION AND PASTEURIZATION...

  17. 9 CFR 109.2 - Sterilizers.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Sterilizers. 109.2 Section 109.2 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STERILIZATION AND PASTEURIZATION...

  18. 9 CFR 109.2 - Sterilizers.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Sterilizers. 109.2 Section 109.2 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE VIRUSES, SERUMS, TOXINS, AND ANALOGOUS PRODUCTS; ORGANISMS AND VECTORS STERILIZATION AND PASTEURIZATION...

  19. Monitoring dental sterilizers' effectiveness using biological indicators.

    PubMed

    Nickerson, A; Bhuta, P; Orton, G; Alvin, B

    1990-02-01

    The purpose of this study was to evaluate the effectiveness of dental office sterilizers as measured by their ability to kill bacterial spores present on biological indicator strips. The biological indicators used in this study contained two different spores, Bacillus stearothermophilus and Bacillus subtilis (Spordi, AMSCO/Medical Products). Ten spore test strips were sent to 87 dental offices; 51 sterilizers were tested. Office personnel were instructed to place four strips in the center of a normal sterilization load and process the load. The procedure was repeated on a second day. The processed strips, along with two unprocessed control strips, were returned by mail for laboratory culturing. The results indicated the overall failure rate (positive test) of sterlizers tested for both days was 51% at the culturing temperature of 37 degrees C and 33.3% at 55 degrees C. McNemar's test indicated a significant difference (p less than .03) in sterilization failures associated with the type and number of microorganisms present on the test strips. This study also showed that the more times a sterilizer was tested, the more likely a failure would occur. Overall, an alarming number of sterilizers (64.7%) were not effective in killing all the spores present on the indicator strips. When office personnel were given information for improving sterilizer performance, there was a noticeable reduction in sterilization failures following retesting. PMID:2370583

  20. Viking heat sterilization - Progress and problems

    NASA Technical Reports Server (NTRS)

    Daspit, L. P.; Cortright, E. M.; Stern, J. A.

    1974-01-01

    The Viking Mars landers to be launched in 1975 will carry experiments in biology, planetology, and atmospheric physics. A terminal dry-heat sterilization process using an inert gas was chosen to meet planetary quarantine requirements and preclude contamination of the biology experiment by terrestrial organisms. Deep sterilization is performed at the component level and terminal surface sterilization at the system level. Solutions to certain component problems relating to sterilization are discussed, involving the gyroscope, tape recorder, battery, electronic circuitry, and outgassing. Heat treatment placed special requirements on electronic packaging, including fastener preload monitoring and solder joints. Chemical and physical testing of nonmetallic materials was performed to establish data on their behavior in heat-treatment and vacuum environments. A Thermal Effects Test Model and a Proof Test Capsule were used. It is concluded that a space vehicle can be designed and fabricated to withstand heat sterilization requirements.

  1. Disinfection, sterilization, and antisepsis: An overview.

    PubMed

    Rutala, William A; Weber, David J

    2016-05-01

    All invasive procedures involve contact by a medical device or surgical instrument with a patient's sterile tissue or mucous membranes. The level of disinfection or sterilization is dependent on the intended use of the object: critical (items that contact sterile tissue such as surgical instruments), semicritical (items that contact mucous membrane such as endoscopes), and noncritical (devices that contact only intact skin such as stethoscopes) items require sterilization, high-level disinfection and low-level disinfection, respectively. Cleaning must always precede high-level disinfection and sterilization. Antiseptics are essential to infection prevention as part of a hand hygiene program as well as several other uses such as surgical hand antisepsis and pre-operative skin preparation. PMID:27131128

  2. Sterilization and contraceptive services in Catholic hospitals.

    PubMed

    O'Lane, J M

    1979-02-15

    Sterilization and contraceptive practices in United States Catholic hospitals were surveyed by anonymous mail questionnaires, obtaining a 57% response rate (340 of 598). Twenty per cent of the hospitals permitted medically indicated sterilization operations. Forty-seven per cent of those hospitals not allowing sterilization procedures reported that their medical staffs were interested in performing medically indicated sterilizations. The types of contraceptive services offered varied widely. The rhythm method was most frequently available, with oral contraceptives in second place; many hospitals did not provide any family-planning services; 13% utilized all types of contraception. The thesis is advanced that improvement in availability of sterilization and contraceptive services is a duty of hospital medical staffs. PMID:433994

  3. Vapor Hydrogen Peroxide Sterilization Certification

    NASA Astrophysics Data System (ADS)

    Chen, Fei; Chung, Shirley; Barengoltz, Jack

    For interplanetary missions landing on a planet of potential biological interest, United States NASA planetary protection currently requires that the flight system must be assembled, tested and ultimately launched with the intent of minimizing the bioload taken to and deposited on the planet. Currently the only NASA approved microbial reduction method is dry heat sterilization process. However, with utilization of such elements as highly sophisticated electronics and sensors in modern spacecraft, this process presents significant materials challenges and is thus an undesirable bioburden reduction method to design engineers. The objective of this work is to introduce vapor hydrogen peroxide (VHP) as an alternative to dry heat microbial reduction to meet planetary protection requirements. The VHP sterilization technology is widely used by the medical industry, but high doses of VHP may degrade the performance of flight hardware, or compromise material compatibility. The goal of our study is determine the minimum VHP process conditions for PP acceptable microbial reduction levels. A series of experiments were conducted using Geobacillus stearothermophilus to determine VHP process parameters that provided significant reductions in spore viability while allowing survival of sufficient spores for statistically significant enumeration. In addition to the obvious process parameters -hydrogen peroxide concentration, number of pulses, and exposure duration -the investigation also considered the possible effect of environmental pa-rameters. Temperature, relative humidity, and material substrate effects on lethality were also studied. Based on the results, a most conservative D value was recommended. This recom-mended D value was also validated using VHP "hardy" strains that were isolated from clean-rooms and environmental populations collected from spacecraft relevant areas. The efficiency of VHP at ambient condition as well as VHP material compatibility will also be

  4. Iran eases limits on sterilization.

    PubMed

    Roudi, N

    1991-03-01

    The government of Iran announced in November 1990, in an abrupt reversal of previous policies, the legislation of sterilization and its provision free-of-charge upon request, as well as the distribution of other contraceptive gratis. At the time of the Islamic Revolution in 1979 the government adopted a pronatalist policy, family planning programs were interrupted, legal ages of marriage were lowered, and barriers against polygamy were loosened. Iran had a 3.5% growth rate in 1990 and a total fertility rate of 6.3 lifetime births/woman. After the end of the war between Iran and Iraq in 1988, the population explosion became an obstacle to reconstruction. In 1950, the population numbered 14.2 million; by 1970 it had doubled to 28.4 million. In 1990, the country had 54.6 million people. According to a 1990 UN assessment the population will soar to 100 million by 2020. Over 8 million live in Tehran where overcrowding, traffic congestion, air pollution, and high living costs are the norm. the 1989 National Birth Control Policy Summary adopted targets to reduce the average number of lifetime births per woman to 4 children and natural growth rate to 2.3% by 2011, and to provide family planning to 24% of reproductive-age women whereby 1 million conceptions would be prevented. Indirect measures to curb fertility include raising literacy promoting the education of girls, improving the status and health conditions of women, and reducing maternal and child mortality. A media campaign has started to encourage a small family model. The low legal, social, educational, and employment status of women poses obstacles to this plan, however, the revision of laws that conflict with these goals has been urged. In other Islamic countries such as Turkey, Tunisia, Indonesia, Pakistan, and Bangladesh, female sterilization is legal. Abortion in Iran remains banned except for saving the life of the mother. PMID:12343087

  5. An investigation of a sterile access technique for the repair and adjustment of sterile spacecraft

    NASA Technical Reports Server (NTRS)

    Farmer, F. H.; Fuller, H. V.; Hueschen, R. M.

    1973-01-01

    A description is presented of a unique system for the sterilization and sterile repair of spacecraft and the results of a test program designed to assess the biological integrity and engineering reliability of the system. This trailer-mounted system, designated the model assembly sterilizer for testing (MAST), is capable of the dry-heat sterilization of spacecraft and/or components less than 2.3 meters in diameter at temperatures up to 433 K and the steam sterilization of components less than 0.724 meter in diameter. Sterile access to spacecraft is provided by two tunnel suits, called the bioisolator suit systems (BISS), which are contiguous with the walls of the sterilization chambers. The test program was designed primarily to verify the biological and engineering reliability of the MAST system by processing simulated space hardware. Each test cycle simulated the initial sterilization of a spacecraft, sterile repair of a failed component, removal of the spacecraft from the MAST for mating with the bus, and a sterile recycle repair.

  6. EPR STUDIES OF THERMALLY STERILIZED VASELINUM ALBUM.

    PubMed

    Ramos, Paweł; Pilawa, Barbara

    2015-01-01

    Electron paramagnetic resonance (EPR) spectroscopy was used for examination of free radicals in thermally treated vaselinum album (VA). Thermal treatment in hot air as sterilization process was tested. Conditions of thermal sterilization were chosen according to the pharmaceutical norms. Vaselinum album was heated at the following conditions (T--temperature, t--time): T = 160°C and t = 120 min, T = 170°C and t = 60 min and T = 180°C and t = 30 min. The aim of this work was to determine concentration and free radical properties of thermally sterilized VA. EPR analysis for VA was done 15 min after sterilization. EPR measurements were done at room temperature. EPR spectra were recorded in the range of microwave power of 2.2-70 mW. g-Factor, amplitudes (A) and line width (ΔBpp) of the spectra were determined. The shape of the EPR spectra was analyzed. Free radical concentration (N) in the heated samples was determined. EPR spectra were not obtained for the non heated VA. EPR spectra were detected for all thermally sterilized samples. The spectra revealed complex character, their asymmetry depends on microwave power. The lowest free radicals concentration was found for the VA sterilized at 180°C during 30 min. EPR spectroscopy is proposed as the method useful for optimization of sterilization process of drugs. PMID:26647625

  7. New sterilization technologies alternative to ethylene oxide

    NASA Astrophysics Data System (ADS)

    Tabrizian, Maryam; Lerouge, Sophie; Debrie, Anne; Yahia, L'Hocine

    1997-06-01

    Sterilization of biomedical devices may induce bulk and surface modification, responsible for the decrease or loss of their biofunctionality. Pure ethylene oxide (EO) at low temperature and new alternative techniques such as cold gas plasma sterilization have been developed for heat-sensitive polymers. There is a lack of the knowledge concerning their safety in terms of materials damage and consequences on the biofunctionality of sterilized devices. The objective of our work consists in studying bulk and surface changes in biomedical devices induced by these two sterilization techniques. Samples from PVC, Polyurethane, Polyacrylate and Polyethylene-based medical devices are subjected to 1, 5, and 10 sterilization cycles by Steri-Vac-3M (pure EO), Sterrad-100$TM, J&J (gas plasma + H2O2), and studied by X-rays photoelectron spectroscopy. Preliminary results show an increasing in Oxygen/Carbon ratio by a factor of 1.3 to 4.4 between the first and tenth cycle indicating the surface oxidation by gas plasma sterilization processes. Some changes in C-C chemical bounding are associated with EO sterilization.

  8. Characteristics of Surface Sterilization using ECR Plasma

    NASA Astrophysics Data System (ADS)

    Yonesu, Akira; Hara, Kazufumi; Nishikawa, Tatsuya; Hayashi, Nobuya

    2015-09-01

    Plasma sterilization techniques have superior characteristics such as a short treatment times, non-toxicity and low thermal damages on the sterilized materials. In plasma sterilization, microorganisms can be sterilized by active radicals, energetic charged particles, and vacuum UV radiation. The influence of each factor depends on the plasma operating parameters. Microwave discharges under the electron cyclotron resonance (ECR) condition produce higher electron temperature and density plasma as compared with other plasma generation techniques. In the present study, characteristics of surface sterilization using ECR plasma have been investigated.The experiment was performed in the vacuum chamber which contains a magnet holder. A pair of rectangular Sm-Co permanent magnets is aligned parallel to each other within the magnet holder. The region of the magnetic field for ECR exists near the magnet holder surface. When the microwave is introduced into the vacuum chamber, a ECR plasma is produced around surface of the magnet holder. High energy electrons and oxygen radicals were observed at ECR zone by electric probe method and optical spectroscopic method. Biological indicators (B.I.) having spore of 106 was sterilized in 2min for oxygen discharge. The temperature of the B.I. installation position was about 55°. The sterilization was achieved by the effect of oxygen radicals and high energy electrons.

  9. Prospects for vector control through sterilization procedures

    PubMed Central

    Smith, Carroll N.

    1963-01-01

    Interest in sterilization as a possible method for controlling insects of public health importance can be said to have arisen first in the mid-fifties, when the screw-worm fly was successfully eradicated from the island of Curaçao by the release over the entire island of large numbers of male flies sterilized by gamma-radiation. Since then, many studies on the sterilization of various insect vectors of disease have been carried out. This paper reviews these studies and discusses the present position regarding vector control by sterilization procedures, with special reference to the use of chemosterilants. These compounds have certain advantages over radiation since they can be used not only as a substitute for X-rays or gamma-rays in the sterilization of insects specially reared for release in large numbers, but also as a means of inducing sterility in natural populations of insects. The author emphasizes that chemosterilants cannot at present be recommended as a practical control or eradication procedure for any vector species of insect, but considers that this extension of the sterilization method holds great promise and merits intensive investigation. PMID:20604181

  10. Parameters governing steam sterilization of deadlegs.

    PubMed

    Young, J H; Ferko, B L; Gaber, R P

    1994-01-01

    Use of saturated steam for sterilization-in-place (SIP) is limited by factors effecting displacement of air from deadlegs. Effects of tube diameter, length, orientation and position within a deadleg were quantitatively studied by examining temperature profiles and rates of kill of Bacillus stearothermophilus spores. Tube diameter had the greatest effect on sterilization. For small diameter tubes, 0.4 cm inside diameter (ID), air displacement was minimal and due mainly to diffusion. 8.8 cm long tubes with 0.4 cm IDs could not be sterilized at 121 degrees C. As tube diameter was increased and buoyant driven convective flow became dominant over viscous forces, sterilization was achieved and tube orientation became critical. Sterilization time, as defined by a twelve log reduction in spore population, was 75 minutes in a 19.0 cm long vertical tube with 1.7 cm ID, whereas 167 minutes were required for an 8.8 cm long tube with 1.0 cm ID. For 8.8 cm long tubes, only the 1.7 cm ID tube could be sterilized when orientated 5 degrees above horizontal. Data show that length to diameter ratios, L/Ds, do not provide a general guideline which can be used to predict sterilization. In the absence of steam bleeders, equipment should be designed to assure strong buoyancy driven convective flow to assure adequate air removal. This requires elimination of small diameter deadlegs (0.4 cm ID and less) and vertical positioning of deadlegs. PMID:8069515