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Sample records for surprisingly il-2 knockout

  1. Quantitative Contribution of IL2Rγ to the Dynamic Formation of IL2-IL2R Complexes.

    Directory of Open Access Journals (Sweden)

    Luis F Ponce

    Full Text Available Interleukin-2 (IL2 is a growth factor for several immune cells and its function depends on its binding to IL2Rs in the cell membrane. The most accepted model for the assembling of IL2-IL2R complexes in the cell membrane is the Affinity Conversion Model (ACM. This model postulates that IL2R receptor association is sequential and dependent on ligand binding. Most likely free IL2 binds first to IL2Rα, and then this complex binds to IL2Rβ, and finally to IL2Rγ (γc. However, in previous mathematical models representing this process, the binding of γc has not been taken into account. In this work, the quantitative contribution of the number of IL2Rγ chain to the IL2-IL2R apparent binding affinity and signaling is studied. A mathematical model of the affinity conversion process including the γ chain in the dynamic, has been formulated. The model was calibrated by fitting it to experimental data, specifically, Scatchard plots obtained using human cell lines. This paper demonstrates how the model correctly explains available experimental observations. It was estimated, for the first time, the value of the kinetic coefficients of IL2-IL2R complexes interaction in the cell membrane. Moreover, the number of IL2R components in different cell lines was also estimated. It was obtained a variable distribution in the number of IL2R components depending on the cell type and the activation state. Of most significance, the study predicts that not only the number of IL2Rα and IL2Rβ, but also the number of γc determine the capacity of the cell to capture and retain IL2 in signalling complexes. Moreover, it is also showed that different cells might use different pathways to bind IL2 as consequence of its IL2R components distribution in the membrane.

  2. Ontological Surprises

    DEFF Research Database (Denmark)

    Leahu, Lucian

    2016-01-01

    This paper investigates how we might rethink design as the technological crafting of human-machine relations in the context of a machine learning technique called neural networks. It analyzes Google’s Inceptionism project, which uses neural networks for image recognition. The surprising output of...... a hybrid approach where machine learning algorithms are used to identify objects as well as connections between them; finally, it argues for remaining open to ontological surprises in machine learning as they may enable the crafting of different relations with and through technologies....

  3. Surprise Trips

    DEFF Research Database (Denmark)

    Korn, Matthias; Kawash, Raghid; Andersen, Lisbet Møller

    We report on a platform that augments the natural experience of exploration in diverse indoor and outdoor environments. The system builds on the theme of surprises in terms of user expectations and finding points of interest. It utilizes physical icons as representations of users' interests and a...

  4. 126Gln is the residue of human IL-2 binding to IL-2R γ subunit

    Institute of Scientific and Technical Information of China (English)

    王志勇; 郑仲承; 孙兰英; 刘新垣

    1997-01-01

    The 126Gln of human interleukin-2 (IL-2) is a conserved amino acid residue. After substitution of 126Gln with Asp, the binding abilities of this mutant to different composites of IL-2 receptor (R) subunits have been determined. Results show that 126Asp-IL-2 has higher affinity to IL-2R α βγ complex and normal affinity to IL-2R α β complex, but loses its binding ability to IL-2R β γ complex, demonstrating that the 126Gln is the residue of human IL-2 which binds to IL-2R 7 subunit.

  5. Biological significance of soluble IL-2 receptor

    Directory of Open Access Journals (Sweden)

    Calogero Caruso

    1993-01-01

    Full Text Available A NUMBER of receptors for growth factors and differentiation antigens have been found to be secreted or released by cells. Following mononuclear cell (MNC activation and interleukin-2 receptor (IL-2R expression, a soluble form of the Alpha;-chain of IL-2R (sIL-2R is released. The sIL-2R has been shown to be present in the culture supernatants of activated MNCs as well as in normal sera and, in higher amounts, in sera from subjects affected by several diseases including neoplastic, infectious and autoimmune ones, and in sera from transplanted patients suffering allograft rejection. The blood sIL-2R levels depend on the number of producing cells and the number of molecules per cell, so that sIL-2R blood values may represent an index of the number and the functional state of producing cells, both normal and neoplastic. Thus, monitoring of the immune system, mostly T-cells and haematological malignancies might be targets for the measurement of sIL-2R. Since many conditions may influence sIL-2R production, little diagnostic use may result from these measurements. However, since blood sIL-2R levels may correlate with disease progression and/or response to therapy, their measurement may be a useful index of activity and extent of disease. The precise biological role of the soluble form of the IL-2R is still a matter of debate. However, we know that increased sIL-2R levels may be observed in association with several immunological abnormalities and that sIL-2R is able to bind IL-2. It is conceivable then that in these conditions the excess sIL-2R released in vivo by activated lymphoid cells or by neoplastic cells may somehow regulate IL-2-dependent processes. On the other hand, it cannot exclude that sIL-2R is a by-product without biological significance. Finally, it is puzzling that in many conditions in which an increase of blood sIL-2R values has been observed, MNCs display a decreased in vitro capacity to produce sIL-2R. These seemingly contrasting

  6. Charming surprise

    CERN Multimedia

    Antonella Del Rosso

    2011-01-01

    The CP violation in charm quarks has always been thought to be extremely small. So, looking at particle decays involving matter and antimatter, the LHCb experiment has recently been surprised to observe that things might be different. Theorists are on the case.   The study of the physics of the charm quark was not in the initial plans of the LHCb experiment, whose letter “b” stands for “beauty quark”. However, already one year ago, the Collaboration decided to look into a wider spectrum of processes that involve charm quarks among other things. The LHCb trigger allows a lot of these processes to be selected, and, among them, one has recently shown interesting features. Other experiments at b-factories have already performed the same measurement but this is the first time that it has been possible to achieve such high precision, thanks to the huge amount of data provided by the very high luminosity of the LHC. “We have observed the decay modes of t...

  7. Charming surprise

    CERN Multimedia

    Antonella Del Rosso

    2011-01-01

    The CP violation in charm quarks has always been thought to be extremely small. So, looking at particle decays involving matter and antimatter, the LHCb experiment has recently been surprised to observe that things might be different. Theorists are on the case. The study of the physics of the charm quark was not in the initial plans of the LHCb experiment, whose letter “b” stands for “beauty quark”. However, already one year ago, the Collaboration decided to look into a wider spectrum of processes that involve charm quarks among other things. The LHCb trigger allows a lot of these processes to be selected, and, among them, one has recently shown interesting features. Other experiments at b-factories have already performed the same measurement but this is the first time that it has been possible to achieve such high precision, thanks to the huge amount of data provided by the very high luminosity of the LHC. “We have observed the decay modes of the D0, a pa...

  8. IL-2 suppression of IL-12p70 by a recombinant HSV-1 expressing IL-2 induces T-cell auto-reactivity and CNS demyelination.

    Directory of Open Access Journals (Sweden)

    Mandana Zandian

    Full Text Available To evaluate the role of cellular infiltrates in CNS demyelination in immunocompetent mice, we have used a model of multiple sclerosis (MS in which different strains of mice are infected with a recombinant HSV-1 expressing IL-2. Histologic examination of the mice infected with HSV-IL-2 demonstrates that natural killer cells, dendritic cells, B cells, and CD25 (IL-2rα do not play any role in the HSV-IL-2-induced demyelination. T cell depletion, T cell knockout and T cell adoptive transfer experiments suggest that both CD8(+ and CD4(+ T cells contribute to HSV-IL-2-induced CNS demyelination with CD8(+ T cells being the primary inducers. In the adoptive transfer studies, all of the transferred T cells irrespective of their CD25 status at the time of transfer were positive for expression of FoxP3 and depletion of FoxP3 blocked CNS demyelination by HSV-IL-2. The expression levels of IL-12p35 relative to IL-12p40 differed in BM-derived macrophages infected with HSV-IL-2 from those infected with wild-type HSV-1. HSV-IL-2-induced demyelination was blocked by injecting HSV-IL-2-infected mice with IL-12p70 DNA. This study demonstrates that suppression of the IL-12p70 function of macrophages by IL-2 causes T cells to become auto-aggressive. Interruption of this immunoregulatory axis results in demyelination of the optic nerve, the spinal cord and the brain by autoreactive T cells in the HSV-IL-2 mouse model of MS.

  9. IL-2 Suppression of IL-12p70 by a Recombinant HSV-1 Expressing IL-2 Induces T-Cell Auto-Reactivity and CNS Demyelination

    Science.gov (United States)

    Zandian, Mandana; Mott, Kevin R.; Allen, Sariah J.; Chen, Shuang; Arditi, Moshe; Ghiasi, Homayon

    2011-01-01

    To evaluate the role of cellular infiltrates in CNS demyelination in immunocompetent mice, we have used a model of multiple sclerosis (MS) in which different strains of mice are infected with a recombinant HSV-1 expressing IL-2. Histologic examination of the mice infected with HSV-IL-2 demonstrates that natural killer cells, dendritic cells, B cells, and CD25 (IL-2rα) do not play any role in the HSV-IL-2-induced demyelination. T cell depletion, T cell knockout and T cell adoptive transfer experiments suggest that both CD8+ and CD4+ T cells contribute to HSV-IL-2-induced CNS demyelination with CD8+ T cells being the primary inducers. In the adoptive transfer studies, all of the transferred T cells irrespective of their CD25 status at the time of transfer were positive for expression of FoxP3 and depletion of FoxP3 blocked CNS demyelination by HSV-IL-2. The expression levels of IL-12p35 relative to IL-12p40 differed in BM-derived macrophages infected with HSV-IL-2 from those infected with wild-type HSV-1. HSV-IL-2-induced demyelination was blocked by injecting HSV-IL-2-infected mice with IL-12p70 DNA. This study demonstrates that suppression of the IL-12p70 function of macrophages by IL-2 causes T cells to become auto-aggressive. Interruption of this immunoregulatory axis results in demyelination of the optic nerve, the spinal cord and the brain by autoreactive T cells in the HSV-IL-2 mouse model of MS. PMID:21364747

  10. Data on interleukin (IL)-2- and IL-15-dependent changes in IL-2Rβ and IL-2Rγ complexes

    DEFF Research Database (Denmark)

    Osinalde, Nerea; Sánchez-Quiles, Virginia; Blagoev, Blagoy

    2017-01-01

    We provide detailed datasets from our analysis of the proteins that associate with IL-2Rβ and IL-2Rγ in T-cells stimulated with IL-2 or IL-15 compared with resting T-cells, as identified by SILAC-based quantitative proteomics. We also include quantitative data regarding site-specific phosphorylat...... "Characterization of receptor-associated protein complex assembly in Interleukin (IL)-2- and IL-15-activated T-lymphocytes" (Osinalde et al., 2016 [1]). The mass spectrometry data have been deposited to the ProteomeEXchange Constorium with the identifier PXD002386....

  11. Role of IL-2 in cancer immunotherapy.

    Science.gov (United States)

    Jiang, Tao; Zhou, Caicun; Ren, Shengxiang

    2016-06-01

    Interleukin-2 (IL-2) is one of the key cytokines with pleiotropic effects on immune system. It has been approved for the treatment of metastatic renal cell carcinoma and metastatic melanoma. Recent progress has been made in our understanding of IL-2 in regulating lymphocytes that has led to exciting new directions for cancer immunotherapy. While improved IL-2 formulations might be used as monotherapies, their combination with other anticancer immunotherapies, such as adoptive cell transfer regimens, antigen-specific vaccination, and blockade of immune checkpoint inhibitory molecules, for example cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) mono-antibodies, would held the promise of treating metastatic cancer. Despite the comprehensive studies of IL-2 on immune system have established the application of IL-2 for cancer immunotherapy, a number of poignant obstacles remain for future research. In the present review, we will focus on the key biological features of IL-2, current applications, limitations, and future directions of IL-2 in cancer immunotherapy.

  12. Curcumin blocks interleukin (IL)-2 signaling in T-lymphocytes by inhibiting IL-2 synthesis, CD25 expression, and IL-2 receptor signaling

    Energy Technology Data Exchange (ETDEWEB)

    Forward, Nicholas A.; Conrad, David M. [Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia (Canada); Power Coombs, Melanie R.; Doucette, Carolyn D. [Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Furlong, Suzanne J. [Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia (Canada); Lin, Tong-Jun [Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia (Canada); Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia (Canada); Hoskin, David W., E-mail: d.w.hoskin@dal.ca [Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia (Canada); Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Department of Surgery, Dalhousie University, Halifax, Nova Scotia (Canada)

    2011-04-22

    Highlights: {yields} Curcumin inhibits CD4{sup +} T-lymphocyte proliferation. {yields} Curcumin inhibits interleukin-2 (IL-2) synthesis and CD25 expression by CD4{sup +} T-lymphocytes. {yields} Curcumin interferes with IL-2 receptor signaling by inhibiting JAK3 and STAT5 phosphorylation. {yields} IL-2-dependent regulatory T-lymphocyte function and Foxp3 expression is downregulated by curcumin. -- Abstract: Curcumin (diferulomethane) is the principal curcuminoid in the spice tumeric and a potent inhibitor of activation-induced T-lymphocyte proliferation; however, the molecular basis of this immunosuppressive effect has not been well studied. Here we show that micromolar concentrations of curcumin inhibited DNA synthesis by mouse CD4{sup +} T-lymphocytes, as well as interleukin-2 (IL-2) and CD25 ({alpha} chain of the high affinity IL-2 receptor) expression in response to antibody-mediated cross-linking of CD3 and CD28. Curcumin acted downstream of protein kinase C activation and intracellular Ca{sup 2+} release to inhibit I{kappa}B phosphorylation, which is required for nuclear translocation of the transcription factor NF{kappa}B. In addition, IL-2-dependent DNA synthesis by mouse CTLL-2 cells, but not constitutive CD25 expression, was impaired in the presence of curcumin, which demonstrated an inhibitory effect on IL-2 receptor (IL-2R) signaling. IL-2-induced phosphorylation of STAT5A and JAK3, but not JAK1, was diminished in the presence of curcumin, indicating inhibition of critical proximal events in IL-2R signaling. In line with the inhibitory action of curcumin on IL-2R signaling, pretreatment of CD4{sup +}CD25{sup +} regulatory T-cells with curcumin downregulated suppressor function, as well as forkhead box p3 (Foxp3) expression. We conclude that curcumin inhibits IL-2 signaling by reducing available IL-2 and high affinity IL-2R, as well as interfering with IL-2R signaling.

  13. Increased number of IL-2, IL-2 receptor and IL-10 positive cells in premalignant lesions of the cervix.

    Science.gov (United States)

    Mindiola, Raimy; Caulejas, Diana; Núñez-Troconis, José; Araujo, Mary; Delgado, Mariela; Mosquera, Jesús

    2008-12-01

    Previous studies have shown the involvement of the immune response in the progression of human uterine cervix cancer. The aim of this study was to determine the expression of Interleukin-2 (IL-2), IL-2 receptor (IL-2R) and Interleukin 10 (IL-10) in different grades of cervical intraepithelial neoplasias of the exocervix (CIN 1, 2 and 3), and its relationship with the serum cytokine profiles and human papilomavirus (HPV) infection status. Indirect immunofluorescence was used to study the expression of IL-2, IL-2R and IL-10 in human cervical samples from 50 patients and 9 normal controls. Serum IL-2, IL-2R and IL-10 were measured by ELISA and HPV DNA and HPV types were identified by PCR. Increased number of IL-2, IL-2R and IL-10 positive cells were observed in the cervix from patients with CIN, associated with the grades of dysplasia. A significant correlation was observed between IL-2 and IL-2R (p>0.0001), IL-2 and IL-10 (p>0.0001), as well as IL-10 and IL-2R (p>0.0001). Twenty percent of patients were HPV positive and 84% of those patients were tissue cytokine positive. These results suggest that IL-2, IL-2R and IL-10 tissue expression may play a role in the development of cervical intraepithelial dysplasias.

  14. Re-examining the proposed lectin properties of IL-2.

    Science.gov (United States)

    Papalia, Giuseppe A; Rini, James M

    2008-03-01

    Early work examining the interactions of IL-2 and the urinary glycoprotein uromodulin led to the suggestion that IL-2 was a lectin with specificity for high-mannose and mannan ligands. Subsequent studies have attributed various roles to these properties, some critical to the cell proliferative activity of IL-2. In an attempt to verify the reported interaction between IL-2 and mannose containing carbohydrate ligands we studied two biologically active forms of IL-2 using various techniques including affinity chromatography, equilibrium dialysis, and NMR methods. Despite previous reports we have not been able to demonstrate that IL-2 possesses the ability to bind carbohydrate.

  15. Kinetic analysis of interleukin 2 (IL-2) production and expression of IL-2 receptors by uraemic and normal lymphocytes

    DEFF Research Database (Denmark)

    Langhoff, E; Hofmann, B; Ladefoged, J

    1987-01-01

    The in vitro immune response of lymphocytes from uraemic patients was studied by comparing the in vitro kinetics of interleukin 2 (IL-2) production, the mitogen-induced proliferative response, and the expression of IL-2 receptors by T lymphocytes. The IL-2 production in 26 uraemic cell cultures...

  16. More Supernova Surprises

    Science.gov (United States)

    2010-09-24

    SEP 2010 2. REPORT TYPE 3. DATES COVERED 00-00-2010 to 00-00-2010 4. TITLE AND SUBTITLE More Supernova Surprises 5a. CONTRACT NUMBER 5b. GRANT...PERSPECTIVES More Supernova Surprises ASTRONOMY J. Martin Laming Spectroscopic observations of the supernova SN1987A are providing a new window into high...a core-collapse supernova ) have stretched and motivated research that has expanded our knowledge of astrophysics. The brightest such event in

  17. Il2rg gene-targeted severe combined immunodeficiency pigs.

    Science.gov (United States)

    Suzuki, Shunichi; Iwamoto, Masaki; Saito, Yoriko; Fuchimoto, Daiichiro; Sembon, Shoichiro; Suzuki, Misae; Mikawa, Satoshi; Hashimoto, Michiko; Aoki, Yuki; Najima, Yuho; Takagi, Shinsuke; Suzuki, Nahoko; Suzuki, Emi; Kubo, Masanori; Mimuro, Jun; Kashiwakura, Yuji; Madoiwa, Seiji; Sakata, Yoichi; Perry, Anthony C F; Ishikawa, Fumihiko; Onishi, Akira

    2012-06-14

    A porcine model of severe combined immunodeficiency (SCID) promises to facilitate human cancer studies, the humanization of tissue for xenotransplantation, and the evaluation of stem cells for clinical therapy, but SCID pigs have not been described. We report here the generation and preliminary evaluation of a porcine SCID model. Fibroblasts containing a targeted disruption of the X-linked interleukin-2 receptor gamma chain gene, Il2rg, were used as donors to generate cloned pigs by serial nuclear transfer. Germline transmission of the Il2rg deletion produced healthy Il2rg(+/-) females, while Il2rg(-/Y) males were athymic and exhibited markedly impaired immunoglobulin and T and NK cell production, robustly recapitulating human SCID. Following allogeneic bone marrow transplantation, donor cells stably integrated in Il2rg(-/Y) heterozygotes and reconstituted the Il2rg(-/Y) lymphoid lineage. The SCID pigs described here represent a step toward the comprehensive evaluation of preclinical cellular regenerative strategies.

  18. Autophagy is required for IL-2-mediated fibroblast growth

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Rui [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219 (United States); Tang, Daolin, E-mail: tangd2@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219 (United States); Lotze, Michael T., E-mail: lotzemt@upcm.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219 (United States); Zeh III, Herbert J., E-mail: zehh@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15219 (United States)

    2013-02-15

    Autophagy is an evolutionarily conserved pathway responsible for delivery of cytoplasmic material into the lysosomal degradation pathway to enable vesicular exocytosis. Interleukin (IL)-2 is produced by T-cells and its activity is important for immunoregulation. Fibroblasts are an immune competent cell type, playing a critical role in wound healing, chronic inflammation, and tumor development. Although autophagy plays an important role in each of these processes, whether it regulates IL-2 activity in fibroblasts is unknown. Here, we show that autophagy is required for IL-2-induced cell growth in fibroblasts. IL-2 significantly induced autophagy in mouse embryonic fibroblasts (MEFs) and primary lung fibroblasts. Autophagy inhibitors (e.g., 3-methylamphetamine and bafilomycin A1) or knockdown of ATG5 and beclin 1 blocked clinical grade IL-2-induced autophagy. Moreover, IL-2 induced HMGB1 cytoplasmic translocation in MEFs and promoted interaction between HMGB1 and beclin1, which is required for autophagy induction. Pharmacological and genetic inhibition of autophagy inhibited IL-2-induced cell proliferation and enhanced IL-2-induced apoptosis. These findings suggest that autophagy is an important pro-survival regulator for IL-2-induced cell growth in fibroblasts.

  19. Transcriptional regulation of IL-2 in health and autoimmunity

    Science.gov (United States)

    Crispín, José C.; Tsokos, George C.

    2009-01-01

    The regulation of IL-2 production is central to our understanding of the immune system. Key during T cell activation, it also plays an essential role in the regulation of the immune response. This review discusses the function of recently described factors that modulate transcription and chromatin remodeling at the IL2 promoter. Also, it addresses the role of FoxP3 as a transcriptional regulator in conventional T cells and regulatory T cells, and the mechanisms whereby CD28 stabilizes IL2 transcription and translation. Finally, the alterations that prevent T cells from SLE patients from producing normal amounts of IL-2 upon stimulation are described. PMID:18723131

  20. Involvement of IL-2 in homeostasis of regulatory T cells: the IL-2 cycle.

    Science.gov (United States)

    Yarkoni, Shai; Kaminitz, Ayelet; Sagiv, Yuval; Yaniv, Isaac; Askenasy, Nadir

    2008-09-01

    A large body of evidence on the activity of regulatory T (Treg) cells was gathered during the last decade, and a similar number of reviews and opinion papers attempted to integrate the experimental findings. The abundant literature clearly delineates an exciting area of research but also underlines some major controversies. A linear cause-result interpretation of experimental maneuvers often ignores the fact that the activity of Treg cells is orchestrated with the effector T (Teff) cells within an intricate network of physiological immune homeostasis. Every modulation of the activity of the effector (cytotoxic) immune system revolves to affect the activity of regulatory (suppressive) cells through elaborate feedback loops of negative and positive regulation. The lack of IL-2 production by innate Treg cells makes this cytokine a prime coupler of the effector and suppressive mechanisms. Here we attempt to integrate evidence that delineates the involvement of IL-2 in primary and secondary feedback loops that regulate the activity of suppressive cells within the elaborate network of physiological immune homeostasis.

  1. Surprises with Nonrelativistic Naturalness

    CERN Document Server

    Horava, Petr

    2016-01-01

    We explore the landscape of technical naturalness for nonrelativistic systems, finding surprises which challenge and enrich our relativistic intuition already in the simplest case of a single scalar field. While the immediate applications are expected in condensed matter and perhaps in cosmology, the study is motivated by the leading puzzles of fundamental physics involving gravity: The cosmological constant problem and the Higgs mass hierarchy problem.

  2. The IL-2 cytokine family in cancer immunotherapy.

    Science.gov (United States)

    Sim, Geok Choo; Radvanyi, Laszlo

    2014-08-01

    The use of cytokines from the IL-2 family (also called the common γ chain cytokine family) such as interleukin (IL)-2, IL-7, IL-15, and IL-21 to activate the immune system of cancer patients is one of the most important areas of current cancer immunotherapy research. The infusion of IL-2 at low or high doses for multiple cycles in patients with metastatic melanoma and renal cell carcinoma was the first successful immunotherapy for cancer proving that the immune system could completely eradicate tumor cells under certain conditions. The initial clinical success observed in some IL-2-treated patients encouraged further efforts focused on developing and improving the application of other IL-2 family cytokines (IL-4, IL-7, IL-9, IL-15, and IL-21) that have unique biological effects playing important roles in the development, proliferation, and function of specific subsets of lymphocytes at different stages of differentiation with some overlapping effects with IL-2. IL-7, IL-15, and IL-21, as well as mutant forms or variants of IL-2, are now also being actively pursued in the clinic with some measured early successes. In this review, we summarize the current knowledge on the biology of the IL-2 cytokine family focusing on IL-2, IL-15 and IL-21. We discuss the similarities and differences between the signaling pathways mediated by these cytokines and their immunomodulatory effects on different subsets of immune cells. Current clinical application of IL-2, IL-15 and IL-21 either as single agents or in combination with other biological agents and the limitation and potential drawbacks of these cytokines for cancer immunotherapy are also described. Lastly, we discuss the future direction of research on these cytokines, such as the development of new cytokine mutants and variants for improving cytokine-based immunotherapy through differential binding to specific receptor subunits.

  3. Locoregional IL-2 low dose applications for gastrointestinal tumors

    Institute of Scientific and Technical Information of China (English)

    Zachary Krastev; Willem Den Otter; V Koltchakov; R Tomova; S Deredjian; A Alexiev; D Popov; B Tomov; Jan-Willem Koten; John Jacobs

    2005-01-01

    AIM: To explore the feasibility of local interleukin 2 (IL-2)in patients with different forms of abdominal cancer. This required experimentation with the time interval between IL-2 applications and the methods of application.METHODS: Sixteen patients with stages Ⅲ and Ⅳ of gastrointestinal malignancies (primary or metastatic) who were admitted to our Department of Gastroenterology were treated with locoregionally applied IL-2 in low doses.RESULTS: No major problems applying locoregional IL-2 were encountered. In 6 out of 16 patients, a modest but clinically worthwhile improvement was obtained. Adverse effects were minimal, The therapeutic scheme was well tolerated, even in patients in a poor condition.CONCLUSION: This study demonstrates the feasibility of low dose locoregional IL-2 application in advanced abdominal cancer. Local IL-2 therapy gives only negligible adverse effects. The results suggest that it is important to apply intratumorally. Local IL-2 may be given adjunct to standard therapeutic regimes and does not imply complex surgical interventions. These initial results are encouraging.

  4. Surprises in astrophysical gasdynamics

    CERN Document Server

    Balbus, Steven A

    2016-01-01

    Much of astrophysics consists of the study of ionised gas under the influence of gravitational and magnetic fields. Thus, it is not possible to understand the astrophysical universe without a detailed knowledge of the dynamics of magnetised fluids. Fluid dynamics is, however, a notoriously tricky subject, in which it is all too easy for one's a priori intuition to go astray. In this review, we seek to guide the reader through a series of illuminating yet deceptive problems, all with an enlightening twist. We cover a broad range of topics including the instabilities acting in accretion discs, the hydrodynamics governing the convective zone of the Sun, the magnetic shielding of a cooling galaxy cluster, and the behaviour of thermal instabilities and evaporating clouds. The aim of this review is to surprise and intrigue even veteran astrophysical theorists with an idiosynchratic choice of problems and counterintuitive results. At the same time, we endeavour to bring forth the fundamental ideas, to set out import...

  5. Surprises in astrophysical gasdynamics

    Science.gov (United States)

    Balbus, Steven A.; Potter, William J.

    2016-06-01

    Much of astrophysics consists of the study of ionized gas under the influence of gravitational and magnetic fields. Thus, it is not possible to understand the astrophysical universe without a detailed knowledge of the dynamics of magnetized fluids. Fluid dynamics is, however, a notoriously tricky subject, in which it is all too easy for one’s a priori intuition to go astray. In this review, we seek to guide the reader through a series of illuminating yet deceptive problems, all with an enlightening twist. We cover a broad range of topics including the instabilities acting in accretion discs, the hydrodynamics governing the convective zone of the Sun, the magnetic shielding of a cooling galaxy cluster, and the behaviour of thermal instabilities and evaporating clouds. The aim of this review is to surprise and intrigue even veteran astrophysical theorists with an idiosyncratic choice of problems and counterintuitive results. At the same time, we endeavour to bring forth the fundamental ideas, to set out important assumptions, and to describe carefully whatever novel techniques may be appropriate to the problem at hand. By beginning at the beginning, and analysing a wide variety of astrophysical settings, we seek not only to make this review suitable for fluid dynamic veterans, but to engage novice recruits as well with what we hope will be an unusual and instructive introduction to the subject.

  6. Surprises in astrophysical gasdynamics.

    Science.gov (United States)

    Balbus, Steven A; Potter, William J

    2016-06-01

    Much of astrophysics consists of the study of ionized gas under the influence of gravitational and magnetic fields. Thus, it is not possible to understand the astrophysical universe without a detailed knowledge of the dynamics of magnetized fluids. Fluid dynamics is, however, a notoriously tricky subject, in which it is all too easy for one's a priori intuition to go astray. In this review, we seek to guide the reader through a series of illuminating yet deceptive problems, all with an enlightening twist. We cover a broad range of topics including the instabilities acting in accretion discs, the hydrodynamics governing the convective zone of the Sun, the magnetic shielding of a cooling galaxy cluster, and the behaviour of thermal instabilities and evaporating clouds. The aim of this review is to surprise and intrigue even veteran astrophysical theorists with an idiosyncratic choice of problems and counterintuitive results. At the same time, we endeavour to bring forth the fundamental ideas, to set out important assumptions, and to describe carefully whatever novel techniques may be appropriate to the problem at hand. By beginning at the beginning, and analysing a wide variety of astrophysical settings, we seek not only to make this review suitable for fluid dynamic veterans, but to engage novice recruits as well with what we hope will be an unusual and instructive introduction to the subject.

  7. Increased and prolonged human norovirus infection in RAG2/IL2RG deficient gnotobiotic pigs with severe combined immunodeficiency.

    Science.gov (United States)

    Lei, Shaohua; Ryu, Junghyun; Wen, Ke; Twitchell, Erica; Bui, Tammy; Ramesh, Ashwin; Weiss, Mariah; Li, Guohua; Samuel, Helen; Clark-Deener, Sherrie; Jiang, Xi; Lee, Kiho; Yuan, Lijuan

    2016-04-27

    Application of genetically engineered (GE) large animals carrying multi-allelic modifications has been hampered by low efficiency in production and extended gestation period compared to rodents. Here, we rapidly generated RAG2/IL2RG double knockout pigs using direct injection of CRISPR/Cas9 system into developing embryos. RAG2/IL2RG deficient pigs were immunodeficient, characterized by depletion of lymphocytes and either absence of or structurally abnormal immune organs. Pigs were maintained in gnotobiotic facility and evaluated for human norovirus (HuNoV) infection. HuNoV shedding lasted for 16 days in wild type pigs, compared to 27 days (until the end of trials) in RAG2/IL2RG deficient pigs. Additionally, higher HuNoV titers were detected in intestinal tissues and contents and in blood, indicating increased and prolonged HuNoV infection in RAG2/IL2RG deficient pigs and the importance of lymphocytes in HuNoV clearance. These results suggest that GE immunodeficient gnotobiotic pigs serve as a novel model for biomedical research and will facilitate HuNoV studies.

  8. Increased and prolonged human norovirus infection in RAG2/IL2RG deficient gnotobiotic pigs with severe combined immunodeficiency

    Science.gov (United States)

    Lei, Shaohua; Ryu, Junghyun; Wen, Ke; Twitchell, Erica; Bui, Tammy; Ramesh, Ashwin; Weiss, Mariah; Li, Guohua; Samuel, Helen; Clark-Deener, Sherrie; Jiang, Xi; Lee, Kiho; Yuan, Lijuan

    2016-01-01

    Application of genetically engineered (GE) large animals carrying multi-allelic modifications has been hampered by low efficiency in production and extended gestation period compared to rodents. Here, we rapidly generated RAG2/IL2RG double knockout pigs using direct injection of CRISPR/Cas9 system into developing embryos. RAG2/IL2RG deficient pigs were immunodeficient, characterized by depletion of lymphocytes and either absence of or structurally abnormal immune organs. Pigs were maintained in gnotobiotic facility and evaluated for human norovirus (HuNoV) infection. HuNoV shedding lasted for 16 days in wild type pigs, compared to 27 days (until the end of trials) in RAG2/IL2RG deficient pigs. Additionally, higher HuNoV titers were detected in intestinal tissues and contents and in blood, indicating increased and prolonged HuNoV infection in RAG2/IL2RG deficient pigs and the importance of lymphocytes in HuNoV clearance. These results suggest that GE immunodeficient gnotobiotic pigs serve as a novel model for biomedical research and will facilitate HuNoV studies. PMID:27118081

  9. Local administration of cells containing an inserted IL-2 gene and producing IL-2 inhibits growth of human tumours in nu/nu mice.

    Science.gov (United States)

    Bubenik, J; Voitenok, N N; Kieler, J; Prassolov, V S; Chumakov, P M; Bubenikova, D; Simova, J; Jandlova, T

    1988-12-01

    We have prepared a retroviral expression construct, pPS-IL-2, in which human IL-2 cDNA has been inserted into the polylinker region, and have used the retroviral vector to introduce the functional IL-2 gene into a fibroblast cell line, RAT-1. Peritumoral administration of IL-2-producing RAT-1 cells into congenitally athymic (nu/nu) mice carrying subcutaneous transplants of human carcinoma cells inhibited the growth of the human tumour xenografts.

  10. Surprise... Surprise..., An Empirical Investigation on How Surprise is Connected to Customer Satisfaction

    NARCIS (Netherlands)

    J. Vanhamme (Joëlle)

    2003-01-01

    textabstractThis research investigates the specific influence of the emotion of surprise on customer transaction-specific satisfaction. Four empirical studies-two field studies (a diary study and a cross section survey) and two experiments-were conducted. The results show that surprise positively

  11. Surprise... Surprise..., An Empirical Investigation on How Surprise is Connected to Customer Satisfaction

    NARCIS (Netherlands)

    J. Vanhamme (Joëlle)

    2003-01-01

    textabstractThis research investigates the specific influence of the emotion of surprise on customer transaction-specific satisfaction. Four empirical studies-two field studies (a diary study and a cross section survey) and two experiments-were conducted. The results show that surprise positively [n

  12. The Knockout Mouse Project

    OpenAIRE

    Austin, Christopher P.; Battey, James F.; Bradley, Allan; Bucan, Maja; Capecchi, Mario; Collins, Francis S; Dove, William F.; Duyk, Geoffrey; Dymecki, Susan; Eppig, Janan T.; Grieder, Franziska B.; Heintz, Nathaniel; Hicks, Geoff; Insel, Thomas R; Joyner, Alexandra

    2004-01-01

    Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and e...

  13. [Effect of IL-2 on the growth and apoptosis of intestinal epithelial cells radiated by neutron and mechanisms of IL-2 on the injured IEC-6].

    Science.gov (United States)

    Fu, Kai-fei; Peng, Rui-yun; Gao, Ya-bing; Wang, De-wen; Luo, Qing-liang; Dong, Bo; Ma, Jun-jie

    2007-08-01

    To observe the effect of neutron radiation on intestinal epithelial cells 6 (IEC-6), to study the effect of IL-2 on the proliferation and recovery of neutron-injured IEC-6, and to investigate the regulatory mechanisms of IL-2 on the injured IEC-6. 4Gy-neutron-injured IEC-6 were treated by IL-2, with or without the blocking agent JAK(1) (A77-1726). The change of proliferative activity and death manner of the treated IEC-6 were detected by MTT colorimetry and flow cytometry at 10, 15, 30 minutes and 1, 3, 6, 12, 24, 48, 72 hours respectively. The expression of IL-2Rbeta and the activation of JAK(1) of neutron-injured IEC-6 treated by IL-2 were detected by immunocytochemical stainning and Western blot. After IEC-6 were radiated by 4 Gy neutron for 24 hours, the proliferative activity of IEC-6 decreased markedly but increased strikingly after IL-2 treatment (PIEC-6 in IL-2-treated group decreased (PIEC-6 were treated by IL-2, JAK(1) was activated at 10 and 15 minutes, and the expression of IL-2Rbeta increased apparently at 24 hours. When treated by JAK(1) and IL-2, the proliferative activity of neutron-injured IEC-6 was much lower than that in IL-2-treated group. IL-2 can accelerate the proliferation of neutron-radiated IEC-6 and protect them from neutron injury. IL-2Rbeta and JAK(1) participate in the regulation of neutron-injured IEC-6 by IL-2.

  14. 脐血IL-2,mIL-2R,sIL-2R和T细胞免疫功能%Expression levels of IL-2, sIL-2R and mIL-2R of cord blood and the immune function of T cells

    Institute of Scientific and Technical Information of China (English)

    许礼发; 王健; 李朝品

    2004-01-01

    1实验资料ELISA法IL-2、可溶性白细胞介素-2受体(soluble interleukin-2 receptor,sIL-2R),IL-6,IL-10和可溶性细胞间黏附分子-1(soluble intercellular adhesion molecule-1,sICAM-1)检测试剂盒均购自法国Dia Clone公司和美国Biosource公司,PHA为广州医药公司产品,生物素-链霉亲和素(biotin-streptavidin,BSA)法膜白细胞介素-2受体(membrane

  15. Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: Overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines

    Science.gov (United States)

    Klein, Christian; Waldhauer, Inja; Nicolini, Valeria G.; Freimoser-Grundschober, Anne; Nayak, Tapan; Vugts, Danielle J.; Dunn, Claire; Bolijn, Marije; Benz, Jörg; Stihle, Martine; Lang, Sabine; Roemmele, Michaele; Hofer, Thomas; van Puijenbroek, Erwin; Moser, Samuel; Ast, Oliver; Brünker, Peter; Gorr, Ingo H.; Neumann, Sebastian; Hinton, Heather; Crameri, Flavio; Gerdes, Christian; Bacac, Marina; van Dongen, Guus; Moessner, Ekkehard; Umaña, Pablo

    2017-01-01

    ABSTRACT We developed cergutuzumab amunaleukin (CEA-IL2v, RG7813), a novel monomeric CEA-targeted immunocytokine, that comprises a single IL-2 variant (IL2v) moiety with abolished CD25 binding, fused to the C-terminus of a high affinity, bivalent carcinoembryonic antigen (CEA)-specific antibody devoid of Fc-mediated effector functions. Its molecular design aims to (i) avoid preferential activation of regulatory T-cells vs. immune effector cells by removing CD25 binding; (ii) increase the therapeutic index of IL-2 therapy by (a) preferential retention at the tumor by having a lower dissociation rate from CEA-expressing cancer cells vs. IL-2R-expressing cells, (b) avoiding any FcγR-binding and Fc effector functions and (c) reduced binding to endothelial cells expressing CD25; and (iii) improve the pharmacokinetics, and thus convenience of administration, of IL-2. The crystal structure of the IL2v-IL-2Rβγ complex was determined and CEA-IL2v activity was assessed using human immune effector cells. Tumor targeting was investigated in tumor-bearing mice using 89Zr-labeled CEA-IL2v. Efficacy studies were performed in (a) syngeneic mouse models as monotherapy and combined with anti-PD-L1, and in (b) xenograft mouse models in combination with ADCC-mediating antibodies. CEA-IL2v binds to CEA with pM avidity but not to CD25, and consequently did not preferentially activate Tregs. In vivo, CEA-IL2v demonstrated superior pharmacokinetics and tumor targeting compared with a wild-type IL-2-based CEA immunocytokine (CEA-IL2wt). CEA-IL2v strongly expanded NK and CD8+ T cells, skewing the CD8+:CD4+ ratio toward CD8+ T cells both in the periphery and in the tumor, and mediated single agent efficacy in syngeneic MC38-CEA and PancO2-CEA models. Combination with trastuzumab, cetuximab and imgatuzumab, all of human IgG1 isotype, resulted in superior efficacy compared with the monotherapies alone. Combined with anti-PD-L1, CEA-IL2v mediated superior efficacy over the respective

  16. Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: Overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines.

    Science.gov (United States)

    Klein, Christian; Waldhauer, Inja; Nicolini, Valeria G; Freimoser-Grundschober, Anne; Nayak, Tapan; Vugts, Danielle J; Dunn, Claire; Bolijn, Marije; Benz, Jörg; Stihle, Martine; Lang, Sabine; Roemmele, Michaele; Hofer, Thomas; van Puijenbroek, Erwin; Wittig, David; Moser, Samuel; Ast, Oliver; Brünker, Peter; Gorr, Ingo H; Neumann, Sebastian; de Vera Mudry, Maria Cristina; Hinton, Heather; Crameri, Flavio; Saro, Jose; Evers, Stefan; Gerdes, Christian; Bacac, Marina; van Dongen, Guus; Moessner, Ekkehard; Umaña, Pablo

    2017-01-01

    We developed cergutuzumab amunaleukin (CEA-IL2v, RG7813), a novel monomeric CEA-targeted immunocytokine, that comprises a single IL-2 variant (IL2v) moiety with abolished CD25 binding, fused to the C-terminus of a high affinity, bivalent carcinoembryonic antigen (CEA)-specific antibody devoid of Fc-mediated effector functions. Its molecular design aims to (i) avoid preferential activation of regulatory T-cells vs. immune effector cells by removing CD25 binding; (ii) increase the therapeutic index of IL-2 therapy by (a) preferential retention at the tumor by having a lower dissociation rate from CEA-expressing cancer cells vs. IL-2R-expressing cells, (b) avoiding any FcγR-binding and Fc effector functions and (c) reduced binding to endothelial cells expressing CD25; and (iii) improve the pharmacokinetics, and thus convenience of administration, of IL-2. The crystal structure of the IL2v-IL-2Rβγ complex was determined and CEA-IL2v activity was assessed using human immune effector cells. Tumor targeting was investigated in tumor-bearing mice using (89)Zr-labeled CEA-IL2v. Efficacy studies were performed in (a) syngeneic mouse models as monotherapy and combined with anti-PD-L1, and in (b) xenograft mouse models in combination with ADCC-mediating antibodies. CEA-IL2v binds to CEA with pM avidity but not to CD25, and consequently did not preferentially activate Tregs. In vivo, CEA-IL2v demonstrated superior pharmacokinetics and tumor targeting compared with a wild-type IL-2-based CEA immunocytokine (CEA-IL2wt). CEA-IL2v strongly expanded NK and CD8(+) T cells, skewing the CD8(+):CD4(+) ratio toward CD8(+) T cells both in the periphery and in the tumor, and mediated single agent efficacy in syngeneic MC38-CEA and PancO2-CEA models. Combination with trastuzumab, cetuximab and imgatuzumab, all of human IgG1 isotype, resulted in superior efficacy compared with the monotherapies alone. Combined with anti-PD-L1, CEA-IL2v mediated superior efficacy over the respective

  17. LPS nephropathy in mice is ameliorated by IL-2 independently of regulatory T cells activity.

    Directory of Open Access Journals (Sweden)

    Roberta Bertelli

    Full Text Available Immunosuppressive regulatory T cells (Tregs have been hypothesized to exert a protective role in animal models of spontaneous (Buffalo/Mna and/or drug induced (Adriamycin nephrotic syndrome. In this study, we thought to define whether Tregs can modify the outcome of LPS nephropathy utilizing IL-2 as inducer of tissue and circulating Tregs. LPS (12 mg/Kg was given as single shot in C57BL/6, p2rx7⁻/⁻ and Foxp3EGFP; free IL-2 (18.000 U or, in alternative, IL-2 coupled with JES6-1 mAb (IL-2/anti-IL-2 were injected before LPS. Peripheral and tissue Tregs/total CD4+ cell ratio, urinary parameters and renal histology were evaluated for 15 days. IL-2 administration to wild type mice had no effect on peripheral Tregs number, whereas a significant increase was induced by the IL-2/anti-IL-2 immunocomplex after 5 days. Spleen and lymph nodes Tregs were comparably increased. In p2rx7⁻/⁻ mice, IL-2/anti-IL-2 treatment resulted in increase of peripheral Tregs but did not modify the spleen and lymph nodes quota. LPS induced comparable and transient proteinuria in both wild type and p2rx7⁻/⁻ mice. Proteinuria was inhibited by co-infusion of human IL-2, with reduction at each phase of the disease (24 -48 and 72 hours whereas IL-2/anti-IL-2 produced weaker effects. In all mice (wild type and p2rx7⁻/⁻ and irrespective of treatment (IL-2, IL-2/anti-IL-2, LPS was associated with progressive signs of renal pathologic involvement resulting in glomerulosclerosis. In conclusion, IL-2 plays a transient protective effect on proteinuria induced by LPS independent of circulating or tissue Tregs but does not modify the outcome of renal degenerative renal lesions.

  18. Surprise as a design strategy

    NARCIS (Netherlands)

    Ludden, G.D.S.; Schifferstein, H.N.J.; Hekkert, P.P.M.

    2008-01-01

    Imagine yourself queuing for the cashier’s desk in a supermarket. Naturally, you have picked the wrong line, the one that does not seem to move at all. Soon, you get tired of waiting. Now, how would you feel if the cashier suddenly started to sing? Many of us would be surprised and, regardless of

  19. Surprise as a design strategy

    NARCIS (Netherlands)

    Ludden, G.D.S.; Schifferstein, H.N.J.; Hekkert, P.P.M.

    2008-01-01

    Imagine yourself queuing for the cashier’s desk in a supermarket. Naturally, you have picked the wrong line, the one that does not seem to move at all. Soon, you get tired of waiting. Now, how would you feel if the cashier suddenly started to sing? Many of us would be surprised and, regardless of th

  20. Pleiotropic Effects of IL-2 on Cancer: Its Role in Cervical Cancer

    Directory of Open Access Journals (Sweden)

    Arturo Valle-Mendiola

    2016-01-01

    Full Text Available IL-2 receptor (IL-2R signalling is critical for normal lymphocyte proliferation, but its role in cervical cancer is not fully understood. The receptor is composed of three chains: IL-2α, IL-2β, and IL-2γ. Intracellular signalling is initiated by ligand-induced heterodimerization of the IL-2β and IL-2γ chains, resulting in the activation of multiple intracellular kinases. Recently, IL-2R was shown to be expressed on nonhaematopoietic cells, especially on several types of tumour cells. However, the function of this receptor on malignant cells has not been clearly defined. The expression of IL-2R and the production of IL-2 in cervical cancer cells have been documented as well as expression of molecules of the JAK-STAT pathway. In the current review we have highlighted the differences in the responses of molecules downstream from the IL-2R in normal lymphocytes and tumour cells that could explain the presence of tumour cells in an environment in which cytotoxic lymphocytes also exist and compete and also the effect of different concentrations of IL-2 that could activate effector cells of the immune system cells, which favour the elimination of tumour cells, or concentrations that may promote a regulatory microenvironment in which tumour cells can easily grow.

  1. Pleiotropic Effects of IL-2 on Cancer: Its Role in Cervical Cancer

    Science.gov (United States)

    Valle-Mendiola, Arturo; Gutiérrez-Hoya, Adriana; Lagunas-Cruz, María del Carmen; Weiss-Steider, Benny; Soto-Cruz, Isabel

    2016-01-01

    IL-2 receptor (IL-2R) signalling is critical for normal lymphocyte proliferation, but its role in cervical cancer is not fully understood. The receptor is composed of three chains: IL-2α, IL-2β, and IL-2γ. Intracellular signalling is initiated by ligand-induced heterodimerization of the IL-2β and IL-2γ chains, resulting in the activation of multiple intracellular kinases. Recently, IL-2R was shown to be expressed on nonhaematopoietic cells, especially on several types of tumour cells. However, the function of this receptor on malignant cells has not been clearly defined. The expression of IL-2R and the production of IL-2 in cervical cancer cells have been documented as well as expression of molecules of the JAK-STAT pathway. In the current review we have highlighted the differences in the responses of molecules downstream from the IL-2R in normal lymphocytes and tumour cells that could explain the presence of tumour cells in an environment in which cytotoxic lymphocytes also exist and compete and also the effect of different concentrations of IL-2 that could activate effector cells of the immune system cells, which favour the elimination of tumour cells, or concentrations that may promote a regulatory microenvironment in which tumour cells can easily grow. PMID:27293315

  2. Construction of IL-2 gene-modified human hepatocyte and its cultivation with microcarrier

    Institute of Scientific and Technical Information of China (English)

    Nan-Hong Tang; Yian-Ling Chen; Xiao-Qian Wang; Xiu-Jin Li; Feng-Zhi Yin; Xiao-Zhong Wang

    2003-01-01

    AIM: To construct interleukin-2 gene-modified humanhepatocyte line (L-02/IL-2) and investigate the changes ofthe function of liver cells and IL-2 secretion in culture withmicrocarrier, laying the foundation for further experimentationon hepatocyte transplantation.METHODS: hIL-2 gene was transduced into L-02hepatocytes by recombinant retroviral vector pLNCIL-2, andthe changes of morphology and clonogeneicity rate of thetransduced cells were observed, the secretion levels of hIL-2 in cultural supernatant were detected by ELISA and NeoRgene was amplified by PCR. The growth of L-02/IL-2, thespecial biochemistry items and the levels of IL-2 weredetected after cultivation with microcarrier.RESULTS: The clonogeneicity rate of the L-02/IL-2 cellswas lower than that of L-02/Neo cells and L-02 cells. Thelevels of hIL-2 could reach 32 000 pg/106 cells per day andkept secreting for more than ten weeks. NeoR gene segmentwas respectively obtained by PCR from both L-02/IL-2 andL-02/Neo cell's genomic DNA. At the 6th day in culture withmicrocarrier, the matrix-induced liver cell aggregates wereformed, the number of alive L-02/IL-2 cell were 16.8±0.53x106/flask and the levels of ALB and UREA were 52.54±1.28mg/L and 5.29±0.17 mmol/L, respectively. These data hadnot significantly changed as compared with those of L-02cells (P>0.05); However, the levels of IL-2 in IL-2/L-02 cellsremarkably exceeded that in L-02 cells in the whole cultureprocess (P<0.001).CONCLUSION: The IL-2 gene-modified hepatooyte line hasbeen successfully constructed. The L-02/IL-2 cellularaggregates cultured with microcarrier have a high capacityof IL-2 production as well as protein synthesis and aminoacid metabolism.

  3. Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: Overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines

    OpenAIRE

    Klein, Christian; Waldhauer, Inja; Nicolini, Valeria G.; Freimoser-Grundschober, Anne; Nayak, Tapan; Vugts, Danielle J.; Dunn, Claire; Bolijn, Marije; Benz, J?rg; Stihle, Martine; Lang, Sabine; Roemmele, Michaele; Hofer, Thomas; van Puijenbroek, Erwin; Wittig, David

    2017-01-01

    ABSTRACT We developed cergutuzumab amunaleukin (CEA-IL2v, RG7813), a novel monomeric CEA-targeted immunocytokine, that comprises a single IL-2 variant (IL2v) moiety with abolished CD25 binding, fused to the C-terminus of a high affinity, bivalent carcinoembryonic antigen (CEA)-specific antibody devoid of Fc-mediated effector functions. Its molecular design aims to (i) avoid preferential activation of regulatory T-cells vs. immune effector cells by removing CD25 binding; (ii) increase the ther...

  4. Brazilian rescue plan sparks surprise

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    According to Financial Times,when Guido Mantega,Brazil's finance minister,suddenly proposed a “Bric” rescue package for the eurozone this week,he caught not only other world leaders by surprise but also many of his fellow countrymen.Even as officials from other members of the so-called Bric grouping,Russia,India and China,said it was the first they heard of the idea,many ordinary Brazilians expressed shock at the notion of bailing out the world's richest trading bloc.

  5. Knockout reactions: experimental aspects

    Energy Technology Data Exchange (ETDEWEB)

    Cortina Gil, D. [Santiago de Compostela Univ. (Spain)

    2007-07-01

    The availability of radioactive beams has given rise to intense activity in the field of direct reactions. The removal of one(two)-nucleon (referred to as nucleon knockout in this text) from a fast exotic projectile has been extensively investigated. This lecture provides a general overview of the experimental results achieved using this technique. The sensitivity of the method to different experimental aspects is illustrated with a few examples. Special attention is given to the application of nucleon-knockout reactions as a general purpose spectroscopic tool. (author)

  6. 紫茜胶囊对慢性原发性血小板减少性紫癜患者IL-2、sIL-2R的影响%The Effect on IL - 2 and sIL - 2R of chronic Idiopathic Thrombocytopenic Purpura treated by Zi Qian capsule

    Institute of Scientific and Technical Information of China (English)

    孙凤; 朱云丽

    2007-01-01

    目的:探讨紫茜胶囊对慢性原发性血小板减少性紫癜(CIIp)患者血清IL-2及sIL-2R的影响及作用机理.方法:将64例CITP患者分为紫茜胶囊治疗组和升血小板胶囊对照组各32例,用ELISA方法检测CITp患者治疗前后血清IL-2、sIL-2R的含量变化.结果:CITP患者的IL-2水平明显低于正常对照组,sIL-2R则高于正常对照组,二者经治疗后均有明显改善,但治疗组优于对照组.结论:血清IL-2及sIL-2R水平变化与CITP的发病有关,紫茜胶囊可通过降低IL-2、升高sIL-2R改善CITP患者的细胞免疫功能.

  7. Analysis of IL-2-like factor in lymphocyte culture supernatant of olive flounder, Paralichthys oliveaceus

    Institute of Scientific and Technical Information of China (English)

    WU Riqin; ZHANG Peijun; LI Jun; XU Yongli

    2005-01-01

    To study immune mechanism of fish lymphocyte we performed a proliferation assay and ELISA using monoclonal antibody against human IL-2. The result showed that an interleukin-2 (IL-2)-like factor was detected in the supernatant of plant haemoglutinin (PHA)-stimulated lymphocyte culture from peripheral blood,spleen and head kidney of olive flounder, Paralichthys olivaceus. The quantities of IL-2-1ike factor in the supematant from different lymphoid tissues were quite different. The IL-2 like factor in the supernatant from cultured head kidney lymphocytes was much higher than those of peripheral blood lymphocytes and spleen lymphocytes (P<0.01). The IL-2 activity was found in either mouse thymocyte proliferation assay or flounder head kidney lymphocyte proliferation assay and shown to have obvious enhancing effect on proliferation of the above two types of cell. The recombinant human IL-2 (rhIL-2) was able to stimulate flounder thymocyte proliferation and used to detect the IL-2 receptor (IL-2R) on the surface of flounder lymphocyte. The cross-reaction between the lymphocytes of flounder peripheral blood and CD25(IL-2R) was detected with flow cytometry and shown that the percentage of CD25-positive cell in peripheral blood was 7.74± 0.67%.

  8. 哮喘患儿血清中sIL-2R,IL-2,IL-4,IL-13的测定与临床意义

    Institute of Scientific and Technical Information of China (English)

    张国祥; 许文龙

    2007-01-01

    目的 探讨哮喘患儿血清中sIL-2R,IL-2,IL-4,IL-13的水平变化及其与哮喘发病机制的关系.方法 每例患儿及正常对照组均取空腹静脉血并即时分离血清1 ml,用ELISA法检测血清中sIL-2R,IL-2,IL-4,IL-13的水平,并对检测结果 进行医学统计学分析处理.结果 哮喘急性发作组、哮喘缓解组的患儿血清中sIL-2R,IL-2,IL-4,IL-13的测定结果与正常对照组相比较经统计学分析均存在极其显著的差异(P<0.05).其中患儿哮喘急性发作组、哮喘缓解组血清中sIL-2R,IL-4,IL-13的测定结果 要明显高于正常对照组,而IL-2则明显低于正常对照组.此外,哮喘急性发作组与哮喘缓解组血清中IL-2,IL-4,IL-13的测定结果 相比较经统计学分析均存在显著的差异(P<0.05),而sIL-2R则无显著差异.结论 哮喘患儿血清中sIL-2R,IL-2,IL-4,IL-13的水平均存在显著的变化,说明它们在哮喘的发病机制中起着重要的作用.

  9. Some Surprises in Relativistic Gravity

    CERN Document Server

    Santos, N O

    2016-01-01

    General Relativity has had tremendous success both on the theoretical and the experimental fronts for over a century now. However, the contents of the theory are far from exhausted. Only very recently, with the detection of gravitational waves from colliding black holes, we have started probing the behavior of gravity in the strongly non-linear regime. Even today, the studies of black holes keep revealing more and more paradoxes and bizarre results. In this paper, inspired by David Hilbert's startling observation, we show that, contrary to the conventional wisdom, a freely falling test particle feels gravitational repulsion by a black hole as seen by the asymptotic observer. We dig deeper into this surprising behavior of relativistic gravity and offer some explanations.

  10. KnockoutJS blueprints

    CERN Document Server

    Russo, Carlo

    2015-01-01

    If you are a JavaScript developer and already know the basics of KnockoutJS and you want to get the most out of it, then this book is for you. This book will help in your transition from a small site to a large web application that is easily maintainable.

  11. Influence of Ginkgo biloba exocarp polysaccharides (GBEP) on interleukin-2 (IL-2)activity and solubility interleukin-2 receptor (sIL-2R) level in mice under lower immune function%银杏外种皮多糖对免疫功能低下小鼠IL-2活性及sIL-2R的影响

    Institute of Scientific and Technical Information of China (English)

    陈华圣; 许爱华; 王翊; 王茜; 王晓玲

    2001-01-01

    目的:观测银杏外种皮多糖对免疫功能低下小鼠IL-2活性及sIL-2R的影响.方法:用银杏外种皮多糖给荷瘤小鼠及环磷酰胺损伤小鼠灌胃治疗,分别检测小鼠脾淋巴细胞IL-2活性及血清sIL-2R含量.结果:银杏外种皮多糖可促进荷瘤小鼠及CTX损伤小鼠脾淋巴细胞的IL-2活性,并减少其血清sIL-2R的形成.结论:银杏外种皮多糖可促进荷瘤小鼠及CTX损伤小鼠的免疫功能.

  12. Stimulation of AIDS lymphocytes with calcium ionophore (A23187) and phorbol ester (PMA): studies of cytoplasmic free Ca, IL-2 receptor expression, IL-2 production, and proliferation

    DEFF Research Database (Denmark)

    Hofmann, B; Moller, J; Langhoff, E

    1989-01-01

    nine patients with AIDS with the response of lymphocytes from nine control subjects showed that the response of AIDS lymphocytes was severely decreased when stimulated with PHA and no further response could be achieved by stimulation with A23187/PMA. On the other hand, no significant difference between...... the PHA-induced rise of cytoplasmic free calcium concentration ([Ca2+]1) in normal and AIDS lymphocytes was observed. The percentage of cells expressing IL-2 receptors (CD25) was also normal both after addition of PHA and after addition of A23187/PMA and the expression was normal on both CD4 and CD8 cells....... The production of IL-2 in normal lymphocytes stimulated with A23187/PMA was 33 times higher than that after stimulation with PHA. In AIDS lymphocytes the production of IL-2 induced by all activators was severely decreased compared to control subjects, although the production of IL-2 after stimulation with A23187...

  13. IL-2 and IL-15 Exhibit Opposing Effects on Fas Mediated Apoptosis

    Institute of Scientific and Technical Information of China (English)

    Gulcin Demirci; Xian Chang Li

    2004-01-01

    It has been shown that IL-2 and IL-15 can have opposing effects on life and death of T cells. However, the role of IL-2 and IL-15 in regulating the fate of other cell types is less clear. In the present study, we examined the impact of IL-2 and IL-15 on life and death of pre-B cells using the BAF-B03 line. We showed that BAF-B03 cells constitutively expressed the private IL-2Rα chain and IL-15Rα chain, and the shared IL-2Rβ chain and γc chain. Stimulation of BAF-B03 cells in vitro with IL-2 and IL-15 induced vigorous cell proliferation in a dose-dependent fashion. Titration of IL-2 and IL-15 in the assay showed that the mitotic effects of IL-2 and IL-15 were remarkably similar, Howerer, the sensitivities of BAF-B03 cells to Fas mediated apoptosis after IL-2 and IL-15 stimulation were strikingly different. Cells cultured in IL-2 readily underwent apoptotic cell deathupon cross-linking of the Fas receptor whereas cells cultured in IL-15 were extremely resistant to Fas triggered cell death. The anti-apoptotic effect of IL-15 in this model was associated with increased expression of Bcl-xL. FLIP expression, however, was comparable between IL-2 and IL-15 stimulated cells. We conclude that IL-2 and IL-15 have diametrically opposite effect on the fate of BAF-B03 cells, although both cytokines share similar receptor structure and exhibitsimilarmitoticactivities.

  14. IL-2 and IL-15 Exhibit Opposing Effects on Fas Mediated Apoptosis

    Institute of Scientific and Technical Information of China (English)

    GulcinDemirci; XianChangLi

    2004-01-01

    It has been shown that IL-2 and IL-15 can have opposing effects on life and death of T cells. However, the roie of IL-2 and IL-15 in regulating the fate of other cell types is less clear. In the present study, we examined the impact of IL-2 and IL-15 on life and death of pre-B cells using the BAF-B03 line. We showed that BAF-B03 cells constitutively expressed the private IL-2Rα chain and IL-15Rα chain, and the shared IL-2Rβ chain and γc hain. Stimulation of BAF-B03 cells in vitro with IL-2 and IL-15 induced vigorous cell proliferation in a dose-dependent fashion. Titration of IL-2 and IL-15 in the assay showed that the mitotic effects of IL-2 and IL-15 were remarkably similar. However, the sensitivities of BAF-B03 cells to Fas mediated apoptosis after IL-2 and IL-15 stimulation were strikingly different. Cells cultured in IL-2 readily underwent apoptotic cell death upon cross-linking of the Fas receptor whereas cells cultured in IL-15 were extremely resistant to Fas triggered cell death. The anti-apoptotic effect of IL-15 in this model was associated with increased expression of Bcl-xL. FLIP expression, however, was comparable between IL-2 and IL-15 stimulated cells. We conclude that IL-2 and IL-15 have diametrically opposite effect on the fate of BAF-B03 cells, although both cytokines share similar receptor structure and exhibit similar mitotic activities. Cellular & Molecular Immunology. 2004;1(2):123-128.

  15. On the Role of sIL-2R Measurements in Rheumatoid Arthritis and Cancers

    Directory of Open Access Journals (Sweden)

    Anna Maria Witkowska

    2005-01-01

    diseases of different pathology. Moreover, the soluble receptor has been considered, at least in part, responsible for unsuccessful immunotherapy with IL-2 in cancers. Several lines of evidence indicate sIL-2R measurements to be useful in determining disease progress and prognosis. This review summarizes current knowledge on the sIL-2R behavior in RA and solid cancers of varied etiology.

  16. mIL-2R, T cell subsets & hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Chao-Pin Li; Ke-Xia Wang; Jian Wang; Bo-Rong Pan

    2002-01-01

    AIM: To study the levels of membrane interleukin-2 receptor(mIL-2R ) and T cell subsets in peripheral bloodmononuclear cells (PBMC) from patients with hepatitis Cand their role in the pathogenesis of hepatitis C.METHODS: The levels of mlL-2R and T cells subsets in PBMCWere detected by biotin- streptstividin (BSA) technique beforeand after stimulation with PHA in 203 patients with hepatitis Cwith HCV-RNA( + ), anti-HCV( + ), anti-HCV(-).RESULTS: The total expressive levels of mlL-2R before andafter stimulation with PHA(0.03 ± 0.01, 0.03 ± 0.02, 0.04 ± 0.02, 0.36±0.03), and Tcell subsets in PBMC (0.62±0.06,0.37 ± 0.05, 0.35 ± 0.07) were all lower in patients withhepatitis C than those in normal controls (0.66 ± 0.07, 0.41± 0.06, 0.31 ± 0.05, P < 0.01 ). Among the patients, thelevels of mlL-2R were lower in silence than those in situationof PHA inducting (P< 0.01). However, the levels of mlL-2Rwere similar in acute hepatitis C to that in chronic hepatitis C(P>0.05). The levels of CD3+, CD4+, CD4 +/CD8+ Were lov erand CD8 + was higher in patients with acute and chronichepatitis C with anti-HCV( + ) than those in normal controls (0.62±0.06, 0.37±0.05, 0.35±0.07, 1.18±0.30, 0.61±0.07, 0.37±0.05, 1.39±0.33, 0.31±0.05, P<0.05-P<0.01).CONCLUSION: The cellular immunity is obviously changed inpatients with hepatitis C. The levels of mlL-2R end activationof T cells am closely associated with chronicity of hepatitis C.

  17. IL-2 induces pulmonary edema and vasoconstriction independent of circulating lymphocytes

    Energy Technology Data Exchange (ETDEWEB)

    Ferro, T.J.; Johnson, A.; Everitt, J.; Malik, A.B.

    1989-03-15

    We investigated the effect of IL-2 in the isolated guinea pig lung perfused with phosphate-buffered Ringer's solution (containing 0.5 g/100 ml albumin and 5.5 mM dextrose) to determine the mechanism of IL-2-induced pulmonary edema. IL-2 (0 to 10,000 U/ml) was added to the perfusate following a 10 min baseline steady-state period. Pulmonary arterial pressure (Ppa), pulmonary capillary pressure (Ppc), and change in lung weight (as a measure of developing pulmonary edema) were recorded at 0, 10, 30, 40, and 60 min. The capillary filtration coefficient (Kf.c), an index of vascular permeability to water, was measured at 30 and 60 min. Infusion of IL-2 increased Ppc (from 3.9 +/- 0.1 cm H2O at baseline to 8.8 +/- 1.1 cm H2O at 60 min for IL-2 at 2000 U/ml, p less than 0.01; and from 3.8 +/- 0.1 cm H2O at baseline to 8.9 +/- 0.6 cm H2O at 60 min for IL-2 at 10,000 U/ml, p less than 0.01. The lung weight also increased (32% at IL-2 concentration of 2000 U/ml, and 26% at IL-2 concentration of 10,000 U/ml) The capillary filtration coefficient did not change with IL-2 infusion. The IL-2 response was prevented using the pulmonary vasodilator, papaverine. The infusion of IL-2 was associated with the generation of thromboxane A2(TxA2) in the effluent perfusate. Inhibition of TxA2 synthetase using Dazoxiben prevented the pulmonary vasoconstriction and edema response to IL-2. In addition, IL-2 had no effect on the transendothelial clearance of 125I-albumin. The results indicate that IL-2 causes pulmonary edema secondary to an increase in Ppc. The response is mediated by IL-2 stimulation of TxA2 generation from the lung.

  18. KnockoutJS essentials

    CERN Document Server

    Ferrando, Jorge

    2015-01-01

    If you are a JavaScript developer who has been using DOM manipulation libraries such as Mootools or Scriptaculous, and you want go further in modern JavaScript development with a simple and well-documented library, then this book is for you. Learning how to use Knockout will be perfect as your next step towards building JavaScript applications that respond to user interaction.

  19. Some Surprising Introductory Physics Facts and Numbers

    Science.gov (United States)

    Mallmann, A. James

    2016-01-01

    In the entertainment world, people usually like, and find memorable, novels, short stories, and movies with surprise endings. This suggests that classroom teachers might want to present to their students examples of surprising facts associated with principles of physics. Possible benefits of finding surprising facts about principles of physics are…

  20. Dynamic changes of IL-2, sIL-2R, IL-6 and IL-8 in children with mycoplasma pneumonia and their clinical significance%肺炎支原体肺炎IL-2、sIL-2R、IL-6、IL-8检测

    Institute of Scientific and Technical Information of China (English)

    刘文彬; 赵文利; 汤雪琴; 袁丽

    2012-01-01

    目的 探讨肺炎支原体肺炎(MPP)急性期和恢复期免疫功能动态变化及临床意义.方法 检测IL-2、sIL-2R、IL-6、IL-8均采用ELISA双抗体夹心法.结果 与对照组比较,MPP患儿急性期sIL-2R、IL-6,IL-8值均明显升高(P<0.01),IL-2值均明显下降(P<0.01),与急性期比较,MPP患儿恢复期IL-2值均明显升高(P<0.01),而sIL-2R、IL-6、IL-8值均明显下降(P<0.01);与对照组比较,MPP患儿恢复期IL-2、sIL-2R、IL-6、IL-8均无明显改变(P>0.05).结论 MPP患儿存在细胞免疫功能低下及紊乱,IL-2、sIL-2R、IL-6及IL-8值恢复较快,检测MPP患儿免疫功能,特别是IL-2、sIL-2R、IL-6和IL-8水平对疗效及预后的判定有重要价值.%Objective To observe the dynamic changes of IL-2, sIL-2R, IL-6 and IL-8 in children with mycoplasma pneumonia( MPP) and to study their clinical significance. Methods The serum levels of IL-2, sIL-2R, IL-6 and IL-8 in 40 children with MPP during the acute stage and convalescent stage were examined with double-antibody sandwich enzyme-linked immu-nosobent assay, and the results were compared with those in 30 normal children. Results The levels of slL-2R, IL-6 and IL-8 were higher and IL-2 was lower during acute stage than those in the normal subjects (P <0. 01). Compared those during the convalescent stage, the level of IL-2 was higher and sIL-2R, IL-6 and IL-8 were lower (P <0. 01) during the acute stage. There were not any significant differences of the levels of these four substances between the normal children and MPP children during the convalescent stage. Conclusion The cellular immune function of children with MPP is impaired and the changes of IL-2, sIL-2R, IL-6 and IL-8 can be used to evaluate the curative effects and prognosis of MPP in children.

  1. Application of PHA, IL-2, PHA+IL-2 in cytogenetic study of chronic lymphocytic leukemia%PHA、IL-2和PHA/IL-2在慢性淋巴细胞性白血病染色体研究中的应用

    Institute of Scientific and Technical Information of China (English)

    李倩; 薛永权; 姜海燕; 潘金兰; 吴亚芳

    2004-01-01

    目的探讨植物血凝素(PHA)、白细胞介素2(IL-2)和PHA/IL-2作为有丝分裂原对提高慢性淋巴细胞性白血病(慢淋,CLL)有丝分裂相的数量及染色体异常检出率的价值.方法分别用PHA、IL-2和PHA+IL-2作为有丝分裂原,对25例CLL患者的外周血或骨髓细胞进行短期培养后,按常规收获并制备染色体标本,然后进行R显带核型分析.同时做美洲商陆(PWM)平行培养作为对照.比较各组的有丝分裂指数和异常核型的类型及其检出率.结果CLL经各种丝裂原刺激后,平均有丝分裂指数分别为:PWM 5.03‰,PHA 8.5‰,IL-2 5.33‰,PHA/IL-2 9.24‰;染色体异常核型检出率为:PWM 4%(1/25),PHA 32%(8/25),IL-2(8/25),PHA/IL-2 32%(8/25);染色体异常总检出率为44%(11/25).结论与PWM相比,PHA、IL-2和PHA+IL-2均可有效地刺激CLL白血病细胞分裂并提高其染色体异常检出率.

  2. IL-2 regulates SEB induced toxic shock syndrome in BALB/c mice.

    Directory of Open Access Journals (Sweden)

    Aslam Ali Khan

    Full Text Available BACKGROUND: Toxic Shock Syndrome (TSS is characterized by fever, rash, hypotension, constitutional symptoms, and multi-organ involvement and is caused by Staphylococcus aureus enterotoxins such as Staphylococcal Enterotoxin B (SEB. SEB binds to the MHC-IIalpha chain and is recognized by the TCRbeta chain of the Vbeta8 TCR(+ T cells. The binding of SEB to Vbeta chain results in rapid activation of T cells and production of inflammatory cytokines, such as Interleukin-2 (IL-2, Interferon-gamma and Tumor Necrosis Factor-alpha which mediate TSS. Although IL2 was originally identified as the T cell growth factor and was proposed to contribute to T cell differentiation, its role in TSS remains unexplored. METHODOLOGY/PRINCIPAL FINDINGS: Mice were injected with D-Gal (25 mg/mouse. One hour after D-Galactosamine (D-Gal injection each mouse was injected with SEB (20 microg/mouse. Mice were then observed for 72 hrs and death was recorded at different times. We tested Interleukin-12, IFNgamma, and IL-2 deficient mice (IL-2(-/-, but only the IL-2 deficient mice were resistant to SEB induced toxic shock syndrome. More importantly reconstitution of IL-2 in IL-2 deficient mice restored the shock. Interestingly, SEB induced IL-2 production from T cells was dependent on p38MAPK activation in macrophages as inhibition of it in macrophages significantly inhibited IL-2 production from T cells. CONCLUSION: This study shows the importance of IL -2 in TSS which has not been previously explored and it also shows that regulating macrophages function can regulate T cells and TSS.

  3. Young Galaxy's Magnetism Surprises Astronomers

    Science.gov (United States)

    2008-10-01

    Astronomers have made the first direct measurement of the magnetic field in a young, distant galaxy, and the result is a big surprise. Looking at a faraway protogalaxy seen as it was 6.5 billion years ago, the scientists measured a magnetic field at least 10 times stronger than that of our own Milky Way. They had expected just the opposite. The GBT Robert C. Byrd Green Bank Telescope CREDIT: NRAO/AUI/NSF The scientists made the discovery using the National Science Foundation's ultra-sensitive Robert C. Byrd Green Bank Telescope (GBT) in West Virginia. "This new measurement indicates that magnetic fields may play a more important role in the formation and evolution of galaxies than we have realized," said Arthur Wolfe, of the University of California-San Diego (UCSD). At its great distance, the protogalaxy is seen as it was when the Universe was about half its current age. According to the leading theory, cosmic magnetic fields are generated by the dynamos of rotating galaxies -- a process that would produce stronger fields with the passage of time. In this scenario, the magnetic fields should be weaker in the earlier Universe, not stronger. The new, direct magnetic-field measurement comes on the heels of a July report by Swiss and American astronomers who made indirect measurements that also implied strong magnetic fields in the early Universe. "Our results present a challenge to the dynamo model, but they do not rule it out," Wolfe said. There are other possible explanations for the strong magnetic field seen in the one protogalaxy Wolfe's team studied. "We may be seeing the field close to the central region of a massive galaxy, and we know such fields are stronger toward the centers of nearby galaxies. Also, the field we see may have been amplified by a shock wave caused by the collision of two galaxies," he said. The protogalaxy studied with the GBT, called DLA-3C286, consists of gas with little or no star formation occurring in it. The astronomers suspect that

  4. Superinduction of IL-2 gene transcription in the presence of cycloheximide.

    Science.gov (United States)

    Zubiaga, A M; Muñoz, E; Huber, B T

    1991-06-01

    Lymphokine production is regulated both at the transcriptional and the posttranscriptional level. To date, it has been shown that the protein synthesis inhibitor cycloheximide (CHX) up-regulates IL-2 expression in T cells by stabilizing its mRNA. In this report we have examined the effect of CHX on IL-2 at the transcriptional level. We have found that CHX has a positive regulatory function in IL-2 transcription, which is dependent on prior activation of this gene. This is not due to posttranslational conversion of inactive NFkB into its active form by CHX, because a clustered mutation in the kB-like sequence in the IL-2 enhancer that abrogates NFkB binding does not affect the up-regulation of IL-2 transcription. These results favor the hypothesis that, in addition to positive factors, negative elements regulate IL-2 transcription. Furthermore, we have tested the effect of CHX on IL-4 and granulocyte-macrophage-CSF transcription of both lymphokines. These results suggest that transcriptional up-regulation by CHX may be specific for IL-2 with respect to lymphokine expression.

  5. Cluster knockout reactions

    Indian Academy of Sciences (India)

    Arun K Jain; B N Joshi

    2014-04-01

    Cluster knockout reactions are expected to reveal the amount of clustering (such as that of , d and even of heavier clusters such as 12C, 16O etc.) in the target nucleus. In simple terms, incident medium high-energy nuclear projectile interacts strongly with the cluster (present in the target nucleus) as if it were existing as a free entity. Theoretically, the relatively softer interactions of the two outgoing particles with the residual nucleus lead to optical distortions and are treated in terms of distorted wave (DW) formalism. The long-range projectile–cluster interaction is accounted for, in terms of the finite range (FR) direct reaction formalism, as against the more commonly adopted zero-range (ZR) distorted wave impulse approximation (DWIA) formalism. Comparison of the DWIA calculations with the observed data provide information about the momentum distribution and the clustering spectroscopic factor of the target nucleus. Interesting results and some recent advancements in the area of (, 2) reactions and heavy cluster knockout reactions are discussed. Importance of the finite-range vertex and the final-state interactions are brought out.

  6. Dendritic cells control CD4+CD25+ Treg cell suppressor function in vitro through juxtacrine delivery of IL-2.

    Directory of Open Access Journals (Sweden)

    Katarina Kulhankova

    Full Text Available CD4(+CD25(+Foxp3(+ regulatory T cells (Tregs restrict inflammatory responses to self and nonself. Aberrant Treg activity is pathologic: Insufficient Treg activity is implicated in autoimmunity, allergy, and graft-versus-host-disease; overabundant activity is implicated in chronic infection and cancer. Tregs require IL-2 for their expansion and acquisition/execution of suppressor function; however, because Tregs cannot produce IL-2, they depend on IL-2 from an exogenous source. Until now, that IL-2 source had not been established. We asked whether dendritic cells (DCs could supply IL-2 to Tregs and, if so, what was required for that delivery. We used flow cytometry, IL-2 ELISPOT, RT-qPCR, and IL-2 promoter-driven reporter assays to measure intracytoplasmic IL-2, secreted protein, IL-2 message and IL-2 promoter activity in bone marrow-derived (BMDC and splenic DCs. We examined conjugate formation between Tregs, conventional CD4(+ cells, and IL-2-expressing DCs. We measured Treg levels of CD25, Foxp3, and suppressor function after co-culture with IL-2 sufficient and IL-2(-/- DCs. We generated IL-2-mCherry-expressing DCs and used epifluorescence microscopy and flow cytometry to track IL-2 transfer to Tregs and test requirements for transfer. Between 0.7 to 2.4% of DCs constitutively produced IL-2 and diverted IL-2 secretion to Tregs by preferentially forming conjugates with them. Uptake of DC IL-2 by Tregs required cell-cell contact and CD25. Tregs increased levels of CD25 and Foxp3 from baseline and showed greater suppressor function when co-cultured with IL-2-sufficient DCs, but not when co-cultured with IL-2(-/- DCs. Exogenous IL-2, added in excess of 500 U/ml to co-cultures with IL-2(-/- DCs, restored Treg suppressor function. These data support a model of juxtacrine delivery of IL-2 from DCs to Tregs and suggest that a subset of DCs modulates Treg function through controlled, spatial delivery of IL-2. Knowledge of how DCs regulate Tregs should

  7. Inability of a Fusion Protein of IL-2 and Diphtheria Toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to Eliminate Regulatory T Lymphocytes in Patients With Melanoma

    Science.gov (United States)

    Attia, Peter; Maker, Ajay V.; Haworth, Leah R.; Rogers-Freezer, Linda; Rosenberg, Steven A.

    2006-01-01

    Summary Elimination of regulatory T lymphocytes may provide a way to break self-tolerance and unleash the anti-tumor properties of circulating lymphocytes. The use of fusion proteins, which link cytotoxic molecules to receptor targets, provides one approach to this problem. This study examined the ability of a fusion protein of interleukin-2 (IL-2) and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes based on their expression of high-affinity IL-2 receptors. Thirteen patients (12 with metastatic melanoma, 1 with metastatic renal cell carcinoma) were treated at one of the two Food and Drug Administration–approved doses of Denileukin Diftitox (seven patients at 9 μg/kg, six patients at 18 μg/kg). None of the patients experienced an objective clinical response. Foxp3 expression did not decrease significantly overall, although it did decrease minimally among patients receiving 18 μg/kg (−2.01 ± 0.618 copies of Foxp3/103 copies of β-actin; P = 0.031). Denileukin Diftitox did not decrease the suppressive ability of CD4+CD25+ cells as quantified by an in vitro co-culture suppression assay. Furthermore, the increased numbers of lymphocytes in patients resulting from treatment with IL-2 were not susceptible to Denileukin Diftitox. Administration of Denileukin Diftitox does not appear to eliminate regulatory T lymphocytes or cause regression of metastatic melanoma. PMID:16224276

  8. Maintenance immunosuppression with intermittent intravenous IL-2 receptor antibody therapy in renal transplant recipients.

    LENUS (Irish Health Repository)

    Gabardi, Steven

    2011-09-01

    To report what we believe to be the first 2 cases of long-term (>24 months) intermittent intravenous interleukin-2 receptor antibody (IL-2RA) therapy for maintenance immunosuppression following renal transplantation.

  9. Resolving Early Signaling Events in T-Cell Activation Leading to IL-2 and FOXP3 Transcription

    Directory of Open Access Journals (Sweden)

    Jeffrey P. Perley

    2014-11-01

    Full Text Available Signal intensity and feedback regulation are known to be major factors in the signaling events stemming from the T-cell receptor (TCR and its various coreceptors, but the exact nature of these relationships remains in question. We present a mathematical model of the complex signaling network involved in T-cell activation with cross-talk between the Erk, calcium, PKC and mTOR signaling pathways. The model parameters are adjusted to fit new and published data on TCR trafficking, Zap70, calcium, Erk and Isignaling. The regulation of the early signaling events by phosphatases, CD45 and SHP1, and the TCR dynamics are critical to determining the behavior of the model. Additional model corroboration is provided through quantitative and qualitative agreement with experimental data collected under different stimulating and knockout conditions. The resulting model is analyzed to investigate how signal intensity and feedback regulation affect TCR- and coreceptor-mediated signal transduction and their downstream transcriptional profiles to predict the outcome for a variety of stimulatory and knockdown experiments. Analysis of the model shows that: (1 SHP1 negative feedback is necessary for preventing hyperactivity in TCR signaling; (2 CD45 is required for TCR signaling, but also partially suppresses it at high expression levels; and (3 elevated FOXP3 and reduced IL-2 signaling, an expression profile often associated with T regulatory cells (Tregs, is observed when the system is subjected to weak TCR and CD28 costimulation or a severe reduction in CD45 activity.

  10. Evaluative Appraisals of Environmental Mystery and Surprise

    Science.gov (United States)

    Nasar, Jack L.; Cubukcu, Ebru

    2011-01-01

    This study used a desktop virtual environment (VE) of 15 large-scale residential streets to test the effects of environmental mystery and surprise on response. In theory, mystery and surprise should increase interest and visual appeal. For each VE, participants walked through an approach street and turned right onto a post-turn street. We designed…

  11. Evaluative Appraisals of Environmental Mystery and Surprise

    Science.gov (United States)

    Nasar, Jack L.; Cubukcu, Ebru

    2011-01-01

    This study used a desktop virtual environment (VE) of 15 large-scale residential streets to test the effects of environmental mystery and surprise on response. In theory, mystery and surprise should increase interest and visual appeal. For each VE, participants walked through an approach street and turned right onto a post-turn street. We designed…

  12. Analyst Information Precision and Small Earnings Surprises

    NARCIS (Netherlands)

    S. Bissessur; D. Veenman

    2014-01-01

    Prior research attributes zero and small positive earnings surprises to managers’ incentives for earnings management. In contrast, this study introduces and empirically tests an explanation for zero and small positive earnings surprises based on predictable variation in analyst forecast errors. We a

  13. Cognitive and Social Perspectives on Surprise

    Science.gov (United States)

    Adhami, Mundler

    2007-01-01

    Meanings of "surprise" are wide and include uplifting and engaging facets like wonder and amazement on the one hand as well as ones that may be of the opposite nature like interruption and disrupt on the other. Pedagogically, educators who use surprise in class activities are focusing on students being "taken aback" by a situation, hopefully…

  14. Contrasting genetic association of IL2RA with SLE and ANCA – associated vasculitis

    Directory of Open Access Journals (Sweden)

    Todd John A

    2009-03-01

    Full Text Available Abstract Background Autoimmune diseases are complex and have genetic and environmental susceptibility factors. The objective was to test the genetic association of systemic lupus erythematosus (SLE and anti-neutrophil cytoplasmic antibody (ANCA – associated systemic vasculitis (AAV with SNPs in the IL2RA region and to correlate genotype with serum levels of IL-2RA. Methods Using a cohort of over 700 AAV patients, two SLE case-control studies and an SLE trio collection (totalling over 1000 SLE patients, and a TaqMan genotyping approach, we tested 3 SNPs in the IL2RA locus, rs11594656, rs2104286 & rs41295061, each with a prior association with autoimmune disease; rs11594656 and rs41295061 with type 1 diabetes (T1D and rs2104286 with multiple sclerosis (MS and T1D. Results We show that SLE is associated with rs11594656 (P = 3.87 × 10-7 and there is some evidence of association of rs41295061 with AAV (P = 0.0122, which both have prior association with T1D. rs2104286, an MS and T1D – associated SNP in the IL2RA locus, is not associated with either SLE or AAV. Conclusion We have confirmed a previous suggestion that the IL2RA locus is associated with SLE and showed some evidence of association with AAV. Soluble IL-2RA concentrations correlate with rs11594656 genotype in quiescent disease in both AAV and SLE. Differential association of autoimmune diseases and SNPs within the IL2RA locus suggests that the IL2RA pathway may prove to play differing, as yet undefined, roles in each disease.

  15. PDI-, PPI- and chaperone-catalyzed refolding of recombinant human IL-2 and GM-CSF

    Institute of Scientific and Technical Information of China (English)

    徐明波; 孟文华; 马贤凯

    1995-01-01

    The studies on PDI-, PP1- and chaperone-catalyzed refolding of recombinant human IL-2 and GM-CSF show that PDI can prevent the mismatch of disalfide bonds and formation of aggregates by interchains linkage, furthermore, PDI can correct, the mismatching of disulflde bonds in IL-2 isomers. PPI can increase the rate of folding reaction while chaperone can prevent the aggregation during the folding process. In addition, there is a synergistic effect between them.

  16. Assay of sIL-2R and TNF-α in experimental allergic encephalomyelitis

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective: To investigate the change and effect of sIL-2R and TNF-α in the immunopathogenesis of experimental allergic encephalomyelitis(EAE). Methods: The EAE model was induced in guinea pigs. And the EAE animals were killed on the 8th, 15th and 22nd day after the MBP+CFA challenge. ConA-treated guinea pig spleen cells were cultured and supernatants were collected. The level of sIL-2R in supernatant was detected by ELISA, and the level of TNF-α in EAE was examined by biologic assay. Results: The EAE animals showed higher levels of sIL-2R and TNF-α than those of the normal control group. Conclusion: sIL-2R and TNF-α play an important role in the immunopathogenesis of EAE. This experiment offered thoretical evidence for further study of multiple sclerosis(MS) on pathogenesis and gave the clues for clinical use of immunospecific agents on MS.%目的:研究sIL-2R和TNF-α在实验性变态反应性脑脊髓炎(EAE)免疫发病机制中的变化与作用.方法:应用豚鼠诱导EAE动物模型.在MBP+CFA免疫豚鼠的第8、15、22天处死动物,取脾细胞,加入ConA诱生培养,收集上清液,采用ELISA方法测定sIL-2R水平,采用生物活性测定法检测TNF-α水平.结果:EAE组的sIL-2R与TNF-α水平明显高于正常对照组.结论:sIL-2R及TNF-α在EAE免疫发病机制中具有重要作用.

  17. SODIUM POLYPRENYL PHOSPHATE (PHOSPRENYL EXERTS AN IL-2-DEPENDENT RESTORATIVE EFFECT UPON IN VIVO DTH INHIBITION

    Directory of Open Access Journals (Sweden)

    S. M. Sobolev

    2012-01-01

    Full Text Available Abstract. We have shown that polyprenyl phosphate (phosprenyl competes with interleukin 2 for binding with serum γ-globulin. It was also demonstrated that phosprenyl restores delayed type hypersensitivity induced by Listeria monocytogenes, after its inhibition with a γ-globulin which binds to IL-2 and blocks its activity. A role of serum γ-globulin and Phosprenyl in regulation of IL-2-dependent processes is discussed.

  18. Ets-1 facilitates nuclear entry of NFAT proteins and their recruitment to the IL-2 promoter.

    Science.gov (United States)

    Tsao, Hsiao-Wei; Tai, Tzong-Shyuan; Tseng, William; Chang, Hui-Hsin; Grenningloh, Roland; Miaw, Shi-Chuen; Ho, I-Cheng

    2013-09-24

    E26 transformation-specific sequence 1 (Ets-1), the prototype of the ETS family of transcription factors, is critical for the expression of IL-2 by murine Th cells; however, its mechanism of action is still unclear. Here we show that Ets-1 is also essential for optimal production of IL-2 by primary human Th cells. Although Ets-1 negatively regulates the expression of Blimp1, a known suppressor of IL-2 expression, ablation of B lymphocyte-induced maturation protein 1 (Blimp1) does not rescue the expression of IL-2 by Ets-1-deficient Th cells. Instead, Ets-1 physically and functionally interacts with the nuclear factor of activated T-cells (NFAT) and is required for the recruitment of NFAT to the IL-2 promoter. In addition, Ets-1 is located in both the nucleus and cytoplasm of resting Th cells. Nuclear Ets-1 quickly exits the nucleus in response to calcium-dependent signals and competes with NFAT proteins for binding to protein components of noncoding RNA repressor of NFAT complex (NRON), which serves as a cytoplasmic trap for phosphorylated NFAT proteins. This nuclear exit of Ets-1 precedes rapid nuclear entry of NFAT and Ets-1 deficiency results in impaired nuclear entry, but not dephosphorylation, of NFAT proteins. Thus, Ets-1 promotes the expression of IL-2 by modulating the activity of NFAT.

  19. Loss of immune tolerance to IL-2 in type 1 diabetes

    Science.gov (United States)

    Pérol, Louis; Lindner, John M.; Caudana, Pamela; Nunez, Nicolas Gonzalo; Baeyens, Audrey; Valle, Andrea; Sedlik, Christine; Loirat, Delphine; Boyer, Olivier; Créange, Alain; Cohen, José Laurent; Rogner, Ute Christine; Yamanouchi, Jun; Marchant, Martine; Leber, Xavier Charles; Scharenberg, Meike; Gagnerault, Marie-Claude; Mallone, Roberto; Battaglia, Manuela; Santamaria, Pere; Hartemann, Agnès; Traggiai, Elisabetta; Piaggio, Eliane

    2016-01-01

    Type 1 diabetes (T1D) is characterized by a chronic, progressive autoimmune attack against pancreas-specific antigens, effecting the destruction of insulin-producing β-cells. Here we show interleukin-2 (IL-2) is a non-pancreatic autoimmune target in T1D. Anti-IL-2 autoantibodies, as well as T cells specific for a single orthologous epitope of IL-2, are present in the peripheral blood of non-obese diabetic (NOD) mice and patients with T1D. In NOD mice, the generation of anti-IL-2 autoantibodies is genetically determined and their titre increases with age and disease onset. In T1D patients, circulating IgG memory B cells specific for IL-2 or insulin are present at similar frequencies. Anti-IL-2 autoantibodies cloned from T1D patients demonstrate clonality, a high degree of somatic hypermutation and nanomolar affinities, indicating a germinal centre origin and underscoring the synergy between cognate autoreactive T and B cells leading to defective immune tolerance. PMID:27708334

  20. The protective efficacy of chimeric SO7/IL-2 DNA vaccine against coccidiosis in chickens.

    Science.gov (United States)

    Song, Hongyan; Qiu, Baofeng; Yan, Ruofeng; Xu, Lixin; Song, Xiaokai; Li, Xiangrui

    2013-06-01

    The protective efficacy of recombinant vaccines encoding an Eimeria refractile body antigen SO7 was assessed in broiler chickens following oral infection with Eimeria tenella. The SO7 and chicken IL-2 genes were cloned into the expression vector pVAX1 consecutively to construct DNA vaccines pVAX-SO7 and pVAX-SO7-IL-2. Expression of SO7 and IL-2 gene transcripts and proteins encoded by the plasmid DNAs in vivo was detected by reverse transcription-polymerase chain reaction and Western blot. Chickens were inoculated with 100 μg of plasmids pVAX-SO7 or pVAX-SO7-IL-2, or 200 μg of recombinant SO7 protein or chicken IL-2 protein by leg intramuscular injection. At 28days of age, all chickens except the unchallenged control group were challenged orally with 5×10(4) sporulated oocysts of E. tenella. All chickens were euthanized to determine the effects of immunization on the 7th day post-challenge. The results showed that both DNA vaccines containing the SO7 gene and the recombinant SO7 protein could obviously alleviate body weight loss and cecal lesions compared with unvaccinated and challenged control. These findings also suggested that chicken IL-2 could effectively enhance the immunity of SO7 against E. tenella challenge compared with vaccination using pVAX-SO7 alone. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. EXPRESSION OF IL-2 AND SIL-2R AND ALTERATION OF CELL IMMUNITY IN PATIENTS WITH HYPERTENSIVE CEREBRAL HEMORRHAGE

    Institute of Scientific and Technical Information of China (English)

    张越林; 邱曙东; 师蔚; 党小军

    2006-01-01

    Interleukin-2(IL-2),an i mportant cytokinewith the other name as T cell growth factor,func-tions to promote the mitosis of hymphocytes,cani mprove the power of killer cells and help the pro-duction of antibody on the condition that it is com-bined with the specific hyperaviditic IL-2Rintargetcells.The t wo kinds of IL-2R,membrane boundIL-2R(mIL-2R)and soluble IL-2R(sIL-2R),com-pete with each other to combine with IL-2and thenbecome i mmunosuppressant[1].The i mportance oferythrocytes and T cells in the defe...

  2. Bac-to-Bac杆状病毒表达系统在BHK细胞表达鼠IL-2蛋白的研究%Bac-to-Bac Baculovirus Expression System in IL-2 Protein of BHK

    Institute of Scientific and Technical Information of China (English)

    黄大林; 戴支凯; 王鑫; 李彬彬; 钟江

    2011-01-01

    目的:利用Bac-to-Bac杆状病毒表达系统在BHK细胞表达重组鼠白细胞介素(IL)-2蛋白.方法:用Flag标记鼠IL-2并加入真核细胞启动子CMV,构建重组质粒pFB-CMV-IL-2并予酶切和PCR鉴定;将鼠IL-2克隆入杆状病毒表达载体pFastBacDual中,将pFB-CMV-IL-2转化到含杆状病毒穿梭载体Bacmid的DH10Bac感受态菌中,筛选阳性克隆,获得重组杆状病毒载体Bacmid-pFB-CMV-IL-2,抽提质粒;用脂质体转染法将Bacmid-pFB-CMV-IL-2转染Sf9昆虫细胞包装病毒,收获重组杆状病毒,将构建病毒转导BHK细胞培养,用Western blot检测IL-2蛋白.结果:通过杆状病毒表达系统,在BHK细胞成功表达重组的鼠IL-2蛋白.结论:重组杆状病毒在真核细胞巾成功表达重组鼠IL-2蛋白.%Objective :To construct recombinant mouse IL-2 protein in BHK cells using Bac-to-Bac baculovirus expression system. Methods : The mouse IL-2 was marked by Flag, and joined the eukaryotic cell promoter CMV. The plasmid pFB-CMV-IL-2 was constructed to recombinant, restriction enzyme was used to digest, and was amplified by PCR. The mouse IL-2 was cloned into the baculovirus expression vector pFastBacDual and pFB-CMV-IL-2 was transformed into baculovirus shuttle vector containing the DH10Bac competent bacmid bacteria. The clones were recombinant baculovirus vector Bacmid-pFB-CMV-IL-2, extracted plasmid with Iiposome transfection method Bacmid-pFB-CMV-IL-2 transfected Sf9 insect cells packaging the virus, harvested recombinant baculovirus. A virus transduction of BHK cell culture was built using Western blot to detect the IL-2 protein. Results: By baculovirus expression system, mouse recombinant IL-2 protein was successfully expressed in BHK cells. Conclusion: Recombinant baculovirus was successfully expressed mouse IL-2 protein in eukaryotic cells.

  3. Production of an active anti-CD20-hIL-2 immunocytokine in Nicotiana benthamiana.

    Science.gov (United States)

    Marusic, Carla; Novelli, Flavia; Salzano, Anna M; Scaloni, Andrea; Benvenuto, Eugenio; Pioli, Claudio; Donini, Marcello

    2016-01-01

    Anti-CD20 murine or chimeric antibodies (Abs) have been used to treat non-Hodgkin lymphomas (NHLs) and other diseases characterized by overactive or dysfunctional B cells. Anti-CD20 Abs demonstrated to be effective in inducing regression of B-cell lymphomas, although in many cases patients relapse following treatment. A promising approach to improve the outcome of mAb therapy is the use of anti-CD20 antibodies to deliver cytokines to the tumour microenvironment. In particular, IL-2-based immunocytokines have shown enhanced antitumour activity in several preclinical studies. Here, we report on the engineering of an anti-CD20-human interleukin-2 (hIL-2) immunocytokine (2B8-Fc-hIL2) based on the C2B8 mAb (Rituximab) and the resulting ectopic expression in Nicotiana benthamiana. The scFv-Fc-engineered immunocytokine is fully assembled in plants with minor degradation products as assessed by SDS-PAGE and gel filtration. Purification yields using protein-A affinity chromatography were in the range of 15-20 mg/kg of fresh leaf weight (FW). Glycopeptide analysis confirmed the presence of a highly homogeneous plant-type glycosylation. 2B8-Fc-hIL2 and the cognate 2B8-Fc antibody, devoid of hIL-2, were assayed by flow cytometry on Daudi cells revealing a CD20 binding activity comparable to that of Rituximab and were effective in eliciting antibody-dependent cell-mediated cytotoxicity of human PBMC versus Daudi cells, demonstrating their functional integrity. In 2B8-Fc-hIL2, IL-2 accessibility and biological activity were verified by flow cytometry and cell proliferation assay. To our knowledge, this is the first example of a recombinant immunocytokine based on the therapeutic Rituximab antibody scaffold, whose expression in plants may be a valuable tool for NHLs treatment.

  4. A toolkit for detecting technical surprise.

    Energy Technology Data Exchange (ETDEWEB)

    Trahan, Michael Wayne; Foehse, Mark C.

    2010-10-01

    The detection of a scientific or technological surprise within a secretive country or institute is very difficult. The ability to detect such surprises would allow analysts to identify the capabilities that could be a military or economic threat to national security. Sandia's current approach utilizing ThreatView has been successful in revealing potential technological surprises. However, as data sets become larger, it becomes critical to use algorithms as filters along with the visualization environments. Our two-year LDRD had two primary goals. First, we developed a tool, a Self-Organizing Map (SOM), to extend ThreatView and improve our understanding of the issues involved in working with textual data sets. Second, we developed a toolkit for detecting indicators of technical surprise in textual data sets. Our toolkit has been successfully used to perform technology assessments for the Science & Technology Intelligence (S&TI) program.

  5. Deciphering network community structure by surprise

    National Research Council Canada - National Science Library

    Aldecoa, Rodrigo; Marín, Ignacio

    2011-01-01

    .... A fundamental, unsolved problem is how to characterize the community structure of a network. Here, using both standard and novel benchmarks, we show that maximization of a simple global parameter, which we call Surprise...

  6. A Surprising Culprit Behind Celiac Disease?

    Science.gov (United States)

    ... news/fullstory_164503.html A Surprising Culprit Behind Celiac Disease? Study suggests harmless viruses may set stage ... typically harmless type of virus might sometimes trigger celiac disease, a new study suggests. Celiac disease is ...

  7. Relationship Between Cysteine, Interleukin (Il-2, and Interleukin (Il-10 in Children with Marasmus Type Malnutrition

    Directory of Open Access Journals (Sweden)

    Teguh Wahyudi

    2016-04-01

    Full Text Available Malnutrition is one of the health issues in developing countries. The most commonly found malnutrition is the marasmus type. Infection in marasmus patient is the main cause of morbidity and mortality in developing countries. In marasmus, there is a decrease in protein level such as cysteine which is one of the glutathione forming components that plays a significant role in immune system. In malnutrition, there is a disturbance of lymphocyte in the form of down-regulation of type 1 cytokine (IL-2 and IFN-γ and up-regulation of type 2 cytokine (IL-4 and IL-10. IL-2 is needed for the development of regulatory T produced by thymus and for NK cell cytotoxicity which plays a role in infection process, while IL-10 inhibits activation of lymphocyte T so the cellular immunity reaction ends. Several studies about the relationship between cysteine, IL-2, and IL-10 have been done in malnutrition-patients, but there is no study focusing on patients with marasmus. This study is to find out the relationship between cysteine, IL-2, and IL-10 in patients with marasmus type malnutrition. This study was an observational analytic study using cross-sectional design consisting of 20 children with marasmus type malnutrition and 20 well-nourished children treated in Saiful Anwar Hospital Malang. The cysteine, IL-2, and IL-10 level then measured using Elisa method. Normality and the various test were done. The Pearson correlation test was done to find out the relationship between cysteine and IL-2 level, cysteine and IL-10 level, and IL-2 and IL-10. The standard of cysteine and IL-2 level in children with marasmus is significantly lower than the control group, which was 1.616 ± 1.039 vs 3.298 ± 0.519 pg/mL; p = 0.000 dan 12.38±4.94 vs. 16.58 ± 4.80 pg/mL; p = 0.010, respectively. IL-10 in children with marasmus was significantly higher than control group (19.08± 5.93 vs 10.46 ± 3.90 pg/mL; p = 0.000. The cysteine level was positively correlated to the IL-2 level

  8. Serum sIL-2R, TNF-α and IFN-γ in alveolar echinococcosis

    Institute of Scientific and Technical Information of China (English)

    Da-Zhong Shi; Fu-Rong Li; B Bartholomot; DA Vuitton; PS Craig

    2004-01-01

    AIM: To approach the relationship between alveolar echinococcosis (AE) pathology and level of sIL-2R,TNF-αand IFN-γ in sera and the significance of cytokines in development of AE.METHODS: After 23 patients with AE were confirmed by ELISA and ultrasound, their sera were collected and the concentrations of sIL-2R,TNF-α and IFN-γ were detected by double antibody sandwich. Twelve healthy adults served as controls. According to the status of livers of AE patients by ultrasound scanning, they were divided into 4 groups: P2,P3, P4 groups and C group (control). Average of concentrations of sIL-2R, TNF-α and IFN-yin homologous group was statistically analyzed by both ANOV and Newman-Keuls, respectively.RESULTS: The mean of sIL-2R in P2 group was 97±29, P3:226±80, P4:194±23 and control group (111±30)x103 u/L(P0.05).CONCLUSION:Low sIL-2R level indicates an early stage of AE or stable status, per contra, a progression stage. Higher level of TNF-α might be related to the lesion of liver. The role of single IFN-y is limited in immunological defense against AE and it can not fully block pathological progression.

  9. Competition for IL-2 between regulatory and effector T cells to chisel immune responses

    Directory of Open Access Journals (Sweden)

    Thomas eHöfer

    2012-09-01

    Full Text Available In this review we discuss how the competition for cytokines between different cells of the immune system can shape the system wide immune response. We focus on interleukin-2 (IL-2 secretion by activated effector T cells (Teff and on the competition for IL-2 consumption between Teff and regulatory T cells (Treg. We discuss the evidence for the mechanism in which the depletion of IL-2 by Treg cells would be sufficient to suppress an autoimmune response, yet not strong enough to prevent an immune response. We present quantitative estimations and summarize our modeling effort to show that the tug-of-war between Treg and Teff cells for IL-2 molecules can be won by Treg cells in the case of weak activation of Teff leading to the suppression of the immune response. Or, for strongly activated Teff cells, it can be won by Teff cells bringing about the activation of the whole adaptive immune system. Finally, we discuss some recent applications attempting to achieve clinical effects through the modulation of IL-2 consumption by Treg compartment.

  10. Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus.

    Science.gov (United States)

    Humrich, Jens Y; Morbach, Henner; Undeutsch, Reinmar; Enghard, Philipp; Rosenberger, Stefan; Weigert, Olivia; Kloke, Lutz; Heimann, Juliane; Gaber, Timo; Brandenburg, Susan; Scheffold, Alexander; Huehn, Jochen; Radbruch, Andreas; Burmester, Gerd-Rüdiger; Riemekasten, Gabriela

    2010-01-05

    The origins and consequences of a regulatory T cell (Treg) disorder in systemic lupus erythematosus (SLE) are poorly understood. In the (NZBxNZW) F(1) mouse model of lupus, we found that CD4(+)Foxp3(+) Treg failed to maintain a competitive pool size in the peripheral lymphoid organs resulting in a progressive homeostatic imbalance of CD4(+)Foxp3(+) Treg and CD4(+)Foxp3(-) conventional T cells (Tcon). In addition, Treg acquired phenotypic changes that are reminiscent of IL-2 deficiency concomitantly to a progressive decline in IL-2-producing Tcon and an increase in activated, IFN-gamma-producing effector Tcon. Nonetheless, Treg from lupus-prone mice were functionally intact and capable to influence the course of disease. Systemic reduction of IL-2 levels early in disease promoted Tcon hyperactivity, induced the imbalance of Treg and effector Tcon, and strongly accelerated disease progression. In contrast, administration of IL-2 partially restored the balance of Treg and effector Tcon by promoting the homeostatic proliferation of endogenous Treg and impeded the progression of established disease. Thus, an acquired and self-amplifying disruption of the Treg-IL-2 axis contributed essentially to Tcon hyperactivity and the development of murine lupus. The reversibility of this homeostatic Treg disorder provides promising approaches for the treatment of SLE.

  11. 表达IL-2的重组非复制型痘苗病毒的构建及活性检测%Construction and bioactivity detection of a recombinant non-replicating vaccinia virus expressing IL-2

    Institute of Scientific and Technical Information of China (English)

    阳静; 庞聪; 任皎; 赵莉; 王平兴; 阮力; 谭文杰; 田厚文; 让蔚清

    2015-01-01

    Objective To generate a recombinant non-replicating vaccinia virus expressing IL-2 and detect its bioactivity in vitro.Methods Based on the non-replicating vaccinia virus (Tiantan strain) vectors,recombinant virus rNTV1175IL2H6LacZ which expressed IL-2 was constructed through homologous recombination and purified by blue-white screening.Then objective gene and protein expression was identified and the bioactivity of objective protein in vitro was detected.Results Recombinant virus was identified by PCR and Western Blot indicating that IL-2 gene with 51 1bp was correctly inserted downstream TK promoter and the molecular weight of IL-2 expressed by recombinant virus rNTV1175IL2H6LacZ was about 15000 in accordance with the molecular weight of standard IL-2.The IL-2 in the culture supernatants which was secreted by CEF with rNTV1175IL2H6LacZ promoted the growth of IL-2-dependent CTLL-2 cell lines,and the biological activity was 8.79 IU/ml measured by MTT method.Conclusion Recombinant non-replicating vaccinia virus rNTV1175IL2H6LacZ could express IL-2 with biological activity in CEF.It lay the foundation of adjust research and benefited the application of IL-2 in the field of biotherapy.%目的 构建表达IL-2的重组非复制型痘苗病毒株并体外检测其生物活性.方法 以非复制型痘苗病毒天坛株为载体,通过同源重组、蓝白斑纯化筛选表达IL-2的非复制型重组痘苗病毒rNTV1175IL2H6LacZ,并通过PCR对其进行IL-2基因插入鉴定,Western Blot鉴定IL-2的表达,同时对其进行体外生物活性检测.结果 经PCR鉴定,痘苗病毒TK区7.5启动子下正确插入了IL-2基因511bp,Western Blot结果表明其表达IL-2蛋白相对分子质量大小为15000,与标准品IL-2一致.rNTV1175 IL2H6LacZ分泌表达在细胞培养液中的IL-2能使IL-2依赖CTLL-2细胞株生长,MTT法测得重组病毒表达在细胞培养液中的IL-2生物活性值为8.79 IU/ml.结论 成功构建了表达具有生物活性IL-2的重组非

  12. Efficient genetic manipulation of the NOD-Rag1-/-IL2RgammaC-null mouse by combining in vitro fertilization and CRISPR/Cas9 technology.

    Science.gov (United States)

    Li, Feng; Cowley, Dale O; Banner, Debra; Holle, Eric; Zhang, Liguo; Su, Lishan

    2014-06-17

    Humanized mouse models have become increasingly important and widely used in modeling human diseases in biomedical research. Immunodeficient mice such as NOD-Rag1-/-IL2RgammaC-null (NRG) or NOD-SCID-IL2RgammaC-null (NSG) mice are critical for efficient engraftment of human cells or tissues. However, their genetic modification remains challenging due to a lack of embryonic stem cells and difficulty in the collection of timed embryos after superovulation. Here, we report the generation of gene knockout NRG mice by combining in vitro fertilization (IVF) and CRISPR/Cas9 technology. Sufficient numbers of fertilized embryos were produced through IVF, and a high rate of Fah gene targeting was achieved with microinjection of Cas9 mRNA, gRNA and single strand oligonucleotide DNA (ssDNA) into the embryos. The technology paves the way to construct NRG or NSG mutant mice to facilitate new humanized mouse models. The technology can also be readily adapted to introduce mutations in other species such as swine and non-human primates.

  13. Effects of intermittent IL-2 alone or with peri-cycle antiretroviral therapy in early HIV infection: the STALWART study

    DEFF Research Database (Denmark)

    Tavel, Jorge A; Babiker, Abdel; Fox, Lawrence;

    2010-01-01

    BACKGROUND: The Study of Aldesleukin with and without antiretroviral therapy (STALWART) evaluated whether intermittent interleukin-2 (IL-2) alone or with antiretroviral therapy (ART) around IL-2 cycles increased CD4(+) counts compared to no therapy. METHODOLOGY: Participants not on continuous ART...... with > or = 300 CD4(+) cells/mm(3) were randomized to: no treatment; IL-2 for 5 consecutive days every 8 weeks for 3 cycles; or the same IL-2 regimen with 10 days of ART administered around each IL-2 cycle. CD4(+) counts, HIV RNA, and HIV progression events were collected monthly. PRINCIPAL FINDINGS: A total...... of 267 participants were randomized. At week 32, the mean CD4(+) count was 134 cells greater in the IL-2 alone group (ptherapy group. Twelve participants in the IL-2 groups compared to 1 participant in the group...

  14. CLONING AND EXPRESSION OF THE GENE CODING FOR IL-2 (60)-PE40, A MOLECULAR TARGETED PROTEIN

    Institute of Scientific and Technical Information of China (English)

    张萌; 赵雪; 李焕娄; 卢圣栋

    1995-01-01

    It has recently been shown that chimeric toxin composed of IL2 fused tp PE40,a mutant form of Pseu-domonas Exotoxin A devoid of its native cell recognition and binding domain was cytotoxic to IL-2 receptor bearing cells.We here amplified the gene IL-2 (60),which codes for the N-terminal 1-60 amino acids of human IL-2 by PCR.After that,we fused it to PE40 and the new chimteric protein IL-2 (60)-PE40 was expressed in E.coli.SDS-PAGE revealed that IL-2(60)-PE40 chimeric protein accounts for more than 18% of total cell proteins.As the region IL-2 binds with its receptor was defined in the N-terminal residuse 8-54 of IL-2,such fusion proteins will have the same activity with IL-2-PE40.Following primany purification,IL-2(60)-PE40 was shown to be very toxic to IL-2 receptor-positive cells but non measurable effect on the cells lacking IL-2 receptors.Such a structure has not been reported by now.The fusion pro-tein is useful for suppressing the immune response in cases of rejection of allografts and organ transplants and as therapeutic agents for the treatment of IL-2 receptor related diseases such as autoimmune disease,and as therapeutic agents for the treatment of IL-2 receptor related diseases such as autoimmune disease,ATL(adult T-cell leukemia),et al.

  15. β-cell-specific IL-2 therapy increases islet Foxp3+Treg and suppresses type 1 diabetes in NOD mice.

    Science.gov (United States)

    Johnson, Mark C; Garland, Alaina L; Nicolson, Sarah C; Li, Chengwen; Samulski, R Jude; Wang, Bo; Tisch, Roland

    2013-11-01

    Interleukin-2 (IL-2) is a critical cytokine for the homeostasis and function of forkhead box p3-expressing regulatory T cells (Foxp3(+)Tregs). Dysregulation of the IL-2-IL-2 receptor axis is associated with aberrant Foxp3(+)Tregs and T cell-mediated autoimmune diseases such as type 1 diabetes. Treatment with recombinant IL-2 has been reported to enhance Foxp3(+)Tregs and suppress different models of autoimmunity. However, efficacy of IL-2 therapy is dependent on achieving sufficient levels of IL-2 to boost tissue-resident Foxp3(+)Tregs while avoiding the potential toxic effects of systemic IL-2. With this in mind, adeno-associated virus (AAV) vector gene delivery was used to localize IL-2 expression to the islets of NOD mice. Injection of a double-stranded AAV vector encoding IL-2 driven by a mouse insulin promoter (dsAAVmIP-IL2) increased Foxp3(+)Tregs in the islets but not the draining pancreatic lymph nodes. Islet Foxp3(+)Tregs in dsAAVmIP-IL2-treated NOD mice exhibited enhanced fitness marked by increased expression of Bcl-2, proliferation, and suppressor function. In contrast, ectopic IL-2 had no significant effect on conventional islet-infiltrating effector T cells. Notably, β-cell-specific IL-2 expression suppressed late preclinical type 1 diabetes in NOD mice. Collectively, these findings demonstrate that β-cell-specific IL-2 expands an islet-resident Foxp3(+)Tregs pool that effectively suppresses ongoing type 1 diabetes long term.

  16. Trans-active factors controlling the IL-2 gene in adult human T-cell subsets

    Directory of Open Access Journals (Sweden)

    A. Mouzaki

    1992-01-01

    Full Text Available IL-2 secretion in total or subsets of PHA/PMA-stimulated PBMC-derived human T-lymphocytes was monitored and found to be largely due to CD4+CD8− cells. The presence and functional state of transcription factors (TF was assessed by protein-DNA interaction assays and functional transactivation experiments in the Xenopts oocyte system, modulating IL-2 transcription by injection of proteins. The results reveal that CD4+CD8− cells contain both, functional silencer in their resting, and positive TF in their activated states while the CD4+CD8− group contains only non-functional positive TF. This demonstrates that the on/off switch of IL-2 transcription is based on the same mechanism in primary T-lymphocytes of mouse spleen and in peripheral human CD4+CD8− cells.

  17. Family based association analysis of the IL2 and IL15 genes in allergic disorders

    DEFF Research Database (Denmark)

    Christensen, Ulla; Haagerup, Annette; Binderup, Helle G;

    2006-01-01

    (4q27). IL15 is located approximately 20 Mb distal to IL2. The two genes encode cytokines that are structurally and functionally related, both inducing T-cell activation and proliferation. We screened the two genes for sequence variation and applied the seven single-nucleotide polymorphisms (SNPs...... both separately and in haplotypes with several atopic phenotypes, most significantly with IgE-mediated allergy. (single SNP P-value 0.0005 for positive skin prick test, haplotype P-value 0.019 for positive RAST test). To our knowledge, this is the first study reporting association between IL2 and Ig...

  18. Nuclear Phosphoproteomic Screen Uncovers ACLY as Mediator of IL-2-induced Proliferation of CD4+ T lymphocytes.

    Science.gov (United States)

    Osinalde, Nerea; Mitxelena, Jone; Sánchez-Quiles, Virginia; Akimov, Vyacheslav; Aloria, Kerman; Arizmendi, Jesus M; Zubiaga, Ana M; Blagoev, Blagoy; Kratchmarova, Irina

    2016-06-01

    Anti-cancer immunotherapies commonly rely on the use of interleukin-2 (IL-2) to promote the expansion of T lymphocytes. IL-2- dependent proliferation is the culmination of a complex network of phosphorylation-driven signaling events that impact on gene transcription through mechanisms that are not clearly understood. To study the role of IL-2 in the regulation of nuclear protein function we have performed an unbiased mass spectrometry-based study of the nuclear phosphoproteome of resting and IL-2-treated CD4(+) T lymphocytes. We detected 8521distinct phosphosites including many that are not yet reported in curated phosphorylation databases. Although most phosphorylation sites remained unaffected upon IL-2 treatment, 391 sites corresponding to 288 gene products showed robust IL-2-dependent regulation. Importantly, we show that ATP-citrate lyase (ACLY) is a key phosphoprotein effector of IL-2-mediated T-cell responses. ACLY becomes phosphorylated on serine 455 in T lymphocytes upon IL-2-driven activation of AKT, and depletion or inactivation of ACLY compromises IL-2-promoted T-cell growth. Mechanistically, we demonstrate that ACLY is required for enhancing histone acetylation levels and inducing the expression of cell cycle regulating genes in response to IL-2. Thus, the metabolic enzyme ACLY emerges as a bridge between cytokine signaling and proliferation of T lymphocytes, and may be an attractive candidate target for the development of more efficient anti-cancer immunotherapies.

  19. Activation of the IL-2 Receptor in Podocytes: A Potential Mechanism for Podocyte Injury in Idiopathic Nephrotic Syndrome?

    Science.gov (United States)

    Zea, Arnold H.; Stewart, Tyrus; Ascani, Jeannine; Tate, David J.; Finkel-Jimenez, Beatriz; Wilk, Anna; Reiss, Krzysztof; Smoyer, William E.; Aviles, Diego H.

    2016-01-01

    The renal podocyte plays an important role in maintaining the structural integrity of the glomerular basement membrane. We have previously reported that patients with idiopathic nephrotic syndrome (INS) have increased IL-2 production. We hypothesized that podocytes express an IL-2 receptor (IL-2R) and signaling through this receptor can result in podocyte injury. To confirm the presence of the IL-2R, we tested a conditionally immortalized murine podocyte cell line by flow cytometry, qPCR, and Western blot. To test for the presence of the IL-2R in vivo, immunohistochemical staining was performed on human renal biopsies in children with FSGS and control. Podocytes were stimulated with IL-2 in vitro, to study signaling events via the JAK/STAT pathway. The results showed that stimulation with IL-2 resulted in increased mRNA and protein expression of STAT 5a, phosphorylated STAT 5, JAK 3, and phosphorylated JAK 3. We then investigated for signs of cellular injury and the data showed that pro-apoptotic markers Bax and cFLIP were significantly increased following IL-2 exposure, whereas LC3 II was decreased. Furthermore, mitochondrial depolarization and apoptosis were both significantly increased following activation of the IL-2R. We used a paracellular permeability assay to monitor the structural integrity of a podocyte monolayer following IL-2 exposure. The results showed that podocytes exposed to IL-2 have increased albumin leakage across the monolayer. We conclude that murine podocytes express the IL-2R, and that activation through the IL-2R results in podocyte injury. PMID:27389192

  20. Activation of the IL-2 Receptor in Podocytes: A Potential Mechanism for Podocyte Injury in Idiopathic Nephrotic Syndrome?

    Directory of Open Access Journals (Sweden)

    Arnold H Zea

    Full Text Available The renal podocyte plays an important role in maintaining the structural integrity of the glomerular basement membrane. We have previously reported that patients with idiopathic nephrotic syndrome (INS have increased IL-2 production. We hypothesized that podocytes express an IL-2 receptor (IL-2R and signaling through this receptor can result in podocyte injury. To confirm the presence of the IL-2R, we tested a conditionally immortalized murine podocyte cell line by flow cytometry, qPCR, and Western blot. To test for the presence of the IL-2R in vivo, immunohistochemical staining was performed on human renal biopsies in children with FSGS and control. Podocytes were stimulated with IL-2 in vitro, to study signaling events via the JAK/STAT pathway. The results showed that stimulation with IL-2 resulted in increased mRNA and protein expression of STAT 5a, phosphorylated STAT 5, JAK 3, and phosphorylated JAK 3. We then investigated for signs of cellular injury and the data showed that pro-apoptotic markers Bax and cFLIP were significantly increased following IL-2 exposure, whereas LC3 II was decreased. Furthermore, mitochondrial depolarization and apoptosis were both significantly increased following activation of the IL-2R. We used a paracellular permeability assay to monitor the structural integrity of a podocyte monolayer following IL-2 exposure. The results showed that podocytes exposed to IL-2 have increased albumin leakage across the monolayer. We conclude that murine podocytes express the IL-2R, and that activation through the IL-2R results in podocyte injury.

  1. Surprises in numerical expressions of physical constants

    CERN Document Server

    Amir, Ariel; Tokieda, Tadashi

    2016-01-01

    In science, as in life, `surprises' can be adequately appreciated only in the presence of a null model, what we expect a priori. In physics, theories sometimes express the values of dimensionless physical constants as combinations of mathematical constants like pi or e. The inverse problem also arises, whereby the measured value of a physical constant admits a `surprisingly' simple approximation in terms of well-known mathematical constants. Can we estimate the probability for this to be a mere coincidence, rather than an inkling of some theory? We answer the question in the most naive form.

  2. Association of IL-2RA/CD25 with type 1 diabetes in the Belgian population

    NARCIS (Netherlands)

    Aminkeng, Folefac; Weets, Ilse; Van Autreve, Jan E.; Koeleman, Bobby P. C.; Quartier, Erik; Van Schravendijk, Chris; Gorus, Frans K.; Van der Auwera, Bart J. R.

    2010-01-01

    Our goals were to study the proposed association of IL-2RA /CD25 with type 1 diabetes in the Belgian population over a broad age range and to explore possible correlations with disease phenotypes immune markers HLA DQ INS and PTPN22 Patients (n = 1954) healthy controls (n = 2082) and families (n = 4

  3. The positive and negative control actions of PTPase on IL-2 signaling

    Institute of Scientific and Technical Information of China (English)

    朱锦芳; 季红斌; 鲁林荣; 郭丽英; 郑仲承; 刘新垣

    1999-01-01

    The tyrosine phosphorylation of intracellular proteins was greatly increased after the treatment of cells with sodium n-vanadate, the inhibitor of protein tyrosine phosphatase (PTPase) . It was found by using EMSA that during this period the signal transducer and activator of transcription 5 (STAT5) were tyrosine-phosphorylated and activated STAT5 may bind to ν-interferon activated sequence (GAS). Contrast to the activation of STATS by interleukin-2 (IL-2), the activation for STAT5 by sodium n-vanadate cannot be completely blocked by the inhibitor of protein tyrosine kinase (PTK). In addition, sodium n-vanadate may augment the IL-2 up-regulation on the expression of reporter genes containing GAS in their promoter regions. All the results here show that PTPase may negatively regulate the JAK-STAT signal transduction pathway induced by IL-2. However, the inhibition of PTPase activity may block the induction of tnf-β gene and c- myc gene transcription by IL-2 and ultimately results in cell death. Therefo

  4. Data of evolutionary structure change: 1D5IL-2GJJA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1D5IL-2GJJA 1D5I 2GJJ L A -DIKMTQSPSSMYASLGERVTITCKASQDIN------SY... 219 ALA CA 310 SER CA 336 2GJJ A 2GJJA PEVVKTGASVK 5.283660888671875 1 2GJJ... A 2GJJA RLEIK----RGEVQ

  5. Surprising Connections between Partitions and Divisors

    Science.gov (United States)

    Osler, Thomas J.; Hassen, Abdulkadir; Chandrupatla, Tirupathi R.

    2007-01-01

    The sum of the divisors of a positive integer is one of the most interesting concepts in multiplicative number theory, while the number of ways of expressing a number as a sum is a primary topic in additive number theory. In this article, we describe some of the surprising connections between and similarities of these two concepts.

  6. Surprises from extragalactic propagation of UHECRs

    CERN Document Server

    Boncioli, Denise; Grillo, Aurelio

    2015-01-01

    Ultra-high energy cosmic ray experimental data are now of very good statistical significance even in the region of the expected GZK feature. The identification of their sources requires sophisticate analysis of their propagation in the extragalactic space. When looking at the details of this propagation some unforeseen features emerge. We will discuss some of these "surprises".

  7. Local tumor irradiation augments the response to IL-2 therapy in a murine renal adenocarcinoma.

    Science.gov (United States)

    Younes, E; Haas, G P; Dezso, B; Ali, E; Maughan, R L; Kukuruga, M A; Montecillo, E; Pontes, J E; Hillman, G G

    1995-10-15

    We have previously demonstrated that local tumor irradiation effectively enhanced the therapeutic effect of IL-2 therapy on pulmonary metastases from a murine renal adenocarcinoma, Renca. Irradiation with 300 rad to the left lung only, followed by systemic IL-2 therapy, results in increased tumor reduction in both lungs, suggesting that radiation enhances the systemic effect of immunotherapy. In this study, we show that irradiation of the tumor-bearing organ is essential for the combined effect of both modalities. This effect is radiation dose-dependent as increases in the radiation dosage result in greater tumor reduction in the irradiated field as well as systemically in nonirradiated fields when combined with immunotherapy. We find that irradiation has a direct inhibitory effect on Renca cell growth in vitro. Irradiation of Renca cells also causes an upregulation in H-2Kd class I MHC antigen detectable at 300 rad and more pronounced with 800 rad. By in vivo selective depletion of lymphocyte subsets, we demonstrate the involvement of Lyt-2+ and L3T4+ T cell subsets and AsGM1+ cells, including NK cells, in the antitumor effect mediated by tumor irradiation and IL-2 therapy. Immunohistochemistry studies, performed on lung sections, showed a significant infiltration of CD3+ T cells and macrophages in the tumor nodules following treatment with tumor irradiation and IL-2 therapy. Our studies indicate that the mechanism of interaction between tumor irradiation and immunotherapy may include radiation-induced alterations in the tumor growth and antigenicity which may enhance or trigger an anti-tumor response elicited by IL-2 and mediated by T cells, AsGM1+ cells, and macrophages.

  8. Expression of IL-2 and IL-11 and its significance in patients with ankylosing spondylitis

    Institute of Scientific and Technical Information of China (English)

    Feng Liu; Fan Wang; Cong-Cong Wang; Nuo Li; Shu-Feng Li

    2013-01-01

    Objective: To explore the expression of IL-2 and IL-11 and its significance in patients with ankylosing spondylitis (AS). Methods: A total of 48 active AS patients in our hospital and 40 normal control subjects were selected in our study. Bath ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), Bath ankylosing spondylitis metrology index (BASMI), ESR and CRP expression levels were compared before treatment, 12 h after treatment and 24 h after treatment. IL-2 and IL-11 expression were also compared between these two groups. Results: The BASDAI score, BASFI score and BASMI score of the AS patients before treatment significantly decreased compared with those 12 weeks and 24 weeks after treatment (P0.05). Pearson's linear-correlation analysis showed that serum IL-2 level had a positive correlation with BASDAI, BASFI, BASMI, ESR and CRP (r=0.661,0.547,0.474,0.362,0.416, P<0.05) and serum IL-11 level had a negative correlation with BASDAI, BASFI, BASMI, ESR and CRP (r=-0.629,-0.412, -0.422, -0.387, -0.408, -0.315, P<0.05). Conclusions: Serum levels of IL-2 in active AS patients significantly increase and will decrease after treatment. However, serum levels of IL-11 significantly decrease and will increase after treatment, which indicates that serum IL-2 has a positive correlation with the degree of AS and serum IL-11 has a negative correlation with the degree of AS, both of which are correlated closely with the onset of AS.

  9. Negative modulation of suppressive HIV-specific regulatory T cells by IL-2 adjuvanted therapeutic vaccine.

    Science.gov (United States)

    Brezar, Vedran; Hani, Lylia; Surenaud, Mathieu; Hubert, Audrey; Lacabaratz, Christine; Lelièvre, Jean-Daniel; Levy, Yves; Seddiki, Nabila

    2017-07-01

    The potential benefit in using IL-2 in immunotherapy for cancer and autoimmunity has been linked to the modulation of immune responses, which partly relies on a direct effect on Tregs populations. Here, we revisited the role of IL-2 in HIV infection and investigated whether its use as an adjuvant with therapeutic vaccination, impacts on HIV-specific responses. Antiretroviral therapy treated-patients were randomized to receive 4 boosts of vaccination (ALVACHIV/Lipo-6T, weeks 0/4/8/12) followed by 3 cycles of IL-2 (weeks 16/24/32) before treatment interruption (TI) at week40. IL-2 administration increased significantly HIV-specific CD4+CD25+CD134+ T-cell responses, which inversely correlated with viral load after TI (r = -0.7, p increased global CD25+CD127lowFoxP3+Tregs (p Tregs (p Tregs were inversely correlated with IFN-γ producing specific-effectors (p = 0.03) and positively correlated with viral load (r = 0.7, p = 0.01), revealing their undesired presence during chronic infection. Global Tregs, but not HIV-specific Tregs, inversely correlated with a decrease in exhausted PD1+CD95+ T-cells (p = 0.001). Altogether, our results underline the negative impact of HIV-specific Tregs on HIV-specific effectors and reveal the beneficial use of IL-2 as an adjuvant as its administration increases global Tregs that impact on T-cell exhaustion and decreases HIV-specific CD39+Tregs by shifting the balance towards effectors.

  10. High numbers of IL-2-producing CD8+ T cells during viral infection: correlation with stable memory development

    DEFF Research Database (Denmark)

    Kristensen, Nanna Ny; Christensen, Jan Pravsgaard; Thomsen, Allan Randrup

    2002-01-01

    that IL-2-producing cells appear slightly delayed compared with the majority of IFN-gamma producing cells, and the relative frequency of the IL-2-producing subset increases with transition into the memory phase. In contrast to acute immunizing infection, few IL-2-producing cells are generated during......Using infections with lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus in mice as model systems, we have investigated the ability of antigen-primed CD8+ T cells generated in the context of viral infections to produce IL-2. Our results indicate that acute immunizing infection...

  11. Relationship between the serum levels of IL-2 and recurrence of pemphigus vulgaris

    Directory of Open Access Journals (Sweden)

    Mohsen Masjedi

    2014-09-01

    Full Text Available To EditorPamphigus vulagaris (PV is an autoimmune disease with the characteristics of the epithelial layer destruction and production of blister lesions. Antibodies attack desmoglein 1 and 3 which play a crucial role in the epithelial cell adhesion, and this event is the main cause of this disease. If PV left untreated it would be fatal [1]. From the epidemiological point of view, it is more prevalent in females than males and it is more common in the 4th and 5th decades of life. Its treatment is mainly by the administration of corticosteroids, nevertheless in spite of appropriate curative measures, PV sometimes relapses and becomes problematic [2]; hence finding suitable solutions to prevent its recurrence will be of great help for the patients.In this regard two men aged 56 and 59 years old from Isfahan, Iran, were referred to the Dermatology Clinic of the Alzahra Hospital. They showed some lesions on their trunks. Referring to their past medical history, we found that both of them had PV, and the direct immunofluorescence test corroborated the disease by showing the characteristics deposition of IgG in a lace like pattern. The patients were treated by corticosteroids, (prednisolone 70 mg/day and azathioprine 50mg/Day. Finally, they were discharged from the hospital after successful remedy.Cytokines profile analysis by the ELISA method (ELISA kit for IL-2 supplied by the U-CyTech Biosciences, Yalelaan 48, 3584 CM Utrecht and Netherlands showed that the serum levels of IL-2 increased in the two patients (95 pg/ml and 169 pg/ml, respectively.This finding is consistent with the finding of Blitstein et al. [4]  who have  found  that  an  increase  in  the serum levels of  IL-2 plays an essential role in the PV recurrence. In addition, Prussick et al. [3] have also found that IL-2 therapy has been associated with the recurrence of PV, perhaps due to its ability to trigger autoantibody generation due to stimulation of both T and B cells

  12. Radar Design to Protect Against Surprise

    Energy Technology Data Exchange (ETDEWEB)

    Doerry, Armin W. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-02-01

    Technological and doctrinal surprise is about rendering preparations for conflict as irrelevant or ineffective . For a sensor, this means essentially rendering the sensor as irrelevant or ineffective in its ability to help determine truth. Recovery from this sort of surprise is facilitated by flexibility in our own technology and doctrine. For a sensor, this mean s flexibility in its architecture, design, tactics, and the designing organizations ' processes. - 4 - Acknowledgements This report is the result of a n unfunded research and development activity . Sandia National Laboratories is a multi - program laboratory manage d and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's National Nuclear Security Administration under contract DE - AC04 - 94AL85000.

  13. Surprise Leads to Noisier Perceptual Decisions

    Directory of Open Access Journals (Sweden)

    Marta I Garrido

    2011-02-01

    Full Text Available Surprising events in the environment can impair task performance. This might be due to complete distraction, leading to lapses during which performance is reduced to guessing. Alternatively, unpredictability might cause a graded withdrawal of perceptual resources from the task at hand and thereby reduce sensitivity. Here we attempt to distinguish between these two mechanisms. Listeners performed a novel auditory pitch—duration discrimination, where stimulus loudness changed occasionally and incidentally to the task. Responses were slower and less accurate in the surprising condition, where loudness changed unpredictably, than in the predictable condition, where the loudness was held constant. By explicitly modelling both lapses and changes in sensitivity, we found that unpredictable changes diminished sensitivity but did not increase the rate of lapses. These findings suggest that background environmental uncertainty can disrupt goal-directed behaviour. This graded processing strategy might be adaptive in potentially threatening contexts, and reflect a flexible system for automatic allocation of perceptual resources.

  14. Radar Design to Protect Against Surprise.

    Energy Technology Data Exchange (ETDEWEB)

    Doerry, Armin W.

    2015-02-01

    Technological and doctrinal surprise is about rendering preparations for conflict as irrelevant or ineffective . For a sensor, this means essentially rendering the sensor as irrelevant or ineffective in its ability to help determine truth. Recovery from this sort of surprise is facilitated by flexibility in our own technology and doctrine. For a sensor, this mean s flexibility in its architecture, design, tactics, and the designing organizations ' processes. - 4 - Acknowledgements This report is the result of a n unfunded research and development activity . Sandia National Laboratories is a multi - program laboratory manage d and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the U.S. Department of Energy's National Nuclear Security Administration under contract DE - AC04 - 94AL85000.

  15. Surprise-Based Learning for Autonomous Systems

    Science.gov (United States)

    2009-02-28

    for scientific theories containing recursive theoretical terms". British Journal of Philosophy of Science, 44. 641-652, 1993. Piaget J.. "The Origins...paradigm stems from Piaget’s theory of Developmental Psychology [5], Herben Simon’s theory on dual-space search for knowledge and problem solving [6...34, Twenty-First Conference on Uncertainty in Artificial Intelligence, Edinburgh, Scotland, July 2005. [34] Itti L., Baldi P., "A Surprising Theory of

  16. Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis.

    Science.gov (United States)

    Neitzke, Daniel J; Bowers, Jacob S; Andrijauskaite, Kristina; O'Connell, Nathaniel S; Garrett-Mayer, Elizabeth; Wrangle, John; Li, Zihai; Paulos, Chrystal M; Cole, David J; Rubinstein, Mark P

    2017-03-09

    Adoptive cellular therapy (ACT) with the Th17 subset of CD4(+) T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2Rγ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that these cytokines are important for Th17 cells. We found that Th17 cells proliferated in response to IL-2, IL-7, and IL-15 in vitro. However, in contrast to many other T cell subsets, including conventionally activated CD8(+) T cells, we found that Th17 cells were resistant to apoptosis in the absence of IL2Rγ-chain cytokines. To determine whether Th17 cells utilize IL2Rγ-chain cytokines in vivo, we tracked Th17 cell engraftment after adoptive transfer with or without cytokine depletion. Depletion of IL-7 and/or IL-2 decreased initial engraftment, while depletion of IL-15 did not. Supplementation of IL-2 increased initial Th17 engraftment. To assess the clinical relevance of these findings, we treated melanoma-bearing mice with Th17 cell adoptive transfer and concurrent cytokine depletion or supplementation. We found that simultaneous depletion of IL-2 and IL-7 decreased therapeutic efficacy, depletion of IL-15 had no effect, and IL-2 supplementation increased therapeutic efficacy. Our results show that Th17 cells are responsive to IL2Rγ-chain cytokines, and provide insight into the application of these cytokines for Th17-based therapeutic strategies.

  17. KnockoutJS web development

    CERN Document Server

    Farrar, John

    2015-01-01

    This book is for web developers and designers who work with HTML and JavaScript to help them manage data and interactivity with data using KnockoutJS. Knowledge about jQuery will be useful but is not necessary.

  18. Effects of subcutaneous IL-2 therapy on telomere lengths in PBMC in HIV-infected patients

    DEFF Research Database (Denmark)

    Aladdin, H; Larsen, C S; Schjerling, P

    2001-01-01

    times a week for 24 weeks. Mean TRF length was decreased on average by 267 bp at week 4 (P = 0.03) and 286 bp at week 8 (P = 0.09). Individual TRF changes at weeks 12, 16, 20 and 24 were highly variable. However, in the 12 weeks following therapy, TRF lengths generally increased reaching baseline levels...... by the end of the study. At baseline, mean TRF lengths were positively correlated to the ratio of naïve and memory phenotype within both CD4+ and CD8+ cells. This study shows that IL-2 treatment induces transient shortened mean TRF lengths in PBMC from HIV-infected individuals, indicating that IL-2 enhances...

  19. Mechanics of the IL2RA gene activation revealed by modeling and atomic force microscopy.

    Science.gov (United States)

    Milani, Pascale; Marilley, Monique; Sanchez-Sevilla, Albert; Imbert, Jean; Vaillant, Cédric; Argoul, Françoise; Egly, Jean-Marc; Rocca-Serra, José; Arneodo, Alain

    2011-04-13

    Transcription implies recruitment of RNA polymerase II and transcription factors (TFs) by DNA melting near transcription start site (TSS). Combining atomic force microscopy and computer modeling, we investigate the structural and dynamical properties of the IL2RA promoter and identify an intrinsically negative supercoil in the PRRII region (containing Elf-1 and HMGA1 binding sites), located upstream of a curved DNA region encompassing TSS. Conformational changes, evidenced by time-lapse studies, result in the progressive positioning of curvature apex towards the TSS, likely facilitating local DNA melting. In vitro assays confirm specific binding of the General Transcription Factors (GTFs) TBP and TFIIB over TATA-TSS position, where an inhibitory nucleosome prevented preinitiation complex (PIC) formation and uncontrolled DNA melting. These findings represent a substantial advance showing, first, that the structural properties of the IL2RA promoter are encoded in the DNA sequence and second, that during the initiation process DNA conformation is dynamic and not static.

  20. Increased plasma levels of soluble IL-2R are associated with severe Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Jakobsen, P H; Morris-Jones, S; Theander, T G;

    1994-01-01

    Plasma samples from children with mild and severe Plasmodium falciparum malaria and from children with unrelated diseases were collected to investigate whether the clinical outcome of infection was associated with plasma factors which reflected the activity of different cells of the immune system....... Children with severe P. falciparum malaria had significantly higher plasma levels of soluble IL-2R than children with mild malaria. Plasma levels of IL-2R and levels of parasitaemia were significantly correlated. Neither parasitaemia nor plasma levels of tumour necrosis factor-alpha (TNF-alpha), IL-6......, lymphotoxin (LT), interferon-gamma (IFN-gamma), IL-4, soluble IL-4R or soluble CD8 differed significantly between the two groups of children with malaria. High plasma levels of soluble CD8 were associated with failure of lymphocytes to produce IFN-gamma in vitro following stimulation with P. falciparum...

  1. Fever and the use of paracetamol during IL-2-based immunotherapy in metastatic melanoma.

    Science.gov (United States)

    Køstner, Anne Helene; Ellegaard, Mai-Britt Bjørklund; Christensen, Ib Jarle; Bastholt, Lars; Schmidt, Henrik

    2015-03-01

    Fever is frequently observed in conjunction with interleukin-2 (IL-2)-based immunotherapy. Traditionally, fever has been regarded as an undesirable side effect and treated with fever-lowering drugs. However, new insights in tumor immunology suggest that elevated temperature may facilitate a more effective antitumor immune response. The purpose of this retrospective study was to examine the potential role of the IL-2-induced fever in melanoma patients treated with or without paracetamol in two consecutive cohorts. One hundred and seventy-nine patients with metastatic melanoma treated with a modified decrescendo regimen of IL-2 and Interferon (IFN) between 2004 and 2010 were retrospectively studied. 87 patients treated before 2007 received paracetamol as part of the treatment schedule, and 92 patients treated after 2007 did not receive paracetamol routinely. Body temperature was analyzed as dichotomized and continuous variables and correlated to objective tumor response and overall survival using logistic regression and Cox proportional hazard analysis. Patients experiencing peak temperature of ≥ 39.5 °C had a median OS of 15.2 months compared to 8.7 months among patients with lower temperatures (P = 0.01). In the multivariate analysis, peak temperature of ≥ 39.5 °C (HR 0.53; P = 0.026) and high mean temperature (HR 0.56; P = 0.004) were independent prognostic factors for improved survival. We suggest high fever as a biomarker for improved survival in melanoma patients treated with IL-2/IFN. The routine use of fever-reducing drugs during immunotherapy can therefore be questioned. More studies are needed to evaluate the role of fever and the use of antipyretics during cytokine-based immunotherapy.

  2. Mechanics of the IL2RA Gene Activation Revealed by Modeling and Atomic Force Microscopy

    OpenAIRE

    Pascale Milani; Monique Marilley; Albert Sanchez-Sevilla; Jean Imbert; Cédric Vaillant; Françoise Argoul; Jean-Marc Egly; José Rocca-Serra; Alain Arneodo

    2011-01-01

    Transcription implies recruitment of RNA polymerase II and transcription factors (TFs) by DNA melting near transcription start site (TSS). Combining atomic force microscopy and computer modeling, we investigate the structural and dynamical properties of the IL2RA promoter and identify an intrinsically negative supercoil in the PRRII region (containing Elf-1 and HMGA1 binding sites), located upstream of a curved DNA region encompassing TSS. Conformational changes, evidenced by time-lapse studi...

  3. Fever and the use of paracetamol during IL-2-based immunotherapy in metastatic melanoma

    DEFF Research Database (Denmark)

    Køstner, Anne Helene; Ellegaard, Mai-Britt Bjørklund; Christensen, Ib Jarle

    2015-01-01

    Fever is frequently observed in conjunction with interleukin-2 (IL-2)-based immunotherapy. Traditionally, fever has been regarded as an undesirable side effect and treated with fever-lowering drugs. However, new insights in tumor immunology suggest that elevated temperature may facilitate a more......-reducing drugs during immunotherapy can therefore be questioned. More studies are needed to evaluate the role of fever and the use of antipyretics during cytokine-based immunotherapy....

  4. [Experience with rIL2 in the treatment of metastatic renal carcinoma].

    Science.gov (United States)

    Cardellini, P; Vicini, D; Ruggieri, M; Franceschetti, G P; Nicrosini, S

    1993-04-01

    Eight patients with metastatic renal cell carcinoma, all nephrectomized, were treated with rIL2 continuous i.v. infusion or subcutaneous administering (+/- INF). Six patients alive. Continuous infusion is possible event out of Intensive Care Unity. Adverse effects, sometimes serious, rapidly decrease with suspension. Subcutaneous infusion is more easy and with lower adverse effects. We don't know methodic of which can give more security.

  5. EBI2 augments Tfh cell fate by promoting interaction with IL-2-quenching dendritic cells.

    Science.gov (United States)

    Li, Jianhua; Lu, Erick; Yi, Tangsheng; Cyster, Jason G

    2016-05-05

    T follicular helper (Tfh) cells are a subset of T cells carrying the CD4 antigen; they are important in supporting plasma cell and germinal centre responses. The initial induction of Tfh cell properties occurs within the first few days after activation by antigen recognition on dendritic cells, although how dendritic cells promote this cell-fate decision is not fully understood. Moreover, although Tfh cells are uniquely defined by expression of the follicle-homing receptor CXCR5 (refs 1, 2), the guidance receptor promoting the earlier localization of activated T cells at the interface of the B-cell follicle and T zone has been unclear. Here we show that the G-protein-coupled receptor EBI2 (GPR183) and its ligand 7α,25-dihydroxycholesterol mediate positioning of activated CD4 T cells at the interface of the follicle and T zone. In this location they interact with activated dendritic cells and are exposed to Tfh-cell-promoting inducible co-stimulator (ICOS) ligand. Interleukin-2 (IL-2) is a cytokine that has multiple influences on T-cell fate, including negative regulation of Tfh cell differentiation. We demonstrate that activated dendritic cells in the outer T zone further augment Tfh cell differentiation by producing membrane and soluble forms of CD25, the IL-2 receptor α-chain, and quenching T-cell-derived IL-2. Mice lacking EBI2 in T cells or CD25 in dendritic cells have reduced Tfh cells and mount defective T-cell-dependent plasma cell and germinal centre responses. These findings demonstrate that distinct niches within the lymphoid organ T zone support distinct cell fate decisions, and they establish a function for dendritic-cell-derived CD25 in controlling IL-2 availability and T-cell differentiation.

  6. Serum concentration of IL-6, IL-2, TNF-α, and IFNγ in Vitiligo patients

    Directory of Open Access Journals (Sweden)

    Suman Singh

    2012-01-01

    Full Text Available Background: Vitiligo is an acquired depigmenting disorder characterized by the loss of functional melanocytes from the epidermis. Although the etiology of vitiligo is unknown, over the last few years, substantial data from clinical research has greatly supported the ′Autoimmune theory′ and this is supported by the frequent association of vitiligo with disorders that have an autoimmune origin, including Hashimoto′s thyroiditis, Graves disease, type 1 insulin-dependent diabetes mellitus, and Addison′s disease. As cytokines are important mediators of immunity, there is evidence to suggest that they play a major role in the pathogenesis of autoimmune diseases. Aim: Keeping this in view we have assayed sera for cytokine IL-6, IL-2, Tumor necrosis factor (TNF-α, and IFNγ in 80 cases of vitiligo and compared it with healthy subjects, in order to find out whether they play a role in the pathogenesis of vitiligo or not. Materials and Methods: Serum IL-6, IL-2, TNF-α, and IFNγ were done by the indirect enzyme linked immunosorbent assay (ELISA. Results: The mean serum IL-6 and IL-2 levels in the patient group were significantly higher when compared with those of the normal controls. The mean serum IFNγ level in patients with vitiligo was significantly lower than that in the control group. There was no significant difference in the serum level of TNF-α between vitiligo and healthy controls. Conclusion : An increase in the production of proinflammatory cytokines such as IL-6 and IL-2 in vitiligo patients may play an important role in melanocytic cytotoxicity. Thus, we speculate that the cytokine production of epidermal microenvironment may be involved in vitiligo.

  7. Silent IL2RG Gene Editing in Human Pluripotent Stem Cells.

    Science.gov (United States)

    Li, Li B; Ma, Chao; Awong, Geneve; Kennedy, Marion; Gornalusse, German; Keller, Gordon; Kaufman, Dan S; Russell, David W

    2016-03-01

    Many applications of pluripotent stem cells (PSCs) require efficient editing of silent chromosomal genes. Here, we show that a major limitation in isolating edited clones is silencing of the selectable marker cassette after homologous recombination and that this can be overcome by using a ubiquitous chromatin opening element (UCOE) promoter-driven transgene. We use this strategy to edit the silent IL2RG locus in human PSCs with a recombinant adeno-associated virus (rAAV)-targeting vector in the absence of potentially genotoxic, site-specific nucleases and show that IL2RG is required for natural killer and T-cell differentiation of human PSCs. Insertion of an active UCOE promoter into a silent locus altered the histone modification and cytosine methylation pattern of surrounding chromatin, but these changes resolved when the UCOE promoter was removed. This same approach could be used to correct IL2RG mutations in X-linked severe combined immunodeficiency patient-derived induced PSCs (iPSCs), to prevent graft versus host disease in regenerative medicine applications, or to edit other silent genes.

  8. [Cytogenetics of chronic lymphocytic leukemia stimulated by CpG-oligodeoxynucleotides and IL-2].

    Science.gov (United States)

    Wang, Dong-Mei; Xu, Wei; Dong, Hua-Jie; Fang, Cheng; Zhu, Dan-Xia; Cao, Xin; Zhu, Hua-Yuan; Zhuang, Yun; Qiu, Hai-Rong; Yang, Hui; Li, Jian-Yong

    2010-10-01

    This study was to explore the stimulating effect of CpG-oligodeoxynucleotides (CpG-ODN) in combination with interleukin-2 (IL-2) on cytogenetic features of chronic lymphocytic leukemia (CLL) cells. Peripheral blood or bone marrow cells of 115 patients with CLL were cultured for 72 hours with CpG-ODN plus interleukin-2 (IL-2), and routine karyotype analysis was performed with R-banding technique. The metaphase number≥20 was considered as successful stimulation. The results showed that among the 115 CLL patients, successful stimulation rate was 74.8%. The rate of chromosome aberrations was 58.1%. One kind of aberration was detected in 21 cases (24.4%), two kinds of aberration in 6 cases (7.0%), complex aberrant karyotype in 23 cases (26.7%), included highly complex aberrant karyotype in 9 cases (10.5%), respectively. A total of 163 abnormalities of 102 kinds were detected in 86 patients. Number aberrations were 116 (71.2%), and structural abnormalities were 47 (28.8%). The most frequent number aberration was trisomy 12 (14.0%), and structural aberration was 15q+ (5.8%). It is concluded that most of CLL patients have chromosome abnormality, and the number abnormality are more frequent than the structural aberrations. CpG-ODN plus IL-2 can effectively raise the number of cells at metaphase and the detection rate of chromosome aberrations in CLL patients.

  9. IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach.

    Science.gov (United States)

    Stepensky, Polina; Weintraub, Michael; Yanir, Asaf; Revel-Vilk, Shoshana; Krux, Frank; Huck, Kirsten; Linka, Rene M; Shaag, Avraham; Elpeleg, Orly; Borkhardt, Arndt; Resnick, Igor B

    2011-03-01

    Mutations in the IL-2-inducible T-cell kinase gene have recently been shown to cause an autosomal recessive fatal Epstein Barr virus (EBV) associated lymphoproliferation. We report 3 cases from a single family who presented with EBV-positive B-cell proliferation diagnosed as Hodgkin's lymphoma. Single nucleotide polymorphism array-based genome-wide linkage analysis revealed IL-2-inducible T-cell kinase as a candidate gene for this disorder. All 3 patients harbored the same novel homozygous nonsense mutation C1764G which causes a premature stop-codon in the kinase domain. All cases were initially treated with chemotherapy. One patient remains in durable remission, the second patient subsequently developed severe hemophagocytic lymphohistiocytosis with multi-organ failure and died, and the third patient underwent a successful allogeneic bone marrow transplantation. IL-2-inducible T-cell kinase deficiency underlies a new primary immune deficiency which may account for part of the spectrum of Epstein Barr virus related lymphoproliferative disorders which can be successfully corrected by bone marrow transplantation.

  10. Cystatin F regulates proteinase activity in IL-2-activated natural killer cells.

    Science.gov (United States)

    Maher, Katarina; Konjar, Spela; Watts, Colin; Turk, Boris; Kopitar-Jerala, Natasa

    2014-01-01

    Cystatin F is a unique member of the cystatin family of cysteine protease inhibitors, which is synthesized as an inactive dimer and it is activated by N-terminal cleavage in the endolysosomes. It is expressed in the cells of the immune system: myeloid cells and the cells involved in target cell killing: natural killer (NK) cells and cytotoxic T cells (CTLs). Upon activation of the NK cells with interleukin 2 (IL-2), cystatin F was found upregulated and co-localized in cytotoxic granules with cathepsin C (CatC) and CatV. However, cystatin F inhibits the CatC in cells only when its N-terminal part is processed. Although cystatin F could inhibit both CatV and CatC, the IL-2 stimulation of the YT cells resulted in an increased CatV activity, while the CatC activity was unchanged. The incubation of IL-2 activated NK cells with a cysteine proteinase inhibitor E-64d increased the cystatin F dimer formation. Our results suggest that cystatin F not only inhibits CatV, but it is processed by the CatV in order to inhibit the CatC activity in cytotoxic granules. The regulation of the CatC activity in the cytotoxic granules of the NK cells by the cystatin F could be important for the processing and activation of granule-associated serine proteases - granzymes.

  11. Activated human T cells secrete exosomes that participate in IL-2 mediated immune response signaling.

    Directory of Open Access Journals (Sweden)

    Jessica Wahlgren

    Full Text Available It has previously been shown that nano-meter sized vesicles (30-100 nm, exosomes, secreted by antigen presenting cells can induce T cell responses thus showing the potential of exosomes to be used as immunological tools. Additionally, activated CD3⁺ T cells can secrete exosomes that have the ability to modulate different immunological responses. Here, we investigated what effects exosomes originating from activated CD3⁺ T cells have on resting CD3⁺ T cells by studying T cell proliferation, cytokine production and by performing T cell and exosome phenotype characterization. Human exosomes were generated in vitro following CD3⁺ T cell stimulation with anti-CD28, anti-CD3 and IL-2. Our results show that exosomes purified from stimulated CD3⁺ T cells together with IL-2 were able to generate proliferation in autologous resting CD3⁺ T cells. The CD3⁺ T cells stimulated with exosomes together with IL-2 had a higher proportion of CD8⁺ T cells and had a different cytokine profile compared to controls. These results indicate that activated CD3⁺ T cells communicate with resting autologous T cells via exosomes.

  12. Evaluation in mice of the capillary leak syndrome (CLS) mediated by the systemic administration of recombinant interleukin-2 (IL-2)

    Energy Technology Data Exchange (ETDEWEB)

    Ettinghausen, S.E.; Rosenstein, M.; Rosenberg, S.A.

    1986-03-01

    Since a CLS with interstitial pulmonary edema has been the major toxicity of IL-2 administration in humans, the authors studied this CLS in mice by quantitating the IL-2 mediated, tissue extravasation (Ex) of intravenously injected /sup 125/I-bovine serum albumin (BSA). Mice received saline (HBSS) or 200,000 U of IL-2 intraperitoneally thrice daily from day 0-6 before tissues were counted. A permeability index (PI) was calculated by dividing the mean counts per minute (CPM) from tissues of treated mice by those from controls. In a representative experiment, increased BSA Ex was noted in the lungs of mice treated with IL-2 when compared with HBSS (6187 +/- 141 and 638 +/- 64 CPM +/- SEM, respectively; p2 < .001; PI = 9.7). Other tissues with increased BSA Ex included the liver, spleen, kidneys and mesenteric lymph nodes (PI = 6.7, 10.0, 6.3, 6.0, respectively). BSA Ex, which did not occur with the excipient control, was dependent upon the dose and the duration of IL-2. Serial lung weights showed dramatic increases in water weight induced by IL-2. Treatment of mice with radiation (500R), cyclophosphamide, or cortisone acetate significantly reduced IL-2 mediated BSA Ex. Thus, IL-2 induced a generalized CLS which is mediated directly or indirectly by cellular mechanisms.

  13. MHC class II molecules deliver costimulatory signals in human T cells through a functional linkage with IL-2-receptors

    DEFF Research Database (Denmark)

    Odum, Niels; Kanner, S B; Ledbetter, J A;

    1993-01-01

    tyrosine phosphorylation of specific substrates including PLC-gamma 1. Combined stimulation of IL-2R and class II molecules had an additive effect on tyrosine phosphorylation. Pretreatment of T cells with a protein tyrosine kinase inhibitor, herbimycin A, inhibited IL-2 and class II-induced proliferation...

  14. Sustained stimulation and expansion of Tregs by IL2 control autoimmunity without impairing immune responses to infection, vaccination and cancer.

    Science.gov (United States)

    Churlaud, Guillaume; Jimenez, Veronica; Ruberte, Jesus; Amadoudji Zin, Martin; Fourcade, Gwladys; Gottrand, Gaelle; Casana, Estefania; Lambrecht, Benedicte; Bellier, Bertrand; Piaggio, Eliane; Bosch, Fatima; Klatzmann, David

    2014-04-01

    Interleukin 2 (IL2) is the key cytokine supporting survival and function of regulatory T cells (Tregs). We recently reported that low-dose IL2 safely expands/stimulates Tregs and improves autoimmune conditions in humans. Further development of IL2 in autoimmune diseases will require chronic IL2 administration, which could affect beneficial effector immune responses regulated by Tregs. We used recombinant adeno-associated viral vector (rAAV)-mediated gene transfer to continuously release IL2 in mice and assessed its long-term effects on immune responses. A single rAAV-IL2 injection enabled sustained stimulation and expansion of Tregs without inducing Teff activation and prevented diabetes in NOD mice. After several weeks of IL2 production, mice responded normally to a viral challenge and to vaccination, and had pregnancies with offspring that developed normally. They showed no change in the occurrence and growth of chemically-induced tumors. Altogether, chronic low-dose IL2 treatment does not affect beneficial effector immune responses at doses that prevent autoimmune diabetes. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Nuclear Phosphoproteomic Screen Uncovers ACLY as Mediator of IL-2-induced Proliferation of CD4+ T lymphocytes

    DEFF Research Database (Denmark)

    Osinalde, Nerea; Mitxelena, Jone; Sánchez-Quiles, Virginia

    2016-01-01

    Anti-cancer immunotherapies commonly rely on the use of interleukin-2 (IL-2) to promote the expansion of T lymphocytes. IL-2- dependent proliferation is the culmination of a complex network of phosphorylation-driven signaling events that impact on gene transcription through mechanisms that are no...

  16. Reduced interleukin-2 responsiveness impairs the ability of Treg cells to compete for IL-2 in nonobese diabetic mice.

    Science.gov (United States)

    James, Cini R; Buckle, Irina; Muscate, Franziska; Otsuka, Masayuki; Nakao, Mari; Oon, Jack Sh; Steptoe, Raymond J; Thomas, Ranjeny; Hamilton-Williams, Emma E

    2016-05-01

    Enhancement of regulatory T cell (Treg cell) frequency and function is the goal of many therapeutic strategies aimed at treating type 1 diabetes (T1D). The interleukin-2 (IL-2) pathway, which has been strongly implicated in T1D susceptibility in both humans and mice, is a master regulator of Treg cell homeostasis and function. We investigated how IL-2 pathway defects impact Treg cells in T1D-susceptible nonobese diabetic (NOD) mice in comparison with protected C57BL/6 and NOD congenic mice. NOD Treg cells were reduced in frequency specifically in the lymph nodes and expressed lower levels of CD25 and CD39/CD73 immunosuppressive molecules. In the spleen and blood, Treg cell frequency was preserved through expansion of CD25(low), effector phenotype Treg cells. Reduced CD25 expression led to decreased IL-2 signaling in NOD Treg cells. In vivo, treatment with IL-2-anti-IL-2 antibody complexes led to effective upregulation of suppressive molecules on NOD Treg cells in the spleen and blood, but had reduced efficacy on lymph node Treg cells. In contrast, NOD CD8(+) and CD4(+) effector T cells were not impaired in their response to IL-2 therapy. We conclude that NOD Treg cells have an impaired responsiveness to IL-2 that reduces their ability to compete for a limited supply of IL-2.

  17. Changes in Gab2 phosphorylation and interaction partners in response to interleukin (IL)-2 stimulation in T-lymphocytes

    DEFF Research Database (Denmark)

    Osinalde, Nerea; Sánchez-Quiles, Virginia; Blagoev, Blagoy

    2016-01-01

    Interleukin-2 (IL-2) stimulation results in T-cell growth as a consequence of activation of highly sophisticated and fine-tuned signaling pathways. Despite lacking intrinsic enzymatic activity, scaffold proteins such as Gab2, play a pivotal role in IL-2-triggered signal transduction integrating...

  18. Requirement for noncognate interaction with T cells for the activation of B cell immunoglobulin secretion by IL-2

    DEFF Research Database (Denmark)

    Owens, T

    1991-01-01

    responses or T cell activation. Other antibodies (anti-IL-3, IL-4, IL-5, Thy-1.2, CD5) were not inhibitory. After 2 days of culture with F23.1-activated T cells, B cells appeared to have become responsive to IL-2, in that they could be driven to immunoglobulin production by the addition of IL-2. Flow...

  19. Splenocytes cultured in low concentrations of IL-2 generate NK cell specificities toward syngenic and allogenic targets

    DEFF Research Database (Denmark)

    Nissen, Mogens Holst; Jeppesen, M; Claesson, M H

    2000-01-01

    Splenocytes cultured in the presence of 30-60 units/ml IL-2 for 5 days develop natural killer activity toward syngeneic and allogeneic tumor cell targets. The IL-2 activated splenocytes, themselves, are partially resistant, whereas concanavalin A-activated T blast cells are completely resistant...

  20. Multi-cellular natural killer (NK) cell clusters enhance NK cell activation through localizing IL-2 within the cluster

    Science.gov (United States)

    Kim, Miju; Kim, Tae-Jin; Kim, Hye Mi; Doh, Junsang; Lee, Kyung-Mi

    2017-01-01

    Multi-cellular cluster formation of natural killer (NK) cells occurs during in vivo priming and potentiates their activation to IL-2. However, the precise mechanism underlying this synergy within NK cell clusters remains unclear. We employed lymphocyte-laden microwell technologies to modulate contact-mediated multi-cellular interactions among activating NK cells and to quantitatively assess the molecular events occurring in multi-cellular clusters of NK cells. NK cells in social microwells, which allow cell-to-cell contact, exhibited significantly higher levels of IL-2 receptor (IL-2R) signaling compared with those in lonesome microwells, which prevent intercellular contact. Further, CD25, an IL-2R α chain, and lytic granules of NK cells in social microwells were polarized toward MTOC. Live cell imaging of lytic granules revealed their dynamic and prolonged polarization toward neighboring NK cells without degranulation. These results suggest that IL-2 bound on CD25 of one NK cells triggered IL-2 signaling of neighboring NK cells. These results were further corroborated by findings that CD25-KO NK cells exhibited lower proliferation than WT NK cells, and when mixed with WT NK cells, underwent significantly higher level of proliferation. These data highlights the existence of IL-2 trans-presentation between NK cells in the local microenvironment where the availability of IL-2 is limited.

  1. A fusion protein composed of IL-2 and caspase-3 ameliorates the outcome of experimental inflammatory colitis.

    Science.gov (United States)

    Sagiv, Yuval; Kaminitz, Ayelet; Lorberboum-Galski, Haya; Askenasy, Nadir; Yarkoni, Shai

    2009-09-01

    Targeted depletion of immune cells expressing the interleukin-2 (IL-2) receptor can exacerbate inflammatory bowel disease (IBD) through elimination of regulatory T (Treg) cells, or ameliorate its course by depletion of cytotoxic cells. To answer this question we used a fusion protein composed of IL-2 and caspase-3 (IL2-cas) in an experimental model of DSS-induced toxic colitis. In a preventive setting, co-administration of DSS with a daily therapeutic dose of IL2-cas for seven days improved all disease parameters. Although CD4(+)CD25(+) T cells were depleted in the mesenteric lymph nodes, a fractional increase in CD4(+)FoxP3(+) T cells was observed in the spleen. Likewise, IL2-cas therapy improved the outcome of established disease in a chronic model of colitis. These data demonstrate that therapies that use IL-2 as a targeting moiety exert a protective effect over the colon under conditions of inflammation. The efficacy of IL-2-targeted therapy is attributed to reduced activity of reactive T cells, which ameliorates the secondary inflammatory infiltration. IL2-cas evolves as a potential therapeutic tool in IBD.

  2. Estabishment of A Human Liver Cancer Cell Line Transfected with IL-2 cDNA and Its Biologic Activity

    Institute of Scientific and Technical Information of China (English)

    孙跃明; 王学浩; 杜竞辉

    2001-01-01

    Objective To obtain IL-2 gene transfected human liver cancer cells and study IL-2 expression and its biologic activity in vivo. Methods Human liver cancer cells SMMC-7721 were cocultured with recombinant retroviral vector LNC-IL-2,and screening was performed in G418 medium.The exogenous IL-2 cDNA at the DNA,RNA,and protein levels were determined by using dot hybridization,PR-PCR and MTT methods respectively.The tumorigenesis and antitumorigenesis of the screened liver cancer cell with subcutaneous injection in nude mice were observed. Results and Conclusion The IL-2 cDNA was successfully integrated into SMMC-7721 cell genomic DNA and continuously expressed for more than 88 days.Subcutaneous vaccination of the nude mice with transfected cells revealed an obvious suppression of its tumorigenicity,and could induce antitumor activity in vivo.

  3. Pupil size tracks perceptual content and surprise.

    Science.gov (United States)

    Kloosterman, Niels A; Meindertsma, Thomas; van Loon, Anouk M; Lamme, Victor A F; Bonneh, Yoram S; Donner, Tobias H

    2015-04-01

    Changes in pupil size at constant light levels reflect the activity of neuromodulatory brainstem centers that control global brain state. These endogenously driven pupil dynamics can be synchronized with cognitive acts. For example, the pupil dilates during the spontaneous switches of perception of a constant sensory input in bistable perceptual illusions. It is unknown whether this pupil dilation only indicates the occurrence of perceptual switches, or also their content. Here, we measured pupil diameter in human subjects reporting the subjective disappearance and re-appearance of a physically constant visual target surrounded by a moving pattern ('motion-induced blindness' illusion). We show that the pupil dilates during the perceptual switches in the illusion and a stimulus-evoked 'replay' of that illusion. Critically, the switch-related pupil dilation encodes perceptual content, with larger amplitude for disappearance than re-appearance. This difference in pupil response amplitude enables prediction of the type of report (disappearance vs. re-appearance) on individual switches (receiver-operating characteristic: 61%). The amplitude difference is independent of the relative durations of target-visible and target-invisible intervals and subjects' overt behavioral report of the perceptual switches. Further, we show that pupil dilation during the replay also scales with the level of surprise about the timing of switches, but there is no evidence for an interaction between the effects of surprise and perceptual content on the pupil response. Taken together, our results suggest that pupil-linked brain systems track both the content of, and surprise about, perceptual events.

  4. Association of the IL2RA/CD25 Gene With Juvenile Idiopathic Arthritis

    Science.gov (United States)

    Hinks, Anne; Ke, Xiayi; Barton, Anne; Eyre, Steve; Bowes, John; Worthington, Jane; Thompson, Susan D; Langefeld, Carl D; Glass, David N; Thomson, Wendy

    2009-01-01

    Objective IL2RA/CD25, the gene for interleukin-2 receptor α, is emerging as a general susceptibility gene for autoimmune diseases because of its role in the development and function of regulatory T cells and the association of single-nucleotide polymorphisms (SNPs) within this gene with type 1 diabetes mellitus (DM), Graves' disease, rheumatoid arthritis (RA), and multiple sclerosis (MS). The aim of this study was to determine whether SNPs within the IL2RA/CD25 gene are associated with juvenile idiopathic arthritis (JIA). Methods Three SNPs within the IL2RA/CD25 gene, that previously showed evidence of an association with either RA, MS, or type 1 DM, were selected for genotyping in UK JIA cases (n = 654) and controls (n = 3,849). Data for 1 SNP (rs2104286) were also available from North American JIA cases (n = 747) and controls (n = 1,161). Association analyses were performed using Plink software. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results SNP rs2104286 within the IL2RA/CD25 gene was significantly associated with UK JIA cases (OR for the allele 0.76 [95% CI 0.66–0.88], P for trend = 0.0002). A second SNP (rs41295061) also showed modest evidence for association with JIA (OR 0.80 [95% CI 0.63–1.0], P = 0.05). Association with rs2104286 was convincingly replicated in the North American JIA cohort (OR 0.84 [95% CI 0.65–0.99], P for trend = 0.05). Meta-analysis of the 2 cohorts yielded highly significant evidence of association with JIA (OR 0.76 [95% CI 0.62–0.88], P = 4.9 × 10−5). Conclusion These results provide strong evidence that the IL2RA/CD25 gene represents a JIA susceptibility locus. Further investigation of the gene using both genetic and functional approaches is now required. PMID:19116909

  5. Expression of sIL-2R before and after Chemotherapy in Patients with Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    FAN Yuan-ming; SUN Zhi-jun

    2008-01-01

    Objective:To investigate the difference of peripheral blood sIL-2R before and after chemotherapy in breast cancer patients,and evaluate the clinical value of the sIL-2R in breast cancer's diagnosis and therapy.Methods:The peripheral blood sIL-2R levels of the breast cancer patients with or without chemotherapy were detected by ELISA.The healthy persons were made as the control group.Results:The slL-2R levels of the breast cancer patients were higher than that of the control group(P<0.05);the slL-2R's levels in Ⅰ~Ⅱ stage breast cancer were lower than that in Ⅲ~Ⅳ stag e breast cancer (P<0.05);the sIL-2R levels of the patients before chemotherapy were higher than that of the patients undergone chemotherapy(P<0.05);The level of the patient with chemotherapy was still higher than that of the control group(P<0.05);the sIL-2R levels of the patients whose chemotherapies were noneffective were higher than that of the patients received effective chemotherapies(P<0.05).There was no significant difference between the group with ER(+)or PR(+)and the group with ER(-)or PR(-)(P>0.05).Conclusion:The breast cancer patients have the high slL-2R levels.There is a close relationship between the cancer incidence and the patients,immune situation.The level of slL-2R could be a clinical index which Can be used for evaluating the cancer degree,because the higher levels of slL-2R can indicate that the immune ability of patient is worse.There is a significant difference between the slL-2R levels of the patients before chemotherapy and that of the patients undergone chemotherapy.

  6. Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells.

    Science.gov (United States)

    Bell, Charles J M; Sun, Yongliang; Nowak, Urszula M; Clark, Jan; Howlett, Sarah; Pekalski, Marcin L; Yang, Xin; Ast, Oliver; Waldhauer, Inja; Freimoser-Grundschober, Anne; Moessner, Ekkehard; Umana, Pablo; Klein, Christian; Hosse, Ralf J; Wicker, Linda S; Peterson, Laurence B

    2015-01-01

    Regulatory T cells (Tregs) expressing FOXP3 are essential for the maintenance of self-tolerance and are deficient in many common autoimmune diseases. Immune tolerance is maintained in part by IL-2 and deficiencies in the IL-2 pathway cause reduced Treg function and an increased risk of autoimmunity. Recent studies expanding Tregs in vivo with low-dose IL-2 achieved major clinical successes highlighting the potential to optimize this pleiotropic cytokine for inflammatory and autoimmune disease indications. Here we compare the clinically approved IL-2 molecule, Proleukin, with two engineered IL-2 molecules with long half-lives owing to their fusion in monovalent and bivalent stoichiometry to a non-FcRγ binding human IgG1. Using nonhuman primates, we demonstrate that single ultra-low doses of IL-2 fusion proteins induce a prolonged state of in vivo activation that increases Tregs for an extended period of time similar to multiple-dose Proleukin. One of the common pleiotropic effects of high dose IL-2 treatment, eosinophilia, is eliminated at doses of the IL-2 fusion proteins that greatly expand Tregs. The long half-lives of the IL-2 fusion proteins facilitated a detailed characterization of an IL-2 dose response driving Treg expansion that correlates with increasingly sustained, suprathreshold pSTAT5a induction and subsequent sustained increases in the expression of CD25, FOXP3 and Ki-67 with retention of Treg-specific epigenetic signatures at FOXP3 and CTLA4. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  7. Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells

    Science.gov (United States)

    Bell, Charles J.M.; Sun, Yongliang; Nowak, Urszula M.; Clark, Jan; Howlett, Sarah; Pekalski, Marcin L.; Yang, Xin; Ast, Oliver; Waldhauer, Inja; Freimoser-Grundschober, Anne; Moessner, Ekkehard; Umana, Pablo; Klein, Christian; Hosse, Ralf J.; Wicker, Linda S.; Peterson, Laurence B.

    2015-01-01

    Regulatory T cells (Tregs) expressing FOXP3 are essential for the maintenance of self-tolerance and are deficient in many common autoimmune diseases. Immune tolerance is maintained in part by IL-2 and deficiencies in the IL-2 pathway cause reduced Treg function and an increased risk of autoimmunity. Recent studies expanding Tregs in vivo with low-dose IL-2 achieved major clinical successes highlighting the potential to optimize this pleiotropic cytokine for inflammatory and autoimmune disease indications. Here we compare the clinically approved IL-2 molecule, Proleukin, with two engineered IL-2 molecules with long half-lives owing to their fusion in monovalent and bivalent stoichiometry to a non-FcRγ binding human IgG1. Using nonhuman primates, we demonstrate that single ultra-low doses of IL-2 fusion proteins induce a prolonged state of in vivo activation that increases Tregs for an extended period of time similar to multiple-dose Proleukin. One of the common pleiotropic effects of high dose IL-2 treatment, eosinophilia, is eliminated at doses of the IL-2 fusion proteins that greatly expand Tregs. The long half-lives of the IL-2 fusion proteins facilitated a detailed characterization of an IL-2 dose response driving Treg expansion that correlates with increasingly sustained, suprathreshold pSTAT5a induction and subsequent sustained increases in the expression of CD25, FOXP3 and Ki-67 with retention of Treg-specific epigenetic signatures at FOXP3 and CTLA4. PMID:25457307

  8. Helicobacter pylori arginase mutant colonizes arginase Ⅱ knockout mice

    Institute of Scientific and Technical Information of China (English)

    Songhee H Kim; Melanie L Langford; Jean-Luc Boucher; Traci L Testerman; David J McGee

    2011-01-01

    AIM: To investigate the role of host and bacterial argi-nases in the colonization of mice by Helicobacter pylori (H. Pylori).METHODS: H. Pylori produces a very powerful urease that hydrolyzes urea to carbon dioxide and ammonium, which neutralizes acid. Urease is absolutely essential to H. Pylori pathogenesis; therefore, the urea substrate must be in ample supply for urease to work efficiently. The urea substrate is most likely provided by arginase activity, which hydrolyzes L-arginine to L-ornithine and urea. Previous work has demonstrated that H. Pylori arginase is surprisingly not required for colonization of wild-type mice. Hence, another in vivo source of the critical urea substrate must exist. We hypothesized that the urea source was provided by host arginase Ⅱ, since this enzyme is expressed in the stomach, and H. Pylori has previously been shown to induce the expres-sion of murine gastric arginase Ⅱ. To test this hypoth-esis, wild-type and arginase (rocF) mutant H. Pylori strain SS1 were inoculated into arginase Ⅱ knockout mice. RESULTS: Surprisingly, both the wild-type and rocF mutant bacteria still colonized arginase Ⅱ knock-out mice. Moreover, feeding arginase Ⅱ knockout mice the host arginase inhibitor S-(2-boronoethyl)-L-cysteine (BEC), while inhibiting > 50% of the host arginase Ⅰactivity in several tissues, did not block the ability of the rocF mutant H. Pylori to colonize. In con-trast, BEC poorly inhibited H. Pylori arginase activity. CONCLUSION: The in vivo source for the essential urea utilized by H. Pylori urease is neither bacterial arginase nor host arginase Ⅱ; instead, either residual host arginase Ⅰor agmatinase is probably responsible.

  9. Some surprising facts about (the problem of) surprising facts (from the Dusseldorf Conference, February 2011).

    Science.gov (United States)

    Mayo, D

    2014-03-01

    A common intuition about evidence is that if data x have been used to construct a hypothesis H, then x should not be used again in support of H. It is no surprise that x fits H, if H was deliberately constructed to accord with x. The question of when and why we should avoid such "double-counting" continues to be debated in philosophy and statistics. It arises as a prohibition against data mining, hunting for significance, tuning on the signal, and ad hoc hypotheses, and as a preference for predesignated hypotheses and "surprising" predictions. I have argued that it is the severity or probativeness of the test--or lack of it--that should determine whether a double-use of data is admissible. I examine a number of surprising ambiguities and unexpected facts that continue to bedevil this debate.

  10. Stroke Recovery: Surprising Influences and Residual Consequences

    Directory of Open Access Journals (Sweden)

    Argye E. Hillis

    2014-01-01

    Full Text Available There is startling individual variability in the degree to which people recover from stroke and the duration of time over which recovery of some symptoms occurs. There are a variety of mechanisms of recovery from stroke which take place at distinct time points after stroke and are influenced by different variables. We review recent studies from our laboratory that unveil some surprising findings, such as the role of education in chronic recovery. We also report data showing that the consequences that most plague survivors of stroke and their caregivers are loss of high level cortical functions, such as empathy or written language. These results have implications for rehabilitation and management of stroke.

  11. Effect of Symbiotic Supplementation to the Immune Response Ifn-Γ and Il-2 on Elderly

    Directory of Open Access Journals (Sweden)

    Rudy Hartono

    2016-10-01

    Full Text Available Along with the increasing age it will have an impact on the emergence of a variety of life issues such as: social, economic, cultural, educational, health primarily because of the function of organs will decrease either due to natural or due to illness. The result will be an increase in the number of elderly people that is one indicator of the success of development as well as challenges in development. If it is not anticipated at this time, it is probable that the development process will encounter a variety of obstacles. Nutritional factors play an important role of the immune response in healthy elderly. One factor is the nutritional functional foods in this case is symbiotic. The purpose of this study was to analyze the effect of supplementation on the immune response symbiotic with marker IFN-γ and IL-2 in elderly patients. This research is a study pre-experiment in the treatment group were given supplementation symbiotic. We then measured IFN-γ and IL-2 in this group. Analysis of normality and homogeneity test for determining the parametric or non-parametric statistics with the Shapiro-Wilk test. Furthermore, if eligible, the parametric analysis used in this research is to use before after t test to see the effects of the intervention. The results showed that supplementation symbiotic effect on the increase in the levels of IL-2, but not significantly to the increase in IFN-γ. Based on the results of the study are advised to consume as food symbiotic functional in order to maintain the immune system of the elderly.

  12. Surprises and mysteries in urban soils

    Science.gov (United States)

    Groffman, P. M.

    2015-12-01

    In the Baltimore Ecosystem Study, one of two urban long-term ecological research (LTER) projects funded by the U.S. National Science Foundation, we are using "the watershed approach" to integrate ecological, physical and social sciences. Urban and suburban watershed input/output budgets for nitrogen have shown surprisingly high retention which has led to detailed analysis of sources and sinks in soils these watersheds. Home lawns, thought to be major sources of reactive nitrogen in suburban watersheds, have more complex coupled carbon and nitrogen dynamics than previously thought, and are likely the site of much nitrogen retention. Riparian zones, thought to be an important sink for reactive nitrogen in many watersheds, have turned out be nitrogen sources in urban watersheds due to hydrologic changes that disconnect streams from their surrounding landscape. Urban effects on atmospheric carbon dioxide levels and nitrogen deposition have strong effects on soil nitrogen cycling processes and soil:atmosphere fluxes of nitrous oxide, carbon dioxide and methane. Efforts to manage urban soils and watersheds through geomorphic stream restoration, creation of stormwater management features and changes in lawn and forest management can have significant effects on watershed carbon and nitrogen dynamics. Urban soils present a basic and applied science frontier that challenges our understanding of biological, physical, chemical and social science processes. The watershed approach provides an effective platform for integrating these disciplines and for articulating critical questions that arise from surprising results. This approach can help us to meet the challenge of urban soils, which is critical to achieving sustainability goals in cities across the world.

  13. Nuclear Phosphoproteomic Screen Uncovers ACLY as Mediator of IL-2-induced Proliferation of CD4+ T lymphocytes

    DEFF Research Database (Denmark)

    Osinalde, Nerea; Mitxelena, Jone; Sánchez-Quiles, Virginia;

    2016-01-01

    Anti-cancer immunotherapies commonly rely on the use of interleukin-2 (IL-2) to promote the expansion of T lymphocytes. IL-2- dependent proliferation is the culmination of a complex network of phosphorylation-driven signaling events that impact on gene transcription through mechanisms...... and inducing the expression of cell cycle regulating genes in response to IL-2. Thus, the metabolic enzyme ACLY emerges as a bridge between cytokine signaling and proliferation of T lymphocytes, and may be an attractive candidate target for the development of more efficient anti-cancer immunotherapies....

  14. 哮喘患儿血清中sIL-2R、IL-2、IL-4、IL-13的水平变化与临床意义

    Institute of Scientific and Technical Information of China (English)

    许文龙; 张国祥; 楚旭

    2007-01-01

    [目的]探讨哮喘患儿清中可溶性白细胞介素-2受体(sIL-2R)、白细胞介素-2(IL-2)、白细胞介素-4(IL-4)、白细胞介素-13(IL-13)的水平变化及其与哮喘发病机制的关系.[方法]每例样本均取空腹静脉血并即时分离血清1 ml,用ELISA法检测血清中sIL-2R、IL-2、IL-4、IL-13的水平并对结果进行统计学分析.[结果]哮喘急性发作组、缓解组的血清中sIL-2R、IL-2、IL-4、IL-13的结果与正常对照组比较差异均有显著性(P<0.05).其中哮喘急性发作组、缓解组血清中sIL-2R,IL-4、IL-13的结果要明显高于正常对照组,而IL-2则明显低于正常对照组.此外,哮喘急性发作组与缓解组血清中IL-2、IL-4、IL-13的结果相比较差异均有显著性(P均<0.05),而SIL-2R则无明显差异.[结论]哮喘患儿血清中sIL-2R、IL-2、IL-4、IL-13的水平伴随病情进展发生显著的变化,说明它们在哮喘的免疫病理过程中起着重要的作用.

  15. The conceptualization model problem—surprise

    Science.gov (United States)

    Bredehoeft, John

    2005-03-01

    The foundation of model analysis is the conceptual model. Surprise is defined as new data that renders the prevailing conceptual model invalid; as defined here it represents a paradigm shift. Limited empirical data indicate that surprises occur in 20-30% of model analyses. These data suggest that groundwater analysts have difficulty selecting the appropriate conceptual model. There is no ready remedy to the conceptual model problem other than (1) to collect as much data as is feasible, using all applicable methods—a complementary data collection methodology can lead to new information that changes the prevailing conceptual model, and (2) for the analyst to remain open to the fact that the conceptual model can change dramatically as more information is collected. In the final analysis, the hydrogeologist makes a subjective decision on the appropriate conceptual model. The conceptualization problem does not render models unusable. The problem introduces an uncertainty that often is not widely recognized. Conceptual model uncertainty is exacerbated in making long-term predictions of system performance. C'est le modèle conceptuel qui se trouve à base d'une analyse sur un modèle. On considère comme une surprise lorsque le modèle est invalidé par des données nouvelles; dans les termes définis ici la surprise est équivalente à un change de paradigme. Des données empiriques limitées indiquent que les surprises apparaissent dans 20 à 30% des analyses effectuées sur les modèles. Ces données suggèrent que l'analyse des eaux souterraines présente des difficultés lorsqu'il s'agit de choisir le modèle conceptuel approprié. Il n'existe pas un autre remède au problème du modèle conceptuel que: (1) rassembler autant des données que possible en utilisant toutes les méthodes applicables—la méthode des données complémentaires peut conduire aux nouvelles informations qui vont changer le modèle conceptuel, et (2) l'analyste doit rester ouvert au fait

  16. In vivo expansion of regulatory T cells with IL-2/IL-2 mAb complexes prevents anti-factor VIII immune responses in hemophilia A mice treated with factor VIII plasmid-mediated gene therapy.

    Science.gov (United States)

    Liu, Chao-Lien; Ye, Peiqing; Yen, Benjamin C; Miao, Carol H

    2011-08-01

    Generation of transgene-specific immune responses can constitute a major complication following gene therapy treatment. An in vivo approach to inducing selective expansion of Regulatory T (Treg) cells by injecting interleukin-2 (IL-2) mixed with a specific IL-2 monoclonal antibody (JES6-1) was adopted to modulate anti-factor VIII (anti-FVIII) immune responses. Three consecutive IL-2 complexes treatments combined with FVIII plasmid injection prevented anti-FVIII formation and achieved persistent, therapeutic-level of FVIII expression in hemophilia A (HemA) mice. The IL-2 complexes treatment expanded CD4(+)CD25(+)Foxp3(+) Treg cells five- to sevenfold on peak day, and they gradually returned to normal levels within 7-14 days without changing other lymphocyte populations. The transiently expanded Treg cells are highly activated and display suppressive function in vitro. Adoptive transfer of the expanded Treg cells protected recipient mice from generation of high-titer antibodies following FVIII plasmid challenge. Repeated plasmid transfer is applicable in tolerized mice without eliciting immune responses. Mice treated with IL-2 complexes mounted immune responses against both T-dependent and T-independent neoantigens, indicating that IL-2 complexes did not hamper the immune system for long. These results demonstrate the important role of Treg cells in suppressing anti-FVIII immune responses and the potential of developing Treg cell expansion therapies that induce long-term tolerance to FVIII.

  17. Detecting IL-2 and IL-10 to predicate treatment outcome for Graves disease%IL-2与IL-10浓度变化对Graves病治疗效果的预测

    Institute of Scientific and Technical Information of China (English)

    李春北

    2010-01-01

    目的:探讨IL-2和IL-10变化对Graves病(Graves disease,GD)治疗转归的影响.方法:以2007年1月至2008年12月入我院治疗的GD患者72例,分别于治疗前及治疗后5月检测IL-2和IL-10及甲状腺素水平,评价IL-2和IL-10水平与治疗转归的关系.结果:72例GD患者甲亢未控制者21例,甲亢控制者35例,早发性甲减者16例.IL-2在甲亢未控制者水平最高,甲亢控制者次之,而早发性甲减者最低(P0.05).结论:IL-2/IL-10比值越高甲亢越难控制,比值越低越易产生甲减;IL-2/IL-10是较好的GD治疗效果预测指标.

  18. Mechanics of the IL2RA gene activation revealed by modeling and atomic force microscopy.

    Directory of Open Access Journals (Sweden)

    Pascale Milani

    Full Text Available Transcription implies recruitment of RNA polymerase II and transcription factors (TFs by DNA melting near transcription start site (TSS. Combining atomic force microscopy and computer modeling, we investigate the structural and dynamical properties of the IL2RA promoter and identify an intrinsically negative supercoil in the PRRII region (containing Elf-1 and HMGA1 binding sites, located upstream of a curved DNA region encompassing TSS. Conformational changes, evidenced by time-lapse studies, result in the progressive positioning of curvature apex towards the TSS, likely facilitating local DNA melting. In vitro assays confirm specific binding of the General Transcription Factors (GTFs TBP and TFIIB over TATA-TSS position, where an inhibitory nucleosome prevented preinitiation complex (PIC formation and uncontrolled DNA melting. These findings represent a substantial advance showing, first, that the structural properties of the IL2RA promoter are encoded in the DNA sequence and second, that during the initiation process DNA conformation is dynamic and not static.

  19. Transcription Factor Ets-2 Acts as a Preinduction Repressor of Interleukin-2 (IL-2) Transcription in Naive T Helper Lymphocytes.

    Science.gov (United States)

    Panagoulias, Ioannis; Georgakopoulos, Tassos; Aggeletopoulou, Ioanna; Agelopoulos, Marios; Thanos, Dimitris; Mouzaki, Athanasia

    2016-12-23

    IL-2 is the first cytokine produced when naive T helper (Th) cells are activated and differentiate into dividing pre-Th0 proliferating precursors. IL-2 expression is blocked in naive, but not activated or memory, Th cells by the transcription factor Ets-2 that binds to the antigen receptor response element (ARRE)-2 of the proximal IL-2 promoter. Ets-2 acts as an independent preinduction repressor in naive Th cells and does not interact physically with the transcription factor NFAT (nuclear factor of activated T-cells) that binds to the ARRE-2 in activated Th cells. In naive Th cells, Ets-2 mRNA expression, Ets-2 protein levels, and Ets-2 binding to ARRE-2 decrease upon cell activation followed by the concomitant expression of IL-2. Cyclosporine A stabilizes Ets-2 mRNA and protein when the cells are activated. Ets-2 silences directly constitutive or induced IL-2 expression through the ARRE-2. Conversely, Ets-2 silencing allows for constitutive IL-2 expression in unstimulated cells. Ets-2 binding to ARRE-2 in chromatin is stronger in naive compared with activated or memory Th cells; in the latter, Ets-2 participates in a change of the IL-2 promoter architecture, possibly to facilitate a quick response when the cells re-encounter antigen. We propose that Ets-2 expression and protein binding to the ARRE-2 of the IL-2 promoter are part of a strictly regulated process that results in a physiological transition of naive Th cells to Th0 cells upon antigenic stimulation. Malfunction of such a repression mechanism at the molecular level could lead to a disturbance of later events in Th cell plasticity, leading to autoimmune diseases or other pathological conditions. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. EXPRESSION OF IL-2 AND SIL-2R AND ALTERATION OF CELL IMMUNITY IN PATIENTS WITH HYPERTENSIVE CEREBRAL HEMORRHAGE

    Institute of Scientific and Technical Information of China (English)

    Zhang Yuelin; Qiu Shudong; Shi Wei; Dang Xiaojun

    2006-01-01

    Objective To study the expression of interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R),determine the alteration of erythrocytic immunity and T cell subgroup in the blood of outer circulation in patients with hypertensive cerebral hemorrhage so and to probe into the relationship between them, and to explore the clinical significance. Methods Enzyme linked immnunosorbent assay (ELISA) was used to determine the content of IL-2 and sIL-2R. The immunoadsorption was employed to examine the erythrocytic immune activity and its regulating function.Streptavidin-peroxidase(S-P) was used to determine the cell number of CD3 (cluster of differentiation3), CD4 and CD8. Results The content of IL-2 in the group with hypertensive cerebral hemorrhage was significantly lower than that in the control group (P<0.01), and the content of sIL-2R increased. Red blood cell C3b receptor (RBC. C3b R)and RBC immune adherence enhancing factor (RFEB) dropped greatly (P<0.01), while RBC immune complex rosette (RBC. ICR) and RBC immune adherence inhibiting factor (RFIR) increased greatly. The cell number of CD3 and CD4decreased (P<0.01) and there was no obvious change in CD8 (P<0.05). Conclusion The decrease of immune function was observed in patients with hypertensive cerebral hemorrhage. The determination of the content of IL-2, sIL-2R, erythrocytic immunity and the activity of T subgroup has an important clinical significance in the occurrence,development, treatment, and prognosis of hypertensive cerebral hemorrhage.

  1. {sup 18}F-FDG PET, genotype-corrected ACE and sIL-2R in newly diagnosed sarcoidosis

    Energy Technology Data Exchange (ETDEWEB)

    Keijsers, Ruth G.; Verzijlbergen, Fred J. [St. Antonius Hospital Nieuwegein, Department of Nuclear Medicine, P.O. Box 2500, Nieuwegein (Netherlands); Oyen, Wim J. [Radboud University Nijmegen Medical Center, Department of Nuclear Medicine, Nijmegen (Netherlands); Bosch, Jules M. van den; Grutters, Jan C. [St. Antonius Hospital Nieuwegein, Department of Pulmonology, Nieuwegein (Netherlands); Ruven, Henk J. [St. Antonius Hospital Nieuwegein, Department of Clinical Chemistry, Nieuwegein (Netherlands); Velzen-Blad, Heleen van [St. Antonius Hospital Nieuwegein, Department of Medical Microbiology and Immunology, Nieuwegein (Netherlands)

    2009-07-15

    Angiotensin-converting enzyme (ACE) and soluble interleukin-2 receptor (sIL-2R) are serological markers, widely used for determining sarcoidosis activity. {sup 18}F-FDG PET has proven to be a sensitive technique in the imaging of sarcoidosis. The aim of this study was to determine sensitivity of {sup 18}F-FDG PET, genotype-corrected ACE and sIL-2R in active sarcoidosis as well as their correlation. This retrospective study included 36 newly diagnosed, symptomatic sarcoidosis patients. ACE and sIL-2R levels were simultaneously obtained within 4 weeks of {sup 18}F-FDG PET. ACE was corrected for genotype and expressed as Z-score. {sup 18}F-FDG PET was visually evaluated and scored as positive or negative. Maximum and average standardized uptake values (SUV{sub max} and SUV{sub avg}) were compared with ACE and sIL-2R. {sup 18}F-FDG PET was found positive in 34 of 36 patients (94%). Thirteen patients (36%) showed an increased ACE with the highest sensitivity found in patients with the I/I genotype (67%). Seventeen patients (47%) showed an increased sIL-2R. No correlation was found between SUV and ACE or sIL-2R. Increased ACE and sIL-2R correlated with a positive {sup 18}F-FDG PET in 12 patients (92%) and 16 patients (94%), respectively. {sup 18}F-FDG PET is a very sensitive technique to assess active sarcoidosis, in contrast with ACE and sIL-2R, suggesting a pivotal role for {sup 18}F-FDG PET in future sarcoidosis assessment. (orig.)

  2. The Observation of Changes in Erythrocytes Immune and Expression of IL - 2、 sIL - 2R、TNF- α in Peripheral Blood of Patients With Nervous System Disorder%神经系统疾病患者外周血中IL-2、sIL-2R TNF-α的表达以及红细胞免疫的变化观察

    Institute of Scientific and Technical Information of China (English)

    刘景田; 党小军; 李彦玲

    2001-01-01

    目的研究IL-2、sIL-2R、TNF-α在神经系统疾病患者血清中的表达以及神经系统疾病红细胞免疫及其调节功能的变化规律.方法采用双抗体夹心酶联免疫吸附法(ELISA)定量测定患者血清中IL-2、sIL-2R、TNF-α的含量,采用红细胞与酵母菌免疫粘附法测定红细胞免疫功能及其调节功能.结果神经系统疾病患者IL-2IL-2R和TNF-α含量低于健康对照组(P<0.001、P<0.05、P<0.05),RBC-C3bRR和CR1FER低于健康对照组(P<0.01),RBC-ICR和CR1FIR高于健康对照组(P<0.01).结论提示该病的发生和发展过程与IL-2、sIL-2R、TNF-α的含量和红细胞免疫功能及其调节功能的变化有着密切的关系.

  3. Antigen-specific regulatory T cells and low dose of IL-2 in treatment of type 1 diabetes

    Directory of Open Access Journals (Sweden)

    Minh N. Pham

    2016-01-01

    Full Text Available Regulatory T cells (Tregs play an important role in preventing effector T-cell (Teff targeting of self-antigens that can lead to tissue destruction in autoimmune settings, including type 1 diabetes (T1D. Autoimmunity is caused in part by an imbalance between Teff and Tregs. Early attempts to treat with immunosuppressive agents have led to serious side effects, thus requiring a more targeted approach. Low-dose IL-2 (LD IL-2 can provide immuno-regulation with few side effects by preferentially acting on Tregs to drive tolerance. The concept of LD IL-2 as a therapeutic approach is supported by data in mouse models where autoimmunity is cured and further strengthened by success in human clinical studies in Hepatitis C Virus (HCV induced vasculitis, chronic graft vs host disease (GVHD and Alopecia areata (AA. Treatment will require identification of a safe therapeutic window, which is a difficult task given that patients are reported to have deficient or defective IL-2 production or signalling and have experienced mild activation of NK cells and eosinophils with LD IL-2 therapy. In T1D, a LD IL-2 clinical trial concluded that Tregs can be safely expanded in humans; however, the study was not designed to address efficacy. Antigen-specific therapies have also aimed at regulation of the autoimmune response, but have been filled with disappointment despite an extensive list of diverse islet antigens tested in humans. This approach could be enhanced through the addition of LD IL-2 to the antigenic treatment regimen to improve the frequency and function of antigen-specific Tregs, without global immunosuppression. Here we will discuss the use of LD IL-2 and islet antigen to enhance antigen-specific Tregs in T1D and focus on what is known about their immunological impact, their safety and potential efficacy, and need for better methods to identify therapeutic effectiveness.

  4. Surprising characteristics of visual systems of invertebrates.

    Science.gov (United States)

    González-Martín-Moro, J; Hernández-Verdejo, J L; Jiménez-Gahete, A E

    2017-01-01

    To communicate relevant and striking aspects about the visual system of some close invertebrates. Review of the related literature. The capacity of snails to regenerate a complete eye, the benefit of the oval shape of the compound eye of many flying insects as a way of stabilising the image during flight, the potential advantages related to the extreme refractive error that characterises the ocelli of many insects, as well as the ability to detect polarised light as a navigation system, are some of the surprising capabilities present in the small invertebrate eyes that are described in this work. The invertebrate eyes have capabilities and sensorial modalities that are not present in the human eye. The study of the eyes of these animals can help us to improve our understanding of our visual system, and inspire the development of optical devices. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

  5. Surprises from Saturn: Implications for Other Environments

    Science.gov (United States)

    Coates, A. J.

    2014-05-01

    The exploration of Saturn by Cassini has provided many surprises regarding: Saturn's rapidly rotating magnetosphere, interactions with its diverse moons, and interactions with the solar wind. Enceladus, orbiting at 4 Saturn radii (RS), was found to have plumes of water vapour and ice which are the dominant source for the inner magnetosphere. Charged water clusters, charged dust and photoelectrons provide key populations in the 'dusty plasma' observed. Direct pickup is seen near Enceladus and field-aligned currents create a spot in Saturn's aurora. At Titan, orbiting at 20 RS, unexpected heavy negative and positive ions are seen in the ionosphere, which provide the source for Titan's haze. Ionospheric plasma is seen in Titan's tail, enabling ion escape to be estimated at 7 tonnes per day. Saturn's ring ionosphere was seen early in the mission and a return will be made in 2017. In addition, highly accelerated electrons are seen at Saturn's high Mach number (MA˜100) quasi-parallel bow shock. Here we review some of these key new results, and discuss the implications for other solar system objects.

  6. The clinical use of BCG-CWS and IL-2 for preventing recurrence of superficial bladder cancer%BCG-CWS联合IL-2预防浅表性膀胱癌术后复发

    Institute of Scientific and Technical Information of China (English)

    秦自科; 林奕中; 周志伟; 梅骅; 戴宇平

    2001-01-01

    Objective To study the therapeutic effects of intravesical instillation of cell wall skeleton of bacillus Calmett-Guerin ( BCG-CWS ) and interleukin 2 (IL-2 ) in preventing bladder cancers from recurring after local ablation.Methods 56 patients with superficial bladder cancers were randomized in using BCG-CWS and IL-2 or MMC for preventing bladder cancers from recurring after local ablation.Results The patients have been followed up for 12~30 months (mean 22.9 months).One patient had tumor recurrence in the group using BCG-CWS and IL-2 and five in the MMC group,the rates of tumor recurrence were 3.6%(1/28)and 18.0%(5/28) respectively, and the difference was statistically significant(P<0.05). There were obviously more side effects in intravesical instillation with MMC than BCG-CWS and IL-2.Conclusions Intravesical instillation of BCG-CWS and IL-2 is effective in preventing superficial bladder cancer from recurring after local ablation with fewer adverse effects.The ragimen is not only reliable but also safe.%目的 探讨卡介苗细胞壁骨架(BCG-CWS)+白细胞介素2(IL-2)膀胱灌注预防浅表性膀胱癌术后复发的临床效果。方法 56例浅表性膀胱癌局部手术后随机分为两组,每组28例。分别采用BCG-CWS加IL-2和单用丝裂霉素C(MMC)进行膀胱灌注。结果 56例随访12~30个月,平均22.9个月。BCG-CWS+IL-2组有1例肿瘤复发,MMC组有5例肿瘤复发,两组肿瘤复发率差别有显著性意义(P<0.05);MMC灌注组的毒副反应较BCG-CWS+IL-2组多。结论 BCG-CWS联合IL-2预防浅表性膀胱癌术后复发疗效较好,副反应少,临床使用安全可靠。

  7. In vitro assessment of choline dihydrogen phosphate (CDHP) as a vehicle for recombinant human interleukin-2 (rhIL-2).

    Science.gov (United States)

    Foureau, David M; Vrikkis, Regina M; Jones, Chase P; Weaver, Katherine D; Macfarlane, Douglas R; Salo, Jonathan C; McKillop, Iain H; Elliott, Gloria D

    2012-12-01

    Choline dihydrogen phosphate (CDHP) is an ionic liquid reported to increase thermal stability of model proteins. The current work investigated CDHP effect on structural integrity and biological activity of recombinant human interleukin-2 (rhIL-2), a therapeutic protein used for treating advanced melanoma. In vitro CDHP biocompatibility was also evaluated using primary cell cultures, or B16-F10 cell line, chronically exposed to the ionic liquid. Formulation of rhIL-2 in an aqueous 680mM CDHP pH 7.4 solution resulted in a 12.5°C increase in the Tm of rhIL-2 compared to a basic buffer formulation, and provided conformational rhIL-2 stabilization when the solution was heated to 23.3°C above the Tm. CDHP solutions (≤80mM), exhibited no cytotoxic activity toward primary splenocytes or B16-F10 cells in culture. However, a 10-fold loss in biological activity was observed when rhIL-2 was used in a 30mM CDHP aqueous solution with NaHCO3 (pH≥7.2) compared to controls without CDHP. While increased Tm is associated with a diminished rhIL-2 biological activity, the therapeutic protein remains structurally intact and functional.

  8. Characterization of Receptor-Associated Protein Complex Assembly in Interleukin (IL)-2- and IL-15-Activated T-Cell Lines.

    Science.gov (United States)

    Osinalde, Nerea; Sanchez-Quiles, Virginia; Akimov, Vyacheslav; Aloria, Kerman; Arizmendi, Jesus M; Blagoev, Blagoy; Kratchmarova, Irina

    2017-01-06

    It remains a paradox that IL-2 and IL-15 can differentially modulate the immune response using the same signaling receptors. We have previously dissected the phosphotyrosine-driven signaling cascades triggered by both cytokines in Kit225 T-cells, unveiling subtle differences that may contribute to their functional dichotomy. In this study, we aimed to decipher the receptor complex assembly in IL-2- and IL-15-activated T-lymphocytes that is highly orchestrated by site-specific phosphorylation events. Comparing the cytokine-induced interactome of the interleukin receptor beta and gamma subunits shared by the two cytokines, we defined the components of the early IL-2 and IL-15 receptor-associated complex discovering novel constituents. Additionally, phosphopeptide-directed analysis allowed us to detect several cytokine-dependent and -independent phosphorylation events within the activated receptor complex including novel phosphorylated sites located in the cytoplasmic region of IL-2 receptor β subunit (IL-2Rβ). We proved that the distinct phosphorylations induced by the cytokines serve for recruiting different types of effectors to the initial receptor/ligand complex. Overall, our study sheds new light into the initial molecular events triggered by IL-2 and IL-15 and constitutes a further step toward a better understanding of the early signaling aspects of the two closely related cytokines in T-lymphocytes.

  9. The human IL-2 gene promoter can assemble a positioned nucleosome that becomes remodeled upon T cell activation.

    Science.gov (United States)

    Attema, Joanne L; Reeves, Raymond; Murray, Vincent; Levichkin, Ilya; Temple, Mark D; Tremethick, David J; Shannon, M Frances

    2002-09-01

    Controlled production of the cytokine IL-2 plays a key role in the mammalian immune system. Expression from the gene is tightly regulated with no detectable expression in resting T cells and a strong induction following T cell activation. The IL-2 proximal promoter (+1 to -300) contains many well-defined transcriptional activation elements that respond to T cell stimulation. To determine the role of chromatin structure in the regulation of interleukin-2 gene transcription, nucleosome assembly across the IL-2 promoter region was examined using in vitro chromatin reconstitution assays. The IL-2 promoter assembles a nucleosome that is both translationally and rotationally positioned, spanning some of the major functional control elements. The binding of transcription factors to these elements, with the exception of the architectural protein HMGA1, was occluded by the presence of the nucleosome. Analysis of the chromatin architecture of the IL-2 gene in Jurkat T cells provided evidence for the presence of a similarly positioned nucleosome in vivo. The region encompassed by this nucleosome becomes remodeled following activation of Jurkat T cells. These observations suggest that the presence of a positioned nucleosome across the IL-2 proximal promoter may play an important role in maintaining an inactive gene in resting T cells and that remodeling of this nucleosome is important for gene activation.

  10. Study on the construction of recombinant plasmid coexpressing newcastle disease virus F protein and chicken IL-2

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    This study investigated the protection against the ND in chickens by a recombinant DNA vaccine. A plasmid vector encoding NDV F protein, which is reqired for virus cell fusion and is important for vaccine induced immunity, was used as a model to study how DNA vaccines may be modulated by the simulaneous expression of chicken IL-2. The NDV D26 strain F gene with CMV promotor and BGH polyA signal sequence was amplified by PCR from eukaryotic plasmid pcDNA-F, which contains the full-length NDV F gene, and clond into reconstructed eukaryotic plasmid pcDNA-IL2, which contains chicken IL-2 gene. Restriction endonuclease cleavage and PCR amplification showed that a bicistronic plasmid encoding NDV F gene and chicken IL-2 separately was successfully constructed. Two-week-old SPF chickens were intramuscularly innoculated the recombinant plasmid. Antibody and lymphocyte proliferative assay showed that the humoral and cellular immunity of chickens vaccinated the recombinant plasmid greatly increased compared with those innoculated only plasmid expressing NDV F protein. Challenged with the lethal dose of NDV F48E9 strain, 72% chickens vaccinated recombinant plasmid were survived, and 30% chickens vaccinated plasmid expressing F protein were survived. These results proved the adjuvant effect of chicken IL-2, and further showed that the efficacy of a DNA vaccine can be greatly improved by simultaneous expression of IL-2.

  11. Hormone-Sensitive Lipase Knockouts

    Directory of Open Access Journals (Sweden)

    Shen Wen-Jun

    2006-02-01

    Full Text Available Abstract All treatments for obesity, including dietary restriction of carbohydrates, have a goal of reducing the storage of fat in adipocytes. The chief enzyme responsible for the mobilization of FFA from adipose tissue, i.e., lipolysis, is thought to be hormone-sensitive lipase (HSL. Studies of HSL knockouts have provided important insights into the functional significance of HSL and into adipose metabolism in general. Studies have provided evidence that HSL, though possessing triacylglycerol lipase activity, appears to be the rate-limiting enzyme for cholesteryl ester and diacylglycerol hydrolysis in adipose tissue and is essential for complete hormone stimulated lipolysis, but other triacylglycerol lipases are important in mediating triacylglycerol hydrolysis in lipolysis. HSL knockouts are resistant to both high fat diet-induced and genetic obesity, displaying reduced quantities of white with increased amounts of brown adipose tissue, increased numbers of adipose macrophages, and have multiple alterations in the expression of genes involved in adipose differentiation, including transcription factors, markers of adipocyte differentiation, and enzymes of fatty acid and triglyceride synthesis. With disruption of lipolysis by removal of HSL, there is a drastic reduction in lipogenesis and alteration in adipose metabolism.

  12. Costimulation of IL-2 Production through CD28 Is Dependent on the Size of Its Ligand.

    Science.gov (United States)

    Lim, Hong-Sheng; Cordoba, Shaun-Paul; Dushek, Omer; Goyette, Jesse; Taylor, Alison; Rudd, Christopher E; van der Merwe, P Anton

    2015-12-01

    Optimal T cell activation typically requires engagement of both the TCR and costimulatory receptors, such as CD28. Engagement of CD28 leads to tyrosine phosphorylation of its cytoplasmic region and recruitment of cytoplasmic signaling proteins. Although the exact mechanism of CD28 signal transduction is unknown, CD28 triggering has similarities to the TCR, which was proposed to use the kinetic-segregation (KS) mechanism. The KS model postulates that, when small receptors engage their ligands within areas of close (∼15 nm) contact in the T cell/APC interface, this facilitates phosphorylation by segregating the engaged receptor/ligand complex from receptor protein tyrosine phosphatases with large ectodomains, such as CD45. To test this hypothesis, we examined the effect of elongating the extracellular region of the CD28 ligand, CD80, on its ability to costimulate IL-2 production by primary T cells. CD80 elongation reduced its costimulatory effect without abrogating CD28 binding. Confocal microscopy revealed that elongated CD80 molecules were less well segregated from CD45 at the T cell/APC interface. T cells expressing CD28 harboring a key tyrosine-170 mutation were less sensitive to CD80 elongation. In summary, the effectiveness of CD28 costimulation is inversely proportional to the dimensions of the CD28-CD80 complex. Small CD28-CD80 complex dimensions are required for optimal costimulation by segregation from large inhibitory tyrosine phosphatases. These results demonstrate the importance of ligand dimensions for optimal costimulation of IL-2 production by T cells and suggest that the KS mechanism contributes to CD28 signaling.

  13. Regulatory T cells negatively affect IL-2 production of effector T cells through CD39/adenosine pathway in HIV infection.

    Directory of Open Access Journals (Sweden)

    Mohammad-Ali Jenabian

    Full Text Available The mechanisms by which Regulatory T cells suppress IL-2 production of effector CD4+ T cells in pathological conditions are unclear. A subpopulation of human Treg expresses the ectoenzyme CD39, which in association with CD73 converts ATP/ADP/AMP to adenosine. We show here that Treg/CD39+ suppress IL-2 expression of activated CD4+ T-cells more efficiently than Treg/CD39-. This inhibition is due to the demethylation of an essential CpG site of the il-2 gene promoter, which was reversed by an anti-CD39 mAb. By recapitulating the events downstream CD39/adenosine receptor (A2AR axis, we show that A2AR agonist and soluble cAMP inhibit CpG site demethylation of the il-2 gene promoter. A high frequency of Treg/CD39+ is associated with a low clinical outcome in HIV infection. We show here that CD4+ T-cells from HIV-1 infected individuals express high levels of A2AR and intracellular cAMP. Following in vitro stimulation, these cells exhibit a lower degree of demethylation of il-2 gene promoter associated with a lower expression of IL-2, compared to healthy individuals. These results extend previous data on the role of Treg in HIV infection by filling the gap between expansion of Treg/CD39+ in HIV infection and the suppression of CD4+ T-cell function through inhibition of IL-2 production.

  14. IL-2在自然感染兔脑炎原虫獭兔体内免疫作用的研究%Study of IL-2 Immunity about Otter Rabbits Naturally Infected with Encephalitozoon cuniculi

    Institute of Scientific and Technical Information of China (English)

    张柳平; 段艳; 潘耀谦

    2004-01-01

    为观察IL-2在自然感染兔脑炎原虫獭兔体内的免疫作用,用双抗体夹心ELISA试剂盒对8只自然感染兔脑炎原虫的獭兔和4只健康长耳白对照兔的血清及培养3d和4d的脾和淋巴结的细胞培养上清中的IL-2进行了检测.检测结果为病兔与对照兔IL-2平均含量差异不显著(P>0.05),但病兔IL-2平均含量高于对照兔.提示IL-2对病兔产生了一定的免疫作用,但可能不扮演主要角色.

  15. A Shocking Surprise in Stephan's Quintet

    Science.gov (United States)

    2006-01-01

    This false-color composite image of the Stephan's Quintet galaxy cluster clearly shows one of the largest shock waves ever seen (green arc). The wave was produced by one galaxy falling toward another at speeds of more than one million miles per hour. The image is made up of data from NASA's Spitzer Space Telescope and a ground-based telescope in Spain. Four of the five galaxies in this picture are involved in a violent collision, which has already stripped most of the hydrogen gas from the interiors of the galaxies. The centers of the galaxies appear as bright yellow-pink knots inside a blue haze of stars, and the galaxy producing all the turmoil, NGC7318b, is the left of two small bright regions in the middle right of the image. One galaxy, the large spiral at the bottom left of the image, is a foreground object and is not associated with the cluster. The titanic shock wave, larger than our own Milky Way galaxy, was detected by the ground-based telescope using visible-light wavelengths. It consists of hot hydrogen gas. As NGC7318b collides with gas spread throughout the cluster, atoms of hydrogen are heated in the shock wave, producing the green glow. Spitzer pointed its infrared spectrograph at the peak of this shock wave (middle of green glow) to learn more about its inner workings. This instrument breaks light apart into its basic components. Data from the instrument are referred to as spectra and are displayed as curving lines that indicate the amount of light coming at each specific wavelength. The Spitzer spectrum showed a strong infrared signature for incredibly turbulent gas made up of hydrogen molecules. This gas is caused when atoms of hydrogen rapidly pair-up to form molecules in the wake of the shock wave. Molecular hydrogen, unlike atomic hydrogen, gives off most of its energy through vibrations that emit in the infrared. This highly disturbed gas is the most turbulent molecular hydrogen ever seen. Astronomers were surprised not only by the turbulence

  16. The serotonin transporter knockout rat : A review

    NARCIS (Netherlands)

    Olivier, Jocelien; Cools, Alexander; Ellenbroek, Bart A.; Cuppen, E.; Homberg, Judith; Kalueff, Allan V.; LaPorte, Justin L.

    2010-01-01

    This chapter dicusses the most recent data on the serotonin transporter knock-out rat, a unique rat model that has been generated by target-selected N-ethyl-N-nitrosourea (ENU) driven mutagenesis. The knock-out rat is the result of a premature stopcodon in the serotonin transporter gene, and the abs

  17. Construction of recombinant attenuated Salmonella typhimurium DNA vaccine expressing H pylori ureB and IL-2

    Institute of Scientific and Technical Information of China (English)

    Can Xu; Zhao-Shen Li; Yi-Qi Du; Yan-Fang Gong; Hua Yang; Bo Sun; Jing Jin

    2007-01-01

    AIM: To construct a recombinant live attenuated Salmonella typhimurium DNA vaccine encoding H pylori ureB gene and mouse IL-2 gene and to detect its immunogenicity in vitro and in vivo.METHODS: H pylori ureB and mouse IL-2 gene fragments were amplified by potymerase chain reaction (PCR) and cloned into pUCmT vector. DNA sequence of the amplified ureB and IL-2 genes was assayed, then cloned into the eukaryotic expression vector pIRES through enzyme digestion and ligation reactions resulting in pIRES-ureB and pIRES-ureB-IL-2. The recombinant plasmids were used to transform competent E. Coli DH5a, and the positive clones were screened by PCR and restriction enzyme digestion. Then, the recombinant pIRES-ureB and pIRES-ureB-IL-2 were used to transform LB5000 and the recombinant plasmids extracted from LB5000 were finally introduced into the final host SL7207. After that, recombinant strains were grown in vitro repeatedly. In order to detect the immunogenicity of the vaccine in vitro, pIRES-ureB and pIRES-ureB-IL-2 were transfected to COS-7 cells using Lipofectamine TM 2000, the immunogenicity of expressed UreB and IL-2 proteins was assayed with SDS-PAGE and Western blot. C57BL/6 mice were orally immunized with 1 x 108 recombinant attenuated Salmonella typhimurium DNA vaccine. Four weeks after vaccination, mice were challenged with 1 x 107 CFU of live Hpylori SSI. Mice were sacrificed and the stomach was isolated for examination of H pylori 4 wk post-challenge.RESULTS: The 1700 base pair ureB gene fragment amplified from the genomic DNA was consistent with the sequence of H pylori ureB by sequence analysis. The amplified 510 base pair fragment was consistent with the sequence of mouse IL-2 in gene bank. It was confirmed by PCR and restriction enzyme digestion that H pylori ureB and mouse IL-2 genes were inserted into the eukaryotic expression vector pIRES. The experiments in vitro snowed that stable recombinant live attenuated Salmonella typhimurium DNA vaccine carrying

  18. Anti-viral drug treatment along with immune activator IL-2: a control-based mathematical approach for HIV infection

    Science.gov (United States)

    Nath Chatterjee, Amar; Roy, Priti Kumar

    2012-02-01

    Recent development in antiretroviral treatment against HIV can help AIDS patients to fight against HIV. But the question that whether the disease is to be partially or totally eradicated from HIV infected individuals still remains unsolved. Usually, the most effective treatment for the disease is HAART which can only control the disease progression. But as the immune system becomes weak, the patients can not fight against other diseases. Immune cells are activated and proliferated by IL-2 after the identification of antigen. IL-2 production is impaired in HIV positive patients and intermitted administration of immune activator IL-2 together with HAART which is a more effective treatment to fight against the disease. Thus, its expediency is essential and is yet to be explored. In this article we anticipated a mathematical model of the effect of IL-2 together with RTIs therapy in HIV positive patients. Our analytical as well as numerical study shows that the optimal schedule of treatment for best result is to be obtained by systematic drug therapy. But at the last stage of treatment, the infection level raises again due to minimisation of drug dosage. Thus we study the perfect adherence of the drugs and found out if RTIs are taken with sufficient interval then for fixed interval of IL-2 therapy, certain amount of drug dosages may be able to sustain the immune system at pre-infection stage and the infected CD4+T cells are going towards extinction.

  19. Stable Expression of Hantavirus H8205 Strain G1/IL-2 Gene and Immune Protection of the Fusion Gene

    Institute of Scientific and Technical Information of China (English)

    XIONG Ying; YUAN Yuan; JIA Min; YU Bing; HUANG Hanju

    2007-01-01

    To explore the feasibility of stable expression of Hantavirus H8205 strain G1 segment and human IL-2 fusion gene in Vero cells, and to examine the immune protection effects on mice vaccinated with this recombinant eukaryotic expression vector containing Hantavirus G1 gene and IL-2 gene. With the help of lipofectamine, the Vero cells were transfected with pcDNA3.1/HisB-IL-2-G1 and the positive cells were selected by G418. IFAT and SDS-PAGE electrophoresis were used to determine the stable transfection and expression of recombinant protein.Each mouse was inoculated with plasmids intramuscularly (i.m.) three times, 2 boosts were given at 2-week intervals, serum anti-hantavirus antibodies were detected by ELISA and neutralizing antibodies (NAb) were detected by Plaque Reduction Neutralization Test. The fusion protein expressed in Vero cells was 78 kD, corresponding to the estimated molecular size. The neutralizing antibody titers of mice with pcDNA3.1/HisB-IL-2-G1 were 1:20-1:80. IL-2/G1 fusion gene could be transferred in Vero cells and stably express the fusion protein. Specific humeral immune responses in mice can be induced with the recombinant eukaryotic expression vector containing the fusion gene, which lays the foundation for further development of therapeutic HTNV vaccine.

  20. Expression of Cytokines IL-2, IL-10 and TNF-α in Mice with Herpes Simplex Viral Encephalitis

    Institute of Scientific and Technical Information of China (English)

    WEI Guirong; ZHANG Min; MEI Yuanwu; DONG Jihua

    2006-01-01

    The expression of the cytokines IL-2, IL-10, TNF-α and their roles in mice with herpes simplex viral encephalitis (HSE) were studied. By using semiquantitative reverse transcription polymerase chain reaction (RT-PCR), the expressions of IL-2, IL-10 and TNF-α mRNA in control group, HSE group and acyclovir (ACV)-treated group were detected and the pathological changes of brain were observed. It was found that after HSV1 infection, the cerebral lesions of haemorrhage and necrosis in mice were observed under the microscopy, and the levels of IL-2, IL-10 and TNF-α were increased remarkably. After treatment with ACV after HSV1 infection, the cerebral lesions in mice were improved, the level of IL-2 maintained stable, IL-10 was increased consistently, and TNF-α was decreased significantly as compared with those in HSE group. In acute HSE, many cytokines are upregulated, including IL-2, IL-10 and TNF-α to eliminate virus and TH1 type response is dominant. In convalescence, there is a shift in the cytokine expression profile from TH1 profile to TH2 profile and the shift can inhibit the overexpression of immune response in animals. ACV has remarkable effects in the treatment of HSE.

  1. Cloning and sequence analysis of IL-2, IL-4 and IFN-γ from Indian Dromedary camels (Camelus dromedarius).

    Science.gov (United States)

    Nagarajan, G; Swami, Shelesh Kumar; Ghorui, S K; Pathak, K M L; Singh, R K; Patil, N V

    2012-06-01

    The cDNAs of three cytokines, viz., IL-2, IL-4 and IFN-γ from Dromedary camels were amplified by PCR using Bactrian camel sequences and subsequently cloned for sequence analysis. Relationship based on amino acid sequences revealed that Dromedary camel IL-2 shared 99.5% and 99.3% identity at the nucleotide and amino acid levels with Bactrian camel IL-2. In the case of IL-4, the identity of Dromedary camel was 99.7% and 99.2% at the nucleotide and amino acid levels, respectively with that of Bactrian camel. The Dromedary camel IFN-γ shared 100% identity both at nucleotide and amino acid levels with Bactrian camel IFN-γ. Phylogenetic analysis based on amino acid sequences indicated the close relationship in these cytokine genes between the Dromedary camel and other camelids.

  2. The Use of Registries to Improve Cancer Treatment: A National Database for Patients Treated with Interleukin-2 (IL-2

    Directory of Open Access Journals (Sweden)

    Howard L. Kaufman

    2014-03-01

    Full Text Available Registries evaluating un-randomized patients have provided valuable information with respect to a therapy’s utility, treatment practices, and evolution over time. While immunotherapy for cancer has been around for more than three decades, data collection in the form of a registry has not been undertaken. The authors believe that establishing a registry to study HD IL-2 immunotherapy, which has been the only systemic therapy producing long term unmaintained remissions for advanced kidney cancer and melanoma for over 20 years, will be an important resource in understanding the impact of immunotherapy with HD IL-2 in a rapidly changing therapeutic environment. Optimizing administration and improving selection of appropriate patients likely to benefit from HD IL-2 immunotherapy are two of many benefits to be derived from this endeavor.

  3. Effect of catecholamines on IL-2 production and NK cytotoxicity of rats in vitro

    Institute of Scientific and Technical Information of China (English)

    Yu-ping PENG; Yi-hua QIU; Jian-lan JIANG; Jian-jun WANGTM

    2004-01-01

    AIM: To explore effects of exogenous and endogenous catecholamines on function of lymphocytes and primary mechanisms mediating the effects. METHODS: Splenocytes of rats were exposed to norepinephrine (NE), α- or β-adrenoceptor antagonists plus NE, or α-methyl-p-tyrosine (α-MT), and then concanavalin A (Con A)-induced intefleukin-2 (IL-2) production and natural killer (NK) cell cytotoxicity were determined by MTT assay and LDH assay, respectively. RESULTS: Optical density (OD) values of NE-treated groups, which reflected IL-2 production,were 0.63, 0.61, and 0.60, respectively for 1×10-10, 1×10-9, and 1×10-8 mol/L NE. They were all significantly reduced in comparison with control value of 0.68 (P<0.01). The effect of NE was blocked by either phentolamine (an α-adrenoceptor antagonist) or propanolol (a β-adrenoceptor antagonist). OD values of α-MT, an inhibitor of tyrosine hydroxylase, at doses of l× 10-10, 1× 10-9, and 1× 10-8 mol/L respectively were 0.71, 0.71, and 0.69, which were all notably higher than that of control (0.65, P<0.01). NK cytotoxicity was markedly attenuated by both NE and α-MT at the three doses mentioned above (17.69 %, 17.06 %, and 16.89 % versus 25.18 % for NE; 18.85 %,18.44 %, and 17.04 % versus 23.22 % for α-MT; all P<0.01). The suppression of NK cytotoxicity by NE was prevented by propranolol but not by phentolamine. CONCLUSION: Exogenous NE exerts a suppressive action in modulating functions of T and NK cells, with the former via both α- and β-adrenoceptor mediated mechanisms and the later mainly through β-adrenoceptors. Endogenous catecholamines synthesized by lymphocytes have also an autoregulatory effect on the lymphocytes themselves.

  4. IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production.

    Directory of Open Access Journals (Sweden)

    Lisa M Maier

    2009-01-01

    Full Text Available Multiple sclerosis (MS and type 1 diabetes (T1D are organ-specific autoimmune disorders with significant heritability, part of which is conferred by shared alleles. For decades, the Human Leukocyte Antigen (HLA complex was the only known susceptibility locus for both T1D and MS, but loci outside the HLA complex harboring risk alleles have been discovered and fully replicated. A genome-wide association scan for MS risk genes and candidate gene association studies have previously described the IL2RA gene region as a shared autoimmune locus. In order to investigate whether autoimmunity risk at IL2RA was due to distinct or shared alleles, we performed a genetic association study of three IL2RA variants in a DNA collection of up to 9,407 healthy controls, 2,420 MS, and 6,425 T1D subjects as well as 1,303 MS parent/child trios. Here, we report "allelic heterogeneity" at the IL2RA region between MS and T1D. We observe an allele associated with susceptibility to one disease and risk to the other, an allele that confers susceptibility to both diseases, and an allele that may only confer susceptibility to T1D. In addition, we tested the levels of soluble interleukin-2 receptor (sIL-2RA in the serum from up to 69 healthy control subjects, 285 MS, and 1,317 T1D subjects. We demonstrate that multiple variants independently correlate with sIL-2RA levels.

  5. The Influence of Negative Surprise on Hedonic Adaptation

    Directory of Open Access Journals (Sweden)

    Ana Paula Kieling

    2016-01-01

    Full Text Available After some time using a product or service, the consumer tends to feel less pleasure with consumption. This reduction of pleasure is known as hedonic adaptation. One of the emotions that interfere in this process is surprise. Based on two experiments, we suggest that negative surprise – differently to positive – influences with the level of pleasure foreseen and experienced by the consumer. Study 1 analyzes the influence of negative (vs. positive surprise on the consumer’s post-purchase hedonic adaptation expectation. Results showed that negative surprise influences the intensity of adaptation, augmenting its strength. Study 2 verifies the influence of negative (vs positive surprise over hedonic adaptation. The findings suggested that negative surprise makes adaptation happen more intensively and faster as time goes by, which brings consequences to companies and consumers in the post-purchase process, such as satisfaction and loyalty.

  6. Cell-autonomous role of TGFβ and IL-2 receptors in CD4+ and CD8+ inducible regulatory T-cell generation during GVHD.

    Science.gov (United States)

    Sawamukai, Norifumi; Satake, Atsushi; Schmidt, Amanda M; Lamborn, Ian T; Ojha, Priti; Tanaka, Yoshiya; Kambayashi, Taku

    2012-06-01

    FoxP3(+) regulatory T cells (Tregs) suppress GVHD while preserving graft-versus-tumor effects, making them an attractive target for GVHD therapy. The donor-derived Treg pool can potentially be derived from the expansion of preexisting natural Tregs (nTregs) or from de novo generation of inducible Tregs (iTregs) from donor Tconvs in the transplantation recipient. Using an MHC-mismatched model of acute GVHD, in the present study we found that the Treg pool was comprised equally of donor-derived nTregs and iTregs. Experiments using various combinations of T cells from wild-type and FoxP3-deficient mice suggested that both preexisting donor nTregs and the generation of iTregs in the recipient mice contribute to protection against GVHD. Surprisingly, CD8(+)FoxP3(+) T cells represented approximately 70% of the iTreg pool. These CD8(+)FoxP3(+) T cells shared phenotypic markers with their CD4(+) counterparts and displayed suppressive activity, suggesting that they were bona fide iTregs. Both CD4(+) and CD8(+) Tregs appeared to be protective against GVHD-induced lethality and required IL-2 and TGFβ receptor expression for their generation. These data illustrate the complex makeup of the donor-derived FoxP3(+) Treg pool in allogeneic recipients and their potential role in protection against GVHD.

  7. In vitro assessment of choline dihydrogen phosphate (CDHP) as a vehicle for recombinant human interleukin-2 (rhIL-2)

    OpenAIRE

    Foureau, David M.; Vrikkis, Regina M.; Jones, Chase P.; Weaver, Katherine D.; MacFarlane, Douglas R.; Salo, Jonathan C.; McKillop, Iain H.; Elliott, Gloria D.

    2012-01-01

    Choline dihydrogen phosphate (CDHP) is an ionic liquid reported to increase thermal stability of model proteins. The current work investigated CDHP effect on structural integrity and biological activity of recombinant human interleukin-2 (rhIL-2), a therapeutic protein used for treating advanced melanoma. In vitro CDHP biocompatibility was also evaluated using primary cell cultures, or B16-F10 cell line, chronically exposed to the ionic liquid. Formulation of rhIL-2 in an aqueous 680mM CDHP p...

  8. Effects of Surprisal and Locality on Danish Sentence Processing

    DEFF Research Database (Denmark)

    Balling, Laura Winther; Kizach, Johannes

    2017-01-01

    An eye-tracking experiment in Danish investigates two dominant accounts of sentence processing: locality-based theories that predict a processing advantage for sentences where the distance between the major syntactic heads is minimized, and the surprisal theory which predicts that processing time...... constructions with two postverbal NP-objects. An eye-tracking experiment showed a clear advantage for local syntactic relations, with only a marginal effect of lexicalised surprisal and no effect of syntactic surprisal. We conclude that surprisal has a relatively marginal effect, which may be clearest for verbs...

  9. The effect of Opuntia dillenii extracts on IL-2 and TNF-alpha in S180 mice%仙人掌提取物对S180荷瘤小鼠IL-2、TNF-α的影响

    Institute of Scientific and Technical Information of China (English)

    韦启后; 韦国锋; 覃淑云; 黄衍强; 覃艳春; 陆金兰

    2005-01-01

    目的观察仙人掌提取物对S180荷瘤小鼠IL-2、TNF-α的影响.方法用S180腹水型肉瘤小鼠的腹水肿瘤细胞悬液接种小鼠左腋皮下复制肿瘤模型.造模后随机分为仙人掌提取物组、肝复乐片组、模型空白组、正常对照组.前两组分别给予仙人掌提取液、肝复乐混悬液灌胃;模空组和正常对照组以生理盐水灌胃.每次0.2 ml/10g*d-1,每天1次,连续10 天.于第11天取材测定小鼠血清IL-2、TNF-α含量.结果仙人掌提取物组小鼠血清IL-2水平比模空组明显提高(P<0.01);TNF-α水平明显降低(P<0.05).结论仙人掌提取物能提高IL-2水平,降低TNF-α水平,有抗肿瘤作用.

  10. Antitumor Effects of A10, 5Fu, GM-CSF and IL-2%抗瘤酮A10、5Fu、GM-CSF和IL-2的抗癌效果

    Institute of Scientific and Technical Information of China (English)

    刘淑玲; 张秀霞; 迟春萍; 王妍; 刘哲; 屈阿妮; 孙妍红; 佟祥山

    2004-01-01

    目的比较A10、5Fu、GM-CSF和IL-2的抗癌效果.方法选取NIH小鼠,分别腹腔接种肝腹水HeP-A-22细胞、骨肉瘤S180细胞及胃癌MFC细胞,10 d后将注射每种细胞的小鼠分为3组,每组12只,分别于小鼠腹腔注射A10、5Fu、GM-CSF和IL-2,每日1次,每次1 ml/只,连续给药8 d后改为每3 d给药1次,观察小鼠生存时间及抑瘤效果.结果A10、5Fu、GM-CSF及IL-2均能延长小鼠生存时间,A10抑制肝HeP-A-22肿瘤效果显著.结论A10、5Fu、GM-CSF和IL-2均有抑制癌细胞生长作用.

  11. Targeted therapy to the IL-2R using diphtheria toxin and caspase-3 fusion proteins modulates Treg and ameliorates inflammatory colitis.

    Science.gov (United States)

    Yarkoni, Shai; Sagiv, Yuval; Kaminitz, Ayelet; Farkas, Daniel L; Askenasy, Nadir

    2009-10-01

    Pathogenic lymphocytes in the enteric wall of inflammatory bowel disease patients display various abnormalities, including reduced sensitivity to apoptosis. We evaluated a therapeutic approach to elimination of cytotoxic cells, using two IL-2 fusion proteins, a diphtheria toxin (IL2-DT) and a caspase-3 (IL2-cas) conjugate. In models of acute (dextran sodium sulfate and trinitrobenzene sulfonic acid) and chronic (dextran sodium sulfate) toxic colitis, therapeutic doses of the fusion proteins improved survival and prevented colon shortening. While both chimeric proteins eradicated CD4(+)CD25(+)Foxp3(+) T cells in mesenteric LN, IL2-DT caused severe lymphopenia. In contrast, IL2-cas was equally protective and increased fractional expression of Foxp3. Similar effects of the fusion proteins were observed in healthy mice: IL2-DT caused lymphopenia and IL2-cas increased fractional expression of FoxP3. The fusion proteins induced apoptosis in CD25(+) T cells in vitro, with lower toxicity of IL2-cas to Foxp3(+) T cells. These data infer that targeted depletion of cells expressing the IL-2 receptor has therapeutic potential in models of inflammatory colitis, despite depletion of CD25(+) Treg. The IL2-cas fusion protein is particularly relevant to inflammatory bowel disease, as direct internalization of toxic moieties overcomes multiple pathways of resistance to apoptosis of colitogenic T cells.

  12. Enhanced inhibition of tumour growth and metastasis, and induction of antitumour immunity by IL-2-IgG2b fusion protein.

    Science.gov (United States)

    Budagian, V; Nanni, P; Lollini, P L; Musiani, P; Di Carlo, E; Bulanova, E; Paus, R; Bulfone-Paus, S

    2002-05-01

    Cytokine-immunoglobulin (Ig)-fusion proteins have attracted increasing interest as antitumour agents. Here, we have investigated the antimetastatic and antitumour responses elicited in vivo by mammary adenocarcinoma cells (TS/A) engineered to secrete interleukin (IL)-2-IgG fusion proteins. TS/A cells were transfected with DNA coding for IL-2-IgG2b, IgG2b or IL-2, and injected subcutaneously into syngeneic mice. Animals injected with TS/A-IL-2 or TS/A-IL-2-IgG2b both efficiently rejected tumours, whereas treatment with parental cells or TS/A-IgG2b was lethal. Interestingly, only mice vaccinated with IL-2-IgG2b fusion protein-secreting cells showed a long-lasting protective immunity against a later challenge with parental tumour cells. Moreover, the metastatic potential of TS/A-IL-2-IgG2b-transfected cells was dramatically decreased compared with TS/A-IL-2-cells, with a virtual absence of lung metastases after intravenous injection. Adenocarcinomas secreting IL-2-IgG2b exhibited a more prominent, early and persistent infiltration of CD4+, CD8+ and natural killer (NK) cells than TS/A-IL-2 cells. Therefore, upon transfection into adenocarcinoma cells, the IgG2b part of IL-2 fusion protein exerts intriguing added antitumour properties over IL-2 alone, thus contributing to a long-lasting tumour immunity, probably by the recruitment of specific immune effector cells. These findings suggest a promising new oncotherapeutic strategy for poorly immunogenic tumours: vaccination with tumour cells engineered to secrete IL-2-IgG2b fusion protein.

  13. Shock Waves Increase T-cell Proliferation or IL-2 Expression by Activating p38 MAP Kinase

    Institute of Scientific and Technical Information of China (English)

    Tie-Cheng YU; Yi LIU; Yan TAN; Yanfang JIANG; Xueqing ZHENG; Xinxiang XU

    2004-01-01

    Shock waves were elicited by transient pressure disturbances, which could be used to treat musculoskeletal disorders. In present studies, we i. nvestigated whether the low-density shock waves (LDSWs), which are able to damage plasma membrane without impairing the vimentin or other organelles, might augment T-cell proliferation as well as IL-2 expression, and if mitogen activated protein kinase p38 (p38 MAPK)might be an underlying mechanism through which the LDSWs enhanced T-cell function. We found that the LDSWs increased activation of p38 MAPK in Jurkat T cells. The LDSWs alone didn't result in the T-cell proliferation and IL-2 expression. However, in combination with other stimuli, LDSWs could augment the T-cell proliferation and IL-2 expression. Inhibition of p38 MAPK using SB203580 reduced the stimulatory effects of the LDSWs, which indicated that the LDSWs enhanced IL-2 expression through a mechanism that involved p38 MAPK activation. We concluded that the p38 MAPK activation played a key role in the regulation of T cell function by the LDSWs.

  14. 18F-FDG PET, genotype-corrected ACE and sIL-2R in newly diagnosed sarcoidosis.

    NARCIS (Netherlands)

    Keijsers, R.G.; Verzijlbergen, F.J.; Oyen, W.J.G.; Bosch, J.M. van den; Ruven, H.J.; Velzen-Blad, H. van; Grutters, J.C.

    2009-01-01

    PURPOSE: Angiotensin-converting enzyme (ACE) and soluble interleukin-2 receptor (sIL-2R) are serological markers, widely used for determining sarcoidosis activity. (18)F-FDG PET has proven to be a sensitive technique in the imaging of sarcoidosis. The aim of this study was to determine sensitivity o

  15. Polymorphic variants of the IL2RA gene and susceptibility to type 1 diabetes in the Polish population.

    Science.gov (United States)

    Fichna, M; Zurawek, M; Fichna, P; Januszkiewicz, D; Nowak, J

    2012-03-01

    Polymorphic variants of the IL2RA gene, which encodes high-affinity alpha subunit (CD25) of the interleukin-2 receptor, were recently found to affect the risk of several autoimmune disorders. This study was aimed to investigate the association of selected IL2RA polymorphisms (rs11594656, rs3118470, rs2104286 and rs7093069) with type 1 diabetes (T1D) in a Polish cohort comprising 445 patients and 671 healthy control subjects. The minor A allele at rs11594656 was found significantly less frequently among T1D subjects, compared with the control group [P = 0.011; odds ratio (OR) = 0.77; 95% confidence interval (CI) = 0.629-0.942]. In contrast, the minor C allele at rs3118470 appeared to be significantly associated with the occurrence of T1D (P = 0.003; OR = 1.30; 95% CI = 1.094-1.550). Two other IL2RA single nucleotide polymorphisms (SNPs) did not show significant differences among investigated groups. In conclusion, the study confirms the association of the IL2RA locus with T1D in the Polish population.

  16. Defective T-cell colony formation and IL-2 receptor expression at all stages of HIV infection.

    Science.gov (United States)

    Winkelstein, A; Kingsley, L A; Klein, R S; Lyter, D W; Evans, T L; Rinaldo, C R; Weaver, L D; Machen, L L; Schadle, R C

    1988-01-01

    The T-cell colony assay is a highly sensitive measure of immunological dysfunction. The present study evaluated this in vitro response in asymptomatic HIV-infected homosexuals, those with chronic adenopathy as their only clinical manifestation and patients with either ARC or AIDS. The mean colony count in antibody-positive asymptomatic individuals was significantly reduced when compared to either heterosexual controls or antibody-negative homosexuals. Furthermore, there were no differences in the responses of these antibody-positive individuals and those with chronic lymphadenopathy as their only clinical manifestation. By contrast, patients with AIDS or ARC showed a profound defect; this suggests that the colony assay can detect a functional gradient across the spectrum of HIV infections. Colony growth was correlated with the absolute number of T-helper cells and the ability of PHA-stimulated lymphocytes to express IL-2 receptors; no correlation was found with the number of suppressor/cytotoxic cells or in vitro production of IL-2. Recent HIV seroconverters had normal colony counts but impaired ability to express IL-2 receptors. These data suggest a sequential loss of T-cell function as a result of HIV infection; the earliest manifestations are impaired expression of IL-2 receptors and reduced proliferative responses, as measured in the colony assay. PMID:2968201

  17. Characterization of receptor-associated protein complex assembly in interleukin (IL)-2- and IL-15-activated T-cell lines

    DEFF Research Database (Denmark)

    Osinalde, Nerea; Sánchez-Quiles, Virginia; Akimov, Vyacheslav

    2017-01-01

    to their functional dichotomy. In this study, we aimed to decipher the receptor complex assembly in IL-2- and IL-15-activated T-lymphocytes that is highly orchestrated by site-specific phosphorylation events. Comparing the cytokine-induced interactome of the interleukin receptor beta and gamma subunits shared...

  18. Cord Blood Cells Responses to IL2, IL7 and IL15 Cytokines for mTOR Expression

    Directory of Open Access Journals (Sweden)

    Anahita Mohammadian

    2017-04-01

    Full Text Available Purpose: Mammalian target of rapamycin (mTORis important in hematopoiesis and affect cell growth,differentiation and survival. Although previous studies were identified the effect of cytokines on the mononuclear cells development however the cytokines effect on mTOR in cord blood mononuclear cells was unclear. The aim of this study was to evaluate mTOR expression in cord blood mononuclear and cord blood stem cells (CD34+ cells in culture conditions for lymphoid cell development. Methods: Isolation of The mononuclear cells (MNCs from umbilical cord blood were done with use of Ficollpaque density gradient. We evaluated cultured cord blood mononuclear and CD34+ cells in presece of IL2, IL7 and IL15 at distinct time points during 21 days by using flow cytometry. In this study, we presented the role of IL2, IL7 and IL15 on the expression of mTOR in cord blood cells. Results: mTOR expression were increased in peresence of IL2, IL7 and IL15 in day 14 and afterword reduced. However in persence of IL2 and IL15 expression of mTOR significantly reduced. mTOR expression in CD34+ cells decreased significantly from day7 to day 21 in culture. Conclusion: cytokines play important role in mTOR expression during hematopoiesis and development of cord blood mononuclear cells.

  19. Low prevalence of antibodies and other plasma factors binding to CC chemokines and IL-2 in HIV-positive patients.

    Science.gov (United States)

    Meyer, C N; Svenson, M; Schade Larsen, C; Odum, N; Skinhøj, P; Bendtzen, K

    2000-02-01

    Neutralizing cytokine antibodies are found in healthy and diseased individuals, including patients treated with recombinant cytokines. Identification of CCR-5 as co-receptor for HIV has focused interest on CC chemokines and their potential therapeutic use. Chemokine-binding components in plasma of HIV-infected patients were therefore assessed by radioimmunoassay and radioreceptor assay. IgG from 4/505 HIV patients and 9/2000 healthy controls (p>0.05) bound rMIP-1alpha and rMIP-1beta, but not rRANTES. No other plasma factors bound the chemokines. The antibodies inhibited receptor binding of both chemokines. There was no association between presence of antibodies and disease stage or HIV progression rate. Three of 11 patients treated with rIL-2 developed IgG antibodies suppressing cellular binding and growth promotion of rIL-2. Hence, circulating factors, including antibodies MIP-1alpha/MIP-1beta, are uncommon in healthy individuals and HIV patients, and are apparently without prognostic significance. In contrast to earlier reports, IL-2 antibodies were found only in HIV patients treated with rIL-2.

  20. 18F-FDG PET, genotype-corrected ACE and sIL-2R in newly diagnosed sarcoidosis.

    NARCIS (Netherlands)

    Keijsers, R.G.; Verzijlbergen, F.J.; Oyen, W.J.G.; Bosch, J.M. van den; Ruven, H.J.; Velzen-Blad, H. van; Grutters, J.C.

    2009-01-01

    PURPOSE: Angiotensin-converting enzyme (ACE) and soluble interleukin-2 receptor (sIL-2R) are serological markers, widely used for determining sarcoidosis activity. (18)F-FDG PET has proven to be a sensitive technique in the imaging of sarcoidosis. The aim of this study was to determine sensitivity

  1. Surprise and Sense Making: Undergraduate Placement Experiences in SMEs

    Science.gov (United States)

    Walmsley, Andreas; Thomas, Rhodri; Jameson, Stephanie

    2006-01-01

    Purpose: This paper seeks to explore undergraduate placement experiences in tourism and hospitality SMEs, focusing on the notions of surprise and sense making. It aims to argue that surprises and sense making are important elements not only of the adjustment process when entering new work environments, but also of the learning experience that…

  2. Knockout Reaction Mechanism for 6He+%Knockout Reaction Mechanism for 6He+

    Institute of Scientific and Technical Information of China (English)

    吕林辉; 叶沿林; 曹中鑫; 肖军; 江栋兴; 郑涛; 华辉; 李智焕; 葛俞成; 李湘庆; 楼建玲; 李阔昂; 李奇特; 乔锐; 游海波; 陈瑞九

    2012-01-01

    A knockout reaction experiment was carried out by using the 6He beam at 82.5 MeV/nucleon impinging on CH2 and C targets. The a core fragments at forward angles were detected in coincidence with the recoiled protons at larger angles. From this exclusive measure- ment the valence nucleon knockout mechanism and the core knockout mechanism are separated. This study provides a basis for the exclusive spectroscopic investigation of the exotic nuclei.

  3. Neural Responses to Rapid Facial Expressions of Fear and Surprise

    Directory of Open Access Journals (Sweden)

    Ke Zhao

    2017-05-01

    Full Text Available Facial expression recognition is mediated by a distributed neural system in humans that involves multiple, bilateral regions. There are six basic facial expressions that may be recognized in humans (fear, sadness, surprise, happiness, anger, and disgust; however, fearful faces and surprised faces are easily confused in rapid presentation. The functional organization of the facial expression recognition system embodies a distinction between these two emotions, which is investigated in the present study. A core system that includes the right parahippocampal gyrus (BA 30, fusiform gyrus, and amygdala mediates the visual recognition of fear and surprise. We found that fearful faces evoked greater activity in the left precuneus, middle temporal gyrus (MTG, middle frontal gyrus, and right lingual gyrus, whereas surprised faces were associated with greater activity in the right postcentral gyrus and left posterior insula. These findings indicate the importance of common and separate mechanisms of the neural activation that underlies the recognition of fearful and surprised faces.

  4. Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression

    Science.gov (United States)

    Traboulsee, Anthony L.; Bernales, Cecily Q.; Ross, Jay P.; Lee, Joshua D.; Sadovnick, A. Dessa; Vilariño-Güell, Carles

    2016-01-01

    Multiple sclerosis (MS) is a common demyelinating neurodegenerative disease with a strong genetic component. Previous studies have associated genetic variants in IL2RA and IL7R in the pathophysiology of the disease. In this study we describe the association between IL2RA (rs2104286) and IL7R (rs6897932) in the Canadian population. Genotyping 1,978 MS patients and 830 controls failed to identify any significant association between these variants and disease risk. However, stratified analysis for family history of disease, and disease course identified a trend towards association for IL2RA in patients without a family history (p = 0.05; odds ratio = 0.77), and a significant association between IL7R and patients who developed progressive MS (PrMS) (p = 0.002; odds ratio = 0.73). Although not statistically significant, the effect of IL2RA (rs2104286) in patients without a family history of MS indicates that the genetic components for familial and sporadic disease are perhaps distinct. This data suggests the onset of sporadic disease is likely determined by a large number of variants of small effect, whereas MS in patients with a family history of disease is caused by a few deleterious variants. In addition, the significant association between PrMS and rs6897932 indicates that IL7R may not be disease-causing but a determinant of disease course. Further characterization of the effect of IL2RA and IL7R genetic variants in defined MS subtypes is warranted to evaluate the effect of these genes on specific clinical outcomes and to further elucidate the mechanisms of disease onset and progression. PMID:24770783

  5. CONSTRUCTION AND EXPRESSION OF ADENOASSOCIATED VIRUS- BASED PLASMID EXPRESSING VECTORS CONTAINING hIL- 2 GENE OR mIFN-γ GENE

    Institute of Scientific and Technical Information of China (English)

    张景迎; 梁宏立; 陈诗书

    2000-01-01

    Objective To improve the plasmid vectors in gene therapy, adeno - associated virus (AA V) based plasmid expressing vectors containing hIL-2 gene or mIFN-γ gene were constructed and its expression in transfected cells was studied. Methods By means of step to step cloning, promoter CMVp was placed at the downstream of 5' inverted terminal repeat from AA V (AA V- ITR) of pAP, hIL- 2 gene or mIFN- γ gene inserted into pAC between CMVp and poly A. Then intron A was inserted into pAC- hIL - 2 or pAC- mIFN- γ between CMVp and IL - 2 gene or IFNγ gene to construct pAI- hIL - 2 or pAI- mIFN - γ. Liposome -plasmid complexes were formed by mixing Dosper with these AAV-based plasmids containing hIL-2 gene or mIFN-γgene. Results High biological activities of IL - 2 or IFN- γ could be detected in the supernatants of NIH3T3 and MM45T. Li cells after transfection. Insertion of intron A into pAC-hIL-2 or pAC-mIFN-γ improved the expression of IL- 2 or IFN- γ. Conclusion These data demonstrated that the constructed AA V- based plasmid expressing vectors could efficiently express therapeutic genes in cultured cells and could be used as a nonviral gene transfer system in human gene therapy.

  6. Defective production of interleukin 2 in patients with Chagas' disease: purified IL-2 augments in vitro response in patients with chagasic cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Luis Briceno

    1996-10-01

    Full Text Available The production of interleukin 2 (IL-2 by peripheral blood mononuclear cells, from patients with different clinical forms of Chagas disease and healthy controls, was evaluated after stimulation with Trypanosoma cruzi antigen, PPD and PHA. PHA induced higher production of IL-2 in infected patients than healthy controls. No diferences were found between infected groups. With PPD the trend was similar, the only difference was that asymptomatic infected patients (INF showed higher levels of IL-2 production than patients with cardiomyopathy (CDM. With T. cruzi antigen, most patients showed little or no IL-2 production at 24 hr, a peak at 48 hr and an abrupt fall at 72 hr. A similar pattern of IL- 2 production was observed in INF and CDM. To evaluate the physiologic relevance of the deficit in IL-2 production, we studied the effect of non-mitogenic concentratios of IL-2 in the proliferative response to specific antigens. The addition of IL-2 only enhanced the proliferative response of CDM patients. These observations suggest that patients suffering Chagas' disease, particularly CDM, have a significant reduction in the capacity to produce IL-2. These findings could be of importance in the pathogenesis of Chagas' disease.

  7. Cloning and Sequence Analysis of Gallus IL-2 Gene and Prediction of Protein Structure%鸡IL-2基因的克隆、序列分析及蛋白结构预测

    Institute of Scientific and Technical Information of China (English)

    谢昆; 蒋成砚; 胡俊杰; 全舒舟; 宋银银

    2011-01-01

    According to GenBank in the IL-2 cDNA sequences, using Premier 5.0 software design a pairs of specific primer, the local Dorking inject 100 μg/ml Con A, total RNA was extracted from feeding 24 hours lymphocyte from spleen, by RT-PCR cloning colony IL-2 cDNA fragment. The DNA fragments were analyzed use DNAStar software between different species identity for comparison. Sequence analysis showed that IL-2 gene has an open reading frames for 432 nucleotide acids, encoding 143 amino acids and most of signal peptide, compared with published on Genbank, the nucleotide identity was 98.8%、 31.2%、 28.2%、 27.3%、30.6%、 26.2%、 31.7%、 30.1%、 30.8%、 26.6%、 30.6%. compared with published on Genbank, the Amino acids was 95.8%, 7.6%、 7.6%、 9.7%、 7.6%、 6.9%、 10.4% 11.8%, 7.6%, 9.0%, 7.6%, 10.4% with cattle, horse, cat,sheep, bovine, canis, people, capra, mice, cow of IL-2 sequence comparison The gallus IL-2 gene was successfully cloned, there is a species-specific. And construct a based on further study the biological effects of IL-2 gene in particular the use of IL-2 enhance the immune effect of DNA vaccine.%根据GenBank中已发表的鸡白细胞介素2(IL-2)mRNA基因序列,利用Premier 5.0软件设计一对特异性引物,采用RT-PCR技术,以ConA刺激的鸡外周血淋巴细胞为材料,从总RNA中扩增出鸡IL-2基因.经琼脂糖凝胶电泳显示扩增片段约为432 bp,分离纯化片段,克隆入pMD-18T载体,转化DH5α感受态细胞,获得阳性重组质粒,经酶切鉴定,测序结果显示,该基因全长432 bp,含有一个432bp的开放阅读框,编码143个氨基酸.生物软件分析结果表明该序列与GenBank中发表的鸡的IL-2的核苷酸序列同源性为98.8%,与黄牛、马、鸡、绵羊、牛、犬、人、山羊、鼠、水牛的核苷酸同源性分别为31.2%、28.2%、273%、30.6%、26.2%、31.7%、30.1%、30.8%、26.6%、30.6%.与GenBank中发表的鸡IL-2编码

  8. 耐力性运动中补糖对自行车运动员IL-2的影响%Influence of carbohydrate intake on IL - 2 of cyclists during endurance exercise

    Institute of Scientific and Technical Information of China (English)

    张海

    2007-01-01

    目的 通过给耐力自行车运动员在运动过程中补充8%低聚糖饮料,观察NK细胞的数量变化以及IL-2的活性变化,并探讨其机制.方法 10名自行车运动员以70%的摄氧量进行功率车运动1 h,运动前、运动后即刻、运动后2 h以及运动后4 h采集静脉血,测试机体NK细胞数量和IL-2的活性.结果 在耐力性运动中补糖可以增加NK细胞的数量,增强IL-2的活性.结论 在耐力性运动中补糖可以增加能量供应,并帮助机体免疫系统的维持.

  9. Purification and Biological Activity of Recombinant Melittin-88 ArgIL-2%重组蜂毒素-基因变构IL-2的纯化与生物活性

    Institute of Scientific and Technical Information of China (English)

    刘明军; 王斌; 钱冬萌; 丁守怡; 闫志勇; 宋旭霞

    2006-01-01

    目的 制备纯化重组蜂毒素-基因变构IL-2(Melittin-88 ArgIL-2)嵌合蛋白,并检测其生物活性.方法 将含表达载体的大肠杆菌DH5α,经IPTG诱导表达.表达产物经离子交换层析与亲和层析进行纯化,SDS-PAGE鉴定,MTT染色法检测嵌合蛋白对Hela细胞增殖的抑制作用.结果 所表达的可溶性蛋白,纯化后纯度达95%,蛋白浓度0.5 g/L.纯化后的嵌合蛋白在体外能抑制Hela细胞的增殖.结论 已成功地制备并纯化了重组melittin-88 ArgIL-2嵌合蛋白,该蛋白具有生物活性,为中试放大和纯化工艺研究奠定了基础.

  10. Sodium arsenite-induced inhibition of cell proliferation is related to inhibition of IL-2 mRNA expression in mouse activated T cells

    Energy Technology Data Exchange (ETDEWEB)

    Conde, Patricia; Acosta-Saavedra, Leonor C.; Calderon-Aranda, Emma S. [Centro de Investigacion y de Estudios Avanzados, CINVESTAV, Seccion Toxicologia, P.O. Box 14-740, Mexico, D.F. (Mexico); Goytia-Acevedo, Raquel C. [Universidad Juarez del Estado de Durango, Facultad de Medicina, Gomez Palacio, Durango (Mexico)

    2007-04-15

    A proposed mechanism for the As-induced inhibition of cell proliferation is the inhibition of IL-2 secretion. However, the effects of arsenite on IL-2 mRNA expression or on the ERK pathway in activated-T cells have not yet been described. We examined the effect of arsenite on IL-2 mRNA expression, cell activation and proliferation in PHA-stimulated murine lymphocytes. Arsenite (1 and 10 {mu}M) decreased IL-2 mRNA expression, IL-2 secretion and cell proliferation. Arsenite (10 {mu}M) strongly inhibited ERK-phosphorylation. However, the partial inhibition (50%) of IL-2 mRNA produced by 1 {mu}M, consistent with the effects on IL-2 secretion and cell proliferation, could not be explained by the inhibition of ERK-phosphorylation, which was not affected at this concentration. The inhibition of IL-2 mRNA expression caused by 1 {mu}M could be associated to effects on pathways located downstream or parallel to ERK. Arsenite also decreased early activation (surface CD69{sup +} expression) in both CD4{sup +} and CD8{sup +}, and decreased total CD8{sup +} count without significantly affecting CD4{sup +}, supporting that the cellular immune response mediated by cytotoxic T cells is an arsenic target. Thus, our results suggest that arsenite decreases IL-2 mRNA levels and T-cell activation and proliferation. However, further studies on the effects of arsenite on IL-2 gene transcription and IL-2 mRNA stability are needed. (orig.)

  11. Patients with T⁺/low NK⁺ IL-2 receptor γ chain deficiency have differentially-impaired cytokine signaling resulting in severe combined immunodeficiency.

    Science.gov (United States)

    Fuchs, Sebastian; Rensing-Ehl, Anne; Erlacher, Miriam; Vraetz, Thomas; Hartjes, Lara; Janda, Ales; Rizzi, Marta; Lorenz, Myriam R; Gilmour, Kimberly; de Saint-Basile, Geneviève; Roifman, Chaim M; Cheuk, Steven; Gennery, Andrew; Thrasher, Adrian J; Fuchs, Ilka; Schwarz, Klaus; Speckmann, Carsten; Ehl, Stephan

    2014-10-01

    X-linked severe combined immunodeficiency (X-SCID) leads to a T(-) NK(-) B(+) immunophenotype and is caused by mutations in the gene encoding the IL-2 receptor γ-chain (IL2RG). IL2RG(R222C) leads to atypical SCID with a severe early onset phenotype despite largely normal NK- and T-cell numbers. To address this discrepancy, we performed a detailed analysis of T, B, and NK cells, including quantitative STAT phosphorylation and functional responses to the cytokines IL-2, IL-4, IL-15, and IL-21 in a patient with the IL2RG(R222C) mutation. Moreover, we identified nine additional unpublished patients with the same mutations, all with a full SCID phenotype, and confirmed selected immunological observations. T-cell development was variably affected, but led to borderline T-cell receptor excision circle (TREC) levels and a normal repertoire. T cells showed moderately reduced proliferation, failing enhancement by IL-2. While NK-cell development was normal, IL-2 enhancement of NK-cell degranulation and IL-15-induced cytokine production were absent. IL-2 or IL-21 failed to enhance B-cell proliferation and plasmablast differentiation. These functional alterations were reflected by a differential impact of IL2RG(R222C) on cytokine signal transduction, with a gradient IL-4<IL-2/IL-15IL2RG(R222C) causes a consistently severe clinical phenotype that is not predicted by the variable and moderate impairment of T-cell immunity or TREC analysis.

  12. Leukemogenesis in heterozygous PU.1 knockout mice.

    Science.gov (United States)

    Genik, Paula C; Vyazunova, Irina; Steffen, Leta S; Bacher, Jeffery W; Bielefeldt-Ohmann, Helle; McKercher, Scott; Ullrich, Robert L; Fallgren, Christina M; Weil, Michael M; Ray, F Andrew

    2014-09-01

    Most murine radiation-induced acute myeloid leukemias involve biallelic inactivation of the PU.1 gene, with one allele being lost through a radiation-induced chromosomal deletion and the other allele affected by a recurrent point mutation in codon 235 that is likely to be spontaneous. The short latencies of acute myeloid leukemias occurring in nonirradiated mice engineered with PU.1 conditional knockout or knockdown alleles suggest that once both copies of PU.1 have been lost any other steps involved in leukemogenesis occur rapidly. Yet, spontaneous acute myeloid leukemias have not been reported in mice heterozygous for a PU.1 knockout allele, an observation that conflicts with the understanding that the PU.1 codon 235 mutation is spontaneous. Here we describe experiments that show that the lack of spontaneous leukemia in PU.1 heterozygous knockout mice is not due to insufficient monitoring times or mouse numbers or the genetic background of the knockout mice. The results reveal that spontaneous leukemias that develop in mice of the mixed 129S2/SvPas and C57BL/6 background of knockout mice arise by a pathway that does not involve biallelic PU.1 mutation. In addition, the latency of radiation-induced leukemia in PU.1 heterozygous mice on a genetic background susceptible to radiation-induced leukemia indicates that the codon 235 mutation is not a rate-limiting step in radiation leukemogenesis driven by PU.1 loss.

  13. Defense Science Board (DSB) Summer Study Report on Strategic Surprise

    Science.gov (United States)

    2015-07-01

    DSB Summer Study Report on Strategic Surprise July 2015 Report Documentation Page Form ApprovedOMB No. 0704-0188 Public reporting burden...SUBTITLE DSB Summer Study Report on Strategic Surprise 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) Defense Science Board ( DSB ),The Pentagon ,OUSD(AT&L

  14. Low prevalence of antibodies and other plasma factors binding to CC chemokines and IL-2 in HIV-positive patients

    DEFF Research Database (Denmark)

    Meyer, C N; Svenson, M; Larsen, Carsten Schade;

    2000-01-01

    Neutralizing cytokine antibodies are found in healthy and diseased individuals, including patients treated with recombinant cytokines. Identification of CCR-5 as co-receptor for HIV has focused interest on CC chemokines and their potential therapeutic use. Chemokine-binding components in plasma...... of HIV-infected patients were therefore assessed by radioimmunoassay and radioreceptor assay. IgG from 4/505 HIV patients and 9/2000 healthy controls (p>0.05) bound rMIP-1alpha and rMIP-1beta, but not rRANTES. No other plasma factors bound the chemokines. The antibodies inhibited receptor binding of both...... chemokines. There was no association between presence of antibodies and disease stage or HIV progression rate. Three of 11 patients treated with rIL-2 developed IgG antibodies suppressing cellular binding and growth promotion of rIL-2. Hence, circulating factors, including antibodies MIP-1alpha/MIP-1beta...

  15. Serum levels of soluble IL-2R, CD4 and CD8 in bronChial asthma

    Directory of Open Access Journals (Sweden)

    G. Di Lorenzo

    1995-01-01

    Full Text Available The aim of the present study was to compare serum levels of soluble forms of interleukin-2 receptor, CD4 and CD8, released by lymphocytes during activation of the immune system, in patients with allergic bronchial asthma, with those in healthy subjects. Significantly higher levels of soluble IL-2R and soluble CD4 were found in patients with asthma compared with the control group. In contrast, lower levels of soluble CD8 values were found in patients with asthma compared to the control group. Significant correlations were found for both sIL-2R and sCD4 and these two molecules, with lung function measured as bronchial responsiveness to inhaled methacholine. These results strengthen previous suggestions that in allergic bronchial asthma, activation of T cells plays a significant role in the disease pathogenesis.

  16. Low prevalence of antibodies and other plasma factors binding to CC chemokines and IL-2 in HIV-positive patients

    DEFF Research Database (Denmark)

    Meyer, C N; Svenson, M; Schade Larsen, C;

    2000-01-01

    of HIV-infected patients were therefore assessed by radioimmunoassay and radioreceptor assay. IgG from 4/505 HIV patients and 9/2000 healthy controls (p>0.05) bound rMIP-1alpha and rMIP-1beta, but not rRANTES. No other plasma factors bound the chemokines. The antibodies inhibited receptor binding of both...... chemokines. There was no association between presence of antibodies and disease stage or HIV progression rate. Three of 11 patients treated with rIL-2 developed IgG antibodies suppressing cellular binding and growth promotion of rIL-2. Hence, circulating factors, including antibodies MIP-1alpha/MIP-1beta...

  17. Low prevalence of antibodies and other plasma factors binding to CC chemokines and IL-2 in HIV-positive patients

    DEFF Research Database (Denmark)

    Meyer, C N; Svenson, M; Schade Larsen, C

    2000-01-01

    chemokines. There was no association between presence of antibodies and disease stage or HIV progression rate. Three of 11 patients treated with rIL-2 developed IgG antibodies suppressing cellular binding and growth promotion of rIL-2. Hence, circulating factors, including antibodies MIP-1alpha/MIP-1beta......Neutralizing cytokine antibodies are found in healthy and diseased individuals, including patients treated with recombinant cytokines. Identification of CCR-5 as co-receptor for HIV has focused interest on CC chemokines and their potential therapeutic use. Chemokine-binding components in plasma...... of HIV-infected patients were therefore assessed by radioimmunoassay and radioreceptor assay. IgG from 4/505 HIV patients and 9/2000 healthy controls (p>0.05) bound rMIP-1alpha and rMIP-1beta, but not rRANTES. No other plasma factors bound the chemokines. The antibodies inhibited receptor binding of both...

  18. Effect of Polysaccharide L-2 from Lentinus edodes on TNF- α and IL-2%香菇多糖L-2对荷瘤小鼠TNF-α和IL-2的影响

    Institute of Scientific and Technical Information of China (English)

    阮征; 付晓芳; 周泉城; 胡筱波; 吴谋成

    2006-01-01

    The effects of the polysaccharide (L-2) extracted from Lentinus edodes on the immune response of Sarcoma 180-bearing mice were evaluated. Mice were treated with two doses of polysaccharide L-2 ( 1, 10mg/kg body weight) for 10 days. The concentration of tumor necrosis factor-alpha (TNF- α ), interferon-2 (IL-2) in mice serum and TNF- α mRNA expression were determined. The concentration of TNF- α in serum increased significantly in two doses groups compared to the model control group, but IL-2 not. The level of TNF- α mRNA transcription increased significantly in two doses groups to the model control group. Results of these studies demonstrated the polysaccharide L-2 significantly promoted TNF- α production, immunity potentiating and anti-tumor effects of the polysaccharide L-2 were associated with its potentiation of TNF- α mRNA expression at the transcriptional level.%我们提取纯化得到一种重均分子量为2.03×105、单糖为葡萄糖的香菇多糖级分(L-2)后,评价了香菇多糖L-2对荷S-180小鼠细胞免疫的影响.连续10d通过腹腔注射给予小鼠不同剂量的香菇多糖L-2(10mg/kg体重),测定了正常小鼠与荷S-180小鼠的血清中肿瘤坏死因子(TNF-α)和白介素2(IL-2)的含量,以及香菇多糖L-2对TNF-α和IL-2的mRNA表达的影响.与对照组小鼠相比,血清中TNF-α含量有显著增加,而血清中IL-2含量没有变化,与此同时,香菇多糖L-2可以上调TNF-α的mRNA的表达.结果揭示多糖L-2有增加TNF-α含量的作用,多糖增强免疫力与TNF-α含量增加以及在转录水平上调TNF-α mRNA的表达有关.

  19. TK gene combined with mIL-2 and mGM-CSF genes in treatment of gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Shan-Yu Guo; Qin-Long Gu; Zheng-Gang Zhu; He-Qun Hong; Yan-Zhen Lin

    2003-01-01

    AIM: Cancer gene therapy has received more and moreattentions in the recent decade. Various systems of genetherapy for cancer have been developed. One of the mostpromising choices is the suicide gene. The product ofthymidine kinase (TK) gene can convert ganciclovir (GCV)to phosphorylated GCV, which inhibits the synthesis of cellDNA, and then induces the cells to death. Cytolines play animportant role in anti-tumor immunity. This experiment wasdesigned to combine theTK gene and mIL-2/mGM-CSFgenes to treat gastric cancer, and was expected to producea marked anti-tumor effect.METHODS: TK gene was constructed into the retroviralvector pLxSN, and the mIL-2 and mGM-CSF genes wereinserted into the eukaryotic expressing vector pIRES. Thegastric cancer cells were transfected by retroviral serum thatwas harvested from the package cells. In vitro study, thetransfected gastric cancer cells were maintained in the GCV-contained medium, to assay the cell killing effect andbystander effect. In vivo experiment, retroviral serum andcytokines plasmid were transfected into tumor-bearing mice,to observe the changes of tumor volumes and survival ofthe mice.RESULTS: In vitro experiment, 20 % TK gene transducedcells could cause 70-80 % of total cells to death. In vivoresults showed that there was no treatment effect in controlgroup and TK/GCV could inhibit the tumor growth. Thestrongest anti-tumor effect was shown in TK+mIL-2+mGM-CSF group. The pathologic examination showed necrosis ofthe cancer in the treated groups.CONCLUSION: TK/GCV can kill tumor cells and inhibit thetumor growth in vivo IL-2 and GM-CSF strongly enhancethe anti-tumor effect. Through the retrovirus and liposomemethods, the suicide gene and cytokine genes are allexpressed in the tissues.

  20. Cutting Edge: memory regulatory t cells require IL-7 and not IL-2 for their maintenance in peripheral tissues.

    Science.gov (United States)

    Gratz, Iris K; Truong, Hong-An; Yang, Sara Hsin-Yi; Maurano, Megan M; Lee, Karim; Abbas, Abul K; Rosenblum, Michael D

    2013-05-01

    Thymic Foxp3-expressing regulatory T cells are activated by peripheral self-antigen to increase their suppressive function, and a fraction of these cells survive as memory regulatory T cells (mTregs). mTregs persist in nonlymphoid tissue after cessation of Ag expression and have enhanced capacity to suppress tissue-specific autoimmunity. In this study, we show that murine mTregs express specific effector memory T cell markers and localize preferentially to hair follicles in skin. Memory Tregs express high levels of both IL-2Rα and IL-7Rα. Using a genetic-deletion approach, we show that IL-2 is required to generate mTregs from naive CD4(+) T cell precursors in vivo. However, IL-2 is not required to maintain these cells in the skin and skin-draining lymph nodes. Conversely, IL-7 is essential for maintaining mTregs in skin in the steady state. These results elucidate the fundamental biology of mTregs and show that IL-7 plays an important role in their survival in skin.

  1. Memory regulatory T cells require IL-7 and not IL-2 for their maintenance in peripheral tissues1

    Science.gov (United States)

    Gratz, Iris K.; Truong, Hong-An; Yang, Sara Hsin-Yi; Maurano, Megan M.; Lee, Karim; Abbas, Abul K.; Rosenblum, Michael D.

    2013-01-01

    Thymic Foxp3-expressing regulatory T cells are activated by peripheral self antigen to increase their suppressive function, and a fraction of these cells survive as memory Tregs (mTregs). Memory Tregs persist in non-lymphoid tissue after cessation of antigen expression and have enhanced capacity to suppress tissue-specific autoimmunity. Here, we show that murine mTregs express specific effector memory T cell markers and localize preferentially to hair follicles in skin. Memory Tregs express high levels of both IL-2Rα and IL-7Rα. Using a genetic deletion approach, we show that IL-2 is required to generate mTregs from naive CD4+ T cell precursors in vivo. However, IL-2 is not required to maintain these cells in the skin and skin-draining lymph nodes. Conversely, IL-7 is essential for maintaining mTregs in skin in the steady state. These results elucidate the fundamental biology of mTregs and show that IL-7 plays an important role in their survival in skin. PMID:23543753

  2. CCR3 expression induced by IL-2 and IL-4 functioning as a death receptor for B cells

    DEFF Research Database (Denmark)

    Jinquan, Tan; Jacobi, Henrik H; Jing, Chen

    2003-01-01

    We report that CCR3 is not expressed on freshly isolated peripheral and germinal B cells, but is up-regulated after stimulation with IL-2 and IL-4 (approximately 98% CCR3(+)). Ligation of CCR3 by eotaxin/chemokine ligand (CCL) 11 induces apoptosis in IL-2- and IL-4-stimulated primary CD19......(+) (approximately 40% apoptotic cells) B cell cultures as well as B cell lines, but has no effect on chemotaxis or cell adhesion. Freshly isolated B cells express low levels of CD95 and CD95 ligand (CD95L) (19 and 21%, respectively). Expression is up-regulated on culture in the presence of a combination of IL-2, IL......-4, and eotaxin/CCL11 (88% CD95 and 84% CD95L). We therefore propose that ligation of such newly induced CCR3 on peripheral and germinal B cells by eotaxin/CCL11 leads to the enhanced levels of CD95 and CD95L expression. Ligation of CD95 by its CD95L expressed on neigboring B cells triggers relevant...

  3. IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2.

    Science.gov (United States)

    Jandl, Christoph; Liu, Sue M; Cañete, Pablo F; Warren, Joanna; Hughes, William E; Vogelzang, Alexis; Webster, Kylie; Craig, Maria E; Uzel, Gulbu; Dent, Alexander; Stepensky, Polina; Keller, Bärbel; Warnatz, Klaus; Sprent, Jonathan; King, Cecile

    2017-03-17

    T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3(+) regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.

  4. Recovery and Biodistribution of Ex Vivo Expanded Human Erythroblasts Injected into NOD/SCID/IL2Rγnull mice

    Directory of Open Access Journals (Sweden)

    Barbara Ghinassi

    2011-01-01

    Full Text Available Ex vivo expanded erythroblasts (EBs may serve as advanced transfusion products provided that lodgment occurs in the macrophage-niche of the marrow permitting maturation. EBs expanded from adult and cord blood expressed the receptors (CXCR4, VLA-4, and P-selectin ligand 1 necessary for interaction with macrophages. However, 4-days following transfusion to intact NOD/SCID/IL2Rγnull mice, CD235apos EBs were observed inside CD235aneg splenic cells suggesting that they underwent phagocytosis. When splenectomized and intact NOD/SCID/IL2Rγnull mice were transfused using retrovirally labeled human EBs, human cells were visualized by bioluminescence imaging only in splenectomized animals. Four days after injection, human CD235apos cells were detected in marrow and liver of splenectomized mice but only in spleen of controls. Human CD235apos erythrocytes in blood remained low in all cases. These studies establish splenectomized NOD/SCID/IL2Rγnull mice as a suitable model for tracking and quantification of human EBs in vivo.

  5. Association of CD147 and Calcium Exporter PMCA4 Uncouples IL-2 Expression from Early TCR Signaling.

    Science.gov (United States)

    Supper, Verena; Schiller, Herbert B; Paster, Wolfgang; Forster, Florian; Boulègue, Cyril; Mitulovic, Goran; Leksa, Vladimir; Ohradanova-Repic, Anna; Machacek, Christian; Schatzlmaier, Philipp; Zlabinger, Gerhard J; Stockinger, Hannes

    2016-02-01

    The Ig superfamily member CD147 is upregulated following T cell activation and was shown to serve as a negative regulator of T cell proliferation. Thus, Abs targeting CD147 are being tested as new treatment strategies for cancer and autoimmune diseases. How CD147 mediates immunosuppression and whether association with other coreceptor complexes is needed have remained unknown. In the current study, we show that silencing of CD147 in human T cells increases IL-2 production without affecting the TCR proximal signaling components. We mapped the immunosuppressive moieties of CD147 to its transmembrane domain and Ig-like domain II. Using affinity purification combined with mass spectrometry, we determined the domain specificity of CD147 interaction partners and identified the calcium exporter plasma membrane calcium ATPase isoform 4 (PMCA4) as the interaction partner of the immunosuppressive moieties of CD147. CD147 does not control the proper membrane localization of PMCA4, but PMCA4 is essential for the CD147-dependent inhibition of IL-2 expression via a calcium-independent mechanism. In summary, our data show that CD147 interacts via its immunomodulatory domains with PMCA4 to bypass TCR proximal signaling and inhibit IL-2 expression.

  6. Co-transfection of dendritic cells with AFP and IL-2 genes enhances the induction of tumor antigen-specific antitumor immunity.

    Science.gov (United States)

    Yang, Jing-Yue; Li, Xiao; Gao, Li; Teng, Zeng-Hui; Liu, Wen-Chao

    2012-10-01

    Dendritic cells (DCs) are highly efficient, specialized antigen-presenting cells and DCs transfected with tumor-related antigens are regarded as promising vaccines in cancer immunotherapy. The aim of the present study was to investigate whether DCs co-transfected with the α-fetoprotein (AFP) and human interleukin-2 (IL-2) genes were able to induce stronger therapeutic antitumor immunity in transfected DCs. In this study, DCs from hepatocellular carcinoma (HCC) patients were co-transfected with the IL-2 gene and/or the AFP gene. The reverse transcription-PCR (RT-PCR) data revealed that the DCs transfected with the adenovirus AdAFP/IL-2 expressed AFP and IL-2. The DCs co-transfected with IL-2 and AFP (AFP/IL-2-DCs) enhanced the cytotoxicities of cytotoxic T lymphocytes (CTLs) and increased the production of IL-2 and interferon-γ significantly compared with their AFP-DC, green fluorescent protein (GFP)-DC, DC or phosphate-buffered saline (PBS) counterparts. In vivo data suggested that immunization with AFP-DCs enhances antigen-specific antitumor efficacy more potently than immunization with IL-2-DCs or AFP-DCs. These findings provide a potential strategy to improve the efficacy of DC-based tumor vaccines.

  7. SILAC-based quantification of changes in protein tyrosine phosphorylation induced by Interleukin-2 (IL-2) and IL-15 in T-lymphocytes

    DEFF Research Database (Denmark)

    Osinalde, Nerea; Sánchez-Quiles, Virginia; Akimov, Vyacheslav

    2015-01-01

    enrichment with SILAC-based quantitative mass spectrometry. We report all the proteins and phosphotyrosine-containing peptides identified and quantified in IL-2- and IL-15-stimulated T-lymphocytes. The gene ontology analysis of IL-2 and IL-15 effector proteins detected in the present work is also included...

  8. Qualitatively different T cell phenotypic responses to IL-2 versus IL-15 are unified by identical dependences on receptor signal strength and duration.

    Science.gov (United States)

    Arneja, Abhinav; Johnson, Hannah; Gabrovsek, Laura; Lauffenburger, Douglas A; White, Forest M

    2014-01-01

    IL-2 and IL-15 are common γ-chain family cytokines involved in regulation of T cell differentiation and homeostasis. Despite signaling through the same receptors, IL-2 and IL-15 have non-redundant roles in T cell biology, both physiologically and at the cellular level. The mechanisms by which IL-2 and IL-15 trigger distinct phenotypes in T cells remain elusive. To elucidate these mechanisms, we performed a quantitative comparison of the phosphotyrosine signaling network and resulting phenotypes triggered by IL-2 and IL-15. This study revealed that the signaling networks activated by IL-2 or IL-15 are highly similar and that T cell proliferation and metabolism are controlled in a quantitatively distinct manner through IL-2/15R signal strength independent of the cytokine identity. Distinct phenotypes associated with IL-2 or IL-15 stimulation therefore arise through differential regulation of IL-2/15R signal strength and duration because of differences in cytokine-receptor binding affinity, receptor expression levels, physiological cytokine levels, and cytokine-receptor intracellular trafficking kinetics. These results provide important insights into the function of other shared cytokine and growth factor receptors, quantitative regulation of cell proliferation and metabolism through signal transduction, and improved design of cytokine based clinical immunomodulatory therapies for cancer and infectious diseases.

  9. Effects of Warm Needling at Zusanli (ST 36) on NO and IL-2 Levels in the Middle-Aged and Old People

    Institute of Scientific and Technical Information of China (English)

    李苏; 陈开阳; 吴英; 焦健慧; 陶立富

    2003-01-01

    42 middle-aged and old people at the age between 55-70 years were selected and given the warm needling at Zusanli (ST 36), and their IL-2 and NO contents of peripheral blood before and after acupuncture were determined. The results showed that IL-2 and NO contents increased significantly after the warm needling (P<0.01).

  10. Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen

    DEFF Research Database (Denmark)

    Andersen, Rikke; Donia, Marco; Ellebaek, Eva;

    2016-01-01

    administered together with TILs are severe. To further scrutinize whether similar results can be achieved with lower doses of IL2, we have carried out a phase I/II trial of TIL transfer after classical lymphodepleting chemotherapy followed by an attenuated IL2 regimen. EXPERIMENTAL DESIGN: Twenty-five patients...... decrescendo regimen (ClinicalTrials.gov Identifier: NCT00937625). RESULTS: Classical IL2-related toxicities were observed but patients were manageable in a general oncology ward without the need for intervention from the intensive care unit. RECIST 1.0 evaluation displayed three complete responses and seven...... to treatment. CONCLUSIONS: TIL-ACT with a reduced IL2 decrescendo regimen results in long-lasting complete responses in patients with treatment-refractory melanoma. Larger randomized trials are needed to elucidate whether clinical efficacy is comparable with TIL-ACT followed by HD bolus IL2. Clin Cancer Res...

  11. Generation and characterization of RAG2 knockout pigs as animal model for severe combined immunodeficiency.

    Science.gov (United States)

    Suzuki, Shunichi; Iwamoto, Masaki; Hashimoto, Michiko; Suzuki, Misae; Nakai, Michiko; Fuchimoto, Daiichiro; Sembon, Shoichiro; Eguchi-Ogawa, Tomoko; Uenishi, Hirohide; Onishi, Akira

    2016-10-01

    Pigs with severe combined immunodeficiency (SCID) are versatile animal models for human medical research because of their biological similarities to humans, suitable body size, and longevity for practical research. SCID pigs with defined mutation(s) can be an invaluable tool for research on porcine immunity. In this study, we produced RAG2-knockout pigs via somatic cell nuclear transfer and analyzed their phenotype. The V(D)J recombination processes were confirmed as being inactivated. They consistently lacked mature T and B cells but had substantial numbers of cells considered to be T- or B-cell progenitors as well as NK cells. They also lacked thymic medulla and lymphoid aggregations in the spleen, mesenteric lymph nodes, and ileal Peyer's patches. We showed more severe immunological defects in the RAG2 and IL2RG double-knockout pig through this study. Thus, SCID pigs could be promising animal models not only for translational medical research but also for immunological studies of pigs themselves.

  12. Identification of contact and respiratory sensitizers according to IL-4 receptor α expression and IL-2 production

    Energy Technology Data Exchange (ETDEWEB)

    Goutet, Michèle, E-mail: michele.goutet@inrs.fr; Pépin, Elsa; Langonné, Isabelle; Huguet, Nelly; Ban, Masarin

    2012-04-15

    Identification of allergenic chemicals is an important occupational safety issue. While several methods exist to identify contact sensitizers, there is currently no validated model to predict the potential of chemicals to act as respiratory sensitizers. Previously, we reported that cytometry analysis of the local immune responses induced in mice dermally exposed to the respiratory sensitizer trimellitic anhydride (TMA 10%) and contact sensitizer dinitrochlorobenzene (DNCB 1%) could identify divergent expression of several immune parameters. The present study confirms, first, that IgE-positive B cells, MHC class II molecules, interleukin (IL)-2, IL-4 and IL-4Rα can differentiate the allergic reactions caused by high doses of strong respiratory (TMA, phthalic anhydride and toluene diisocyanate) and contact sensitizers (DNCB, dinitrofluorobenzene and oxazolone). The second part of the study was designed to test the robustness of these markers when classing the weakly immunogenic chemicals most often encountered. Six respiratory allergens, including TMA (2.5%), five contact allergens, including DNCB (0.25%), and two irritants were compared at doses of equivalent immunogenicity. The results indicated that IL-4Rα and IL-2 can be reliably used to discriminate sensitizers. Respiratory sensitizers induced markedly higher IL-4Rα levels than contact allergens, while irritants had no effect on this parameter. Inversely, contact allergens tended to induce higher percentages of IL-2{sup +}CD8{sup +} cells than respiratory allergens. In contrast, the markers MHC-II, IgE and IL-4 were not able to classify chemicals with low immunogenic potential. In conclusion, IL-4Rα and IL-2 have the potential to be used in classifying a variety of chemical allergens. -- Highlights: ► Identification of chemical allergens is an important occupational safety issue. ► There is currently no model to predict the potential of chemicals to induce asthma. ► We analyze immune responses induced

  13. Downregulation of proapoptotic Bim augments IL-2-independent T-cell transformation by human T-cell leukemia virus type-1 Tax.

    Science.gov (United States)

    Higuchi, Masaya; Takahashi, Masahiko; Tanaka, Yuetsu; Fujii, Masahiro

    2014-12-01

    Human T-cell leukemia virus type 1 (HTLV-1), an etiological agent of adult T-cell leukemia, immortalizes and transforms primary human T cells in vitro in both an interleukin (IL)-2-dependent and IL-2-independent manner. Expression of the HTLV-1 oncoprotein Tax transforms the growth of the mouse T-cell line CTLL-2 from being IL-2-dependent to IL-2-independent. Withdrawal of IL-2 from normal activated T cells induces apoptosis, which is mediated through the inducible expression of several proapoptotic proteins, including Bim. In this study, we found that Tax protects IL-2-depleted T cells against Bim-induced apoptosis. Withdrawal of IL-2 from CTLL-2 cells induced a prominent increase in the level of Bim protein in CTLL-2 cells, but not in Tax-transformed CTLL-2 cells. This inhibition of Bim in Tax-transformed CTLL-2 cells was mediated by two mechanisms: downregulation of Bim mRNA and posttranscriptional reduction of Bim protein. Transient expression of Tax in CTLL-2 cells also inhibited IL-2 depletion-induced expression of Bim, however, this decrease in Bim protein expression was not due to downregulation of Bim mRNA, thus indicating that Bim mRNA downregulation in Tax-transformed CTLL-2 occurs only after long-term expression of Tax. Transient expression of Tax in CTLL-2 cells also induced Erk activation, however, this was not involved in the reduction of Bim protein. Knockdown of Bim expression in CTLL-2 cells augmented Tax-induced IL-2-independent transformation. HTLV-1 infection of human T cells also reduced their levels of Bim protein, and restoring Bim expression in HTLV-1-infected cells reduced their proliferation by inducing apoptosis. Taken together, these results indicate that Tax-induced downregulation of Bim in HTLV-1-infected T cells promotes their IL-2-independent growth, thereby supporting the persistence of HTLV-1 infection in vivo.

  14. Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming.

    Science.gov (United States)

    Marzec, Michal; Halasa, Krzysztof; Liu, Xiaobin; Wang, Hong Y; Cheng, Mangeng; Baldwin, Donald; Tobias, John W; Schuster, Stephen J; Woetmann, Anders; Zhang, Qian; Turner, Suzanne D; Ødum, Niels; Wasik, Mariusz A

    2013-12-15

    Anaplastic lymphoma kinase (ALK), physiologically expressed only by nervous system cells, displays a remarkable capacity to transform CD4(+) T lymphocytes and other types of nonneural cells. In this study, we report that activity of nucleophosmin (NPM)/ALK chimeric protein, the dominant form of ALK expressed in T cell lymphomas (TCLs), closely resembles cell activation induced by IL-2, the key cytokine supporting growth and survival of normal CD4(+) T lymphocytes. Direct comparison of gene expression by ALK(+) TCL cells treated with an ALK inhibitor and IL-2-dependent ALK(-) TCL cells stimulated with the cytokine revealed a very similar, albeit inverse, gene-regulation pattern. Depending on the analysis method, up to 67% of the affected genes were modulated in common by NPM/ALK and IL-2. Based on the gene expression patterns, Jak/STAT- and IL-2-signaling pathways topped the list of pathways identified as affected by both IL-2 and NPM/ALK. The expression dependence on NPM/ALK and IL-2 of the five selected genes-CD25 (IL-2Rα), Egr-1, Fosl-1, SOCS3, and Irf-4-was confirmed at the protein level. In both ALK(+) TCL and IL-2-stimulated ALK(-) TCL cells, CD25, SOCS3, and Irf-4 genes were activated predominantly by the STAT5 and STAT3 transcription factors, whereas transcription of Egr-1 and Fosl-1 was induced by the MEK-ERK pathway. Finally, we found that Egr-1, a protein not associated previously with either IL-2 or ALK, contributes to the cell proliferation. These findings indicate that NPM/ALK transforms the target CD4(+) T lymphocytes, at least in part, by using the pre-existing, IL-2-dependent signaling pathways.

  15. A pilot study of denileukin diftitox (DD) in combination with high-dose interleukin-2 (IL-2) for patients with metastatic renal cell carcinoma (RCC).

    Science.gov (United States)

    Atchison, Elizabeth; Eklund, John; Martone, Brenda; Wang, Lili; Gidron, Adi; Macvicar, Gary; Rademaker, Alfred; Goolsby, Charles; Marszalek, Laura; Kozlowski, James; Smith, Norm; Kuzel, Timothy M

    2010-09-01

    High-dose (HD) IL-2 is approved to treat renal cell carcinoma (RCC) with modest response rates and significant toxicity. Enhancement of cytotoxic T-cell activity by IL-2 is 1 mechanism of action. IL-2 also stimulates regulatory T lymphocytes (Tregs), which are associated with poor prognosis. Favorable outcomes are associated with greater rebound absolute lymphocyte count (Fumagalli 2003). DD depletes IL-2 receptor (CD25 component) expressing cells. We hypothesized that sequential therapy could complement each other; DD would deplete Tregs so IL-2 could more effectively stimulate proliferation and activity of cytotoxic T lymphocytes. Patients (n=18) received standard HD IL-2 and 1 dose of DD daily for 3 days; periodic flow cytometry and complete blood counts were performed. Group A included 3 patients to assess safety only with DD 6 μg/kg between the IL-2 courses. Group B included 9 patients at 9 μg/kg DD before the IL-2 courses. Group C included 6 patients at 9 μg/kg DD between the IL-2 courses. Efficacy using the RECIST criteria was assessed after the treatment. Fifteen patients from a study of IL-2 without DD served as controls for toxicity comparison and 13 of these for flow cytometry comparisons. No unusual toxicity was noted. For group B/C patients receiving DD, the median decline in Tregs was 56.3% from pre-DD to post-DD (P=0.013). Peak absolute lymphocyte count change from baseline was +9980/μL for group B, +4470/μL for group C, and +4720/μL for the controls (P=0.005 B vs. C). The overall response rate was 5 of 15 (33%); 3 of 9 (33%) and 2 of 6 (33%) for groups B and C, respectively, including 2 patients with sarcomatoid RCC and 1 with earlier sunitinib therapy.

  16. Preparation of IL-2-loaded magnetic nanoparticle and its targeting accumulation in tumor tissues combining with external magnetic field%载IL-2磁性纳米粒的制备及其联合体外磁场在肿瘤组织中的靶向富集作用

    Institute of Scientific and Technical Information of China (English)

    沈爱蓉; 郭全义; 袁玫; 王桂琴; 卢世璧

    2013-01-01

    Objective: To prepare IL-2-loaded magnetic nanoparticle (IL-2-Fe3O4-PLGA) with Fe3O4 magnetic nanoparticle (Fe3O4-MNP) and poly lactide-co-glycolide (PLGA) , and to investigate its targeted accumulation function in tumor immunotherapy. Methods: The double emulsion method was employed for preparation of IL-2-Fe3O4-PLGA, its size and morphology were observed with a laser particle size analyzer and under a scanning electron microscope, respectively. In addition, the drug encapsulation efficiency and releasing characteristics of IL-2-Fe3O4-PLGA in vitro were measured with ELISA. The biological activity of the IL-2 released from the IL-2-Fe3O4-PLGA was evaluated by MTT assay. Sarcoma 180 cell-transplanted tumor mouse model was established to study the effect of IL-2-Fe3O4-PLGA in combination with external magnetic field on the growth of Sarcoma 180 tumors. The tumor, liver and kidney tissues were examined by Prussian blue staining to determine the accumulation and distribution of the IL-2-Fe3O4-PLGA in the tissue sections. Results: IL-2-Fe3O4-PLGA was constructed successfully, and was spherical with a mean diameter of (697 ±0. 51) nm as well as a drug encapsulation efficiency of (83. 76 ± 1. 24 ) % . In the drug release test in vitro, the mass concentration of released IL-2 was 100 ng/ml during the burst release phase and rose to 180 ng/ml at the end of 15 d. Moreover, the released IL-2 remained 85% -55% of its original activity during the releasing period. A strong IL-2-Fe3O4-PLGA positive reaction was observed in IL-2-Fe3O4-PLGA-treated mice combined with an external magnetic field, but only a weak reaction in mice injected with IL-2-Fe3O4-PLGA alone. Furthermore, in both groups, Prussian blue-stained liver showed occasionally light IL-2-Fe3O4-PLGA positive staining, while IL-2-Fe3O4-PLGA positive reaction was rarely detected in the kidneys. Conclusion: IL-2 loaded magnetic nanoparticle IL-2-Fe3O4-PLGA has controlled IL-2-release function and targeting accumulation

  17. The influence of radiotherapy on IL-2 and IL-6 secretions of mucous membrane epithelial cells of wistar small intestine.

    Science.gov (United States)

    Liu, Bin; Li, Xiaoling; Ai, Fulu; Wang, Tianlu; Chen, Yun; Zhang, Hao

    2015-01-01

    The aim of the study was to investigate the influence of radiotherapy on IL-2 and IL-6 secretions of mucous epithelial cells of small intestine and the inhibition effect of deproteinized calf blood extractive (DCBE, also known as Actovegin in trade name) on apoptosis of mucous epithelial cells of small intestine. 50 wistars were randomly divided into 5 groups with 10 in each including normal group (NG), radiation group (RG), low-dose Actovegin group (L-AG), middle-dose Actovegin group (M-AG), and high-dose Actovegin (H-AG). High-energy X-ray linear accelerator was used for abdominal irradiation of RG, L-AG, M-AG, and H-AG at the exposure dose of 9.0 Gy to establish the wistar radiation damage model. Modeling wistars were injected with medicine for successive 4 days, and their small intestinal mucosas were extracted as pathological sections; then fully automated analyzer was employed to detect their IL-2 and IL-6 levels. Immunohistochemical analysis was carried out to explore the effect of Actovegin on apoptosis of mucous membrane epithelial cells of small intestine. The IL-2 and IL-6 levels of RG are significantly higher than other groups and differences are statistically significant (P 0.05). Compared with RG, the villus height, membrane thickness, crypt depth, and whole layer thickness significantly improved (P < 0.05). However, the expression levels of apoptosis-related protein bax of M-AG and H-AG are significantly lower than RG, and their bcl-2 levels are higher than RG with significant difference between them (P < 0.05). Actovegin is capable of effectively inhibiting the expression of apoptosis-related protein bax and facilitating the expression of anti-apoptosis protein bcl-2, having preferable remediation effect on mucous membrane epithelial cells of radioactive enteritis.

  18. Immune protection duration and efficacy stability of DNA vaccine encoding Eimeria tenella TA4 and chicken IL-2 against coccidiosis.

    Science.gov (United States)

    Song, Xiaokai; Zhao, Xiaofang; Xu, Lixin; Yan, Ruofeng; Li, Xiangrui

    2017-04-01

    In our previous study, an effective DNA vaccine encoding Eimeria tenella TA4 and chicken IL-2 was constructed. In the present study, the immunization dose of the DNA vaccine pVAX1.0-TA4-IL-2 was further optimized. With the optimized dose, the dynamics of antibodies induced by the DNA vaccine was determined using indirect ELISA. To evaluate the immune protection duration of the DNA vaccine, two-week-old chickens were intramuscularly immunized twice and the induced efficacy was evaluated by challenging with E. tenella at 5, 9, 13, 17 and 21weeks post the last immunization (PLI) separately. To evaluate the efficacy stability of the DNA vaccine, two-week-old chickens were immunized with 3 batches of the DNA vaccine, and the induced efficacy was evaluated by challenging with E. tenella. The results showed that the optimal dose was 25μg. The induced antibody level persisted until 10weeks PPI. For the challenge time of 5 and 9weeks PLI, the immunization resulted in ACIs of 182.28 and 162.23 beyond 160, showing effective protection. However, for the challenge time of 13, 17 and 21weeks PLI, the immunization resulted in ACIs below 160 which means poor protection. Therefore, the immune protection duration of the DNA vaccination was at least 9weeks PLI. DNA immunization with three batches DNA vaccine resulted in ACIs of 187.52, 191.57 and 185.22, which demonstrated that efficacies of the three batches DNA vaccine were effective and stable. Overall, our results indicate that DNA vaccine pVAX1.0-TA4-IL-2 has the potential to be developed as effective vaccine against coccidiosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. CCR5 Expression Levels Influence NFAT Translocation, IL-2 Production, and Subsequent Signaling Events during T Lymphocyte Activation1

    OpenAIRE

    2009-01-01

    Ligands of CCR5, the major coreceptor of HIV-1, costimulate T lymphocyte activation. However, the full impact of CCR5 expression on T cell responses remains unknown. Here, we show that compared with CCR5+/+, T cells from CCR5−/− mice secrete lower amounts of IL-2, and a similar phenotype is observed in humans who lack CCR5 expression (CCR5-Δ32/Δ32 homozygotes) as well as after Ab-mediated blockade of CCR5 in human T cells genetically intact for CCR5 expression. Conversely, overexpression of C...

  20. Effect of Chinese Herbal Medicinal Ingredients on IL-2 mRNA Levels of T Lymphocytes in Mice Measured Using Semiquantification RT-PCR

    Institute of Scientific and Technical Information of China (English)

    CHU Yue-feng; YAN Xin-min; LI Xiang-rui; HU Yuan-liang

    2006-01-01

    In this study, the IL-2 mRNA levels of T lymphocytes in normal mice stimulated by nine Chinese herbal medicinal ingredients (CHMIs) were measured using semiquantification reverse transcription polymerase chain reaction. The results showed that astragalus polysaccharide (APS), epimedium polysaccharide (EPS), Chinese angelica polysaccharide (CAPS), propolis flavone (PF), and astrogalosides (AS) promoted IL-2 mRNA levels in T lymphocytes in vitro and in vivo to differing degrees, and the level of IL-2 mRNA induced by propolis polysaccharide (PPS) in vitro was higher than that induced by the control, which differed from that of PPS in vivo.

  1. IL-2R{gamma} gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease

    Energy Technology Data Exchange (ETDEWEB)

    Henthorn, P.S.; Fimiani, V.M.; Patterson, D.F. [Univ. of Pennsylvania School of Veterinary Medicine, Philadelphia, PA (United States)] [and others

    1994-09-01

    X-linked severe combined immunodeficiency (SCID) is characterized by profound defects in cellular and humoral immunity and, in humans, is associated with mutations in the gene for the {gamma} chain of the IL-2 receptor (IL-2R{gamma}). We have examined this gene in a colony of dogs established from a single X-linked SCID carrier female. Affected dogs have a 4-bp deletion in the first exon of the IL-2R{gamma} gene, which precludes the production of a functional protein, demonstrating that the canine disease is a true homologue of human X-linked SCID. 37 refs., 3 figs.

  2. 鸡包涵体肝炎过程中IL-2的mRNA原位杂交%mRNA in situ hybridization of IL-2 in avian inclusion body hepatitis

    Institute of Scientific and Technical Information of China (English)

    郝美艳; 王纯洁; 孙国庆; 赵怀平

    2006-01-01

    FAV-Ⅷ型禽腺病毒口服接种感染2日龄SPF雏鸡,攻毒后取不同日龄的肝脏于福尔马林溶液中固定,并进行石蜡包埋,石蜡切片进行原位杂交染色.结果表明:着染部位主要出现在坏死灶或血管周围成团或散在的淋巴细胞胞浆内,在病情严重时5 dpi开始增多,12 dpi表达量达到高峰,以后逐渐减少,直到30 dpi基本消失.说明鸡包涵体肝炎过程中肝脏IL-2的mRNA大量增加,可能与T淋巴细胞的增多有关;而且IL-2作为免疫增强剂与抗病毒感染和病症恢复也有关.

  3. Combination Therapy Using IL-2/IL-2 Monoclonal Antibody Complexes, Rapamycin, and Islet Autoantigen Peptides Increases Regulatory T Cell Frequency and Protects against Spontaneous and Induced Type 1 Diabetes in Nonobese Diabetic Mice.

    Science.gov (United States)

    Manirarora, Jean N; Wei, Cheng-Hong

    2015-12-01

    Regulatory T cells (Treg) play a crucial role in the maintenance of self-tolerance. In this study, we sought to expand Ag-specific Tregs in vivo and investigate whether the expanded Tregs can prevent or delay the development of type 1 diabetes (T1D) in the NOD mouse model. NOD mice were treated with a combination of IL-2/anti-IL-2 Ab complex, islet Ag peptide, and rapamycin. After the combined treatment, CD4(+)CD25(+)Foxp3(+) Tregs were significantly expanded in vivo, they expressed classical Treg markers, exerted enhanced suppressive functions in vitro, and protected against spontaneous development of T1D in NOD mice. Moreover, treated mice were almost completely protected from the adoptively transferred, aggressive form of T1D caused by in vitro-activated cytotoxic islet Ag-specific CD8 T cells. Protection from T1D was transferrable by Tregs and could be attributed to reduced islet infiltration of immune cells as well as the skewing of the immune response toward a Th2 cytokine profile. This new method of peripheral immune regulation could potentially contribute to development of novel immunotherapeutic strategies to prevent the development of T1D or to promote tolerance to islet transplants without using immunosuppressive drugs for long terms.

  4. Avoiding surprises when implementing a single quality system.

    Science.gov (United States)

    Donawa, Maria

    2009-01-01

    European medical device manufacturers are sometimes surprised to learn that operating ISO 13485 alone is not sufficient to meet United States (US) quality system requirements. This article discusses important considerations for meeting US and European requirements when operating under a single quality system.

  5. Reconsiderations: Donald Murray and the Pedagogy of Surprise

    Science.gov (United States)

    Ballenger, Bruce

    2008-01-01

    Toward the end of his life, Donald Murray felt that his approach to writing instruction was no longer appreciated by journals in his field. Nevertheless, his emphasis on encouraging students to surprise themselves through informal writing still has considerable value. (Contains 1 note.)

  6. Reconsiderations: Donald Murray and the Pedagogy of Surprise

    Science.gov (United States)

    Ballenger, Bruce

    2008-01-01

    Toward the end of his life, Donald Murray felt that his approach to writing instruction was no longer appreciated by journals in his field. Nevertheless, his emphasis on encouraging students to surprise themselves through informal writing still has considerable value. (Contains 1 note.)

  7. Errors and surprise in patients with focal brain lesions

    NARCIS (Netherlands)

    Ullsperger, M.

    2016-01-01

    Recent theories of performance monitoring suggest that not only errors and negative action outcomes but also valence-free expectancy violations can trigger cognitive and behavioral adaptations. EEG and fMRI evidence suggests that monitoring of both errors and surprising but valence-free action

  8. Supernatant from a cloned helper T cell stimulates resting B cells to express transferrin and IL-2 receptors.

    Science.gov (United States)

    Diu, A; Leclercq, L; Dautry-Varsat, A; Theze, J

    1987-07-01

    We describe the properties of the supernatant from a murine cloned helper T cell (clone 52.3) which is able to polyclonally activate most resting B cells in the absence of any additional stimulus. We hypothesize that an activity which we call BCAF (B-cell-activating factor(s] exists in our supernatant which can activate resting B cells alone or in conjunction with other lymphokines. In the present report, we investigate changes in the surface antigen pattern induced on resting B cells by BCAF-containing supernatant. Analysis of the cells by flow cytometry shows that transferrin receptor and IL-2 receptor expression increase on a large fraction of B cells after 2 days of activation by the T-helper-cell clone supernatant. Monoclonal anti-transferrin receptor antibody inhibits cell division but does not affect blastogenesis, while IL-2 has no effect in our experimental system. Our present results confirm that BCAF-containing supernatants can act on most resting B cells and replace helper T cells in inducing B-cell activation and proliferation.

  9. Study on Cytokines IL-2, IL-6, IL-10 in Patients of Chronic Allergic Rhinitis Treated with Acupuncture

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Objectives: To observe the plasmatic concentration of IL-6, IL-10 and IL-2 in the patient of chronic allergic rhinitis before and after acupuncture therapy. Methods: Cytokine levels were determined before and after treatment in 30 healthy volunteers (Group A) and 90 patients of chronic allergic rhinitis (Group B) with an increased plasma IL-10 level. Group B was then divided into 3 subgroups: 30 patients treated with real acupuncture (Group B1); 30 patients treated with sham acupuncture (Group B2); 30 non-treated patients (Group B3). Results: The allergic subjects of group B1, compared with controls, showed a significant reduction of IL-10 after a specific treatment with acupuncture (P<0.05). On the other hand, in those patients treated with sham acupuncture (B2) as well as in non-treated patients (B3), the IL-10 values remained high and unchanged. There was a statistically significant change in IL-2 values at 24 hours (P<0.05) after real acupuncture (Groups A, B1), however the values remained within normal ranges. The IL-6 do not change after therapy. Conclusion: The acupuncture treatment can reduce plasmatic level of IL-10 in chronic allergic rhinitis.

  10. IL-2 production by virus- and tumor-specific human CD8 T cells is determined by their fine specificity.

    Science.gov (United States)

    Mallard, Eric; Vernel-Pauillac, Frédérique; Velu, Thierry; Lehmann, Frédéric; Abastado, Jean-Pierre; Salcedo, Margarita; Bercovici, Nadège

    2004-03-15

    Memory CD8 T cells mediate rapid and effective immune responses against previously encountered Ags. However, these cells display considerable phenotypic and functional heterogeneity. In an effort to identify parameters that correlate with immune protection, we compared cell surface markers, proliferation, and cytokine production of distinct virus- and tumor-specific human CD8 populations. Phenotypic analysis of epitope-specific CD8 T cells showed that Ag specificity is associated with distinct CCR7/CD45RA expression profiles, suggesting that Ag recognition drives the expression of these molecules on effector/memory T cells. Moreover, the majority of central memory T cells (CD45RAlowCCR7dull) secreting cytokines in response to an EBV epitope produces both IL-2 and IFN-gamma, whereas effector memory CD8 cells (CD45RAdullCCR7-) found in EBV, CMV, or Melan-A memory pools are mostly composed of cells secreting exclusively IFN-gamma. However, these various subsets, including Melan-A-specific effector memory cells differentiated in cancer patients, display similar Ag-driven proliferation in vitro. Our findings show for the first time that human epitope-specific CD8 memory pools differ in IL-2 production after antigenic stimulation, although they display similar intrinsic proliferation capacity. These results provide new insights in the characterization of human virus- and tumor-specific CD8 lymphocytes.

  11. Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy

    Science.gov (United States)

    Park, Jason; Wrzesinski, Stephen H.; Stern, Eric; Look, Michael; Criscione, Jason; Ragheb, Ragy; Jay, Steven M.; Demento, Stacey L.; Agawu, Atu; Licona Limon, Paula; Ferrandino, Anthony F.; Gonzalez, David; Habermann, Ann; Flavell, Richard A.; Fahmy, Tarek M.

    2012-10-01

    The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-β (TGF-β), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-β inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.

  12. Chronic hypoxia in pregnancy affects thymus development in Balb/c mouse offspring via IL2 Signaling.

    Science.gov (United States)

    Zhang, Xiaopeng; Zhou, Xiuwen; Li, Lingjun; Sun, Miao; Gao, Qingqing; Zhang, Pengjie; Tang, Jiaqi; He, Yu; Zhu, Di; Xu, Zhice

    2016-04-01

    Hypoxia during pregnancy can adversely affect development. This study, addressed the impact of prenatal hypoxia on thymus development in the rodent offspring. Pregnant Balb/c mice were exposed to hypoxia or normoxia during pregnancy, and the thymuses of their offspring were tested. Chronic hypoxia during pregnancy resulted in significantly decreased fetal body weight, with an increased thymus-to-body weight ratio. Histological analysis revealed a smaller cortical zone in the thymus of the offspring exposed to hypoxia. A reduction in the cortical T lymphocyte population corresponded to increased mRNA abundance of caspase 3 (Casp3) and decreased expression of the proliferation marker Ki-67 (Mki67). Differences in T lymphocyte sub-populations in the thymus further indicate that thymus development in offspring was retarded or stagnated by prenatal hypoxia. The abundance of IL2 and its receptor was reduced in the thymus following prenatal hypoxia. This was accompanied by an increase in thymus HIF1A and IKKβ and a decrease in phosphorylated NFKB, MAP2K1, and MAPK1/3 compared to control pregnancies. Together, these results implicate deficiencies in IL2-mediated signaling as one source of prenatal-hypoxia-impaired thymus development.

  13. Profile of IL-2, IL-4, IL-10, IFN- ? , TNF- ? and KC-like cytokines in pregnant bitches

    Directory of Open Access Journals (Sweden)

    M.A.R. Feliciano

    2014-08-01

    Full Text Available The aim of this study was to determine the profile of IL-2, IL-4, IL-10, IFN-γ, and TNF-α cytokines and KC-like cells (natural killer in pregnant bitches, unpublished values for the species. A total of 27 females of the Shi Tzu, Pug, English Bulldog and French breeds, weighing 4-20kg and aged 4-6 years were used. Blood samples were collected from bitches during the anestrous and on the 2nd, 5th, 6th, 7th and 8th week of pregnancy. Serum levels of cytokines were measured by panel MILLIPLEX MAP (CCYTO-90K, MILLIPORE, Billerica, Massachusetts, USA validated for dogs. Twenty four females showed physiological pregnancy and three bitches showed pathological pregnancy. There was no difference between cytokine values during anestrous and gestational weeks of bitches (P>0.05. However, it was possible to verify the physiological behavior of serum levels during modulation of immune response in the gestational process of animals. In animals with gestational disorders, abnormal values for IL-2, IL-4 and INF-y were noted. It was concluded that serum levels of cytokines evaluated in pregnant bitches can help the better understanding of physiological and pathological gestational processes and correlated immunology in this species.

  14. Universal statistics of the knockout tournament

    OpenAIRE

    Baek, Seung Ki; Yi, Il Gu; Park, Hye Jin; Kim, Beom Jun

    2013-01-01

    We study statistics of the knockout tournament, where only the winner of a fixture progresses to the next. We assign a real number called competitiveness to each contestant and find that the resulting distribution of prize money follows a power law with an exponent close to unity if the competitiveness is a stable quantity and a decisive factor to win a match. Otherwise, the distribution is found narrow. The existing observation of power law distributions in various kinds of real sports tourn...

  15. 狼疮性肾炎患者血清IL-6、sIL-2R水平测定

    Institute of Scientific and Technical Information of China (English)

    胡波; 罗敏琪; 粱家隐; 叶少雄; 李朝霞

    2004-01-01

    To investigate the Changes of sIL - 2R, IL - 6 level in ,serum of patients with lupus nephritis and its clinical meaning. Methods The level of serum sIL - 2R, IL - 6 in 42 cases of lupus nephritis were detected by ELISA, and the data were compared with control group. Results Serum sIL- 2R ,IL-6 levels in lupus nephritis patients were significantly higher than control group and related to convalescent of the disease. Conclusion It suggested that immune dysfunction exist in patients with lupus nephritis higher level of sIL-2 ,IL-6 would associate with genesis and development of lupus nephritis, and it can be a new indicator of lupus nephritis.

  16. Soluble intercellular adhesion molecule-1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) in scleroderma skin

    DEFF Research Database (Denmark)

    Søndergaard, Klaus; Deleuran, Mette; Heickendorff, Lene

    1998-01-01

    In order to investigate whether soluble intercellular adhesion molecule-1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) were present in scleroderma skin, and to compare their levels to concentrations measured in plasma and clinical parameters, we examined suction blister fluid and plasma...... from 13 patients with systemic sclerosis and 11 healthy volunteers. Suction blisters and biopsies were from the transition zone between normal skin and scleroderma, and uninvolved abdominal skin. The levels of sICAM-1 and sIL-2R were significantly increased in both plasma and suction blister fluid from...... systemic sclerosis patients compared with healthy volunteers. ICAM-1 was localized to vessels and perivascular mononuclear infiltrates by immunohistochemical methods. IL-2R was expressed by CD3-positive cells. The elevated levels of sICAM-1 and sIL-2R in suction blister fluid point towards activation...

  17. Soluble intercellular adhesion molecule-1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) in scleroderma skin

    DEFF Research Database (Denmark)

    Søndergaard, Klaus; Deleuran, Mette; Heickendorff, Lene;

    1998-01-01

    In order to investigate whether soluble intercellular adhesion molecule-1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) were present in scleroderma skin, and to compare their levels to concentrations measured in plasma and clinical parameters, we examined suction blister fluid and plasma...... from 13 patients with systemic sclerosis and 11 healthy volunteers. Suction blisters and biopsies were from the transition zone between normal skin and scleroderma, and uninvolved abdominal skin. The levels of sICAM-1 and sIL-2R were significantly increased in both plasma and suction blister fluid from...... systemic sclerosis patients compared with healthy volunteers. ICAM-1 was localized to vessels and perivascular mononuclear infiltrates by immunohistochemical methods. IL-2R was expressed by CD3-positive cells. The elevated levels of sICAM-1 and sIL-2R in suction blister fluid point towards activation...

  18. Detection of T lymphocyte subsets and mIL-2R on surface of PBMC in patients with hepatitis B

    Institute of Scientific and Technical Information of China (English)

    Ke-Xia Wang; Jiang-Long Peng; Xue-Feng Wang; Ye Tian; Jian Wang; Chao-Pin Li

    2003-01-01

    AIM: To study the levels of T lymphocyte subsets andmembrane interleukin-2 receptor (mIL-2R) on surface ofperipheral blood mononuclear cells (PBMCs) of patients withhepatitis B and its role in the pathogenesis of hepatitis B.METHODS: The levels of T lymphocyte subsets and mIL-2R in PBMC before and after being stimulated with PHAwere detected by biotin-streptavidin (BSA) technique in 196cases of hepatitis B.RESULTS: In patients with hepatitis B, the levels of CD3+,CD4+ cells, and the ratio of CD4+ cells/CD8+ cells were lower,but the level of CD8+ cells was higher than those in normalcontrols (42.20±6.01 vs65.96±6.54, 38.17±5.93 vs41.73±6.40,0.91±0.28 vs 1.44±0.31, 39.86±6.36 vs30.02±-4.54, P<0.01).The total expression level of mIL-2R in PBMC before andafter being stimulated with PHA was also lower than thosein normal controls (3.47±1.55 vs4.52±1.49, 34.03±2.94 vs37.95±3.00, P<0.01). In all the patients with hepatitis B, thelevels of T lymphocyte subsets and mIL-2R in PBMC withHBV-DNA (+) were lower than those with HBV-DNA (-),which were significantly different (39.57±7.11 vs44.36±5.43,34.36±7.16 vs 40.75±5.87, 37.82±6.54 vs 41.72±6.21,0.88±0.33 vs0.99±0.27, 2.82±1.62 vs3.85±1.47, 31.56±3.00vs35.84±2.83, P<0.01). In addition, the levels of CD3+, CD4+,CD8+ cells, the ratio of CD4+ cells/CD8+ cells and mIL-2R amongdifferent courses of hepatitis B were all significantly different(F=3 723.18, P<0.01. F=130.43, P<0.01. F=54.01, P<0.01.F=2.99, P<0.05. F=7.16, P<0.01).CONCLUSION: Both cellular and humoral immune functionsare obviously in disorder in patients with hepatitis B, whichmight be closely associated with the chronicity in patients.

  19. CD8+ T Cell Fate and Function Influenced by Antigen-Specific Virus-Like Nanoparticles Co-Expressing Membrane Tethered IL-2.

    Directory of Open Access Journals (Sweden)

    Daniela Wojta-Stremayr

    Full Text Available A variety of adjuvants fostering humoral immunity are known as of today. However, there is a lack of adjuvants or adjuvant strategies, which directly target T cellular effector functions and memory. We here determined whether systemically toxic cytokines such as IL-2 can be restricted to the site of antigen presentation and used as 'natural adjuvants'. Therefore, we devised antigen-presenting virus-like nanoparticles (VNP co-expressing IL-2 attached to different membrane-anchors and assessed their potency to modulate CD8+ T cell responses in vitro and in vivo. Efficient targeting of IL-2 to lipid rafts and ultimately VNP was achieved by fusing IL-2 at its C-terminus to a minimal glycosylphosphatidylinositol (GPI-anchor acceptor sequence. To identify optimal membrane-anchor dimensions we inserted one (1Ig, two (2Ig or four (4Ig immunoglobulin(Ig-like domains of CD16b between IL-2 and the minimal GPI-anchor acceptor sequence of CD16b (GPI. We found that the 2IgGPI version was superior to all other evaluated IL-2 variants (IL-2v in terms of its i degree of targeting to lipid rafts and to the VNP surface, ii biological activity, iii co-stimulation of cognate T cells in the absence of bystander activation and iv potency to induce differentiation and acquisition of CD8+ T cell effector functions in vitro and in vivo. In contrast, the GPI version rather favored memory precursor cell formation. These results exemplify novel beneficial features of membrane-bound IL-2, which in addition to its mere T cell stimulatory capacity include the induction of differential effector and memory functions in CD8+ T lymphocytes.

  20. IL-4 function can be transferred to the IL-2 receptor by tyrosine containing sequences found in the IL-4 receptor alpha chain.

    Science.gov (United States)

    Wang, H Y; Paul, W E; Keegan, A D

    1996-02-01

    IL-4 binds to a cell surface receptor complex that consists of the IL-4 binding protein (IL-4R alpha) and the gamma chain of the IL-2 receptor complex (gamma c). The receptors for IL-4 and IL-2 have several features in common; both use the gamma c as a receptor component, and both activate the Janus kinases JAK-1 and JAK-3. In spite of these similarities, IL-4 evokes specific responses, including the tyrosine phosphorylation of 4PS/IRS-2 and the induction of CD23. To determine whether sequences within the cytoplasmic domain of the IL-4R alpha specify these IL-4-specific responses, we transplanted the insulin IL-4 receptor motif (I4R motif) of the huIL-4R alpha to the cytoplasmic domain of a truncated IL-2R beta. In addition, we transplanted a region that contains peptide sequences shown to block Stat6 binding to DNA. We analyzed the ability of cells expressing these IL-2R-IL-4R chimeric constructs to respond to IL-2. We found that IL-4 function could be transplanted to the IL-2 receptor by these regions and that proliferative and differentiative functions can be induced by different receptor sequences.

  1. IL2RA/CD25 gene polymorphisms: uneven association with multiple sclerosis (MS and type 1 diabetes (T1D.

    Directory of Open Access Journals (Sweden)

    Antonio Alcina

    Full Text Available BACKGROUND: IL-2 receptor (IL2R alpha is the specific component of the high affinity IL2R system involved in the immune response and in the control of autoimmunity. METHODS AND RESULTS: Here we perform a replication and fine mapping of the IL2RA gene region analyzing 3 SNPs previously associated with multiple sclerosis (MS and 5 SNPs associated with type 1 diabetes (T1D in a collection of 798 MS patients and 927 matched Caucasian controls from the south of Spain. We observed association with MS in 6 of 8 SNPs. The rs1570538, at the 3'- UTR extreme of the gene, previously reported to have a weak association with MS, is replicated here (P = 0.032. The most associated T1D SNP (rs41295061 was not associated with MS in the present study. However, the rs35285258, belonging to another independent group of SNPs associated with T1D, showed the maximal association in this study but different risk allele. We replicated the association of only one (rs2104286 of the two IL2RA SNPs identified in the recently performed genome-wide association study of MS. CONCLUSIONS: These findings confirm and extend the association of this gene with MS and reveal a genetic heterogeneity of the associated polymorphisms and risk alleles between MS and T1D suggesting different immunopathological roles of IL2RA in these two diseases.

  2. IL2RA/CD25 Gene Polymorphisms: Uneven Association with Multiple Sclerosis (MS) and Type 1 Diabetes (T1D)

    Science.gov (United States)

    Alcina, Antonio; Fedetz, María; Ndagire, Dorothy; Fernández, Oscar; Leyva, Laura; Guerrero, Miguel; Abad-Grau, María M.; Arnal, Carmen; Delgado, Concepción; Lucas, Miguel; Izquierdo, Guillermo; Matesanz, Fuencisla

    2009-01-01

    Background IL-2 receptor (IL2R) alpha is the specific component of the high affinity IL2R system involved in the immune response and in the control of autoimmunity. Methods and Results Here we perform a replication and fine mapping of the IL2RA gene region analyzing 3 SNPs previously associated with multiple sclerosis (MS) and 5 SNPs associated with type 1 diabetes (T1D) in a collection of 798 MS patients and 927 matched Caucasian controls from the south of Spain. We observed association with MS in 6 of 8 SNPs. The rs1570538, at the 3′- UTR extreme of the gene, previously reported to have a weak association with MS, is replicated here (P = 0.032). The most associated T1D SNP (rs41295061) was not associated with MS in the present study. However, the rs35285258, belonging to another independent group of SNPs associated with T1D, showed the maximal association in this study but different risk allele. We replicated the association of only one (rs2104286) of the two IL2RA SNPs identified in the recently performed genome-wide association study of MS. Conclusions These findings confirm and extend the association of this gene with MS and reveal a genetic heterogeneity of the associated polymorphisms and risk alleles between MS and T1D suggesting different immunopathological roles of IL2RA in these two diseases. PMID:19125193

  3. Sleeping beauties in theoretical physics 26 surprising insights

    CERN Document Server

    Padmanabhan, Thanu

    2015-01-01

    This book addresses a fascinating set of questions in theoretical physics which will both entertain and enlighten all students, teachers and researchers and other physics aficionados. These range from Newtonian mechanics to quantum field theory and cover several puzzling issues that do not appear in standard textbooks. Some topics cover conceptual conundrums, the solutions to which lead to surprising insights; some correct popular misconceptions in the textbook discussion of certain topics; others illustrate deep connections between apparently unconnected domains of theoretical physics; and a few provide remarkably simple derivations of results which are not often appreciated. The connoisseur of theoretical physics will enjoy a feast of pleasant surprises skilfully prepared by an internationally acclaimed theoretical physicist. Each topic is introduced with proper background discussion and special effort is taken to make the discussion self-contained, clear and comprehensible to anyone with an undergraduate e...

  4. The June surprises: balls, strikes, and the fog of war.

    Science.gov (United States)

    Fried, Charles

    2013-04-01

    At first, few constitutional experts took seriously the argument that the Patient Protection and Affordable Care Act exceeded Congress's power under the commerce clause. The highly political opinions of two federal district judges - carefully chosen by challenging plaintiffs - of no particular distinction did not shake that confidence that the act was constitutional. This disdain for the challengers' arguments was only confirmed when the act was upheld by two highly respected conservative court of appeals judges in two separate circuits. But after the hostile, even mocking questioning of the government's advocate in the Supreme Court by the five Republican-appointed justices, the expectation was that the act would indeed be struck down on that ground. So it came as no surprise when the five opined the act did indeed exceed Congress's commerce clause power. But it came as a great surprise when Chief Justice John Roberts, joined by the four Democrat-appointed justices, ruled that the act could be sustained as an exercise of Congress's taxing power - a ground urged by the government almost as an afterthought. It was further surprising, even shocking, that Justices Antonin Scalia, Anthony Kennedy, Clarence Thomas, and Samuel Alito not only wrote a joint opinion on the commerce clause virtually identical to that of their chief, but that in writing it they did not refer to or even acknowledge his opinion. Finally surprising was the fact that Justices Ruth Bader Ginsburg and Stephen Breyer joined the chief in holding that aspects of the act's Medicaid expansion were unconstitutional. This essay ponders and tries to unravel some of these puzzles.

  5. 早期梅毒患者血清中IL-2、IL-4的检测%Detection of IL-2 IL-4 in early phase of syphilis

    Institute of Scientific and Technical Information of China (English)

    陈宏翔; 盛晚香; 宋继权; 孙祥银; 宋韬

    2002-01-01

    @@ 梅毒(syphilis)是由苍白螺旋体(Treponema,pallidum,TP)感染所致的一种慢性传染病,主要通过性接触传染.其临床表现多种多样、免疫机制非常复杂,为了探讨细胞因子在梅毒发病中所起的作用,本文通过对一期和二期梅毒抗心磷脂抗体、抗梅毒螺旋体抗体、IL-2、IL-4等细胞、体液免疫相关因素的检测和比较,来探讨早期梅毒患者免疫学的变化.

  6. Higher susceptibility of NOD/LtSz-scid Il2rg-/- NSG mice to xenotransplanted lung cancer cell lines

    Directory of Open Access Journals (Sweden)

    Kanaji N

    2014-10-01

    Full Text Available Nobuhiro Kanaji,1 Akira Tadokoro,1 Kentaro Susaki,1 Saki Yokokura,1 Kiyomi Ohmichi,2 Reiji Haba,2 Naoki Watanabe,1 Shuji Bandoh,1 Tomoya Ishii,1 Hiroaki Dobashi,1 Takuya Matsunaga11Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan; 2Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, JapanPurpose: No lung cancer xenograft model using non-obese diabetic (NOD-scid Il2rg-/- mice has been reported. The purpose of this study is to select a suitable mouse strain as a xenogenic host for testing tumorigenicity of lung cancer.Materials and methods: We directly compared the susceptibility of four immunodeficient mouse strains, c-nu, C.B-17 scid, NOD-scid, and NOD/LtSz-scid Il2rg-/- (NSG mice, for tumor formation from xenotransplanted lung cancer cell lines. Various numbers (101–105 cells/head of two lung cancer cell lines, A549 and EBC1, were subcutaneously inoculated and tumor sizes were measured every week up to 12 weeks.Results: When 104 EBC1 cells were inoculated, no tumor formation was observed in BALB/c-nu or C.B-17 scid mice. Tumors developed in two of the five NOD-scid mice (40% and in all the five NSG mice (100%. When 103 EBC1 cells were injected, no tumors developed in any strain other than NSG mice, while tumorigenesis was achieved in all the five NSG mice (100%, P=0.0079 within 9 weeks. NSG mice similarly showed higher susceptibility to xenotransplantation of A549 cells. Tumor formation was observed only in NSG mice after inoculation of 103 or fewer A549 cells (40% vs 0% in 15 NSG mice compared with others, respectively, P=0.0169. We confirmed that the engrafted tumors originated from inoculated human lung cancer cells by immunohistochemical staining with human cytokeratin and vimentin.Conclusion: NSG mice may be the most suitable strain for testing tumorigenicity of lung cancer, especially if only a few cells

  7. IL-2 immunotherapy reveals potential for innate beta cell regeneration in the non-obese diabetic mouse model of autoimmune diabetes.

    Directory of Open Access Journals (Sweden)

    Yaiza Diaz-de-Durana

    Full Text Available Type-1 diabetes (T1D is an autoimmune disease targeting insulin-producing beta cells, resulting in dependence on exogenous insulin. To date, significant efforts have been invested to develop immune-modulatory therapies for T1D treatment. Previously, IL-2 immunotherapy was demonstrated to prevent and reverse T1D at onset in the non-obese diabetic (NOD mouse model, revealing potential as a therapy in early disease stage in humans. In the NOD model, IL-2 deficiency contributes to a loss of regulatory T cell function. This deficiency can be augmented with IL-2 or antibody bound to IL-2 (Ab/IL-2 therapy, resulting in regulatory T cell expansion and potentiation. However, an understanding of the mechanism by which reconstituted regulatory T cell function allows for reversal of diabetes after onset is not clearly understood. Here, we describe that Ab/IL-2 immunotherapy treatment, given at the time of diabetes onset in NOD mice, not only correlated with reversal of diabetes and expansion of Treg cells, but also demonstrated the ability to significantly increase beta cell proliferation. Proliferation appeared specific to Ab/IL-2 immunotherapy, as anti-CD3 therapy did not have a similar effect. Furthermore, to assess the effect of Ab/IL-2 immunotherapy well after the development of diabetes, we tested the effect of delaying treatment for 4 weeks after diabetes onset, when beta cells were virtually absent. At this late stage after diabetes onset, Ab/IL-2 treatment was not sufficient to reverse hyperglycemia. However, it did promote survival in the absence of exogenous insulin. Proliferation of beta cells could not account for this improvement as few beta cells remained. Rather, abnormal insulin and glucagon dual-expressing cells were the only insulin-expressing cells observed in islets from mice with established disease. Thus, these data suggest that in diabetic NOD mice, beta cells have an innate capacity for regeneration both early and late in disease

  8. EFFICIENT ACTIVATION OF ANTITUMOR IMMUNITY BY IL-6 GENE-MODIFIED LEUKEMIA VACCINE IN COMBINATION WITH LOW DOSE CYCLOPHOSPHAMIDE AND LOW DOSE IL-2

    Institute of Scientific and Technical Information of China (English)

    Cao Xuetao; Ge Lingfu; Ju Dianwen; Tao Qun; Yu Yizhi

    1998-01-01

    Objective:To investigate the antitumor effect of the IL-6 gene-modified erythroleukemia cells combined with low dose cyclophosphamide (Cy) and low dose IL-2.Methods: Mice inoculated with FBL-3-IL-6 in combination with low dose IL-2 and low dose cyclophosphamide (Cy). Results: Mice received combined therapy of FBL-3-IL-6, IL-2 and Cy developed tumors most slowly and survived much longer when compared with mice in control groups, with 5 out of 8leukemia-bearing mice being tumor free 100 days after the combined treatment. To further explain the mechanism of the antitumor effects by the combined therapy. It was found that combined therapy with low dose Cy, low dose IL-2 and FBL-3-IL-6 achieved maximal cytotoxic effects of nature killer cells and specific cytotoxic T lymphocytes, increased production IL-2, TNF and GM-CSF from spleen lymphocytes in tumor-bearing mice. Vaccination with the FBL3-IL-6 also enhanced the cytotoxic activity of the peritoneal macrophages. The results demonstrated that administration of low dose Cy and low dose IL-2 in combination with IL-6 genemodified leukemia vaccine could elicit potent antileukemia effects, and the mechanisms involved in the antitumor process may include the induction of specific and nonspecific antitumor immunity, reversal of T suppressor cells that mediated local immuno-suppression in tumor bearing mice. Conclusion: The combined therapy with cytokine gene-modified tumor vaccine, low dose of Cy and IL-2 might be a promising approach for the treatment of leukemia.

  9. IL-2 Modulates the TCR Signaling Threshold for CD8 but Not CD4 T Cell Proliferation on a Single-Cell Level.

    Science.gov (United States)

    Au-Yeung, Byron B; Smith, Geoffrey Alexander; Mueller, James L; Heyn, Cheryl S; Jaszczak, Rebecca Garrett; Weiss, Arthur; Zikherman, Julie

    2017-03-15

    Lymphocytes integrate Ag and cytokine receptor signals to make cell fate decisions. Using a specific reporter of TCR signaling that is insensitive to cytokine signaling, Nur77-eGFP, we identify a sharp, minimal threshold of cumulative TCR signaling required for proliferation in CD4 and CD8 T cells that is independent of both Ag concentration and affinity. Unexpectedly, IL-2 reduces this threshold in CD8 but not CD4 T cells, suggesting that integration of multiple mitogenic inputs may alter the minimal requirement for TCR signaling in CD8 T cells. Neither naive CD4 nor naive CD8 T cells are responsive to low doses of IL-2. We show that activated CD8 T cells become responsive to low doses of IL-2 more quickly than CD4 T cells, and propose that this relative delay in turn accounts for the differential effects of IL-2 on the minimal TCR signaling threshold for proliferation in these populations. In contrast to Nur77-eGFP, c-Myc protein expression integrates mitogenic signals downstream of both IL-2 and the TCR, yet marks an invariant minimal threshold of cumulative mitogenic stimulation required for cell division. Our work provides a conceptual framework for understanding the regulation of clonal expansion of CD8 T cells by subthreshold TCR signaling in the context of mitogenic IL-2 signals, thereby rendering CD8 T cells exquisitely dependent upon environmental cues. Conversely, CD4 T cell proliferation requires an invariant minimal intensity of TCR signaling that is not modulated by IL-2, thereby restricting responses to low-affinity or low-abundance self-antigens even in the context of an inflammatory milieu.

  10. IL-2-targeted therapy ameliorates the severity of graft-versus-host disease: ex vivo selective depletion of host-reactive T cells and in vivo therapy.

    Science.gov (United States)

    Yarkoni, Shai; Prigozhina, Tatyana B; Slavin, Shimon; Askenasy, Nadir

    2012-04-01

    T cell depletion prevents graft-versus-host disease (GVHD) but also removes T cell-mediated support of hematopoietic cell engraftment. A chimeric molecule composed of IL-2 and caspase-3 (IL2-cas) has been evaluated as a therapeutic modality for GVHD and selective ex vivo depletion of host-reactive T cells. IL2-cas does not affect hematopoietic cell engraftment and significantly reduces the clinical and histological severity of GVHD. Early administration of IL2-cas reduced the lethal outcome of haploidentical transplants, and survivor mice displayed markedly elevated levels of X-linked forkhead/winged helix (FoxP3(+); 50%) and CD25(+)FoxP3(+) T cells (35%) in the lymph nodes. The chimeric molecule induces in vitro apoptosis in both CD4(+)CD25(-) and CD4(+)CD25(+) subsets of lymphocytes from alloimmunized mice, and stimulates proliferation of cells with highest levels of CD25 expression. Adoptive transfer of IL2-cas-pretreated viable splenocytes into sublethally irradiated haploidentical recipients resulted in 60% survival after a lethal challenge with lipopolysaccharide, which is associated with elevated fractions of CD25(high)FoxP3(+) T cells in the lymph nodes of survivors. These data demonstrate that ex vivo purging of host-presensitized lymphocytes is effectively achieved with IL2-cas, and that IL-2-targeted apoptotic therapy reduces GVHD severity in vivo. Both approaches promote survival in lethal models of haploidentical GVHD. The mechanism of protection includes direct killing of GVHD effectors, prevention of transition to effector/memory T cells, and induction of regulatory T cell proliferation, which becomes the dominant subset under conditions of homeostatic expansion.

  11. Generation of Interleukin-2 Receptor Gamma Gene Knockout Pigs from Somatic Cells Genetically Modified by Zinc Finger Nuclease-Encoding mRNA

    Science.gov (United States)

    Watanabe, Masahito; Nakano, Kazuaki; Matsunari, Hitomi; Matsuda, Taisuke; Maehara, Miki; Kanai, Takahiro; Kobayashi, Mirina; Matsumura, Yukina; Sakai, Rieko; Kuramoto, Momoko; Hayashida, Gota; Asano, Yoshinori; Takayanagi, Shuko; Arai, Yoshikazu; Umeyama, Kazuhiro; Nagaya, Masaki; Hanazono, Yutaka; Nagashima, Hiroshi

    2013-01-01

    Zinc finger nuclease (ZFN) is a powerful tool for genome editing. ZFN-encoding plasmid DNA expression systems have been recently employed for the generation of gene knockout (KO) pigs, although one major limitation of this technology is the use of potentially harmful genome-integrating plasmid DNAs. Here we describe a simple, non-integrating strategy for generating KO pigs using ZFN-encoding mRNA. The interleukin-2 receptor gamma (IL2RG) gene was knocked out in porcine fetal fibroblasts using ZFN-encoding mRNAs, and IL2RG KO pigs were subsequently generated using these KO cells through somatic cell nuclear transfer (SCNT). The resulting IL2RG KO pigs completely lacked a thymus and were deficient in T and NK cells, similar to human X-linked SCID patients. Our findings demonstrate that the combination of ZFN-encoding mRNAs and SCNT provides a simple robust method for producing KO pigs without genomic integration. PMID:24130776

  12. Universal statistics of the knockout tournament

    CERN Document Server

    Baek, Seung Ki; Park, Hye Jin; Kim, Beom Jun

    2014-01-01

    We study statistics of the knockout tournament, where only the winner of a fixture progresses to the next. We assign a real number called competitiveness to each contestant and find that the resulting distribution of prize money follows a power law with an exponent close to unity if the competitiveness is a stable quantity and a decisive factor to win a match. Otherwise, the distribution is found narrow. The existing observation of power law distributions in various kinds of real sports tournaments therefore suggests that the rules of those games are constructed in such a way that it is possible to understand the games in terms of the contestants' inherent characteristics of competitiveness.

  13. Universal statistics of the knockout tournament

    Science.gov (United States)

    Baek, Seung Ki; Yi, Il Gu; Park, Hye Jin; Kim, Beom Jun

    2013-11-01

    We study statistics of the knockout tournament, where only the winner of a fixture progresses to the next. We assign a real number called competitiveness to each contestant and find that the resulting distribution of prize money follows a power law with an exponent close to unity if the competitiveness is a stable quantity and a decisive factor to win a match. Otherwise, the distribution is found narrow. The existing observation of power law distributions in various kinds of real sports tournaments therefore suggests that the rules of those games are constructed in such a way that it is possible to understand the games in terms of the contestants' inherent characteristics of competitiveness.

  14. Claudin-2 knockout by TALEN-mediated gene targeting in MDCK cells: claudin-2 independently determines the leaky property of tight junctions in MDCK cells.

    Directory of Open Access Journals (Sweden)

    Shinsaku Tokuda

    Full Text Available Tight junctions (TJs regulate the movements of substances through the paracellular pathway, and claudins are major determinants of TJ permeability. Claudin-2 forms high conductive cation pores in TJs. The suppression of claudin-2 expression by RNA interference in Madin-Darby canine kidney (MDCK II cells (a low-resistance strain of MDCK cells was shown to induce a three-fold increase in transepithelial electrical resistance (TER, which, however, was still lower than in high-resistance strains of MDCK cells. Because RNA interference-mediated knockdown is not complete and only reduces gene function, we considered the possibility that the remaining claudin-2 expression in the knockdown study caused the lower TER in claudin-2 knockdown cells. Therefore, we investigated the effects of claudin-2 knockout in MDCK II cells by establishing claudin-2 knockout clones using transcription activator-like effector nucleases (TALENs, a recently developed genome editing method for gene knockout. Surprisingly, claudin-2 knockout increased TER by more than 50-fold in MDCK II cells, and TER values in these cells (3000-4000 Ω·cm2 were comparable to those in the high-resistance strains of MDCK cells. Claudin-2 re-expression restored the TER of claudin-2 knockout cells dependent upon claudin-2 protein levels. In addition, we investigated the localization of claudin-1, -2, -3, -4, and -7 at TJs between control MDCK cells and their respective knockout cells using their TALENs. Claudin-2 and -7 were less efficiently localized at TJs between control and their knockout cells. Our results indicate that claudin-2 independently determines the 'leaky' property of TJs in MDCK II cells and suggest the importance of knockout analysis in cultured cells.

  15. Prevention of hepatocellular carcinoma in mice by IL-2 and B7-1genes co-transfected liver cancer cell vaccines

    Institute of Scientific and Technical Information of China (English)

    Ning-Ling Ge; Sheng-Long Ye; Ning Zheng; Rui-Xia Sun; Yin-Kun Liu; Zhao-You Tang

    2003-01-01

    AIM: To study the immunoprotective effect of liver cancer vaccine with co-transfected IL-2 and B7-1 genes on hepatocarcinogenesis in mice.METHODS: The murine liver cancer cell line Hepal-6 was transfected with IL-2 and/or B7-1 gene via recombinant adenoviral vectors and the liver cancer vaccines were prepared. C57BL/6 mice were immunized with these vaccines and challenged with the parental Hepal-6 cells afterwards.The immunoprotection was investigated and the reactive T cell line was assayed.RESULTS: The immunoprotection of the tumor vaccine was demonstrated. The effect of IL-2 and B7-1 genes cotransfected Hepal-6 liver cancer vaccine (Hep6-IL2/B7vaccine) on the onset of tumor formation was the strongest.When attacked with wild Hepal-6 cells, the median survival period of the mice immunized with Hep6-IL2/B7 vaccine was the longest (68 days, χ2=7.70-11.69, P<0.05) and the implanted tumor was the smallest (z =3.20-44.10, P<0.05).The effect of single IL-2 or B7-1 gene-transfected vaccine was next to the IL2/B7 gene co-transfected group, and the mean survival periods were 59 and 54 days, respectively.The mean survival periods of wild or enhanced green fluorescence protein gene modified vaccine immunized group were 51 and 48 days, respectively. The mice in control group all died within 38 days and the implanted tumor was the largest (z=3.20-40.21, P<0.05). The cellular immunofunction test and cytotoxicity study showed that the natural killer (NK) cell, lymphokine activated killer (LAK) cell and cytotoxic T lymphocyte (CTL) activities were significantly increased in mice immunized with the Hep6-IL2/B7 vaccine, (29.5±2.5%,65.0±2.9%, 83.1±1.5% respectively, compared with other groups, P<0.05).CONCLUSION: The Hep6-IL2/B7 liver cancer vaccines can induce the mice to produce activated and specific CTL against the parental tumor cells, and demonstrate stronger effect on the hepatocarcinogenesis than single gene modified or the regular tumor vaccine. Therefore, the

  16. Two Proton Knockout from ^32Mg

    Science.gov (United States)

    Fallon, P.; Rodriguez-Vieitez, E.; Macchiavelli, A. O.; Clark, R. M.; Lee, I.-Y.; Wiedeking, M.; Gade, A.; Adrich, P.; Bazin, D.; Bowen, M.; Campbell, C. M.; Cook, J. M.; Dinca, D. C.; Glasmacher, T.; McDaniel, S.; Mueller, W. F.; Ratiewicz, A. F.; Siwek, K.; Terry, J. R.; Wiesshaar, D.; Yoneda, K.; Brown, B. A.; Otsuka, T.; Tostevin, J. A.; Utsuno, Y.

    2009-05-01

    We present data and calculations on the near-dripline nucleus ^30Ne. Gamma-ray decays from excited states as well as inclusive and exclusive cross-sections were measured in the ^9Be(^32Mg,^30Ne γ)X two-proton knockout reaction at incident beam energies of 99.7 and 86.7 MeV/A. The measured inclusive cross section sigma = 0.22(4)mb is suppressed compared to calculation and is indicative of a reduced overlap of initial and final state wavefunctions. We interpret this reduction as a result of large 4p4h intruder components present in ^30Ne, but not ^32Mg. Large 4p4h amplitudes are predicted to generate increased T=1 paring strengths and to help stabilize the heavier fluorine isotopes against neutron decay. A new gamma-ray transition at 1443 keV is assigned to the decay of the 4^+ state based on the spin dependent sigma for 2 proton knockout from the (d5/2)^4 configuration.

  17. Altered reward circuitry in the norepinephrine transporter knockout mouse.

    Directory of Open Access Journals (Sweden)

    Joseph J Gallagher

    Full Text Available Synaptic levels of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine are modulated by their respective plasma membrane transporters, albeit with a few exceptions. Monoamine transporters remove monoamines from the synaptic cleft and thus influence the degree and duration of signaling. Abnormal concentrations of these neuronal transmitters are implicated in a number of neurological and psychiatric disorders, including addiction, depression, and attention deficit/hyperactivity disorder. This work concentrates on the norepinephrine transporter (NET, using a battery of in vivo magnetic resonance imaging techniques and histological correlates to probe the effects of genetic deletion of the norepinephrine transporter on brain metabolism, anatomy and functional connectivity. MRS recorded in the striatum of NET knockout mice indicated a lower concentration of NAA that correlates with histological observations of subtle dysmorphisms in the striatum and internal capsule. As with DAT and SERT knockout mice, we detected minimal structural alterations in NET knockout mice by tensor-based morphometric analysis. In contrast, longitudinal imaging after stereotaxic prefrontal cortical injection of manganese, an established neuronal circuitry tracer, revealed that the reward circuit in the NET knockout mouse is biased toward anterior portions of the brain. This is similar to previous results observed for the dopamine transporter (DAT knockout mouse, but dissimilar from work with serotonin transporter (SERT knockout mice where Mn(2+ tracings extended to more posterior structures than in wildtype animals. These observations correlate with behavioral studies indicating that SERT knockout mice display anxiety-like phenotypes, while NET knockouts and to a lesser extent DAT knockout mice display antidepressant-like phenotypic features. Thus, the mainly anterior activity detected with manganese-enhanced MRI in the DAT and NET knockout mice is likely

  18. Recoiled Proton Tagged Knockout Reaction for 8He

    Institute of Scientific and Technical Information of China (English)

    曹中鑫; 叶沿林; 江栋兴; 郑涛; 李智焕; 华辉; 葛榆成; 李湘庆; 楼建玲; 肖军; 李奇特; 吕林辉; 李阔昂; 王赫; 乔锐; 游海波; 陈瑞九

    2012-01-01

    An experiment for knockout reaction induced by SHe beam at 82.5 MeV/nucleon on CH2 and C targets was carried out. The 6He and 4He core fragments at forward angles and the recoiled protons at large angles were detected coincidently. From this exclusive measurement the valence nucleon knockout mechanism and the core knockout mechanism are separated, which can be applied to the exclusive spectroscopic study on the structure of exotic nuclei.

  19. 胃癌患者血清中 IL-2,IL-4和 IL-6的动态分析及临床意义

    Institute of Scientific and Technical Information of China (English)

    孙景春; 李锐

    2013-01-01

    目的:探讨胃癌患者血清中 IL-2,IL-4和 IL-6的动态变化及临床意义;方法:应用 ELISA 的方法检测手术前后胃癌患者血清中 IL-2, IL-4和 IL-6的水平,并与良性肿瘤患者和健康体检者(对照组)进行比较.结果:胃癌患者在手术前,IL-4和 IL-6的水平高于良性肿瘤组和对照组(P<0.05),IL-2的水平低于良性肿瘤组和对照组(P<0.05);而在手术后 IL-4和 IL-6的水平明显降低,IL-2的水平呈现升高趋势,与对照组水平接近.结论:胃癌病人存在免疫功能的紊乱,IL-2,IL-4和 IL-6的水平变化参与了胃癌的发生、发展过程,对胃癌患者的诊断和预后判断具有重要的指导意义.

  20. An IL12-IL2-antibody fusion protein targeting Hodgkin's lymphoma cells potentiates activation of NK and T cells for an anti-tumor attack.

    Directory of Open Access Journals (Sweden)

    Tobias Jahn

    Full Text Available Successful immunotherapy of Hodgkin's disease is so far hampered by the striking unresponsiveness of lymphoma infiltrating immune cells. To mobilize both adoptive and innate immune cells for an anti-tumor attack we fused the pro-inflammatory cytokines IL2 and IL12 to an anti-CD30 scFv antibody in a dual cytokine fusion protein to accumulate both cytokines at the malignant CD30(+ Hodgkin/Reed-Sternberg cells in the lymphoma lesion. The tumor-targeted IL12-IL2 fusion protein was superior in activating resting T cells to amplify and secrete pro-inflammatory cytokines compared to targeted IL2 or IL12 alone. NK cells were also activated by the dual cytokine protein to secrete IFN-γ and to lyse target cells. The tumor-targeted IL12-IL2, when applied by i.v. injection to immune-competent mice with established antigen-positive tumors, accumulated at the tumor site and induced tumor regression. Data demonstrate that simultaneous targeting of two cytokines in a spatial and temporal simultaneous fashion to pre-defined tissues is feasible by a dual-cytokine antibody fusion protein. In the case of IL12 and IL2, this produced superior anti-tumor efficacy implying the strategy to muster a broader immune cell response in the combat against cancer.

  1. Restoration of CD28 Expression in CD28− CD8+ Memory Effector T Cells Reconstitutes Antigen-induced IL-2 Production

    Science.gov (United States)

    Topp, Max S.; Riddell, Stanley R.; Akatsuka, Yoshiki; Jensen, Michael C.; Blattman, Joseph N.; Greenberg, Philip D.

    2003-01-01

    The control of many persistent viral infections by Ag-specific cytolytic CD8+ T cells requires a concurrent virus-specific CD4+ Th cell response. This reflects in part a requirement of activated effector CD8+ T cells for paracrine IL-2 production as a growth and survival factor. In human CMV and HIV infection, the majority of differentiated virus-specific CD8+ T cells notably lose the ability to produce IL-2 but also lose expression of CD28, a costimulatory molecule. Analysis of the fraction of memory CD8+ T cells that continue to express CD28 revealed these cells retain the ability to produce IL-2. Therefore, we examined if IL-2 production by CD28− CD8+ T cells could be restored by introduction of a constitutively expressed CD28 gene. Expression of CD28 in CD28− CD8+ CMV- and HIV-specific CD8+ T cells reconstituted the ability to produce IL-2, which could sustain an autocrine proliferative response after Ag recognition. These results suggest that the loss of CD28 expression during differentiation of memory/effector CD8+ T cells represents a decisive step in establishing regulation of responding CD8+ T cells, increasing the dependence on CD4+ Th for proliferation after target recognition, and has implications for the treatment of viral disease with adoptively transferred CD8+ T cells. PMID:12963692

  2. Estimations of expectedness and potential surprise in possibility theory

    Science.gov (United States)

    Prade, Henri; Yager, Ronald R.

    1992-01-01

    This note investigates how various ideas of 'expectedness' can be captured in the framework of possibility theory. Particularly, we are interested in trying to introduce estimates of the kind of lack of surprise expressed by people when saying 'I would not be surprised that...' before an event takes place, or by saying 'I knew it' after its realization. In possibility theory, a possibility distribution is supposed to model the relative levels of mutually exclusive alternatives in a set, or equivalently, the alternatives are assumed to be rank-ordered according to their level of possibility to take place. Four basic set-functions associated with a possibility distribution, including standard possibility and necessity measures, are discussed from the point of view of what they estimate when applied to potential events. Extensions of these estimates based on the notions of Q-projection or OWA operators are proposed when only significant parts of the possibility distribution are retained in the evaluation. The case of partially-known possibility distributions is also considered. Some potential applications are outlined.

  3. 10 years of surprises at Saturn: CAPS and INMS highlights

    Science.gov (United States)

    Coates, A. J.; Waite, J. H.

    2014-04-01

    The Cassini mission at Saturn has provided many surprises on Saturn's rapidly rotating magnetosphere and its interaction with the diverse moons, as well as its interaction with the solar wind. One of the early discoveries was the water-rich composition of the magnetosphere. Its structure and dynamics indicate remarkable injections, periodicities and interchange events. Enceladus, orbiting at 4 RS, was found to have plumes of water vapour and ice which are the dominant source for the inner magnetosphere. Charged water clusters, charged dust and photoelectrons provide key populations in the 'dusty plasma' seen here, as well as chemical complexity in the plume material. Direct pickup is seen near Enceladus and field aligned currents create a spot in Saturn's aurora. At Titan, orbiting at 20 RS, heavy negative and positive ions are seen in the ionosphere, as well as neutrals, all of which have surprising chemical complexity. These provide the source for Titan's haze. Ionospheric plasma is seen in Titan's tail, enabling ion escape to be estimated at 7 tonnes per day. Saturn's ring ionosphere was seen early in the mission, which was oxygen rich and produced photoelectrons; a return will be made in 2017. At Rhea, pickup positive and negative ions indicated weak atmospheres sustained by energetic particle impact, seen in the neutrals also. A weak atmosphere was also seen at Dione. The exosphere production process operates at Jupiter's moons also. Here we review some of the key new results, and discuss the implications for other solar system contexts.

  4. 黄芪有效部位对化疗性贫血小鼠细胞因子IL-2、 IL-4、 IL-6的影响%Effect of Effective Parts of Astragalus on Cytokines IL-2 IL-4and IL-6 of Chemotherapy-induced Anemic Mice

    Institute of Scientific and Technical Information of China (English)

    陈晶晶; 范颖; 张红梅; 林庶茹

    2011-01-01

    目的:探讨黄芪有效部位对化疗性贫血模型小鼠脾组织IL-2、IL-4、IL-6的影响.方法:采用ELISA 法测定脾组织IL-2、IL-4、IL-6含量.结果:模型组脾组织IL-2、IL-4含量下降,IL-6含量升高,均有统计学意义(P<0.05).各治疗组对化疗所致骨髓抑制性贫血的脾组织IL-2、IL-4、IL-6具有不同程度的调控作用.结论:IL-2、IL-4、IL-6与环磷酰胺所致骨髓抑制性贫血的免疫失调有关;黄芪及其有效部位对环磷酰胺引起的骨髓抑制性贫血引发的免疫损伤具有保护作用,并对IL-2、IL-4、IL-6的生成具有不同的调节机制.%Objective: To investigate effect of effective parts of astragalus on cytokines IL-2,IL-4 and IL-6 of chemotherapy-induced anemic mice. Methods : Enzyme-linked immunosorbent assay(ELISA) was applied to measure the content of IL-2, EL-4 and IL-6 in spleen. Results: In spleen of the model group, the content of IL-2 and IL-4 decreased, the content of IL-6 increased, both with significances in statistics(P<0.05). In each treated group, IL-2, IL-4 and IL-6 in spleen of chemotherapy-induced myelosuppression anemic mice are regulated in varying degree. Conclusion: There are relationship between immune disorders caused by cyclophosphamide-induced myelosuppression anemia and the content of IL-2, IL-4 and IL-6. Astragalus and its effective parts can protect immune injury caused by cyclophosphamide-induced myelosuppression anemia, also regulate the production of IL-2, IL-4 and IL-6 in different metabolism.

  5. 松子壳多糖体外诱生小鼠IL-2和TNF-α的研究%Research on Polysaccharide from Pine Seed Shell Inducing Rat IL-2 andTNF-α in Vitro

    Institute of Scientific and Technical Information of China (English)

    刘中禄; 吕铁钢; 张永亮

    2010-01-01

    @@ 松子壳多糖(Pine nut shell polysaccharide,PSP)是从松子壳(松塔)中提取的酸性多糖成分,其在抗肿瘤、抗病毒和免疫促进剂作用方面研究较多(Sak-agami等,1999;Harada等,1991;吕永俊等,2008),我们在前期试验证实了松子壳多糖对小鼠脾T、B淋巴细胞转化、巨噬细胞的吞噬功能、NK细胞杀伤作用均有明显的促进作用,但PSP对细胞冈子的影响未见报道.本次试验进一步考察松子壳多糖对小鼠体外诱生IL-2及TNF-α分泌的影响,旨在为松子壳多糖的深入开发利用奠定一定的实验基础.

  6. Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming

    DEFF Research Database (Denmark)

    Marzec, Michal; Halasa, Krzysztof; Liu, Xiaobin

    2013-01-01

    by the STAT5 and STAT3 transcription factors, whereas transcription of Egr-1 and Fosl-1 was induced by the MEK-ERK pathway. Finally, we found that Egr-1, a protein not associated previously with either IL-2 or ALK, contributes to the cell proliferation. These findings indicate that NPM/ALK transforms......Anaplastic lymphoma kinase (ALK), physiologically expressed only by nervous system cells, displays a remarkable capacity to transform CD4(+) T lymphocytes and other types of nonneural cells. In this study, we report that activity of nucleophosmin (NPM)/ALK chimeric protein, the dominant form of ALK...... expressed in T cell lymphomas (TCLs), closely resembles cell activation induced by IL-2, the key cytokine supporting growth and survival of normal CD4(+) T lymphocytes. Direct comparison of gene expression by ALK(+) TCL cells treated with an ALK inhibitor and IL-2-dependent ALK(-) TCL cells stimulated...

  7. Relationship between XspI Site Polymorphisms of LDL-R Gene and Serum IL-2 and IL-10 in Patients with Hypercholesterolemia.

    Science.gov (United States)

    Zhang, Mingming; Lu, Yamin; Liu, Xin; Zhang, Xiaobin; Zhang, Cuigai; Gao, Wei; Tie, Yanqing

    2016-11-01

    Relationship has been identified in sporadic reports between polymorphisms and hypercholesterolemia. However, the relationship between inflammatory cytokines and polymorphism of low-density lipoprotein receptor (LDL-R) gene in hypercholesterolemia is unclear. This study aimed to explore the relationship and significance between polymorphisms of LDL-R gene and serum Interleukin-2 (IL-2), IL-10 in patients with hypercholesterolemia. PCR-RFLP and direct DNA sequencing assay were employed to determine polymorphism of LDL-R gene in 900 patients with hypercholesterolemia and 400 healthy cases. ELISA was applied to assay serum concentration of IL-2 and IL-10. Blood lipid indexes were tested in all cases. Compared with the healthy controls, level of IL-2 increased significantly, while IL-10 decreased significantly (P hypercholesterolemia. © 2016 Wiley Periodicals, Inc.

  8. The effect of valtrex on T cell subset and IL2, IL6 and IL10 level in patients with herpes zoster

    Institute of Scientific and Technical Information of China (English)

    Gui-E Wang; Jian Chen; Ling Chen

    2015-01-01

    Objective:To explore the effects of valtrex on T cell subset and IL2, IL6 and IL10 level in patients with herpes zoster.Methods: 120 patients with herpes zoster in our hospital were analyzed. The serum T cell subset and IL2, IL6 and IL10 were detected by Western Blotting. Healthy volunteers were enrolled as control group.Results: The CD4+ level was increased significantly while the CD8+ decreased significantly, and the ratio of the two increased too (P all<0.01). The IL6 and IL10 levels were increased significantly (P<0.01). But no significant change in IL2 level was observed.Conclusion:Valtrex is effective on herpes zoster by regulating T cell subset, IL6 and IL10 levels.

  9. Two unique mutations in the interleukin-2 receptor gamma chain gene (IL2RG) cause X-linked severe combined immunodeficiency arising in opposite parental germ lines

    Energy Technology Data Exchange (ETDEWEB)

    Puck, J.M.; Pepper, A.E. [National Institutes of Health, Bethesda, MD (United States)

    1994-09-01

    The gene encoding the gamma chain of the lymphocyte receptor for IL-2 lies in human X13.1 and is mutated in males with X-linked severe combined immunodeficiency (SCID). 27 X-linked SCID mutations have been found in our laboratory. Single strand conformation polymorphism (SSCP) analysis of genomic DNA using primers flanking each of the 8 exons was followed by direct sequencing of abnormally migrating fragments from SCID patients and family members. A 9 bp in-frame duplication insertion was found in IL2RG exon 5 of a patient from a large X-linked SCID pedigree; the resulting duplication of 3 extracellular amino acids, including the first tryptophan of the {open_quotes}WSXWS{close_quotes} cytokine binding motif, is predicted to disrupt interaction of the cytokine receptor chain with its ligand. Genetic linkage studies demonstrated that the grandmaternal X chromosome associated with SCID was contributed to 3 daughters, 2 obligate carriers and 1 woman of unknown status. However, this grandmother`s genomic DNA did not contain the insertion mutation, nor did she have skewed X-chromosome inactivation in her lymphocytes. That both obligate carrier daughters, but not the third daughter, had the insertion proved the grandmother to be a germline mosaic. A second proband had X-linked SCID with a branch point mutation due to substitution of T for A 15 bp 5{prime} of the start of IL2RG exon 3. This mutation resulted in undetectable IL2RG mRNA by Northern blot. Linkage analysis and sequencing of IL2RG DNA in this family proved the mutation to have originated in the germline of the proband`s grandfather, an immunocompetent individual who contributed an X chromosome with normal IL2RG to one daughter and a mutated X to the another.

  10. Innate Response to Human Cancer Cells with or without IL-2 Receptor Common γ-Chain Function in NOD Background Mice Lacking Adaptive Immunity.

    Science.gov (United States)

    Nishime, Chiyoko; Kawai, Kenji; Yamamoto, Takehiro; Katano, Ikumi; Monnai, Makoto; Goda, Nobuhito; Mizushima, Tomoko; Suemizu, Hiroshi; Nakamura, Masato; Murata, Mitsuru; Suematsu, Makoto; Wakui, Masatoshi

    2015-08-15

    Immunodeficient hosts exhibit high acceptance of xenogeneic or neoplastic cells mainly due to lack of adaptive immunity, although it still remains to be elucidated how innate response affects the engraftment. IL-2R common γ-chain (IL-2Rγc) signaling is required for development of NK cells and a subset of dendritic cells producing IFN-γ. To better understand innate response in the absence of adaptive immunity, we examined amounts of metastatic foci in the livers after intrasplenic transfer of human colon cancer HCT116 cells into NOD/SCID versus NOD/SCID/IL-2Rγc (null) (NOG) hosts. The intravital microscopic imaging of livers in the hosts depleted of NK cells and/or macrophages revealed that IL-2Rγc function critically contributes to elimination of cancer cells without the need for NK cells and macrophages. In the absence of IL-2Rγc, macrophages play a role in the defense against tumors despite the NOD Sirpa allele, which allows human CD47 to bind to the encoded signal regulatory protein α to inhibit macrophage phagocytosis of human cells. Analogous experiments using human pancreas cancer MIA PaCa-2 cells provided findings roughly similar to those from the experiments using HCT116 cells except for lack of suppression of metastases by macrophages in NOG hosts. Administration of mouse IFN-γ to NOG hosts appeared to partially compensate lack of IL-2Rγc-dependent elimination of transferred HCT116 cells. These results provide insights into the nature of innate response in the absence of adaptive immunity, aiding in developing tumor xenograft models in experimental oncology.

  11. Measured Zero Net Energy Performance: Results, Lessons, and Surprises

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Carrie; LaRue, Anna; Pigman, Margaret; Roberts, Jon; Kaneda, David; Connelly, Dylan; Elliott, John; Pless, Shanti; Pande, Abhijeet; Dean, Edward; Anbarlilar, Can

    2016-08-26

    As more and more zero net energy (ZNE) buildings are built and monitored, we can learn from both careful case studies of individual projects as well as a broader perspective of trends over time. In a forum sponsored by Pacific Gas and Electric Company (PG&E), eight expert speakers discussed: results and lessons from monitoring occupied ZNE buildings; best practices for setting performance targets and getting actionable performance information, and; things that have surprised them about monitored ZNE buildings. This paper distills the content of the forum by laying out the most common hurdles that are encountered in setting up monitoring projects, frequent performance issues that the monitoring uncovers, and lessons learned that can be applied to future projects.

  12. Surprising hair analysis results following acute carbofuran intoxication.

    Science.gov (United States)

    Dulaurent, S; Gaulier, J M; Zouaoui, K; Moesch, C; François, B; Lachâtre, G

    2011-10-10

    We present two non fatal cases of intoxication with carbofuran (CBF) documented by hair analysis. Carbofuran and 3-hydroxycarbofuran (OHCBF, its main metabolite) hair concentrations were determined using a liquid chromatography-tandem mass spectrometry method. The obtained results were surprising if we consider several hair analyses previously published and based on a theory of the presence of xenobiotic in the only segment that comprised its intake. Among the two intoxication cases, we noticed the presence of CBF and OHCBF in hair segments corresponding to 45 days before, and more than 100 days after, the day of intoxication. Additionally, repeated hair samplings and subsequent analysis revealed a decrease of the carbofuran's concentration during the hair life.

  13. Physics Nobel prize 2004: Surprising theory wins physics Nobel

    CERN Multimedia

    2004-01-01

    From left to right: David Politzer, David Gross and Frank Wilczek. For their understanding of counter-intuitive aspects of the strong force, which governs quarks inside protons and neutrons, on 5 October three American physicists were awarded the 2004 Nobel Prize in Physics. David J. Gross (Kavli Institute of Theoretical Physics, University of California, Santa Barbara), H. David Politzer (California Institute of Technology), and Frank Wilczek (Massachusetts Institute of Technology) made a key theoretical discovery with a surprising result: the closer quarks are together, the weaker the force - opposite to what is seen with electromagnetism and gravity. Rather, the strong force is analogous to a rubber band stretching, where the force increases as the quarks get farther apart. These physicists discovered this property of quarks, known as asymptotic freedom, in 1976. It later became a key part of the theory of quantum chromodynamics (QCD) and the Standard Model, the current best theory to describe the interac...

  14. Probability and Surprisal in Auditory Comprehension of Morphologically Complex Words

    DEFF Research Database (Denmark)

    Balling, Laura Winther; Baayen, R. Harald

    2012-01-01

    Two auditory lexical decision experiments document for morphologically complex words two points at which the probability of a target word given the evidence shifts dramatically. The first point is reached when morphologically unrelated competitors are no longer compatible with the evidence....... Adapting terminology from Marslen-Wilson (1984), we refer to this as the word’s initial uniqueness point (UP1). The second point is the complex uniqueness point (CUP) introduced by Balling and Baayen (2008), at which morphologically related competitors become incompatible with the input. Later initial...... in the course of the word co-determines response latencies. The presence of effects of surprisal, both at the initial uniqueness point of complex words, and cumulatively throughout the word, challenges the Shortlist B model of Norris and McQueen (2008), and suggests that a Bayesian approach to auditory...

  15. 2014 Presidential elections in Romania – surprising result or strategy

    Directory of Open Access Journals (Sweden)

    Dan Mihalache

    2015-03-01

    Full Text Available The presidential elections in Romania which took place in November 2014 were won by Klaus Iohannis, who clearly defeated the incumbent prime-minister Victor Ponta by 10%. The result was considered by many a surprise, as none of the opinion polls were able to predict it. This article reveals a part of the strategy of Klaus Iohannis’s campaign and it offers a few clues about how this is result was possible, without having the aim to explain it fully. As the authors were accountable for strategy and political message in the electoral campaign for Klaus Iohannis, the scientific approach is combined with the inside view, to provide the reader a better understanding of the November 2014 events.

  16. Lysis of pig endothelium by IL-2 activated human natural killer cells is inhibited by swine and human major histocompatibility complex (MHC) class I gene products.

    Science.gov (United States)

    Itescu, S; Artrip, J H; Kwiatkowski, P A; Wang, S F; Minanov, O P; Morgenthau, A S; Michler, R E

    1997-01-01

    We have previously described a form of xenograft rejection, mediated by natural killer (NK) cells, occurring in pig-to-primate organ transplants beyond the period of antibody-mediated hyperacute rejection. In this study, two distinct NK activation pathways were identified as mechanisms of pig aortic endotheliual cell (PAEC) lysis by human NK cells. Using an antibody-dependent cellular cytotoxicity (ADCC) assay, a progressive increase in human NK lysis of PAEC was observed following incubation with human IgG at increasing serum titer. In the absence of IgG, a second mechanism of PAEC lysis by human NK cells was observed following activation with IL-2. IL-2 activation of human NK cells increased lysis of PAEC by over 3-fold compared with ADCC. These results indicate that IL-2 activation of human NK cells induces significantly higher levels of lytic activity than does conventional ADCC involving IgG and FcRIII. We next investigated the role of MHC class I molecules in the regulation of NK lysis following IL-2 activation. PAEC expression of SLA class I molecules was increased by up to 75% by treatment with human TNFa. Following treatment with TNFa at 1 u/ml, IL-2 activated human NK lysis of PAEC was inhibited at every effector:target (E:T) ratio tested. Maximal effect occurred at an E:T ratio of 10:1, with TNFa inhibiting specific lysis by 59% (p < 0.01). Incubation with an anti-SLA class I Mab, but not IgG isotype control, abrogated the protective effects of TNFa on NK lysis of PAEC, suggesting direct inhibitory effects of SLA class I molecules on human NK function. To investigate whether human MHC class I molecules might have similar effects on human NK lysis of PAEC, further experiments were performed using a soluble peptide derived from the alpha-helical region of HLA-B7. Incubation with the HLA-B7 derived peptide significantly reduced the IL-2 activated NK lytic activity against PAEC in a dose-dependent fashion. Maximal effect occurred at a concentration of 10 mg

  17. A FQ-RT-PCR method for quantitative determination of IL-2 mRNA and IL-4 mRNA and its application

    Institute of Scientific and Technical Information of China (English)

    QING HUI ZHU; QING LU; GU SHENG ZHANG

    2006-01-01

    The purpose of the study is to establish a fluorescence quantitative reverse transcription polymerase chain response (FQ-RT-PCR) method for the quantitative determination of IL-2 mRNA and IL-4mRNA in Th cells, with which the Th cells status of the patients with gynaecological tumors and chronic renal failure (CRF) can be analyzed. IL-2 cDNA and IL-4 cDNA were prepared, and the plasmid pMD18 carrying IL-2 cDNA or IL-4 cDNA fragment was constructed and cloned as the template for quantitative determination. The primers and probes labelled with 6-carboxy-fluorescein (FAM) and 6-carboxytetramethylrhodamine (TAMRA) were prepared, and the experimental conditions were optimized to set up the FQ-RT-PCR method for quantitative determination of IL-2 mRNA and IL-4 mRNA. Th cells enriched from peripheral blood mononuclear cells (PBMCs) of 20 healthy volunteers (HVs), 16 gynaecological benign (GB) cases, 18 gynaecological malignant (GM) tumor cases and 16 chronic renal failure (CRF) patients were tested for IL-2 mRNA and IL-4 mRNA by FQ-RT-PCR. The house-keeping gene 3-actin was used as the internal control gene of the experiment. The standard curve for log concentration of series of quantitative templates vs threshold cycle (CT) was established by linear regression, and the linear range was 102-107 copies/μl. The imprecision test showed the CV of inter-assay and intra-assay of a high content sample by FQ-RT-PCR were 7.8% and 12.5%, respectively. The CV of inter-assay and intra-assay of a low content sample were 10.8% and 19.5%, respectively. The IL-2 mRNA expressions in Th of the patients with gynaecological malignant tumor (compared with the HVs and the patients with gynaecological benign disease) and in Th of the CRF patients (compared with the HVs) were declined significantly and at the same time the IL-4 mRNA expression increased significantly ( P < 0. 001 ). A simple, sensitive and accurate FQ-RT-PCR method for the quantitative detection of IL-2 mRNA and IL-4 mRNA has

  18. Observation and study OH IL-1β,IL-2 and IL-10 in serum of inbred HFJ rats%近交系HFJ大鼠血清中IL-1β、IL-2和IL-10观察研究

    Institute of Scientific and Technical Information of China (English)

    段肖翠; 吕占军; 蔡月花; 王秀芳; 侯洁; 刘军须; 刘福英; 谢英

    2011-01-01

    目的 比较观察本实验室培育的近交系HFJ大鼠和Wistar大鼠血清中IL-1β、IL-2和IL-10的含量.方法 HFJ大鼠和远交群Wistar大鼠各10只,应用ELISA法分别检测其血清IL-1β、IL-2和IL-10水平.结果 HFJ大鼠血清中IL-1β、IL-2的含量与Wistar大鼠相比差异无统计学意义(P>0.05),HFJ大鼠血清中IL-10的含量高于Wistar大鼠组,差异有统计学意义(P<0.05).且HFJ大鼠的IL-1β、IL-2和IL-10总体离散度明显小于Wistar大鼠组.结论 HFJ大鼠血清IL-10高于Wistar大鼠且近交系HFJ大鼠的IL-1β、IL-2和IL-10,测定值较为均一,离散度均低于Wistar大鼠.%Objective To comparative study the contents of IL - 1β, IL -2 and IL -10 in serum of Wistar rats and high fecundity inbred HFJ rats bred in our lab. Metbod Selecting 10 cases of HFJ rats and 10 cases of Wistar rats, and using ELISA to detected IL - 1β. IL -2 and IL - 10 in serum of them. Results There was no difference between Wistar group and HFJ group at the level of IL - 1β and IL - 2 (P > 0. 05) . The level of IL - 10 in HFJ group was higher than that in Wistar group (P < 0. 05) . The overall dispersion of IL - 1β. IL -2 and IL - 10 in HFJ rats group was significantly lower than Wistar rats group. Conlcusions IL - 10 in HFJ was higher than Wistar rats, and the measured values of IL -1β IL - 2 and IL - 10 were more relatively uniform in HFJ, and the dispersion of IL - 1β, IL - 2 and IL - 10 in HFJ rats group was lower than Wistar rats group.

  19. IL-2 and GM-CSF are regulated by DNA demethylation during activation of T cells, B cells and macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yan [College of Animal Science and Technology, Northwest A and F University, Yangling, Shaanxi 712100 (China); Department of Genome Biology, John Curtin School of Medical Research, The Australian National University, ACT 2601 (Australia); Ohms, Stephen J. [ACRF Biomolecular Resource Facility, John Curtin School of Medical Research, The Australian National University, ACT 2601 (Australia); Shannon, Frances M. [Department of Genome Biology, John Curtin School of Medical Research, The Australian National University, ACT 2601 (Australia); The University of Canberra, ACT 2602 (Australia); Sun, Chao, E-mail: sunchao2775@163.com [College of Animal Science and Technology, Northwest A and F University, Yangling, Shaanxi 712100 (China); Fan, Jun Y., E-mail: jun.fan@anu.edu.au [Department of Genome Biology, John Curtin School of Medical Research, The Australian National University, ACT 2601 (Australia)

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer DNA methylation is dynamic and flexible and changes rapidly upon cell activation. Black-Right-Pointing-Pointer DNA methylation controls the inducible gene expression in a given cell type. Black-Right-Pointing-Pointer Some enzymes are involved in maintaining the methylation profile of immune cells. -- Abstract: DNA demethylation has been found to occur at the promoters of a number of actively expressed cytokines and is believed to play a critical role in transcriptional regulation. While many DNA demethylation studies have focused on T cell activation, proliferation and differentiation, changes in DNA methylation in other types of immune cells are less well studied. We found that the expression of two cytokines (IL-2 and GM-CSF) responded differently to activation in three types of immune cells: EL4, A20 and RAW264.7 cells. Using the McrBC and MeDIP approaches, we observed decreases in DNA methylation at a genome-wide level and at the promoters of the genes of these cytokines. The expression of several potential enzymes/co-enzymes involved in the DNA demethylation pathways seemed to be associated with immune cell activation.

  20. Late-Onset Combined Immunodeficiency with a Novel IL2RG Mutation and Probable Revertant Somatic Mosaicism.

    Science.gov (United States)

    Okuno, Yusuke; Hoshino, Akihiro; Muramatsu, Hideki; Kawashima, Nozomu; Wang, Xinan; Yoshida, Kenichi; Wada, Taizo; Gunji, Masaharu; Toma, Tomoko; Kato, Tamaki; Shiraishi, Yuichi; Iwata, Atsuko; Hori, Toshinori; Kitoh, Toshiyuki; Chiba, Kenichi; Tanaka, Hiroko; Sanada, Masashi; Takahashi, Yoshiyuki; Nonoyama, Shigeaki; Ito, Masafumi; Miyano, Satoru; Ogawa, Seishi; Kojima, Seiji; Kanegane, Hirokazu

    2015-10-01

    Primary immunodeficiency disease (PID) is caused by mutations of more than two hundred immunity-related genes. In addition to the heterogeneity of the diseases, the atypical presentation of each disease caused by hypomorphic mutations or somatic mosaicism makes genetic diagnosis challenging. Next-generation sequencing tests all genes simultaneously and has proven its innovative efficacy in genomics. We describe a male PID patient without any family history of immunodeficiency. This patient suffered from recurrent infections from 1 year of age. Laboratory analysis showed hypogammaglobulinemia. T, B, and NK cells were present, but the T cell proliferative response decreased. Whole-exome sequencing analysis identified an IL2RG p.P58T missense mutation. CD8(+) and CD56(+) cells showed revertant somatic mosaicism to the wild-type allele. A late-onset and atypical presentation of the X-linked severe combined immunodeficiency (X-SCID) phenotype might be associated with revertant somatic mosaicism in T and NK cells. This patient is the seventh reported case of X-SCID with revertant somatic mosaicism. His classical clinical management did not result in a molecular diagnosis because of the atypical presentation. The coverage that is provided by whole-exome sequencing of most PID genes effectively excluded differential diagnoses other than X-SCID. As next-generation sequencing becomes available in clinical practice, it will enhance our knowledge of PID and rescue currently undiagnosed patients.

  1. Fibrinogen-like protein 2/fibroleukin prothrombinase contributes to tumor hypercoagulability via IL-2 and IFN-γ

    Institute of Scientific and Technical Information of China (English)

    Kai Su; Fang Chen; Wei-Ming Yan; Qi-Li Zeng; Li Xu; Dong Xi; Bin Pi; Xiao-Ping Luo; Qin Ning

    2008-01-01

    AIM: To examine the role of Fibrinogen-like protein 2 (fgl2)/fibroleukin in tumor development. Fgl2 has been reported to play a vital role in the pathogenesis in MHV-3 (mouse hepatitis virus) induced fulminant and severe hepatitis, spontaneous abortion, allo- and xeno- graft rejection by mediating "immune coagulation".METHODS: Tumor tissues from 133 patients with six types of distinct cancers and the animal tumor tissues from human hepatocellular carcinoma (HCC) model on nude mice (established from high metastasis HCC cell line MHCC97LM6) were obtained.RESULTS: Hfgl2 was detected in tumor tissues from 127 out of 133 patients as well as tumor tissues collected from human HCC nude mice. Hfgl2 was highly expressed both in cancer cells and interstitial inflammatory cells including macrophages, NK cells, and CD8+ T lymphocytes and vascular endothelial cells. Hfgl2 mRNA was localized in cells that expressed hfgl2 protein. Fibrin (nogen) co-localization with hfgl2 expression was determined by dual immunohistochemical staining. In vitro, IL-2 and IFN-γ increased hfgl2 mRNA by 10-100 folds and protein expression in both THP-1 and HUVEC cell lines. One-stage clotting assays demonstrated that THP-1 and HUVEC cells expressing hfgl2 had increased procoagulant activity following cytokines stimulation.CONCLUSION: The hfgl2 contributes to the hypercoagulability in cancer and may induce tumor angiogenesis and metastasis via cytokine induction.

  2. Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases.

    Science.gov (United States)

    Linka, R M; Risse, S L; Bienemann, K; Werner, M; Linka, Y; Krux, F; Synaeve, C; Deenen, R; Ginzel, S; Dvorsky, R; Gombert, M; Halenius, A; Hartig, R; Helminen, M; Fischer, A; Stepensky, P; Vettenranta, K; Köhrer, K; Ahmadian, M R; Laws, H-J; Fleckenstein, B; Jumaa, H; Latour, S; Schraven, B; Borkhardt, A

    2012-05-01

    The purpose of this study was the appraisal of the clinical and functional consequences of germline mutations within the gene for the IL-2 inducible T-cell kinase, ITK. Among patients with Epstein-Barr virus-driven lymphoproliferative disorders (EBV-LPD), negative for mutations in SH2D1A and XIAP (n=46), we identified two patients with R29H or D500T,F501L,M503X mutations, respectively. Human wild-type (wt) ITK, but none of the mutants, was able to rescue defective calcium flux in murine Itk(-/-) T cells. Pulse-chase experiments showed that ITK mutations lead to varying reductions of protein half-life from 25 to 69% as compared with wt ITK (107 min). The pleckstrin homology domain of wt ITK binds most prominently to phosphatidylinositol monophosphates (PI(3)P, PI(4)P, PI(5)P) and to lesser extend to its double or triple phosphorylated derivates (PIP2, PIP3), interactions which were dramatically reduced in the patient with the ITK(R29H) mutant. ITK mutations are distributed over the entire protein and include missense, nonsense and indel mutations, reminiscent of the situation in its sister kinase in B cells, Bruton's tyrosine kinase.

  3. Decreased SAP expression in T cells from patients with SLE contributes to early signaling abnormalities and reduced IL-2 production

    Science.gov (United States)

    Karampetsou, Maria P.; Comte, Denis; Kis-Toth, Katalin; Terhorst, Cox; Kyttaris, Vasileios C.; Tsokos, George C.

    2016-01-01

    T cells from patients with systemic lupus erythematosus (SLE) display a number of functions including increased early signaling events following engagement of the T cell receptor (TCR). Signaling lymphocytic activation molecule family (SLAMF) cell surface receptors and the X-chromosome-defined signaling lymphocytic activation molecule-associated protein (SAP) adaptor are important in the development of several immunocyte lineages and modulating immune response. Here we present evidence that SAP protein levels are decreased in T cells and in their main subsets isolated from 32 women and 3 men with SLE independently of disease activity. In SLE T cells the SAP protein is also subject to increased degradation by a caspase-3. Forced expression of SAP in SLE T cells simultaneously heightened IL-2 production, calcium (Ca2+) responses and tyrosine phosphorylation of a number of proteins. Exposure of normal T cells to SLE serum IgG, known to contain anti-CD3/TCR antibodies, resulted in SAP downregulation. We conclude that SLE T cells display reduced levels of the adaptor protein SAP probably as a result of continuous T cell activation and degradation by caspase-3. Restoration of SAP levels in SLE T cells corrects the overexcitable lupus T cell phenotype. PMID:27183584

  4. Role(s of IL-2 inducible T cell kinase and Bruton's tyrosine kinase in mast cell response to lipopolysaccharide

    Directory of Open Access Journals (Sweden)

    Weishan Huang

    2016-06-01

    Full Text Available Mast cells play critical roles during immune responses to the bacterial endotoxin lipopolysaccharide (LPS that can lead to fatal septic hypothermia [1–3]. IL-2 inducible T cell kinase (ITK and Bruton's tyrosine kinase (BTK are non-receptor tyrosine kinases that act downstream of numerous receptors, and have been shown to modulate mast cell responses downstream of FcεRIα [4], however, their roles in regulating mast cell responses to endotoxic stimuli were unclear. We found that the absence of ITK and BTK alters the mast cell response to LPS, and leads to enhanced pro-inflammatory cytokine production by mast cells and more severe LPS-induced hypothermia in mice [5]. Here, we detail our investigation using microarray analysis to study the transcriptomic profiles of mast cell responses to LPS, and the roles of ITK and/or BTK expression in this process. Mouse whole genome array data of WT, Itk−/−, Btk−/−, and Itk−/−Btk−/− bone marrow-derived mast cells (BMMCs stimulated by PBS (control or LPS for 1 h were used in our latest research article [5] and is available in the Gene Expression Omnibus under accession number GSE64287.

  5. Role(s) of IL-2 inducible T cell kinase and Bruton's tyrosine kinase in mast cell response to lipopolysaccharide.

    Science.gov (United States)

    Huang, Weishan; August, Avery

    2016-06-01

    Mast cells play critical roles during immune responses to the bacterial endotoxin lipopolysaccharide (LPS) that can lead to fatal septic hypothermia [1], [2], [3]. IL-2 inducible T cell kinase (ITK) and Bruton's tyrosine kinase (BTK) are non-receptor tyrosine kinases that act downstream of numerous receptors, and have been shown to modulate mast cell responses downstream of FcεRIα [4], however, their roles in regulating mast cell responses to endotoxic stimuli were unclear. We found that the absence of ITK and BTK alters the mast cell response to LPS, and leads to enhanced pro-inflammatory cytokine production by mast cells and more severe LPS-induced hypothermia in mice [5]. Here, we detail our investigation using microarray analysis to study the transcriptomic profiles of mast cell responses to LPS, and the roles of ITK and/or BTK expression in this process. Mouse whole genome array data of WT, Itk (-/-) , Btk (-/-) , and Itk (-/-)  Btk (-/-) bone marrow-derived mast cells (BMMCs) stimulated by PBS (control) or LPS for 1 h were used in our latest research article [5] and is available in the Gene Expression Omnibus under accession number GSE64287.

  6. Exploring the concept of climate surprises. A review of the literature on the concept of surprise and how it is related to climate change

    Energy Technology Data Exchange (ETDEWEB)

    Glantz, M.H.; Moore, C.M. [National Center for Atmospheric Research, Boulder, CO (United States); Streets, D.G.; Bhatti, N.; Rosa, C.H. [Argonne National Lab., IL (United States). Decision and Information Sciences Div.; Stewart, T.R. [State Univ. of New York, Albany, NY (United States)

    1998-01-01

    This report examines the concept of climate surprise and its implications for environmental policymaking. Although most integrated assessment models of climate change deal with average values of change, it is usually the extreme events or surprises that cause the most damage to human health and property. Current models do not help the policymaker decide how to deal with climate surprises. This report examines the literature of surprise in many aspects of human society: psychology, military, health care, humor, agriculture, etc. It draws together various ways to consider the concept of surprise and examines different taxonomies of surprise that have been proposed. In many ways, surprise is revealed to be a subjective concept, triggered by such factors as prior experience, belief system, and level of education. How policymakers have reacted to specific instances of climate change or climate surprise in the past is considered, particularly with regard to the choices they made between proactive and reactive measures. Finally, the report discusses techniques used in the current generation of assessment models and makes suggestions as to how climate surprises might be included in future models. The report concludes that some kinds of surprises are simply unpredictable, but there are several types that could in some way be anticipated and assessed, and their negative effects forestalled.

  7. Effect of Pollen Polysaccharide in Brassica napus L.on Production and mRNA Expression of IL-2 and TNF-a in Tumor-bearing Spleen Cells Mice%油菜花粉多糖对荷瘤鼠脾细胞 IL-2、TNF-α产生及其mRNA表达的影响

    Institute of Scientific and Technical Information of China (English)

    杨晓萍; 吴谋成

    2008-01-01

    [目的]研究油菜花粉多糖(LBPP)对荷瘤鼠脾细胞IL-2、TNF-α的诱生及其mRNA表达的影响.[方法]通过动物抑制性肿瘤法制备肿瘤模型,采用双抗体夹心ELISA法检测IL-2、TNF-α含量,逆转录-聚合酶链反应(RT-PCR)检测IL-2、TNF-a mRNA的表达.[结果] LBPP有明显抗肿瘤作用,200mg·kg-1高剂量组抑瘤率可达51.26%,明显优于环磷酰胺46.22%;LBPP可显著促进荷瘤鼠脾细胞IL-2、TNF-a分泌(P<0.01),提高荷瘤鼠脾细胞IL-2、TNF-a mRNA的表达(P<0.01),高剂量组提高率分别达56.37%、105.24%、1364%和1289%.[结论] LBPP通过提高机体IL-2、TNF-a mRNA的表达而发挥抗肿瘤作用.

  8. Interrater agreement of an observational tool to code knockouts and technical knockouts in mixed martial arts.

    Science.gov (United States)

    Lawrence, David W; Hutchison, Michael G; Cusimano, Michael D; Singh, Tanveer; Li, Luke

    2014-09-01

    Interrater agreement evaluation of a tool to document and code the situational factors and mechanisms of knockouts (KOs) and technical knockouts (TKOs) in mixed martial arts (MMA). Retrospective case series. Professional MMA matches from the Ultimate Fighting Championship-2006-2012. Two nonmedically trained independent raters. The MMA Knockout Tool (MMA-KT) consists of 20 factors and captures and codes information on match characteristics, situational context preceding KOs and TKOs, as well as describing competitor states during these outcomes. The MMA-KT also evaluates the mechanism of action and subsequent events surrounding a KO. The 2 raters coded 125 unique events for a total of 250 events. The 8 factors of Part A had an average κ of 0.87 (SD = 0.10; range = 0.65-0.98); 7 were considered "substantial" agreement and 1 "moderate." Part B consists of 12 factors with an average κ of 0.84 (SD = 0.16; range = 0.59-1.0); 7 classified as "substantial" agreement, 4 "moderate," and 1 "fair." The majority of the factors in the MMA-KT demonstrated substantial interrater agreement, with an average κ of 0.86 (SD = 0.13; range = 0.59-1.0). The MMA-KT is a reliable tool to extract and code relevant information to investigate the situational factors and mechanism of KOs and TKOs in MMA competitions.

  9. Analysis of allelic expression patterns of IL-2, IL-3, IL-4, and IL-13 in human CD4+ T cell clones.

    NARCIS (Netherlands)

    Bayley, J.P.; Bakker, AM; Kaijzel, EL; Wierenga, EA; Pouw Kraan, van der C.T.M.; Huizinga, T.W.; Verweij, C.L.

    2003-01-01

    The occurrence of monoallelic expression of cytokine genes in single cells has been convincingly demonstrated, but there have been few reports of this phenomenon in T cell clones. Here we describe studies on the expression of alleles of the human genes encoding IL-2, IL-3, IL-4, and IL-13 in human C

  10. Assessment of the immune responses to Treponema pallidum Gpd DNA vaccine adjuvanted with IL-2 and chitosan nanoparticles before and after Treponema pallidum challenge in rabbits.

    Science.gov (United States)

    Zhao, Feijun; Zhang, Xiaohong; Liu, Shuangquan; Zeng, Tiebing; Yu, Jian; Gu, Weiming; Zhang, Yuejun; Chen, Xi; Wu, Yimou

    2013-02-01

    Syphilis is a multistage, sexually transmitted disease caused by the spirochete, Treponema pallidum (Tp). A significantly high incidence of syphilis has been reported in several countries, including China, and there is an urgent need for the development of efficacious vaccines against syphilis. DNA vaccines are a major breakthrough in the field of vaccination with several advantages over traditional vaccines. Animal model studies of Tp DNA vaccines have not been reported elsewhere but our previous reports describe the development of a single-gene Tp DNA vaccine and preclinical immunization study. In this study, chitosan (CS) nanoparticles were used as a vector and an interleukin-2 expression plasmid (pIL-2) as an adjuvant to enhance a TpGpd DNA vaccine candidate (pTpGpd) in a rabbit Tp skin challenge model. At week 8 after the first immunization, three rabbits from each group were used to determine cytokine measurements and spleen lymphocyte proliferation assay. pTpGpd in combination with pIL-2 wrapped with CS led to the greatest enhancement of anti-TpGpd antibodies and T-cell proliferation. During infection, levels of anti-TpGpd antibodies and T-cell proliferation were measured. Both the serum special IgG and IL-2, interferon-γ were significantly increased by the co-injection of the IL-2 plasmid compared with the injection of TpGpd DNA alone (Ppallidum spirochetes infection and attenuate syphilitic lesion development.

  11. A study on correlation of serum TNF-α, IL-2, 6 concentration and immune function in patients with recurrent oral ulcers

    Institute of Scientific and Technical Information of China (English)

    Yu-Hong Zou; Jing Yang; Chuan-Hua Chen

    2015-01-01

    Objective: To investigate the correlation of tumor necrosis factor α(TNF-α), interleukin-2, 6 (IL-2, 6) and immune function in patients with recurrent oral ulcers (ROU). Methods:68 patients with recurrent oral ulcers and 60 healthy controls were recruited from January 2014 to December 2014. The levels of TNF-α, IL-2, 6 were measured in both serum and gingival cervical fluid of patients with ROU and control subjects by ELISA assay. The levels of immune cells (CD3+, CD4+, CD4+/CD8+) of two groups were detected using flow cytometry. The correlation of TNF-α, IL-2, IL-6 concentration and immune function were measured with Pearson correlation factor analysis. Results: The levels of TNF-α, IL-2, IL-6 were significantly higher in patients with ROU than those in control groups (P0.05). Conclusion: ROU may be associated with immune dysfunction in patients. TNF-α concentration measurement may reflect immune function, which helps determine the prognosis.

  12. Effects of vitamin E on the proliferation and collagen synthesis of rat hepatic stellate cells treated with IL-2 or TNF-α

    Institute of Scientific and Technical Information of China (English)

    展玉涛; 王宇; 魏来; 陈红松

    2003-01-01

    Objective To study the effects of vitamin E on the proliferation and collagen synthesis of rat hepatic stellate cells treated with interleukin-2 (IL-2 ) or tumor necrosis factor-α (TNF-α).Methods Hepatic stellate cells were isolated from male Sprague-Dawley rats by using modified Friedman's method. Using the isolated cells cultured and treated with IL-2 or TNF-α, we studied the effects of vitamin E on their proliferation and collagen synthesis through an 3 H-thymidine and 3 H-proline incorporation assay, as well as through observation of these cells under a contrary phase microscope. Results Adding IL-2 increased the both proliferation and collagen synthesis of hepatic stellate cells. Their proliferation was also increased by the addition of TNF-α, although it decreased collagen synthesis. Vitamin E had marked inhibitory effects on the ability of cells treated with IL-2 or TNF-α to reproduce or synthesize collagen.Conclusion Vitamin E can inhibit the proliferation and collagen synthesis of hepatic stellate cells. It is possible that vitamin E affects liver fibrosis through these activities.

  13. Testing for the association of the KIAA1109/Tenr/IL2/IL21 gene region with rheumatoid arthritis in a European family-based study.

    NARCIS (Netherlands)

    Teixeira, V.H.; Pierlot, C.; Migliorini, P.; Balsa, A.; Westhovens, R.; Barrera, P.; Alves, H.; Vaz, C.; Fernandes, M.; Pascual-Salcedo, D.; Bombardieri, S.; Dequeker, J.; Radstake, T.R.D.J.; Riel, P.L.C.M. van; Putte, L.B.A. van de; Lopes-Vaz, A.; Bardin, T.; Prum, B.; Cornelis, F.; Petit-Teixeira, E.

    2009-01-01

    INTRODUCTION: A candidate gene approach, in a large case-control association study in the Dutch population, has shown that a 480 kb block on chromosome 4q27 encompassing KIAA1109/Tenr/IL2/IL21 genes is associated with rheumatoid arthritis. Compared with case-control association studies, family-based

  14. 4-1BB Signaling in Conventional T Cells Drives IL-2 Production That Overcomes CD4+CD25+FoxP3+ T Regulatory Cell Suppression.

    Directory of Open Access Journals (Sweden)

    Hampartsoum B Barsoumian

    Full Text Available Costimulation with the recombinant SA-4-1BBL agonist of 4-1BB receptor on conventional CD4+ T cells (Tconvs overcomes the suppression mediated by naturally occurring CD4+CD25+FoxP3+ T regulatory cells (Tregs. The mechanistic basis of this observation has remained largely unknown. Herein we show that Tconvs, but not Tregs, are the direct target of SA-4-1BBL-mediated evasion of Treg suppression. IL-2 produced by Tconvs in response to 4-1BB signaling is both necessary and sufficient for overcoming Treg suppression. Supernatant from Tconvs stimulated with SA-4-1BBL contains high levels of IL-2 and overcomes Treg suppression in ex vivo Tconv:Treg cocultures. Removal of IL-2 from such supernatant restores Treg suppression and repletion of Tconv:Treg cocultures with exogenous recombinant IL-2 overcomes suppression. This study establishes 4-1BB signaling as a key circuit that regulates physical and functional equilibrium between Tregs and Tconvs with important implications for immunotherapy for indications where a fine balance between Tregs and Teffs plays a decisive role.

  15. Safety and efficacy of subcutaneous and continuous intravenous infusion of rIL-2 in patients with metastatic renal cell carcinoma

    DEFF Research Database (Denmark)

    Geertsen, P.F.; Gore, M.E.; Negrier, S.

    2004-01-01

    A retrospective analysis was conducted on data from four open-label, nonrandomised, phase II trials of recombinant interleukin-2 (rIL-2) in patients with metastatic renal cell carcinoma to compare the safety and efficacy of administration by subcutaneous (s.c.) and continuous intravenous (c.i.v.)...

  16. Constitutive Release of IFNγ and IL2 from Peripheral Blood Mononuclear Cells of Rhesus Macaques (Macaca mulatta) Infected with Simian T-Lymphotropic Virus Type 1

    Science.gov (United States)

    Yee, JoAnn L; Montiel, Nestor A; Ardeshr, Amir; Lerche, Nicholas W

    2013-01-01

    Simian T-cell lymphotropic viruses (STLV), the nonhuman primate counterparts of human T-cell lymphotropic viruses (HTLV), are endemic in many populations of African and Asian monkeys and apes. Although an etiologic link between STLV1 infection and lymphoproliferative disorders such as malignant lymphomas has been suggested in some nonhuman primate species, most STLV infections are inapparent, and infected animals remain clinically healthy. The retroviral transactivator, tax, is well known to increase transcription of viral and cellular genes, resulting in altered cytokine profiles. This study compared the cytokine profiles of peripheral blood mononuclear cell (PBMC) cultures from 25 STLV1-seropositive rhesus macaques (Macaca mulatta) with those of age- and sex-matched seronegative controls. IFNγ, TNFα, IL10, and IL2 levels in unstimulated PBMC culture supernatants were measured at 24, 48, and 72 h by using enzyme immunoassays. IFNγ concentrations were found significantly higher in the supernatants of PBMC cultures of seropositive monkeys as compared with seronegative controls. In addition, although IL2 concentrations were not significantly elevated in the supernatants of PBMC cultures of all seropositive monkeys as compared with all seronegative controls, IL2 levels were increased in a subset of 5 pairs. Increased constitutive cytokine release occurred in the absence of spontaneous proliferation. The increased constitutive release of IFNγ and IL2 suggests that STLV1 alters immune functions in infected but clinically healthy rhesus macaques and further characterizes STLV1 infection of rhesus macaques as a potential model for human HTLV1 infection. PMID:24326227

  17. Atg5 but not Atg7 in dendritic cells enhances IL-2 and IFN-γ production by Toxoplasma gondii-reactive CD4+ T cells.

    Science.gov (United States)

    Liu, Elizabeth; Van Grol, Jennifer; Subauste, Carlos S

    2015-04-01

    The autophagy proteins (Atg) modulate not only innate but also adaptive immunity against pathogens. We examined the role of dendritic cell Atg5 and Atg7 in the production of IL-2 and IFN-γ by Toxoplasma gondii-reactive CD4(+) T cells. T. gondii-reactive mouse CD4(+) T cells exhibited unimpaired production of IL-2 and IFN-γ when stimulated with Atg7-deficient mouse dendritic cells that were infected with T. gondii or pulsed with T. gondii lysate antigens. In marked contrast, dendritic cells deficient in Atg5 induced diminished CD4(+) T cell production of IL-2 and IFN-γ. This defect was not accompanied by changes in costimulatory ligand expression on dendritic cells or impaired production of IL-12 p70, IL-1β or TNF-α. Knockdown of Irg6a in dendritic cells did not affect CD4(+) T cell cytokine production. These results indicate that Atg5 and Atg7 in dendritic cells play differential roles in the modulation of IL-2 and IFN-γ production by T. gondii-reactive CD4(+) T cells.

  18. IL-2 and IL-15 Each Mediate De Novo Induction of FOXP3 Expression in Human Tumor Antigen-specific CD8 T Cells

    Science.gov (United States)

    Ahmadzadeh, Mojgan; Antony, Paul A.; Rosenberg, Steven A.

    2007-01-01

    Summary Although FOXP3 is primarily expressed by regulatory CD4 T cells (Treg) in vivo, polyclonal activation of human CD8 T cells can result in the expression of FOXP3 in a fraction of CD8 T cells. However, the cellular lineage and mechanism of FOXP3 induction in CD8 T cells remain unclear. Here, we demonstrate that interleukin-2 (IL-2) induces FOXP3 expression in OKT3-stimulated or antigen-stimulated CD8 T cells, indicating that FOXP3 expression is neither limited to a unique subset of CD8 T cells nor dependent on the mode of T-cell receptor stimulation. In the absence of IL-2, antigen stimulation resulted in T-cell activation and acquisition of effector function without induction of FOXP3, indicating that acquisition of effector function is independent of induction of FOXP3 expression in CD8 T cells. Interestingly, IL-15, but not IL-7 or IL-21, also led to de novo induction of FOXP3 in antigen-specific CD8 T cells, suggesting that signaling by IL-2/IL-15Rβ chain is pivotal for induction of FOXP3 in human CD8 T cells. These findings indicate that induction of FOXP3 is intrinsic to CD8 T cells that are activated in the presence of IL-2 or IL-15, and in vitro-induced expression of FOXP3 cannot be simply interpreted as an indicator of Treg activity or activation marker. PMID:17414320

  19. Study on IL-2 and CA 15-3 level as combined biomarkers in monitoring chemotherapeutic response among invasive breast cancer patients

    Science.gov (United States)

    Hameed, Ahmed Muthanna Abdul; Hamid, Auni Fatin Abdul; Shahfiza Noor, Nurul; Appalanaido, Gokula Kumar; Bariyah Sahul Hamid, Shahrul

    2017-05-01

    In Malaysia, breast cancer is the most frequent type of disease among women. This study was designed to determine the clinical usefulness of carbohydrate antigen (CA 15-3) and interleukin 2 (IL-2) levels as combined biomarkers in monitoring breast cancer patient’s response to chemotherapy. Ethical approval was obtained to recruit patients with histologically confirmed invasive ductal carcinoma (IDC) attending Oncology Clinic at Advanced Medical and Dental Institute. Whole blood was collected from 10 IDC breast cancer patients’ pre and post primary chemotherapy. Plasma was separated from the whole blood to determine the CA 15-3 level and IL-2 level using enzyme-linked immunosorbent assay (ELISA) pre and post-treatment. In addition, the histological findings, tumour stage and other patients’ data were obtained from the medical record. Findings showed that IL-2 had borderline significant changes between pre- and post-chemotherapy (p = 0.074) whereas for CA 15-3, there was insignificant differences of CA 15-3 level between pre and post-chemotherapy (p > 0.05). It was noted that only CA 15-3 level had significant correlation with tumour size. This study demonstrates that IL-2 level requires further investigation in a larger sample size to correlate its potential use as combined biomarker with CA 15-3 in monitoring response to chemotherapy.

  20. Protective immunity induced with the RTS,S/AS vaccine is associated with IL-2 and TNF-α producing effector and central memory CD4 T cells.

    Directory of Open Access Journals (Sweden)

    Joanne M Lumsden

    Full Text Available A phase 2a RTS,S/AS malaria vaccine trial, conducted previously at the Walter Reed Army Institute of Research, conferred sterile immunity against a primary challenge with infectious sporozoites in 40% of the 80 subjects enrolled in the study. The frequency of Plasmodium falciparum circumsporozoite protein (CSP-specific CD4(+ T cells was significantly higher in protected subjects as compared to non-protected subjects. Intrigued by these unique vaccine-related correlates of protection, in the present study we asked whether RTS,S also induced effector/effector memory (T(E/EM and/or central memory (T(CM CD4(+ T cells and whether one or both of these sub-populations is the primary source of cytokine production. We showed for the first time that PBMC from malaria-non-exposed RTS,S-immunized subjects contain both T(E/EM and T(CM cells that generate strong IL-2 responses following re-stimulation in vitro with CSP peptides. Moreover, both the frequencies and the total numbers of IL-2-producing CD4(+ T(E/EM cells and of CD4(+ T(CM cells from protected subjects were significantly higher than those from non-protected subjects. We also demonstrated for the first time that there is a strong association between the frequency of CSP peptide-reactive CD4(+ T cells producing IL-2 and the titers of CSP-specific antibodies in the same individual, suggesting that IL-2 may be acting as a growth factor for follicular Th cells and/or B cells. The frequencies of CSP peptide-reactive, TNF-α-producing CD4(+ T(E/EM cells and of CD4(+ T(E/EM cells secreting both IL-2 and TNF-α were also shown to be higher in protected vs. non-protected individuals. We have, therefore, demonstrated that in addition to TNF-α, IL-2 is also a significant contributing factor to RTS,S/AS vaccine induced immunity and that both T(E/EM and T(CM cells are major producers of IL-2.

  1. Recombinant human B7-H4 expressed in Escherichia coli inhibits T lymphocyte proliferation and IL-2 secretion in vitro

    Institute of Scientific and Technical Information of China (English)

    Yi-xiang MAO; Xue-guang ZHANG; Yong-Jing CHEN; Van GE; Hong-bing MA; Jian-feng YU; Hong-ya WU; Yu-min HU; Qin WANG; Qin SHI

    2006-01-01

    Aim: To explore the biofunctions of human B7-H4 generated from prokaryotic system. Methods: The gene of human B7-H4 extracellular region (IgⅤ-like and IgC-like domains) was obtained by PCR from human cDNA FLJ22418 and then inserted into the prokaryotic expression vector pGEX-5X-3 expressing glutathione. r-transferase (GST) fusion protein. After being identified by restriction enzyme digestion and sequencing, the recombinant vector was transferred into host strain E coli BL21-RIL(DE3). A 47 kDa fusion protein (GST/hB7-H4) was induced by isopropyl-beta-D-thiogalactopyranoside (IPTG) and purified by standard methods reported in the prokaryotic system. The inhibitory effect of GST/hB7-H4 on proliferation of T cells was observed in vitro by CD3mAb activated T-cell cultur-ing system and [3H]-thymidine incorporation assay. The concentrations of interleukin-2 and iterferon-g in the supernatants of T cells were determined by ELISA. Results: We successfully constructed the method for high-level expression and purification of the hB7-H4 extracellular domain as GST fusion protein from E coli. The GST/hB7-H4 fusion protein produced in bacteria had obvious biological activity to inhibit T-lymphocyte proliferation and IL-2 secretion. Conclusion: The prokaryote expression system could be used to generate hB7-H4 protein with natural spatial conformations and biological functions, which provided an efficient and economical way for the preparation of this target protein.

  2. The surprising diversity of clostridial hydrogenases: a comparative genomic perspective.

    Science.gov (United States)

    Calusinska, Magdalena; Happe, Thomas; Joris, Bernard; Wilmotte, Annick

    2010-06-01

    Among the large variety of micro-organisms capable of fermentative hydrogen production, strict anaerobes such as members of the genus Clostridium are the most widely studied. They can produce hydrogen by a reversible reduction of protons accumulated during fermentation to dihydrogen, a reaction which is catalysed by hydrogenases. Sequenced genomes provide completely new insights into the diversity of clostridial hydrogenases. Building on previous reports, we found that [FeFe] hydrogenases are not a homogeneous group of enzymes, but exist in multiple forms with different modular structures and are especially abundant in members of the genus Clostridium. This unusual diversity seems to support the central role of hydrogenases in cell metabolism. In particular, the presence of multiple putative operons encoding multisubunit [FeFe] hydrogenases highlights the fact that hydrogen metabolism is very complex in this genus. In contrast with [FeFe] hydrogenases, their [NiFe] hydrogenase counterparts, widely represented in other bacteria and archaea, are found in only a few clostridial species. Surprisingly, a heteromultimeric Ech hydrogenase, known to be an energy-converting [NiFe] hydrogenase and previously described only in methanogenic archaea and some sulfur-reducing bacteria, was found to be encoded by the genomes of four cellulolytic strains: Clostridum cellulolyticum, Clostridum papyrosolvens, Clostridum thermocellum and Clostridum phytofermentans.

  3. Atom Surprise: Using Theatre in Primary Science Education

    Science.gov (United States)

    Peleg, Ran; Baram-Tsabari, Ayelet

    2011-10-01

    Early exposure to science may have a lifelong effect on children's attitudes towards science and their motivation to learn science in later life. Out-of-class environments can play a significant role in creating favourable attitudes, while contributing to conceptual learning. Educational science theatre is one form of an out-of-class environment, which has received little research attention. This study aims to describe affective and cognitive learning outcomes of watching such a play and to point to connections between theatrical elements and specific outcomes. "Atom Surprise" is a play portraying several concepts on the topic of matter. A mixed methods approach was adopted to investigate the knowledge and attitudes of children (grades 1-6) from two different school settings who watched the play. Data were gathered using questionnaires and in-depth interviews. Analysis suggested that in both schools children's knowledge on the topic of matter increased after the play with younger children gaining more conceptual knowledge than their older peers. In the public school girls showed greater gains in conceptual knowledge than boys. No significant changes in students' general attitudes towards science were found, however, students demonstrated positive changes towards science learning. Theatrical elements that seemed to be important in children's recollection of the play were the narrative, props and stage effects, and characters. In the children's memory, science was intertwined with the theatrical elements. Nonetheless, children could distinguish well between scientific facts and the fictive narrative.

  4. Novelty biases attention and gaze in a surprise trial.

    Science.gov (United States)

    Horstmann, Gernot; Herwig, Arvid

    2016-01-01

    While the classical distinction between task-driven and stimulus-driven biasing of attention appears to be a dichotomy at first sight, there seems to be a third category that depends on the contrast or discrepancy between active representations and the upcoming stimulus, and may be termed novelty, surprise, or prediction failure. For previous demonstrations of the discrepancy-attention link, stimulus-driven components (saliency) may have played a decisive role. The present study was conducted to evaluate the discrepancy-attention link in a display where novel and familiar stimuli are equated for saliency. Eye tracking was used to determine fixations on novel and familiar stimuli as a proxy for attention. Results show a prioritization of attention by the novel color, and a de-prioritization of the familiar color, which is clearly present at the second fixation, and spans over the next couple of fixations. Saliency, on the other hand, did not prioritize items in the display. The results thus reinforce the notion that novelty captures and binds attention.

  5. A Well-Known But Still Surprising Generator

    Science.gov (United States)

    Haugland, Ole Anton

    2014-12-01

    The bicycle generator is often mentioned as an example of a method to produce electric energy. It is cheap and easily accessible, so it is a natural example to use in teaching. There are different types, but I prefer the old side-wall dynamo. The most common explanation of its working principle seems to be something like the illustration in Fig. 1. The illustration is taken from a popular textbook in the Norwegian junior high school.1 Typically it is explained as a system of a moving magnet or coils that directly results in a varying magnetic field through the coils. According to Faraday's law a voltage is induced in the coils. Simple and easy! A few times I have had a chance to glimpse into a bicycle generator, and I was somewhat surprised to sense that the magnet rotated parallel to the turns of the coil. How could the flux through the coil change and induce a voltage when the magnet rotated parallel to the turns of the coil? When teaching electromagnetic induction I have showed the students a dismantled generator and asked them how this could work. They naturally found that this was more difficult to understand than the principle illustrated in Fig. 1. Other authors in this journal have discussed even more challenging questions concerning electric generators.2,3

  6. 首发精神分裂症患者使用阿立哌唑后血清IL-2、IL-4水平变化的探讨%Explore the level changes of IL-2,IL-4 in the first-episode schizophrenia after the treatment of arip-iprazole

    Institute of Scientific and Technical Information of China (English)

    刘倩倩; 李亚飞; 朱祥路; 蒋天玉

    2014-01-01

    Objective To explore the differences of serum IL-2 ,IL-4 in the first-episode schizo-phrenia and healthy controls were explored ,and to compare the changes of symptoms before and after aripiprazole treatment and the changes of serum IL-2 ,IL-4 .Methods Serum of IL-2 ,IL-4 was exam-ined with Flow Cytometry in 35 healthy volunteers and 35 first episode patients .The symptoms of pa-tients were evaluated with Positive and Negative Syndrome Scale .Results There were no statistical sig-nificantly differents in the serum of IL-2 ,IL-4 in the first-episode schizophrenia than normal .controls (P>0 .05) .The serum levels of IL-4 was lower in patients with first-episode schizophrenia after aripi-prazole treatment (P<0 .01) .IL-2 and IL-4 levels were increased in positive symptoms of schizophre-nia patients before aripiprazole treatment (positive symptoms) than normal controls (P<0 .05) .IL-2 and IL-4 levels were different in positive symptoms of schizophrenia patients before and after aripi-prazole treatment (P<0 .05) .Conclusion The patients with schizophrenia have immune dysfunction ;Aripiprazole of antipsychotics have lowered the level of IL-2 ,IL-4 and positive symptoms also im-proved .Conclusion.%目的:探讨首发精神分裂症患者血清细胞因子IL-2、IL-4与正常人的差异,比较分析首发精神分裂症患者经过阿立哌唑治疗前后症状改变及细胞因子IL-2、IL-4的变化。方法选择35例首发精神分裂症患者作为研究组,35例健康志愿者作为对照组,通过流式细胞学技术测定血清标本中IL-2、IL-4的水平,用PANSS量表评定精神症状。结果(1)首发精神分裂症患者IL-2、IL-4水平与正常对照组相比,差异无统计学意义(P>0.05)。(2)首发精神分裂症患者阿立哌唑治疗后较治疗前IL-4水平降低,差异有统计学意义(P<0.01)。(3)首发精神分裂症阳性症状患者血清IL-2、IL-4水平在治疗前均高于对照组(P<0.05

  7. 尖锐湿疣组织IL-2、IL-4、IL-10、IL-18表达的意义

    Institute of Scientific and Technical Information of China (English)

    胡凯; 程方雄; 陈蓓; 韩林; 马鸣

    2012-01-01

    目的:探讨尖锐湿疣(CA)患者治疗前、后血清中白细胞介素(IL)-2、IL-4、IL-10和IL-18的水平变化在CA免疫发病机制中的作用.方法:用酶联免疫吸附法(ELISA)分别检测30例CA患者在治疗前和治疗后3个月未复发时血清IL-2、IL-4 、ID-10和IL-18的水平,并与20例正常人作比较.结果:结果CA患者治疗前血清中IL-2水平明显低于正常对照组(P<0.01),IL-4、IL-10和IL-18水平明显高于正常对照组(P<0.05);治疗后3个月末血清IL-2、IL-4、IL-10、IL-18的水平同正常对照组相比,差异无统计学意义(均P>0.05).结论:人乳头瘤病毒(HPV)感染可造成患者细胞免疫功能异常,IL-2、IL-4、IL-10和IL 18在CA免疫发病机制中可能起重要作用.

  8. 尖锐湿疣组织IL-2、IL-4、IL-1O、IL-18的表达

    Institute of Scientific and Technical Information of China (English)

    胡凯; 程方雄; 陈蓓; 韩林; 马鸣

    2012-01-01

    目的:探讨尖锐湿疣(CA)患者治疗前、后血清中白介素2(IL-2)、白介素4(IL-4)、白介素10(IL-10)和白介素18(IL-18)的水平变化在CA免疫发病机制中的作用.方法:用酶联免疫吸附法(ELISA)分别检测30例CA患者在治疗前和治疗后3个月未复发时血清IL-2、IL-4、IL-10和IL-18的水平,并与20例正常人作比较.结果:CA患者治疗前血清中IL2水平明显低于正常对照组(P>0.01),IL-4、IL-10和IL-18水平明显高于正常对照组(P>0.05);治疗后3个月末血清IL-2、IL-4、IL-10、IL-18的水平同正常对照组相比,差异无统计学意义(P均>0.05).结论:人乳头瘤病毒(HPV)感染可造成患者细胞免疫功能异常,IL2、IL-4、IL-10和IL-18在CA免疫发病机制中可能起重要作用.

  9. Expression of SCM-1alpha/lymphotactin and SCM-1beta in natural killer cells is upregulated by IL-2 and IL-12.

    Science.gov (United States)

    Hennemann, B; Tam, Y K; Tonn, T; Klingemann, H G

    1999-07-01

    Recruitment of lymphocytes is an important feature of the host immune response against pathogens. However, the mechanisms by which lymphocytes are attracted are not yet fully understood. Recently, the cDNA of a lymphocyte-specific chemokine, lymphotactin (Lptn), was isolated from murine and human T cells and was also found to be expressed in murine NK cells and human NK cell clones. This study investigated the influence of interleukin (IL)-2 and IL-12 on the expression of Lptn, also known as SCM (single cysteine motif)-1alpha, and SCM-1beta, a 97% homolog of Lptn, in freshly isolated human NK cells and the human NK cell line NK-92. Northern blot analysis and RT-PCR confirmed that nonactivated human NK cells expressed both genes at low level. After activation with IL-2 or IL-12, the expression of both Lptn and SCM-1beta was upregulated within hours. NK-92 cells maintained in medium supplemented with IL-2 constitutively expressed SCM-1 mRNA. However, after 24 h of IL-2 starvation and subsequent culturing at various IL-2 concentrations, the expression of Lptn/SCM-1alpha was upregulated in a dose-dependent manner, whereas the expression of SCM-1beta remained consistently high. These observations indicate that NK cells, in addition to T lymphocytes, express Lptn/SCM-1alpha and SCM-1beta after cytokine activation. The upregulation of these chemokines in NK cells on activation likely acts to increase the number of effector cells reaching the site of an immune response such as inflammation.

  10. NK cells and CD8+ T cells cooperate to improve therapeutic responses in melanoma treated with interleukin-2 (IL-2) and CTLA-4 blockade.

    Science.gov (United States)

    Kohlhapp, Frederick J; Broucek, Joseph R; Hughes, Tasha; Huelsmann, Erica J; Lusciks, Jevgenijs; Zayas, Janet P; Dolubizno, Hubert; Fleetwood, Vidyaratna A; Grin, Alisa; Hill, Graham E; Poshepny, Joseph L; Nabatiyan, Arman; Ruby, Carl E; Snook, Joshua D; Rudra, Jai S; Schenkel, Jason M; Masopust, David; Zloza, Andrew; Kaufman, Howard L

    2015-01-01

    Melanoma is one of the few types of cancer with an increasing annual incidence. While a number of immunotherapies for melanoma have been associated with significant clinical benefit, including high-dose IL-2 and cytotoxic T lymphocyte antigen 4 (CTLA-4) blockade, clinical response to either of these single agents has been limited to 11-20% of treated patients. Therefore, in this study, we sought to test the hypothesis that the combination of IL-2 and CTLA-4 blockade could mediate a more profound therapeutic response. Here, B6 mice were challenged with poorly immunogenic B16 melanoma on day 0, and treated with CTLA-4 blocking antibody (100 μg/mouse) on days 3, 6, and 9, and IL-2 (100,000 units) twice daily on days 4-8, or both. A highly significant synergistic effect that delayed tumor growth and prolonged survival was demonstrated with the combination immunotherapy compared to either monotherapy alone. The therapeutic effect of combination immunotherapy was dependent on both CD8+ T and NK cells and co-depletion of these subsets (but not either one alone) abrogated the therapeutic effect. CTLA-4 blockade increased immune cell infiltration (including CD8+ T cells and NK cells) in the tumor and IL-2 reduced the proportion of highly differentiated/exhausted tumor-infiltrating NK cells. These results have implications for the design of clinical trials in patients with metastatic melanoma and provide new insights into how the immune system may be mediating anti-tumor activity with combination IL-2 and CTLA-4 blockade in melanoma.

  11. The parallel application of karyotype interphase and metaphase FISH after DSP-30/IL-2 stimulation is necessary for the investigation of chronic lymphocytic leukemia.

    Science.gov (United States)

    Karakosta, Maria; Manola, Kalliopi N

    2016-10-01

    Genomic aberrations are important indicators of prognosis, clinical course and treatment of chronic lymphocytic leukemia (CLL). Two cytogenetic methods, karyotype, and FISH, with still ongoing improvements, are used for CLL investigation, but the panel of chromosomal abnormalities, their prognostic significance and contribution in CLL pathogenesis have not been elucidated yet. Our study deals with the cytogenetic investigation of 237 CLL patients trying to answer ambiguous issues of the disease in the light of new CLL stimulation methodology. More specifically, we compared the detection rate and type of chromosomal aberrations between cultures stimulated with and without the new mitogens and we combined them with the data obtained from interphase (iFISH) and metaphase FISH (mFISH). Approximately 70% of the abnormal karyotypes and all the subclonal abnormalities were detected exclusively in DSP-30/IL-2 cultures. DSP-30/IL-2 exhibited ∼10-fold greater ability to detect abnormalities compared to TPA and unstimulated cultures, revealing >60 different chromosomal aberrations. Moreover, the comparison between DSP-30/IL-2 cultures and unstimulated cultures indicated that loss of chromosome Y is rather an age-related phenomenon and not a specific aberration of CLL. Clonal evolution was also detected in 50% of patients with available follow-up karyotypic data and changed the prognosis in 86.4% of them. Finally, it was shown that mFISH must be performed in DSP-30/IL-2 cultures in addition to iFISH to uncover submicroscopic translocations or insertions undetectable by iFISH. All the above argue in favor of the parallel application of karyotype, iFISH and mFISH after DSP-30/IL-2 stimulation for CLL clinical practice and research.

  12. Drug-induced expansion and differentiation of V gamma 9V delta 2 T cells in vivo: the role of exogenous IL-2.

    Science.gov (United States)

    Casetti, Rita; Perretta, Gemma; Taglioni, Alessandra; Mattei, Maurizio; Colizzi, Vittorio; Dieli, Francesco; D'Offizi, Gianpiero; Malkovsky, Miroslav; Poccia, Fabrizio

    2005-08-01

    Human Vgamma9Vdelta2 T cells recognize nonpeptidic Ags generated by the 1-deoxy-d-xylulose 5-phosphate (many eubacteria, algae, plants, and Apicomplexa) and mevalonate (eukaryotes, archaebacteria, and certain eubacteria) pathways of isoprenoid synthesis. The potent Vgamma9Vdelta2 T cell reactivity 1) against certain cancer cells or 2) induced by infectious agents indicates that therapeutic augmentations of Vgamma9Vdelta2 T cell activities may be clinically beneficial. The functional characteristics of Vgamma9Vdelta2 T cells from Macaca fascicularis (cynomolgus monkey) are very similar to those from Homo sapiens. We have found that the i.v. administration of nitrogen-containing bisphosphonate or pyrophosphomonoester drugs into cynomolgus monkeys combined with s.c. low-dose (6 x 10(5) U/animal) IL-2 induces a large pool of CD27+ and CD27- effector/memory T cells in the peripheral blood of treated animals. The administration of these drugs in the absence of IL-2 is substantially less effective, indicating the importance of additional exogenous costimuli. Shortly after the costimulatory IL-2 treatment, only gammadelta (but not alphabeta) T cells expressed the CD69 activation marker, indicating that Vgamma9Vdelta2 T lymphocytes are more responsive to low-dose IL-2 than alphabeta T cells. Up to 100-fold increases in the numbers of peripheral blood Vgamma9Vdelta2 T cells were observed in animals receiving the gammadelta stimulatory drug plus IL-2. Moreover, the expanded Vgamma9Vdelta2 T cells were potent Th1 effectors capable of releasing large amounts of IFN-gamma. These results may be relevant for designing novel (or modifying current) immunotherapeutic trials with nitrogen-containing bisphosphonate or pyrophosphomonoester drugs.

  13. IFN-γ and IL-2 Responses to Recombinant AlaDH against ESAT-6/CFP-10 Fusion Antigens in the Diagnosis of Latent versus Active Tuberculosis Infection

    Directory of Open Access Journals (Sweden)

    Bahram Movahedi

    2017-05-01

    Full Text Available Background: Discriminating latent tuberculosis infection (LTBI from active TBI may be challenging. The objective of this study was to produce the recombinant L-alanine dehydrogenase (AlaDH antigen and evaluate individuals with LTBI, those with active TBI, and uninfected individuals by enzyme-linked immunospot assay (ELISPOT in order to distinguish LTBI from active TBI. Methods: This exploratory study was performed in the Iranian city of Shiraz from 2014 to 2015. The study population (N=99 was divided into 3 groups: individuals with newly diagnosed active TBI (n=33, their household contacts (n=33, and controls (n=33. AlaDH was produced through PCR and cloning methods. The diagnostic characteristics of AlaDH vs. ESAT-6/CFP-10 were evaluated in responses to interferon-γ (IFN-γ and interleukin-2 (IL-2 with ELISPOT. Differences between the groups were assessed with the Kruskal–Wallis and Mann–Whitney tests for nonparametric data analysis. The statistical analyses were performed with SPSS, version 16. Results: IFN-γ responses to both ESAT-6/CFP-10 (P=0.81 and AlaDH (P=0.18 revealed that there were no significant differences between the individuals with LTBI and those with active TBI. The same results were determined for IL-2 responses to ESAT-6/CFP-10 between the 2 groups, while significantly higher IL-2 responses to AlaDH were observed in LTBI than in active TBI. According to the ROC curve analysis, a cutoff value of 275 SFC showed sensitivity of 75.8% and specificity of 78.8% for distinguishing LTBI from active TBI by IL-2 responses to AlaDH. Conclusion: The current study suggests that it may be possible to discriminate LTBI from active TBI by IL-2 responses to AlaDH.

  14. Development of an antibody to bovine IL-2 reveals multifunctional CD4 T(EM cells in cattle naturally infected with bovine tuberculosis.

    Directory of Open Access Journals (Sweden)

    Adam O Whelan

    Full Text Available Gaining a better understanding of the T cell mechanisms underlying natural immunity to bovine tuberculosis would help to identify immune correlates of disease progression and facilitate the rational design of improved vaccine and diagnostic strategies. CD4 T cells play an established central role in immunity to TB, and recent interest has focussed on the potential role of multifunctional CD4 T cells expressing IFN-γ, IL-2 and TNF-α. Until now, it has not been possible to assess the contribution of these multifunctional CD4 T cells in cattle due to the lack of reagents to detect bovine IL-2 (bIL-2. Using recombinant phage display technology, we have identified an antibody that recognises biologically active bIL-2. Using this antibody, we have developed a polychromatic flow cytometric staining panel that has allowed the investigation of multifunctional CD4 T-cells responses in cattle naturally infected with M. bovis. Assessment of the frequency of antigen specific CD4 T cell subsets reveals a dominant IFN-γ(+IL-2(+TNF-α(+ and IFN-γ(+ TNF-α(+ response in naturally infected cattle. These multifunctional CD4 T cells express a CD44(hiCD45RO(+CD62L(lo T-effector memory (T(EM phenotype and display higher cytokine median fluorescence intensities than single cytokine producers, consistent with an enhanced 'quality of response' as reported for multifunctional cells in human and murine systems. Through our development of these novel immunological bovine tools, we provide the first description of multifunctional T(EM cells in cattle. Application of these tools will improve our understanding of protective immunity in bovine TB and allow more direct comparisons of the complex T cell mediated immune responses between murine models, human clinical studies and bovine TB models in the future.

  15. Surprise disrupts cognition via a fronto-basal ganglia suppressive mechanism.

    Science.gov (United States)

    Wessel, Jan R; Jenkinson, Ned; Brittain, John-Stuart; Voets, Sarah H E M; Aziz, Tipu Z; Aron, Adam R

    2016-04-18

    Surprising events markedly affect behaviour and cognition, yet the underlying mechanism is unclear. Surprise recruits a brain mechanism that globally suppresses motor activity, ostensibly via the subthalamic nucleus (STN) of the basal ganglia. Here, we tested whether this suppressive mechanism extends beyond skeletomotor suppression and also affects cognition (here, verbal working memory, WM). We recorded scalp-EEG (electrophysiology) in healthy participants and STN local field potentials in Parkinson's patients during a task in which surprise disrupted WM. For scalp-EEG, surprising events engage the same independent neural signal component that indexes action stopping in a stop-signal task. Importantly, the degree of this recruitment mediates surprise-related WM decrements. Intracranially, STN activity is also increased post surprise, especially when WM is interrupted. These results suggest that surprise interrupts cognition via the same fronto-basal ganglia mechanism that interrupts action. This motivates a new neural theory of how cognition is interrupted, and how distraction arises after surprising events.

  16. Sleep in Kcna2 knockout mice

    Directory of Open Access Journals (Sweden)

    Messing Albee

    2007-10-01

    Full Text Available Abstract Background Shaker codes for a Drosophila voltage-dependent potassium channel. Flies carrying Shaker null or hypomorphic mutations sleep 3–4 h/day instead of 8–14 h/day as their wild-type siblings do. Shaker-like channels are conserved across species but it is unknown whether they affect sleep in mammals. To address this issue, we studied sleep in Kcna2 knockout (KO mice. Kcna2 codes for Kv1.2, the alpha subunit of a Shaker-like voltage-dependent potassium channel with high expression in the mammalian thalamocortical system. Results Continuous (24 h electroencephalograph (EEG, electromyogram (EMG, and video recordings were used to measure sleep and waking in Kcna2 KO, heterozygous (HZ and wild-type (WT pups (P17 and HZ and WT adult mice (P67. Sleep stages were scored visually based on 4-s epochs. EEG power spectra (0–20 Hz were calculated on consecutive 4-s epochs. KO pups die by P28 due to generalized seizures. At P17 seizures are either absent or very rare in KO pups ( Conclusion Kv1.2, a mammalian homologue of Shaker, regulates neuronal excitability and affects NREM sleep.

  17. Lipid transport in cholecystokinin knockout mice.

    Science.gov (United States)

    King, Alexandra; Yang, Qing; Huesman, Sarah; Rider, Therese; Lo, Chunmin C

    2015-11-01

    Cholecystokinin (CCK) is released in response to lipid feeding and regulates pancreatic digestive enzymes vital to the absorption of nutrients. Our previous reports demonstrated that cholecystokinin knockout (CCK-KO) mice fed for 10 weeks of HFD had reduced body fat mass, but comparable glucose uptake by white adipose tissues and skeletal muscles. We hypothesized that CCK is involved in energy homeostasis and lipid transport from the small intestine to tissues in response to acute treatment with dietary lipids. CCK-KO mice with comparable fat absorption had increased energy expenditure and were resistant to HFD-induced obesity. Using intraduodenal infusion of butter fat and intravenous infusion using Liposyn III, we determined the mechanism of lipid transport from the small intestine to deposition in lymph and adipocytes in CCK-KO mice. CCK-KO mice had delayed secretion of Apo B48-chylomicrons, lipid transport to the lymphatic system, and triglyceride (TG)-derived fatty acid uptake by epididymal fat in response to acute treatment of intraduodenal lipids. In contrast, CCK-KO mice had comparable TG clearance and lipid uptake by white adipocytes in response to TGs in chylomicron-like emulsion. Thus, we concluded that CCK is important for lipid transport and energy expenditure to control body weight in response to dietary lipid feeding.

  18. IL-2R common gamma-chain is epigenetically silenced by nucleophosphin-anaplastic lymphoma kinase (NPM-ALK) and acts as a tumor suppressor by targeting NPM-ALK.

    Science.gov (United States)

    Zhang, Qian; Wang, Hong Yi; Liu, Xiaobin; Bhutani, Gauri; Kantekure, Kanchan; Wasik, Mariusz

    2011-07-19

    Anaplastic lymphoma kinase (ALK), physiologically expressed only by certain neural cells, becomes highly oncogenic, when aberrantly expressed in nonneural tissues as a fusion protein with nucleophosphin (NPM) and other partners. The reason why NPM-ALK succeeds in transforming specifically CD4(+) T lymphocytes remains unknown. The IL-2R common γ-chain (IL-2Rγ) is shared by receptors for several cytokines that play key roles in the maturation and growth of normal CD4(+) T lymphocytes and other immune cells. We show that IL-2Rγ expression is inhibited in T-cell lymphoma cells expressing NPM-ALK kinase as a result of DNA methylation of the IL-2Rγ gene promoter. IL-2Rγ promoter methylation is induced in malignant T cells by NPM-ALK. NPM-ALK acts through STAT3, a transcription factor that binds to the IL-2Rγ gene promoter and enhances binding of DNA methyltransferases (DNMTs) to the promoter. In addition, STAT3 suppresses expression of miR-21, which selectively inhibits DNMT1 mRNA expression. Reconstitution of IL-2Rγ expression leads to loss of the NPM-ALK protein and, consequently, apoptotic cell death of the lymphoma cells. These results demonstrate that the oncogenic tyrosine kinase NPM-ALK induces epigenetic silencing of the IL-2Rγ gene and that IL-2Rγ acts as a tumor suppressor by reciprocally inhibiting expression of NPM-ALK.

  19. Properties and Surprises of Solar Activity XXIII Cycle

    Science.gov (United States)

    Ishkov, V. N.

    2010-12-01

    The main properties of the 23rd cycle match almost completely those of average-magnitude solar cycles, and some of the features of the cycle may indicate a change in the generation mode of magnetic fields in the solar convection zone. If this is the case, the Sun enters a period of intermediate and weak cycles of solar activity (SA) in terms of the Wolf number, which may last for 3 to 6 solar cycles. The main development stages of solar cycle 23 are the following: minimum of solar cycle 22: April 1996 (W* = 8.0); maximum of the smoothed relative sunspot number: April 2000; global polarity reversal of the general solar magnetic field: July to December 2000; secondary maximum of the relative sunspot number: November 2001; maximum of the 10.7-cm radio flux: February 2002; phase of the cycle maximum: October 1999 to June 2002; beginning of the decrease phase: July 2002; the point of minimum of the current SA cycle: December 2008. Solar cycle 23 has presented two powerful flare-active sunspot groups, in September 2005 and December 2006 (+5.5 and +6.6 years from the maximum) which by flare potential occupy 4th and 20th place among the most flare-active regions for the last four solar cycles. The unprecedented duration of the relative sunspot numbers fall that has led to already record duration of the last solar cycle among authentic cycles (since 1849) became the next surprise of development of solar activity during the last cycle. The phase of the minimum began in May 2005 and lasted for 4.5 years. Thus, the new solar cycle 24 has begun in January 2009.

  20. Dracunculiasis eradication - Finishing the job before surprises arise

    Institute of Scientific and Technical Information of China (English)

    Benjamin Jelle Visser

    2012-01-01

    ABSTRACT Dracunculiasis(Guinea worm disease) is a preventable waterborne parasitic disease that affects the poorest people living in remote rural areas in sub-SaharanAfrican countries, who do not have access to safe drinking water.The Guinea Worm Eradication Program, a25-year old campaign to rid the world ofGuineaWorm disease has now reached its final stage accelerating to zero cases in all endemic countries.During the19th and20th centuries, dracunculiasis was common in much ofSouthernAsia and theAfrican continent.The overall number of cases has been reduced tremendously by≥99%, from the3.32 million cases estimated to have occurred in1986 inAfrica to only1797 cases reported in2010 reported in only five countries(Sudan,Mali,Ethiopia,Chad andGhana) andAsia free of the disease.This achievement is unique in its kind - the only previously eradicated disease is smallpox, a viral infection for which vaccination was possible - and it has been achieved through primary community-based prevention and health education programs.Most efforts need to be taken in two countries,SouthSudan(comprising94% or1698 out of1797 of the cases reported world-wide in2010) andMali because of frequent movements of nomads in a vast area inside and outsideMali’s borders.All factors favourable to dracunculiasis eradication are available including adequate financial resources, community and political support and high levels of advocacy.Thus there is no reason that this disabling parasitic disease cannot be eradicated soon before surprises arise such as new civil conflicts in currently endemic countries.

  1. A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle.

    Science.gov (United States)

    Dubois, Vanessa; Laurent, Michaël R; Sinnesael, Mieke; Cielen, Nele; Helsen, Christine; Clinckemalie, Liesbeth; Spans, Lien; Gayan-Ramirez, Ghislaine; Deldicque, Louise; Hespel, Peter; Carmeliet, Geert; Vanderschueren, Dirk; Claessens, Frank

    2014-07-01

    Androgens have well-established anabolic actions on skeletal muscle, although the direct effects of the androgen receptor (AR) in muscle remain unclear. We generated satellite cell-specific AR-knockout (satARKO) mice in which the AR is selectively ablated in satellite cells, the muscle precursor cells. Total-limb maximal grip strength is decreased by 7% in satARKO mice, with soleus muscles containing ∼10% more type I fibers and 10% less type IIa fibers than the corresponding control littermates. The weight of the perineal levator ani muscle is markedly reduced (-52%). Thus, muscle AR is involved in fiber-type distribution and force production of the limb muscles, while it is a major determinant of the perineal muscle mass. Surprisingly, myostatin (Mstn), a strong inhibitor of skeletal muscle growth, is one of the most androgen-responsive genes (6-fold reduction in satARKO) through direct transcription activation by the AR. Consequently, muscle hypertrophy in response to androgens is augmented in Mstn-knockout mice. Our finding that androgens induce Mstn signaling to restrain their own anabolic actions has implications for the treatment of muscle wasting disorders.-Dubois, V., Laurent, M. R., Sinnesael, M., Cielen, N., Helsen, C., Clinckemalie, L., Spans, L., Gayan-Ramirez, G., Deldicque, L., Hespel, P., Carmeliet, G., Vanderschueren, D., and Claessens, F. A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle.

  2. 热化疗治疗非小细胞肺癌对IL-2、IL-6、IL-8、IL-10及TNF的影响%Effect of thermochemotherapy on levels of IL-2 ,IL-6 ,IL-8 ,IL-10 and TNF in non-small cell lung cancer

    Institute of Scientific and Technical Information of China (English)

    李新民; 尉继伟; 刘治邦; 刘建国

    2014-01-01

    目的 探讨热化疗治疗非小细胞肺癌(NSCLC)对白细胞介素-2(IL-2)、白细胞介素-6(IL-6)、白细胞介素-8(IL-8)、白细胞介素-10(IL-10)及肿瘤坏死因子(TNF)的影响.方法 回顾性分析大同大学附属医院2004年10月至2013年1月收治的134例NSCLC患者,进行热疗联合NP方案化疗(NVB+ DDP),并分别在治疗前、治疗3个周期后、治疗6个周期后、治疗结束后3个月对患者血清中IL-2、IL-6、IL-8、IL-10及TNF的变化进行监测.结果 热化疗3个周期后,IL-2、TNF水平逐渐增高,明显高于治疗前;IL-6、IL-8和IL-10水平明显低于化疗前.热化疗6个周期后,血IL-6、IL-8、IL-10、IL-2和TNF都有所下降,其中IL-2、TNF浓度显著低于化疗3个周期后的水平.热化疗结束后3个月,血IL-6、IL-8、IL-10水平继续下降;而IL-2、TNF浓度逐渐增高,低于化疗3个周期后的水平,但高于治疗前水平.结论 热化疗治疗NSCLC对IL-2、TNF水平有明显的增高作用,而对IL-6、IL-8、IL-10有降低作用.%Objective To investigate the effect of hot therapy on interleukin-2 (IL-2),interleukin-6 (IL-6),interlerukin-8 (IL-8),interleukin-10 (IL-10) and tumor necrosis factor (TNF) in nonsmall cell lung cancer(NSCLC).Methods One hundred and thirty-four patients with NSCLC,admitted to our hospital from October 2004 to January 2013,received hot therapy and vinorelbine plus cisplatin (NP) chemotherapy.The IL-6,IL-8,IL-10 and TNF level before therapy,after 3 cycles,after 6 cycles and 3 months after chemotherapy were observed.Results IL-2 and TNF levels increased gradually after 3 cycles of hot therapy,and were significant higher than those before therapy.Compared to before therapy,IL-6,IL-8 and IL-10 levels significantly decreased.IL-6,IL-8,IL-10,IL-2 and TNF levels all decreased at 6 months after hot therapy.IL-2 and TNF levels were significant lowered than those of 3 cycles after chemotherapy.IL-6,IL-8 and IL-10 continued to decrease 3 months after the end of

  3. Detection and its clinical significance of IL-2, IL-10 and TNF-α in the sera of patients with early symptomatic syphilis%早期显性梅毒患者血清IL-2、IL-10和TNF-α检测及其临床意义

    Institute of Scientific and Technical Information of China (English)

    胡晓燕; 聂芳

    2012-01-01

    目的 探讨白细胞介素-2(IL-2)、白细胞介素-10(IL-10)和肿瘤坏死因子-α(TNF-α)在早期显性梅毒发病机制中的作用.方法 采用双抗体夹心酶联免疫吸附试验(DAbS-ELISA)检测53例早期显性梅毒患者(其中一期梅毒25例、二期梅毒28例)和65名正常人血清IL-2、IL-10和TNF-α水平.结果 早期显性梅毒患者血清IL-2、IL-10和TNF-α水平明显高于正常对照组(P<0.01);一期梅毒患者血清IL-2和TNF-α水平明显高于二期梅毒患者(P<0.01),血清IL-10水平则低于二期梅毒患者(P<0.01);早期显性梅毒患者中IL-2与IL-10呈负相关(r=-0.760,P =0.000),与TNF-α呈正相关(r=0.633,P=0.000),而IL-10与INF-α无明显相关性(r=-0.063,P =0.575).结论 IL-2、IL-10和TNF-α均参与了梅毒的发病,IL-10表达上调可能是二期梅毒发生辅助性T(Th)1/Th2细胞免疫应答失衡的主要原因之一.%Objective To investigate the role of interleukin-2 (IL-2), interleukin-10( IL-10) and tumor necrosis factor-alpha (TNF-α) in the pathogenesis of early symptomatic syphilis. Methods Double-antibody sandwich enzyme-linked immunosorbent assay(DAbS-ELISA) was used to detect the serum levels of IL-2,IL-10 and TNF-α in 53 patients with early symptomatic syphilis (25 cases with primary syphilis and 28 cases with secondary syphilis) and 65 healthy subjects. Results Serum levels of IL-2, IL-10 and TNF-α in early symptomatic syphilis group were significantly higher than those in control group (P <0. 01). Serum levels of IL-2 and TNF-α in primary syphilis group were significantly higher than those in secondary syphilis group (P < 0. 01). Serum level of IL-10 in secondary syphilis group was significantly higher than that in primary syphilis group (P<0.01). IL-2 and IL-10 were negatively correlated in early symptomatic syphilis group (r = - 0. 760, P = 0. 000). IL-2 and TNF-α were positively correlated ( r = 0. 633, P = 0.000), and IL-10 and TNF-α were not correlated(r = -0

  4. Imaging of inflamed carotid artery atherosclerotic plaques with the use of {sup 99m}Tc-HYNIC-IL-2 scintigraphy in end-stage renal disease patients

    Energy Technology Data Exchange (ETDEWEB)

    Opalinska, Marta; Pach, Dorota; Sowa-Staszczak, Anna; Glowa, Boguslaw; Hubalewska-Dydejczyk, Alicja [Jagiellonian University Medical School, Nuclear Medicine Unit, Department of Endocrinology, Cracow (Poland); Stompor, Tomasz [University of Warmia and Mazury in Olsztyn, Department of Nephrology, Hypertensiology and Internal Medicine, Faculty of Medicine, Olsztyn (Poland); Mikolajczak, Renata; Garnuszek, Piotr; Maurin, Michal; Karczmarczyk, Urszula [National Centre for Nuclear Research Radioisotope Centre POLATOM, Otwock (Poland); Fedak, Danuta [Jagiellonian University Medical School, Clinical Biochemistry, Cracow (Poland); Krzanowski, Marcin; Sulowicz, Wladyslaw [Jagiellonian University Medical School, Department of Nephrology, Cracow (Poland); Rakowski, Tomasz [Jagiellonian University Medical School, 2nd Department of Cardiology, Institute of Cardiology, Cracow (Poland)

    2012-04-15

    Identification of vulnerable plaques remains crucial for better cardiovascular risk assessment. At least 20% of inflammatory cells within unstable (vulnerable) plaques comprise T lymphocytes, which contain receptors for interleukin-2 (IL-2); those receptors can be identified by scintigraphy with radiolabelled IL-2.The aim of this study was to identify the ''inflamed'' (vulnerable) plaques by scintigraphy using IL-2 labelled with {sup 99m}Tc in the selected, high cardiovascular risk group of end-stage renal disease (ESRD) patients. A total of 28 patients (18 men, 10 women, aged 55.2 {+-} 9.6 years, 17 on peritoneal dialysis, 11 on haemodialysis) underwent common carotid artery (CCA) scintigraphy with the use of {sup 99m}Tc-hydrazinonicotinamide (HYNIC)-IL-2. In all cases, ultrasound examination of the CCA was performed and levels of selected proinflammatory factors, atherogenic markers and calcium-phosphate balance parameters were measured. Finally, the target to non-target (T/nT) ratio of IL-2 uptake in atherosclerotic plaques with intima-media thickness (IMT), classic cardiovascular risk factors and concentrations of the measured factors were compared. Increased {sup 99m}Tc-HYNIC-IL-2 uptake in atherosclerotic plaques in 38/41 (91%) cases was detected. The median T/nT ratio of focal {sup 99m}Tc-HYNIC-IL-2 uptake in atherosclerotic plaques was 2.35 (range 1.23-3.63). The mean IMT value on the side of plaques assessed by scintigraphy was 0.79 {+-} 0.18 mm (median 0.8, range 0.5-1.275). Correlations between T/nT ratio and homocysteine (R = 0.22, p = 0.037), apolipoprotein B (apoB) (R = 0.31, p = 0.008), apoB to apoA-I ratio (R = 0.29, p = 0.012) and triglyceride concentration (R = 0.26, p = 0.021) were detected. A lower T/nT ratio in patients with better parameters of nutritional status (haemoglobin, albumin, adiponectin) in comparison with patients with worse nutritional parameters (3.20 {+-} 0.5 vs 2.16 {+-} 0.68, p = 0.025) was revealed as well

  5. 肺炎嗜衣原体MOMP和人IL-2融合基因DNA疫苗的免疫原性研究%Immunogenicity of the DNA vaccine with monogene and fusion gene of the major outer membrane protein in Chlamydia pneumoniae and human IL-2

    Institute of Scientific and Technical Information of China (English)

    谢长青; 吴移谋; 曾焱华; 陈虹亮; 游晓星; 周洲

    2009-01-01

    目的 构建肺炎嗜衣原体(Chlamydophila pneumoniae,Cpn)主要外膜蛋白(MOMP)单基因及momp和人IL-2融合基因的真核表达载体并比较其免疫反应性,为研制Cpn核酸疫苗提供理论和实验依据. 方法 扩增Cpn momp及人IL-2基因并将二者融合,将momp和momp-IL-2分别克隆至pcDNA3.1(+)真核表达载体;制备纳米粒DNA疫苗免疫BALB/c小鼠,免疫荧光组化法检测重组质粒在小鼠组织内的稳定表达;ELISA法检测小鼠血清中的特异性抗体和小鼠脾细胞培养上清中IFN-γ水平;MTT法测定脾淋巴细胞特异性增殖反应. 结果 成功制备了pcDNA3.1(+)-momp和pcDNA3.1(+)-momp-IL-2的纳米核酸疫苗;Cpn momp单基因和momp-IL-2融合基因核酸疫苗均能刺激小鼠产生特异性抗体,且pcDNA3.1(+)-momp-IL-2能诱导小鼠产生更高效价的特异性抗体(P<0.05);pcDNA3.1(+)-momp-IL-2诱导小鼠脾细胞产生IFN-γ的量及对特异抗原的刺激指数明显高于pcDNA3.1(+)-momp.结论 Cpn momp单基因核酸疫苗和momp-IL-2融合基因核酸疫苗均能刺激小鼠产生较强的体液免疫和细胞免疫应答;pcDNA3.1(+)-momp-IL-2的免疫效果强于pcDNA3.1(+)-momp.

  6. 牛膝多糖衍生物对小鼠脾淋巴细胞增殖及诱生IL-2和TNF-α的影响%Effect of derivatives of Achyranthes bidentata polysaccharides on lymphocyte proliferation and induction of IL-2 and TNF-α

    Institute of Scientific and Technical Information of China (English)

    金丽琴; 薛胜霞; 吕建新; 贾东明

    2008-01-01

    目的 研究牛膝多糖硫酸酯(S-AbP)和磷酸酯(P-AbP)衍生物对小鼠脾淋巴细胞增殖及诱生IL-2和TNF-α的影响.方法 四甲基偶氮唑盐(MTT)法检测淋巴细胞增殖,ELISA法测定培养上清液中IL-2和TNF-α的含量.结果 S-AbP和P-AbP均能剂量依赖性地促进小鼠脾淋巴细胞增殖,S-AbP和P-AbP的促增殖活性较AbP强.P-AbP显著诱导脾淋巴细胞分泌TNF-α,对IL-2的分泌无明显影响.S-AbP能诱生较高含量的IL-2,而对TNF-α的分泌无明显影响.结论 S-AbP和P-AbP较牛膝多糖能更有效地促进淋巴细胞增殖,还可以分别通过IL-2和TNF-α发挥免疫调节作用.

  7. The expressions of serum IL-2, IL-4, IL-13 and IgE levels in patients with bronchial asthma%支气管哮喘患者外周血中IL-2IL-4IL-13和IgE的表达

    Institute of Scientific and Technical Information of China (English)

    胡林贵; 朱纪楼

    2011-01-01

    目的:探讨哮喘患者外周血中IL-2、IL-4、IL-13和IgE的水平变化及临床意义.方法:抽取哮喘患者及正常对照组空腹静脉血2ml,采用双抗体夹心法(ELISA法)检测血清中IL-2、IL-4、IL-13和IgE的含量.结果:急性发作组和缓解组中IL-4、IL-13、IgE的含量明显高于正常对照组,差异有统计学意义(P<0.01),IL-2的含量低于正常对照组,差异具有统计学意义.急性发作组IL-4、IL-13、IgE高于缓解组,IL-2的含量低于缓解组,差异均具有统计学意义(P<0.001).结论:支气管哮喘患者外周血中IL-2、IL-4、IL-13和IgE水平的变化与支气管哮喘发病进程及临床诊治具有密切联系.

  8. Clinical Significance of Changes of Serum IL-2,IL-6 and Gastrin Levels Before and After Treatment in Patients with Chronic Eczema%慢性湿疹患者治疗前后血清IL-2、IL-6和Gas检测的临床意义

    Institute of Scientific and Technical Information of China (English)

    牟勖东; 任虹

    2009-01-01

    目的:探讨慢性湿疹患者治疗前后血清IL-2、IL-6和胃泌素(Gas)水平的变化及意义.方法:应用放射免疫分析对38例慢性湿疹患者进行治疗前后血清IL-2、IL-6和Gas检测,并与35名正常健康人作比较.结果:在治疗前血清IL-2水平非常显著地低于正常人组(P<0.01),而IL-6和Gas则显著地高于正常人组(P<0.01),经治疗1个月后,除IL-6、Gas水平与正常人组比较无显著性差异外(P>0.05),IL-2与正常人组比较仍有显著性差异(P<0.05).结论:检测慢性湿疹患者血清IL-2、IL-6和Gas水平的变化对了解病情、指导临床实践有重要的临床价值.

  9. Clinical Significance of Measurement the Changes on Serum IL-2, IL-8, IL-18 and VEGF Levels After Treatment in Patients with Acute Cerebral Infarction%ACI患者治疗前后血清IL-2、IL-8、IL-18和VEGF检测的临床意义

    Institute of Scientific and Technical Information of China (English)

    张春雷; 章红梅

    2013-01-01

    目的:探讨了急性脑梗死(ACI)患者治疗前后血清IL-2、IL-8、IL-18和VEGF水平的变化及临床意义.方法:应用放射免疫分析、酶联法对33例ACI患者进行了治疗前后血清IL-2、IL-8、IL-18和VEGF检测,并与35名正常健康人作比较.结果:ACI患者在治疗前血清IL-8、IL-18和VEGF水平非常显著地高于正常人组(P<0.01),而血清IL-2水平又非常显著地低于正常人组(P<0.01),经治疗3个月后与正常人组比较仍有显著性差异(P<0.05).且血清IL-2水平与IL-8、IL-18和VEGF水平呈显著负相关(r=-0.4218、-0.4726、-0.5014,P<0.01).结论:ACI的发生、发展与血清IL-2、IL-8、IL-18和VEGF水平密切相关.

  10. 吗啡对福尔马林引起大鼠海马内IL-2RβmRNA表达的影响%EFFECTS OF MORPHINE ON THE FORMALIN INDUCED IL-2R β mRNA EXPRESSION OF RAT HIPPOCAMPUS

    Institute of Scientific and Technical Information of China (English)

    吴旋; 黎海蒂; 李希成; 阮怀珍; 王建

    1998-01-01

    本实验采用原位杂交法观察足底注射福尔马林(For)痛敏对海马内白细胞介素2受体βmRNA(IL-2RβmRNA)生成的影响及其与吗啡、促肾上腺皮质激素(ACTH)的关系.结果表明:正常大鼠海马有IL-2RβmRNA表达,集中分布于CA1-CA4区神经元、齿状回颗粒细胞.足底注射For后6 h,双侧海马IL-2RβmRNA表达均增加(P<0.05),12 h达高峰,24 h仍高于正常.在6 h时,腹腔注射吗啡可大幅度的提高For引起的IL-2RβmRNA表达增多效应,而腹腔注射ACTH却无此类似作用.提示海马内IL-2R可能与痛觉调制有关.

  11. Education, tobacco smoking, alcohol consumption, and IL-2 and IL-6 gene polymorphisms in the survival of head and neck cancer

    Directory of Open Access Journals (Sweden)

    R.V.M. López

    2011-10-01

    Full Text Available The association of education, tobacco smoking, alcohol consumption, and interleukin-2 (IL-2 +114 and -384 and -6 (IL-6 -174 DNA polymorphisms with head and neck squamous cell carcinoma (HNSCC was investigated in a cohort study of 445 subjects. IL-2 and IL-6 genotypes were determined by real-time PCR. Cox regression was used to estimate hazard ratios (HR and 95% confidence intervals (95%CI of disease-specific survival according to anatomical sites of the head and neck. Mean age was 56 years and most patients were males (87.6%. Subjects with 5 or more years of schooling had better survival in larynx cancer. Smoking had no effect on HNSCC survival, but alcohol consumption had a statistically significant effect on larynx cancer. IL-2 gene +114 G/T (HR = 0.52; 95%CI = 0.15-1.81 and T/T (HR = 0.22; 95%CI = 0.02-3.19 genotypes were associated with better survival in hypopharynx cancer. IL-2 +114 G/T was a predictor of poor survival in oral cavity/oropharynx cancer and larynx cancer (HR = 1.32; 95%CI = 0.61-2.85. IL-2 -384 G/T was associated with better survival in oral cavity/oropharynx cancer (HR = 0.80; 95%CI = 0.45-1.42 and hypopharynx cancer (HR = 0.68; 95%CI = 0.21-2.20, but an inverse relationship was observed for larynx cancer. IL-6 -174 G/C was associated with better survival in hypopharynx cancer (HR = 0.68; 95%CI = 0.26-1.78 and larynx cancer (HR = 0.93; 95%CI = 0.42-2.07, and C/C reduced mortality in larynx cancer. In general, our results are similar to previous reports on the value of education, smoking, alcohol consumption, and IL-2 and IL-6 genetic polymorphisms for the prognosis of HNSCC, but the risks due to these variables are small and estimates imprecise.

  12. Increase in IFNγ(-IL-2(+ cells in recent human CD4 T cell responses to 2009 pandemic H1N1 influenza.

    Directory of Open Access Journals (Sweden)

    Jason M Weaver

    Full Text Available Human CD4 T cell recall responses to influenza virus are strongly biased towards Type 1 cytokines, producing IFNγ, IL-2 and TNFα. We have now examined the effector phenotypes of CD4 T cells in more detail, particularly focusing on differences between recent versus long-term, multiply-boosted responses. Peptides spanning the proteome of temporally distinct influenza viruses were distributed into pools enriched for cross-reactivity to different influenza strains, and used to stimulate antigen-specific CD4 T cells representing recent or long-term memory. In the general population, peptides unique to the long-circulating influenza A/New Caledonia/20/99 (H1N1 induced Th1-like responses biased toward the expression of IFNγ(+TNFα(+ CD4 T cells. In contrast, peptide pools enriched for non-cross-reactive peptides of the pandemic influenza A/California/04/09 (H1N1 induced more IFNγ(-IL-2(+TNFα(+ T cells, similar to the IFNγ(-IL-2(+ non-polarized, primed precursor T cells (Thpp that are a predominant response to protein vaccination. These results were confirmed in a second study that compared samples taken before the 2009 pandemic to samples taken one month after PCR-confirmed A/California/04/09 infection. There were striking increases in influenza-specific TNFα(+, IFNγ(+, and IL-2(+ cells in the post-infection samples. Importantly, peptides enriched for non-cross-reactive A/California/04/09 specificities induced a higher proportion of Thpp-like IFNγ(-IL-2(+TNFα(+ CD4 T cells than peptide pools cross-reactive with previous influenza strains, which induced more Th1 (IFNγ(+TNFα(+ responses. These IFNγ(-IL-2(+TNFα(+ CD4 T cells may be an important target population for vaccination regimens, as these cells are induced upon infection, may have high proliferative potential, and may play a role in providing future effector cells during subsequent infections.

  13. Human amniotic epithelial cells inhibit CD4+ T cell activation in acute kidney injury patients by influencing the miR-101-c-Rel-IL-2 pathway.

    Science.gov (United States)

    Liu, Junfeng; Hua, Rong; Gong, Zhangbin; Shang, Bin; Huang, Yongyi; Guo, Lihe; Liu, Te; Xue, Jun

    2017-01-01

    In the pathogenesis of acute kidney injury (AKI), the release of multiple interleukins can lead to increased kidney damage. Human amniotic epithelial cells (HuAECs) can inhibit immune cell activation in vivo and in vitro. We hypothesized that HuAECs could weaken patient-derived peripheral blood CD4+ T-cell activation and decreasing the ability of these cells to express and release IL-2. -Cell proliferation assay revealed that under the same culture conditions, activated AKI patient-derived CD4+ T cells had a significantly reduced proliferation rate when were co-cultured with HuAECs. And the level of IL-2 released was also significantly reduced. Western blot and qRT-PCR assays showed that the expression of c-Rel in the CD4+ T cells was also significantly reduced. However, the expression level of endogenous miR-101 in the CD4+ T cells co-cultured with HuAECs was significantly increased. Luciferase reporter assay results suggested that miR-101 could bind to a specific site in the c-Rel 3' UTR and induce the post-transcriptional silencing of c-Rel. Subsequently, we over-expressed miR-101 in AKI patient-derived CD4+ T cells. The qRT-PCR and western blot assay results revealed that the expression of endogenous c-Rel was significantly reduced, while the ELISA results indicated that the level of IL-2 released was also significantly decreased. Finally, ChIP-PCR assay results showed that the miR-101-overexpressing CD4+ T-cell group and the HuAEC co-culture CD4+ T-cell group exhibited significantly decreased binding capacities between the 'c-Rel-NFκB' complex and the IL-2 gene promoter, and the transcriptional activity of IL-2 was also significantly decreased. Therefore, we confirmed that HuAECs can stimulate miR-101 expression in AKI patient-derived peripheral blood CD4+ T cells, thus inhibiting the expression of the miR-101 target gene c-Rel and leading to a reduction in IL-2 expression and release. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Efficacy of chimeric DNA vaccines encoding Eimeria tenella 5401 and chicken IFN-γ or IL-2 against coccidiosis in chickens.

    Science.gov (United States)

    Song, Xiaokai; Huang, Xinmei; Yan, Ruofeng; Xu, Lixin; Li, Xiangrui

    2015-09-01

    Chimeric DNA vaccines encoding Eimeria tenella (E. tenella) surface antigen 5401 were constructed and their efficacies against E. tenella challenge were studied. The open reading frame (ORF) of 5401 was cloned into the prokaryotic expression vector pGEX-4T2 to express the recombinant protein and the expressed recombinant protein was identified by Western blot. The ORF of 5401 and chicken cytokine gene IFN-γ or IL-2 were cloned into the eukaryotic expression vector pVAX1 consecutively to construct DNA vaccines pVAX-5401-IFN-γ, pVAX-5401-IL-2 and pVAX-5401. The expression of aim genes in vivo was detected by reverse transcription-polymerase chain reaction and Western blot. Fourteen-day-old chickens were inoculated twice at an interval of 7 days with 100 µg of plasmids pVAX-5401, pVAX-5401-IFN-γ and pVAX-5401-IL-2 or 200 µg of recombinant 5401 protein by leg intramuscular injection, respectively. Seven days after the second inoculation, all chickens except the unchallenged control group were challenged orally with 5 × 10(4) sporulated oocysts of E. tenella. Seven days after challenge, all chickens were weighted and slaughtered to determine the effects of immunization. The results showed the recombinant protein was about 90 kDa and reacted with antiserum against soluble sporozoites. The animal experiment showed that all the DNA vaccines pVAX-5401, pVAX-5401-IFN-γ or pVAX-5401-IL-2 and the recombinant 5401 protein could obviously alleviate body weight loss and cecal lesions as compared with non-vaccinated challenged control and empty vector pVAX1control. Furthermore, pVAX-5401-IFN-γ or pVAX-5401-IL-2 induced anti-coccidial index (ACI) of 180.01 or 177.24 which were significantly higher than that of pVAX-5401. The results suggested that 5401 was an effective candidate antigen for vaccine. This finding also suggested that chicken IFN-γ or IL-2 could effectively improve the efficacies of DNA vaccines against avian coccidiosis.

  15. A self-inactivating retrovector incorporating the IL-2 promoter for activation-induced transgene expression in genetically engineered T-cells

    Directory of Open Access Journals (Sweden)

    Lejeune Laurence

    2006-11-01

    Full Text Available Abstract Background T-cell activation leads to signaling pathways that ultimately result in induction of gene transcription from the interleukin-2 (IL-2 promoter. We hypothesized that the IL-2 promoter or its synthetic derivatives can lead to T-cell specific, activation-induced transgene expression. Our objective was to develop a retroviral vector for stable and activation-induced transgene expression in T-lymphocytes. Results First, we compared the transcriptional potency of the full-length IL-2 promoter with that of a synthetic promoter composed of 3 repeats of the Nuclear Factor of Activated T-Cells (NFAT element following activation of transfected Jurkat T-cells expressing the large SV40 T antigen (Jurkat TAg. Although the NFAT3 promoter resulted in a stronger induction of luciferase reporter expression post stimulation, the basal levels of the IL-2 promoter-driven reporter expression were much lower indicating that the IL-2 promoter can serve as a more stringent activation-dependent promoter in T-cells. Based on this data, we generated a self-inactivating retroviral vector with the full-length human IL-2 promoter, namely SINIL-2pr that incorporated the enhanced green fluorescent protein (EGFP fused to herpes simplex virus thymidine kinase as a reporter/suicide "bifunctional" gene. Subsequently, Vesicular Stomatitis Virus-G Protein pseudotyped retroparticles were generated for SINIL-2pr and used to transduce the Jurkat T-cell line and the ZAP-70-deficient P116 cell line. Flow cytometry analysis showed that EGFP expression was markedly enhanced post co-stimulation of the gene-modified cells with 1 μM ionomycin and 10 ng/ml phorbol 12-myristate 13-acetate (PMA. This activation-induced expression was abrogated when the cells were pretreated with 300 nM cyclosporin A. Conclusion These results demonstrate that the SINIL-2pr retrovector leads to activation-inducible transgene expression in Jurkat T-cell lines. We propose that this design can be

  16. Surprising Sensitivities in Simulations of Radiative Convective Equilibrium

    Science.gov (United States)

    Drotos, Gabor; Becker, Tobias; Mauritsen, Thorsten; Stevens, Bjorn

    2017-04-01

    The climate and climate-sensitivity of a global model run in radiative equilibrium is explored. Results from simulations with ECHAM6.3 coupled to a slab ocean and run in a wide range of configurations are presented. Simulations both with and without a parameterised representation of deep convection are conducted for CO2 concentrations ranging from one eighth of present day values to thirty-two times the present day, and for variations in the solar constant of more than a factor of two. Very long simulations, in some case more than a thousand years, are performed to adequately sample the attractor of the different climate states of the model, and provide robust estimates of the system's climate sensitivity parameter. For the standard configuration of the model the climate sensitivity progressively decreases from very large values (6-7K) for the coldest climates to well below 1 K for the warmest climates. For very high CO2 levels (16 and 32 times the present value) fluctuations of globally averaged temperature as large as 10 K arise on decadal time-scales. These fluctuations manifest as quasi-period coolings, driven by large and persistent global scale decks of stratiform low clouds, so that for a period of several years global temperatures drop to levels below the lowest temperatures of the climate with present day values of CO2. The same configuration of the model has more modest sensitivities when the insolation is reduced, but runaway warming results for small (10%) increases. Simulations without parameterised convection have colder (by roughly 10K) climates and smaller (1K) sensitivities, allowing a stable climate with earth-like temperatures even for insolation much (50%) larger than the present day. Such values of insolation are possible because over a large range of the insolation the climate sensitivity parameter is very near zero. The surprising sensitivities of the system, and the limit-cycle like behaviour of the very CO2 rich climates, can be traced to

  17. Phenotype of the taurine transporter knockout mouse.

    Science.gov (United States)

    Warskulat, Ulrich; Heller-Stilb, Birgit; Oermann, Evelyn; Zilles, Karl; Haas, Helmut; Lang, Florian; Häussinger, Dieter

    2007-01-01

    This chapter reports present knowledge on the properties of mice with disrupted gene coding for the taurine transporter (taut-/- mice). Study of those mice unraveled some of the roles of taurine and its membrane transport for the development and maintenance of normal organ functions and morphology. When compared with wild-type controls, taut-/- mice have decreased taurine levels in skeletal and heart muscle by about 98%, in brain, kidney, plasma, and retina by 80 to 90%, and in liver by about 70%. taut-/- mice exhibit a lower body mass as well as a strongly reduced exercise capacity compared with taut+/- and wild-type mice. Furthermore, taut-/- mice show a variety of pathological features, for example, subtle derangement of renal osmoregulation, changes in neuroreceptor expression, and loss of long-term potentiation in the striatum, and they develop clinically relevant age-dependent disorders, for example, visual, auditory, and olfactory dysfunctions, unspecific hepatitis, and liver fibrosis. Taurine-deficient animal models such as acutely dietary-manipulated foxes and cats, pharmacologically induced taurine-deficient rats, and taurine transporter knockout mouse are powerful tools allowing identification of the mechanisms and complexities of diseases mediated by impaired taurine transport and taurine depletion (Chapman et al., 1993; Heller-Stilb et al., 2002; Huxtable, 1992; Lake, 1993; Moise et al., 1991; Novotny et al., 1991; Pion et al., 1987; Timbrell et al., 1995; Warskulat et al., 2004, 2006b). Taurine, which is the most abundant amino acid in many tissues, is normally found in intracellular concentrations of 10 to 70 mmol/kg in mammalian heart, brain, skeletal muscle, liver, and retina (Chapman et al., 1993; Green et al., 1991; Huxable, 1992; Timbrell et al., 1995). These high taurine levels are maintained by an ubiquitous expression of Na(+)-dependent taurine transporter (TAUT) in the plasma membrane (Burg, 1995; Kwon and Handler, 1995; Lang et al., 1998

  18. 二十碳五烯酸影响T细胞膜脂肪微区域中IL-2受体的分布%EICOSAPENTAENOIC ACID ALTERS INTERLEUKIN-2 RECEPTOR DISTRIBUTION IN DETERGENT-INSOLUBLE MEMBRANE DOMAIN

    Institute of Scientific and Technical Information of China (English)

    李秋荣; 马健; 汪灏; 黎介寿

    2005-01-01

    目的:研究二十碳五烯酸(EPA)对T细胞膜脂肪微区域(lipid rafts)中IL-2受体(IL-2R)分布的影响.方法:EPA(20:5)处理Jurkat E6-1 T细胞为实验组,硬脂酸(18:0)处理为阴性对照.用流式细胞仪检测对T细胞表面分子CD25(IL-2α受体)表达的抑制作用.应用蛋白免疫印迹分析,化学发光法检测IL-2α受体所在的T细胞膜脂肪微区域分离组分.结果:用硬脂酸处理T细胞,细胞表面CD25阳性表达细胞为39.53%,不同浓度的EPA(5、12.5、25,50、75μmol/L)处理,CD25阳性表达细胞分别为36.12%、31.30%、23.59%、16.67%和11.65%,EPA可抑制T细胞表面分子CD25的表达.蛋白印迹分析确定IL-2α、IL-2Rβ和IL-2Rγc都存在于微区域组分中,EPA处理使部分IL-2Rα、IL-2Rβ和IL-2Rγc从膜脂肪微区域移位到可溶膜区域.结论:膜脂肪微区域为IL-2受体信号传导的功能性亚区域,EPA通过调节IL-2Rot、IL-2Rβ和IL-2Rγc在膜脂肪微区域的分布,使部分IL-2R从功能性脂肪微区域移位到非功能性可溶膜区域,而产生免疫抑制作用.

  19. Methylphenidate restores novel object recognition in DARPP-32 knockout mice.

    Science.gov (United States)

    Heyser, Charles J; McNaughton, Caitlyn H; Vishnevetsky, Donna; Fienberg, Allen A

    2013-09-15

    Previously, we have shown that Dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32) knockout mice required significantly more trials to reach criterion than wild-type mice in an operant reversal-learning task. The present study was conducted to examine adult male and female DARPP-32 knockout mice and wild-type controls in a novel object recognition test. Wild-type and knockout mice exhibited comparable behavior during the initial exploration trials. As expected, wild-type mice exhibited preferential exploration of the novel object during the substitution test, demonstrating recognition memory. In contrast, knockout mice did not show preferential exploration of the novel object, instead exhibiting an increase in exploration of all objects during the test trial. Given that the removal of DARPP-32 is an intracellular manipulation, it seemed possible to pharmacologically restore some cellular activity and behavior by stimulating dopamine receptors. Therefore, a second experiment was conducted examining the effect of methylphenidate. The results show that methylphenidate increased horizontal activity in both wild-type and knockout mice, though this increase was blunted in knockout mice. Pretreatment with methylphenidate significantly impaired novel object recognition in wild-type mice. In contrast, pretreatment with methylphenidate restored the behavior of DARPP-32 knockout mice to that observed in wild-type mice given saline. These results provide additional evidence for a functional role of DARPP-32 in the mediation of processes underlying learning and memory. These results also indicate that the behavioral deficits in DARPP-32 knockout mice may be restored by the administration of methylphenidate.

  20. Using engineered endonucleases to create knockout and knockin zebrafish models

    OpenAIRE

    Bedell, Victoria M.; Ekker, Stephen C.

    2015-01-01

    Over the last few years, the technology to create targeted knockout and knockin zebrafish animals has exploded. We have gained the ability to create targeted knockouts through the use of zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats/CRISPR associated system (CRISPR/Cas). Furthermore, using the high-efficiency TALEN system, we were able to create knockin zebrafish using a single-stranded DNA ...

  1. Targeted gene knockout in chickens mediated by TALENs

    OpenAIRE

    Park, Tae Sub; Lee, Hong Jo; Kim, Ki Hyun; Kim, Jin-Soo; Han, Jae Yong

    2014-01-01

    Targeted gene knockout by editing specific loci in genome has revolutionized the field of functional genomics. Transcription activator-like effector nucleases (TALENs) are representative next-generation platforms for customized genomic editing in transgenic animals, as well as cultured cells in vitro. In this study, in combination with chicken primordial germ cell line with germ-line transmission capacity, we generated the ovalbumin gene knockout chickens by TALEN-mediated gene targeting. Our...

  2. Stars Form Surprisingly Close to Milky Way's Black Hole

    Science.gov (United States)

    2005-10-01

    The supermassive black hole at the center of the Milky Way has surprisingly helped spawn a new generation of stars, according to observations from NASA's Chandra X-ray Observatory. This novel mode of star formation may solve several mysteries about the supermassive black holes that reside at the centers of nearly all galaxies. "Massive black holes are usually known for violence and destruction," said Sergei Nayakshin of the University of Leicester, United Kingdom, and coauthor of a paper on this research in an upcoming issue of the Monthly Notices of the Royal Astronomical Society. "So it's remarkable that this black hole helped create new stars, not just destroy them." Black holes have earned their fearsome reputation because any material -- including stars -- that falls within the so-called event horizon is never seen again. However, these new results indicate that the immense disks of gas known to orbit many black holes at a "safe" distance from the event horizon can help nurture the formation of new stars. Animation of Stars Forming Around Black Hole Animation of Stars Forming Around Black Hole This conclusion came from new clues that could only be revealed in X-rays. Until the latest Chandra results, astronomers have disagreed about the origin of a mysterious group of massive stars discovered by infrared astronomers to be orbiting less than a light year from the Milky Way's central black hole, a.k.a. Sagittarius A*, or Sgr A*. At such close distances to Sgr A*, the standard model for star formation predicts that gas clouds from which stars form should have been ripped apart by tidal forces from the black hole. Two models to explain this puzzle have been proposed. In the disk model, the gravity of a dense disk of gas around Sgr A* offsets the tidal forces and allows stars to form; in the migration model, the stars formed in a star cluster far away from the black hole and migrated in to form the ring of massive stars. The migration scenario predicts about a

  3. Changes in peripheral blood level of regulatory T cells in patients with malignant melanoma during treatment with dendritic cell vaccination and low-dose IL-2

    DEFF Research Database (Denmark)

    Bjoern, J; Brimnes, M K; Andersen, M H

    2011-01-01

    In this study, changes in peripheral blood regulatory T cell (Treg) levels were evaluated in 46 progressive patients with melanoma treated with a dendritic cell-based vaccine and concomitant low-dose IFN-a and IL-2. The regulatory subset of CD4 T cells, characterized by CD25(high) , was prospecti......In this study, changes in peripheral blood regulatory T cell (Treg) levels were evaluated in 46 progressive patients with melanoma treated with a dendritic cell-based vaccine and concomitant low-dose IFN-a and IL-2. The regulatory subset of CD4 T cells, characterized by CD25(high......) , was prospectively analysed in fresh blood, and treatment-associated quantitative and qualitative changes were analysed. By the 4th vaccine, patients showed a marked increase in CD4+ CD25(high) T cell subset from 6% to 22% (P...

  4. Changes in peripheral blood level of regulatory T cells in patients with malignant melanoma during treatment with dendritic cell vaccination and low-dose IL-2

    DEFF Research Database (Denmark)

    Bjoern, J; Brimnes, M K; Andersen, M H

    2011-01-01

    In this study, changes in peripheral blood regulatory T cell (Treg) levels were evaluated in 46 progressive patients with melanoma treated with a dendritic cell-based vaccine and concomitant low-dose IFN-α and IL-2. The regulatory subset of CD4 T cells, characterized by CD25(high) , was prospecti......In this study, changes in peripheral blood regulatory T cell (Treg) levels were evaluated in 46 progressive patients with melanoma treated with a dendritic cell-based vaccine and concomitant low-dose IFN-α and IL-2. The regulatory subset of CD4 T cells, characterized by CD25(high......) , was prospectively analysed in fresh blood, and treatment-associated quantitative and qualitative changes were analysed. By the 4th vaccine, patients showed a marked increase in CD4+ CD25(high) T cell subset from 6% to 22% (P...

  5. SERUM LEVELS OF IL-13, IL-12,IL-2 AND IFN-γ IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS%系统性红斑狼疮患者血清IL-13、IL-12、IL-2和IFN-γ检测及意义

    Institute of Scientific and Technical Information of China (English)

    邹吉敏; 袁宝军; 安心; 吴俊艳; 周波

    2006-01-01

    目的探讨系统性红斑狼疮(SLE)患者血清IL-13、IL-12、IL-2和IFN-γ水平变化及意义.方法采用双抗体夹心EUSA法检测58例SLE患者(活动期16例,稳定期42例)及30例健康对照者血清IL-13、IL-12、IL-2和IFN-γ的含量.结果SLE活动组、稳定组血清IL-13、IFN-γ水平与对照组比较明显增高,差异有统计学意义(P<0.01),活动组IL-13又较稳定组增高,差异亦有统计学意义(P<0.05),IFN-γ水平略高于稳定组,但差异无统计学意义;IL-12、IL-2与对照组比较,稳定组略高,活动组略低,差异无统计学意义,但疾病活动组与稳定组比较则明显降低,差异有统计学意义(P<0.05).SLE活动期IL-2与IL-13呈负相关(r=-0.52,P<0.05).结论SLE患者存在细胞因子紊乱,IL-13、IL-12、IL-2及IFN-γ可能参与SLE的发病、发展,且IL-13、IL-12、IL-2水平与SLE疾病活动有关.

  6. A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells.

    Science.gov (United States)

    Kuijpers, Taco W; van Leeuwen, Ester M M; Barendregt, Barbara H; Klarenbeek, Paul; aan de Kerk, Daan J; Baars, Paul A; Jansen, Machiel H; de Vries, Niek; van Lier, René A W; van der Burg, Mirjam

    2013-07-01

    Mutations in the common gamma chain (γc, CD132, encoded by the IL2RG gene) can lead to B(+)T(-)NK(-) X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined immunodeficiencies with a variety of clinical presentations. We analyzed peripheral blood mononuclear cells of a 6-year-old boy with normal lymphocyte counts, who suffered from recurrent pneumonia and disseminated mollusca contagiosa. Since proliferative responses of T cells and NK cells to γc -cytokines were severely impaired, we performed IL2RG gene analysis, showing a heterozygous mutation in the presence of a single X-chromosome. Interestingly, an IL2RG reversion to normal predominated in both naïve and antigen-primed CD8(+) T cells and increased over time. Only the revertant CD8(+) T cells showed normal expression of CD132 and the various CD8(+) T cell populations had a different T-cell receptor repertoire. Finally, a fraction of γδ(+) T cells and differentiated CD4(+)CD27(-) effector-memory T cells carried the reversion, whereas NK or B cells were repeatedly negative. In conclusion, in a patient with a novel IL2RG mutation, gene-reverted CD8(+) T cells accumulated over time. Our data indicate that selective outgrowth of particular T-cell subsets may occur following reversion at the level of committed T progenitor cells.

  7. Astaxanthin, a Carotenoid, Stimulates Immune Responses by Enhancing IFN-γ and IL-2 Secretion in Primary Cultured Lymphocytes in Vitro and ex Vivo.

    Science.gov (United States)

    Lin, Kuan-Hung; Lin, Kao-Chang; Lu, Wan-Jung; Thomas, Philip-Aloysius; Jayakumar, Thanasekaran; Sheu, Joen-Rong

    2015-12-29

    Astaxanthin, a potent antioxidant carotenoid, plays a major role in modulating the immune response. In this study, we examined the immunomodulatory effects of astaxanthin on cytokine production in primary cultured lymphocytes both in vitro and ex vivo. Direct administration of astaxanthin (70-300 nM) did not produce cytotoxicity in lipopolysaccharide (LPS, 100 µg/ mL)- or concanavalin A (Con A, 10 µg/ mL)-activated lymphocytes, whereas astaxanthin alone at 300 nM induced proliferation of splenic lymphocytes (p astaxanthin, alone or with Con A, had no apparent effect on interferon (INF-γ) and interleukin (IL-2) production in primary cultured lymphocytes, it enhanced LPS-induced INF-γ production. In an ex vivo experiment, oral administration of astaxanthin (0.28, 1.4 and 7 mg/kg/day) for 14 days did not cause alterations in the body or spleen weights of mice and also was not toxic to lymphocyte cells derived from the mice. Moreover, treatment with astaxanthin significantly increased LPS-induced lymphocyte proliferation ex vivo but not Con A-stimulated lymphocyte proliferation ex vivo. Enzyme linked immunosorbent assay (ELISA) analysis revealed that administration of astaxanthin significantly enhanced INF-γ production in response to both LPS and Con A stimulation, whereas IL-2 production increased only in response to Con A stimulation. Also, astaxanthin treatment alone significantly increased IL-2 production in lymphocytes derived from mice, but did not significantly change production of INF-γ. These findings suggest that astaxanthin modulates lymphocytic immune responses in vitro, and that it partly exerts its ex vivo immunomodulatory effects by increasing INF-γ and IL-2 production without inducing cytotoxicity.

  8. Intratumoral hu14.18-IL-2 (IC) induces local and systemic antitumor effects that involve both activated T and NK cells as well as enhanced IC retention.

    Science.gov (United States)

    Yang, Richard K; Kalogriopoulos, Nicholas A; Rakhmilevich, Alexander L; Ranheim, Erik A; Seo, Songwon; Kim, Kyungmann; Alderson, Kory L; Gan, Jacek; Reisfeld, Ralph A; Gillies, Stephen D; Hank, Jacquelyn A; Sondel, Paul M

    2012-09-01

    hu14.18-IL-2 (IC) is an immunocytokine consisting of human IL-2 linked to hu14.18 mAb, which recognizes the GD2 disialoganglioside. Phase 2 clinical trials of i.v. hu14.18-IL-2 (i.v.-IC) in neuroblastoma and melanoma are underway and have already demonstrated activity in neuroblastoma. We showed previously that intratumoral hu14.18-IL-2 (IT-IC) results in enhanced antitumor activity in mouse models compared with i.v.-IC. The studies presented in this article were designed to determine the mechanisms involved in this enhanced activity and to support the future clinical testing of intratumoral administration of immunocytokines. Improved survival and inhibition of growth of both local and distant tumors were observed in A/J mice bearing s.c. NXS2 neuroblastomas treated with IT-IC compared with those treated with i.v.-IC or control mice. The local and systemic antitumor effects of IT-IC were inhibited by depletion of NK cells or T cells. IT-IC resulted in increased NKG2D receptors on intratumoral NKG2A/C/E⁺ NKp46⁺ NK cells and NKG2A/C/E⁺ CD8⁺ T cells compared with control mice or mice treated with i.v.-IC. NKG2D levels were augmented more in tumor-infiltrating lymphocytes compared with splenocytes, supporting the localized nature of the intratumoral changes induced by IT-IC treatment. Prolonged retention of IC at the tumor site was seen with IT-IC compared with i.v.-IC. Overall, IT-IC resulted in increased numbers of activated T and NK cells within tumors, better IC retention in the tumor, enhanced inhibition of tumor growth, and improved survival compared with i.v.-IC.

  9. Carbon Dioxide: Surprising Effects on Decision Making and Neurocognitive Performance

    Science.gov (United States)

    James, John T.

    2013-01-01

    The occupants of modern submarines and the International Space Station (ISS) have much in common as far as their air quality is concerned. Air is polluted by materials offgassing, use of utility compounds, leaks of systems chemicals, and anthropogenic sources. The primary anthropogenic compound of concern to submariners and astronauts has been carbon dioxide (CO2). NASA and the US Navy rely on the National Research Council Committee on Toxicology (NRC-COT) to help formulate exposure levels to CO2 that are thought to be safe for exposures of 3-6 months. NASA calls its limits Spacecraft Maximum Allowable Concentrations (SMACs). Years of experience aboard the ISS and a recent publication on deficits in decision making in ground-based subjects exposed briefly to 0.25% CO2 suggest that exposure levels that have been presumed acceptable to preserve health and performance need to be reevaluated. The current CO2 exposure limits for 3-6 months set by NASA and the UK Navy are 0.7%, and the limit for US submariners is 0.5%, although the NRC-COT recommended a 90-day level of 0.8% as safe a few years ago. NASA has set a 1000-day SMAC at 0.5% for exploration-class missions. Anecdotal experience with ISS operations approaching the current 180-day SMAC of 0.7% suggest that this limit is too high. Temporarily, NASA has limited exposures to 0.5% until further peer-reviewed data become available. In the meantime, a study published last year in the journal Environmental Health Perspectives (Satish U, et al. 2012) demonstrated that complexdecision- making performance is somewhat affected at 0.1% CO2 and becomes "dysfunctional" for at least half of the 9 indices of performance at concentrations approaching 0.25% CO2. The investigators used the Strategic Management Simulation (SMS) method of testing for decisionmaking ability, and the results were so surprising to the investigators that they declared that their findings need to be independently confirmed. NASA has responded to the

  10. Are seismic hazard assessment errors and earthquake surprises unavoidable?

    Science.gov (United States)

    Kossobokov, Vladimir

    2013-04-01

    Why earthquake occurrences bring us so many surprises? The answer seems evident if we review the relationships that are commonly used to assess seismic hazard. The time-span of physically reliable Seismic History is yet a small portion of a rupture recurrence cycle at an earthquake-prone site, which makes premature any kind of reliable probabilistic statements about narrowly localized seismic hazard. Moreover, seismic evidences accumulated to-date demonstrate clearly that most of the empirical relations commonly accepted in the early history of instrumental seismology can be proved erroneous when testing statistical significance is applied. Seismic events, including mega-earthquakes, cluster displaying behaviors that are far from independent or periodic. Their distribution in space is possibly fractal, definitely, far from uniform even in a single segment of a fault zone. Such a situation contradicts generally accepted assumptions used for analytically tractable or computer simulations and complicates design of reliable methodologies for realistic earthquake hazard assessment, as well as search and definition of precursory behaviors to be used for forecast/prediction purposes. As a result, the conclusions drawn from such simulations and analyses can MISLEAD TO SCIENTIFICALLY GROUNDLESS APPLICATION, which is unwise and extremely dangerous in assessing expected societal risks and losses. For example, a systematic comparison of the GSHAP peak ground acceleration estimates with those related to actual strong earthquakes, unfortunately, discloses gross inadequacy of this "probabilistic" product, which appears UNACCEPTABLE FOR ANY KIND OF RESPONSIBLE SEISMIC RISK EVALUATION AND KNOWLEDGEABLE DISASTER PREVENTION. The self-evident shortcomings and failures of GSHAP appeals to all earthquake scientists and engineers for an urgent revision of the global seismic hazard maps from the first principles including background methodologies involved, such that there becomes: (a) a

  11. The immune response in mice inoculated with maedi-visna virus Gag gene DNA vaccine and IL-2 plasmid%IL-2和绵羊梅迪-维斯纳病病毒核心蛋白Gag核酸疫苗联合免疫小鼠的免疫应答

    Institute of Scientific and Technical Information of China (English)

    丁忠庆; 沈荣显; 相文华; 赵丽荣; 赵立平

    2007-01-01

    构建绵羊梅迪-维斯纳病病毒(MVV)核心蛋白Gag核酸疫苗并与IL-2联合免疫小鼠,为评价其诱导的体液和细胞免疫应答.将MVV gag基因与羊IL-2基因分别插入到核酸疫苗载体质粒pcDNA5.0中,构建真核表达质粒pcDNA5.0-Gag和pcDNA5.0-IL-2,并经酶切以及测序鉴定.分别用阳性质粒pcDNA5.0-Gag、空载体pcDNA5.0及pcDNA5.0-Gag和pcDNA5.0-IL-2共免疫BALB/C小鼠,采用ELISA检测免疫小鼠的特异性抗体以及IFN-γ和IL-4水平,用MTT比色法检测免疫小鼠脾淋巴细胞的增殖.结果表明pcDNA5.0-IL-2联合免疫组小鼠血清抗体效价和IFN-γ、IL-4水平高于pcDNA5.0-Gag免疫组,与空载体pcDNA5.0对照组相比有显著差异(P<0.01).且pcDNA5.0-Gag单独免疫组及与IL-2联合免疫组小鼠脾淋巴细胞增殖的刺激指数均高于空载体pcDNA5-0对照组.因此,构建真核表达质粒pcDNA5.0-Gag和pcDNA5.0-IL-2,用其联合免疫BALB/C小鼠所诱导的免疫反应以特异性细胞免疫应答为主,同时可产生体液免疫,且IL-2发挥了免疫佐剂的作用,为进一步将其用于MVV的防治奠定了基础.

  12. Aging negatively skews macrophage TLR2- and TLR4-mediated pro-inflammatory responses without affecting the IL-2-stimulated pathway.

    Science.gov (United States)

    Boehmer, Eric D; Meehan, Michael J; Cutro, Brent T; Kovacs, Elizabeth J

    2005-12-01

    We recently reported that macrophages from aged mice produced less tumor necrosis factor (TNF)-alpha following lipopolysaccharide (LPS) stimulation than macrophages from young animals. This correlated with decreased levels of phosphorylated and total p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs). Here, we went on to determine if age affects other Toll-like (TLR) and non-TLR signaling pathways. We found that LPS- and zymosan-stimulated TNF-alpha and IL-6 production is attenuated in splenic macrophages from aged mice compared to young. Conversely, LPS-stimulated, but not zymosan-stimulated, IL-10 production from the aged group was elevated over that of the young group. In contrast, IL-2-stimulated TNF-alpha and IL-6 production was not affected by age. The age-associated changes did not correlate with alterations in the cell-surface expression of TLR2, TLR4, or IL-2Rbeta. Macrophages from aged mice demonstrated lower p38 MAPK and MAPK-activated protein kinase (APK)-2 activation. Protein expression of p38, but not MAPK-APK-2, was reduced with age. Additionally, nuclear factor (NF)-kappaB activation was significantly decreased in macrophages from aged mice after exposure to LPS, but not IL-2. These data indicate that age-associated macrophage signaling alterations are pathway-specific and suggest that TLR-mediated pathways are impaired with age at the level of MAPK expression.

  13. Co-administration of inactivated avian influenza virus with CpG or rIL-2 strongly enhances the local immune response after intranasal immunization in chicken.

    Science.gov (United States)

    Xiaowen, Zhang; Qinghua, Yu; Xiaofei, Zhang; Qian, Yang

    2009-09-18

    Intranasal delivery of vaccines is the most effective means of inducing effective immunity in the upper respiratory tract as well as other mucosal lymphoid tissues. To evaluate the effects of the H5N2 inactivated virus with adjuvant, 120 one-day-old chicks were intranasal immunized with the H5N2 inactivated virus respectively mixed with adjuvant CpG or recombinant IL-2 (rIL-2). The local immunocompetent cells on the respiratory tract were detected. The results showed that the number of intraepithelial lymphocytes (IELs), CD3(+) T lymphocytes and mast cells in respiratory tract increased significantly respectively and the number of IgA and IgG secreting cells increased significantly after immunization. However, there was no significant change in the immunocompetent cells of the animals administrated H5N2 inactivated virus alone compared to the control group. Our results indicated that intranasal administration of H5N2 inactivated virus with adjuvant CpG or rIL-2 could be beneficial to the local immune response in the respiratory tract.

  14. The cytokines (IFN-gamma, IL-2, IL-4, IL-10, IL-17) and Treg cytokine (TGF-beta1) levels in adults with immune thrombocytopenia.

    Science.gov (United States)

    Ma, Liangliang; Liang, Yan; Fang, Meiyun; Guan, Yanchun; Si, Yang; Jiang, Feng; Wang, Fangting

    2014-09-01

    Previous studies have indicated that autoimmune diseases might be caused by an imbalance of T helper cells (Th), cytokines, and regulatory T cells (Treg) cytokines. We measured the plasma concentrations of Th1-associated cytokines (IFN-gamma, IL-2), Th2 -associated cytokines (IL-4, IL-10), Th17-associated cytokine (IL-17) and Treg -associated cytokine (TGF-beta1) in adult patients with immune thrombocytopenia (ITP) and evaluated their clinical relevance. Plasma IFN-gamma, IL-2, IL-4, IL-10, IL-17 and TGF-beta1 concentrations of 52 ITP patients and 30 age- and sex-matched healthy controls were measured by enzyme-linked immunosorbent assay method (ELISA). Concentration of Th2 cytokines (IL-4 and IL-10) were significantly higher in ITP patients compared to controls (P cytokines (IFN-gamma, IL-2), Th17 cytokine (IL-17) and Treg cytokine (TGF-beta1) were lower in ITP patients (P cytokine concentration among the other subgroups in ITP patients was found. Among the ITP patients, concentration of IFN-gamma correlated positively and significantly with PAIgG (r = 0.48, P = 0.02). A significant correlation was neither found between other cytokine levels and platelet count, nor between cytokine levels and megakaryocytes number, nor between cytokines levels and PAIgG or GPIIb/IIIa and/or GPIb/IX autoantibodies. The present study demonstrates that an imbalance of Th and Treg cytokines may mediate the pathogenesis of ITP.

  15. A novel deletion mutation in IL2RG gene results in X-linked severe combined immunodeficiency with an atypical phenotype.

    Science.gov (United States)

    Mou, Wenjun; He, Jianxin; Chen, Xi; Zhang, Hui; Ren, Xiaoya; Wu, Xunyao; Ni, Xin; Xu, Baoping; Gui, Jingang

    2017-01-01

    Severe combined immunodeficiency (SCID) is the most serious disorder among primary immunodeficiency diseases threatening children's life. Atypical SCID variant, presenting with mild reduced T cells subsets, is often associated with infection susceptibility but poor clinical diagnosis. The atypical X-SCID patient in the present study showed a mild clinical presentation with a T(low)NK(+)B(+) immunophenotype. The patient has reduced T- cell subpopulations with a subdued thymic output measured by sjTRECs. Further analysis showed that T cells maintained a normal proliferation and a broad Vβ repertoire. NK cells, however, exhibited a skewed development toward immature CD3(-)CD16(+)CD56(-) cells. Genetic analysis revealed a novel deletion at nucleotide 52 in exon 1 of IL2RG gene. Sequence alignment predicted a truncated IL2RG protein missing signal peptide derived from a possible alternative reading frame. The novel mutation in IL2RG gene identified in our study may help the early diagnosis of atypical X-SCID.

  16. The Rag2–Il2rb–Dmd– Mouse: a Novel Dystrophic and Immunodeficient Model to Assess Innovating Therapeutic Strategies for Muscular Dystrophies

    Science.gov (United States)

    Vallese, Denis; Negroni, Elisa; Duguez, Stéphanie; Ferry, Arnaud; Trollet, Capucine; Aamiri, Ahmed; Vosshenrich, Christian AJ; Füchtbauer, Ernst-Martin; Di Santo, James P; Vitiello, Libero; Butler-Browne, Gillian; Mouly, Vincent

    2013-01-01

    The development of innovative therapeutic strategies for muscular dystrophies, particularly cell-based approaches, is still a developing field. Although positive results have been obtained in animal models, they have rarely been confirmed in patients and resulted in very limited clinical improvements, suggesting some specificity in humans. These findings emphasized the need for an appropriate animal model (i.e., immunodeficient and dystrophic) to investigate in vivo the behavior of transplanted human myogenic stem cells. We report a new model, the Rag2–Il2rb–Dmd– mouse, which lacks T, B, and NK cells, and also carries a mutant Dmd allele that prevents the production of any dystrophin isoform. The dystrophic features of this new model are comparable with those of the classically used mdx mouse, but with the total absence of any revertant dystrophin positive fiber. We show that Rag2–Il2rb–Dmd– mice allow long-term xenografts of human myogenic cells. Altogether, our findings indicate that the Rag2–Il2rb–Dmd– mouse represents an ideal model to gain further insights into the behavior of human myogenic stem cells in a dystrophic context, and can be used to assess innovative therapeutic strategies for muscular dystrophies. PMID:23975040

  17. The Rag2(-)Il2rb(-)Dmd(-) Mouse: a Novel Dystrophic and Immunodeficient Model to Assess Innovating Therapeutic Strategies for Muscular Dystrophies.

    Science.gov (United States)

    Vallese, Denis; Negroni, Elisa; Duguez, Stéphanie; Ferry, Arnaud; Trollet, Capucine; Aamiri, Ahmed; Vosshenrich, Christian Aj; Füchtbauer, Ernst-Martin; Di Santo, James P; Vitiello, Libero; Butler-Browne, Gillian; Mouly, Vincent

    2013-10-01

    The development of innovative therapeutic strategies for muscular dystrophies, particularly cell-based approaches, is still a developing field. Although positive results have been obtained in animal models, they have rarely been confirmed in patients and resulted in very limited clinical improvements, suggesting some specificity in humans. These findings emphasized the need for an appropriate animal model (i.e., immunodeficient and dystrophic) to investigate in vivo the behavior of transplanted human myogenic stem cells. We report a new model, the Rag2(-)Il2rb(-)Dmd(-) mouse, which lacks T, B, and NK cells, and also carries a mutant Dmd allele that prevents the production of any dystrophin isoform. The dystrophic features of this new model are comparable with those of the classically used mdx mouse, but with the total absence of any revertant dystrophin positive fiber. We show that Rag2(-)Il2rb(-)Dmd(-) mice allow long-term xenografts of human myogenic cells. Altogether, our findings indicate that the Rag2(-)Il2rb(-)Dmd(-) mouse represents an ideal model to gain further insights into the behavior of human myogenic stem cells in a dystrophic context, and can be used to assess innovative therapeutic strategies for muscular dystrophies.

  18. The Rag2⁻Il2rb⁻Dmd⁻ mouse: a novel dystrophic and immunodeficient model to assess innovating therapeutic strategies for muscular dystrophies.

    Science.gov (United States)

    Vallese, Denis; Negroni, Elisa; Duguez, Stéphanie; Ferry, Arnaud; Trollet, Capucine; Aamiri, Ahmed; Vosshenrich, Christian A J; Füchtbauer, Ernst-Martin; Di Santo, James P; Vitiello, Libero; Butler-Browne, Gillian; Mouly, Vincent

    2013-10-01

    The development of innovative therapeutic strategies for muscular dystrophies, particularly cell-based approaches, is still a developing field. Although positive results have been obtained in animal models, they have rarely been confirmed in patients and resulted in very limited clinical improvements, suggesting some specificity in humans. These findings emphasized the need for an appropriate animal model (i.e., immunodeficient and dystrophic) to investigate in vivo the behavior of transplanted human myogenic stem cells. We report a new model, the Rag2(-)Il2rb(-)Dmd(-) mouse, which lacks T, B, and NK cells, and also carries a mutant Dmd allele that prevents the production of any dystrophin isoform. The dystrophic features of this new model are comparable with those of the classically used mdx mouse, but with the total absence of any revertant dystrophin positive fiber. We show that Rag2(-)Il2rb(-)Dmd(-) mice allow long-term xenografts of human myogenic cells. Altogether, our findings indicate that the Rag2(-)Il2rb(-)Dmd(-) mouse represents an ideal model to gain further insights into the behavior of human myogenic stem cells in a dystrophic context, and can be used to assess innovative therapeutic strategies for muscular dystrophies.

  19. Correction of murine SCID-X1 by lentiviral gene therapy using a codon-optimized IL2RG gene and minimal pretransplant conditioning.

    Science.gov (United States)

    Huston, Marshall W; van Til, Niek P; Visser, Trudi P; Arshad, Shazia; Brugman, Martijn H; Cattoglio, Claudia; Nowrouzi, Ali; Li, Yuedan; Schambach, Axel; Schmidt, Manfred; Baum, Christopher; von Kalle, Christof; Mavilio, Fulvio; Zhang, Fang; Blundell, Mike P; Thrasher, Adrian J; Verstegen, Monique M A; Wagemaker, Gerard

    2011-10-01

    Clinical trials have demonstrated the potential of ex vivo hematopoietic stem cell gene therapy to treat X-linked severe combined immunodeficiency (SCID-X1) using γ-retroviral vectors, leading to immune system functionality in the majority of treated patients without pretransplant conditioning. The success was tempered by insertional oncogenesis in a proportion of the patients. To reduce the genotoxicity risk, a self-inactivating (SIN) lentiviral vector (LV) with improved expression of a codon optimized human interleukin-2 receptor γ gene (IL2RG) cDNA (coγc), regulated by its 1.1 kb promoter region (γcPr), was compared in efficacy to the viral spleen focus forming virus (SF) and the cellular phosphoglycerate kinase (PGK) promoters. Pretransplant conditioning of Il2rg(-/-) mice resulted in long-term reconstitution of T and B lymphocytes, normalized natural antibody titers, humoral immune responses, ConA/IL-2 stimulated spleen cell proliferation, and polyclonal T-cell receptor gene rearrangements with a clear integration preference of the SF vector for proto-oncogenes, contrary to the PGK and γcPr vectors. We conclude that SIN lentiviral gene therapy using coγc driven by the γcPr or PGK promoter corrects the SCID phenotype, potentially with an improved safety profile, and that low-dose conditioning proved essential for immune competence, allowing for a reduced threshold of cell numbers required.

  20. Polymorphic variant at the IL2 region is associated with type 1 diabetes and may affect serum levels of interleukin-2.

    Science.gov (United States)

    Fichna, Marta; Zurawek, Magdalena; Fichna, Piotr; Ziółkowska-Suchanek, Iwona; Januszkiewicz, Danuta; Nowak, Jerzy

    2013-12-01

    Polymorphic variants at the interleukin-2 (IL2) locus affect the risk of several autoimmune disorders. Our aim was to evaluate the association of the four IL2 polymorphisms (rs6822844, rs6534349, rs2069762 and rs3136534) with type 1 diabetes (T1D) in the Polish population, and to correlate them with the serum interleukin-2 levels. 543 unrelated T1D patients and 706 healthy control subjects were enrolled. The minor T allele at rs6822844 was significantly less frequent in T1D compared to controls (p = 0.002; OR 0.71; 95 % CI 0.571-0.880). Likewise, the frequency of the TT genotype was decreased among the affected individuals (p = 0.007). In healthy subjects, stratification according to the rs6822844 genotype revealed significant differences in circulating interleukin-2 (p = 0.037) with the highest levels in TT protective genotypes. Three other IL2 polymorphisms did not display significant differences in allele and genotype distribution. In conclusion, the rs6822844 variant is associated with T1D and may play a functional role, or reflect the influence of another causative genetic variant in linkage disequilibrium.

  1. Protective role of TNF-α, IL-10 and IL-2 in mice infected with the Oshima strain of Tick-borne encephalitis virus

    Science.gov (United States)

    Tun, Mya Myat Ngwe; Aoki, Kotaro; Senba, Masachika; Buerano, Corazon C.; Shirai, Kenji; Suzuki, Ryuji; Morita, Kouichi; Hayasaka, Daisuke

    2014-01-01

    Tick-borne encephalitis virus (TBEV) causes acute central nervous system disease. Here, we investigated the roles of the TNF-α, IL-10 and other cytokines in appropriate KO mice following infection with Oshima and Sofjin strains of TBEV. Following infection with the Oshima strain, mortality rates were significantly increased in TNF-α KO and IL-10 KO mice compared with wild type (WT) mice. These results suggested that TNF-α and IL-10 play protective roles against fatal infection due to Oshima strain infection. However, viral loads and proinflammatory cytokine levels in the brain of TNF-α KO andIL-10 KO mice were not significantly different compared with those of WT mice. On the other hand, all WT, TNF-α KO and IL-10 KO mice died following infection with Sofjin strain. Interestingly, Sofjin-infected mice did not exhibit an up-regulated mRNA level of IL-2 in the spleen in all groups of mice, whereas Oshima-infected mice showed significantly increased level of IL-2 compared with mock-infected mice. From these results, we suggest that TNF-α, IL-10 and IL-2 are key factors for disease remission from fatal encephalitis due to infection with Oshima strain of TBEV. PMID:24938868

  2. Association of interleukin 2 (IL-2), interleukin 6 (IL-6), and TNF-alpha (TNFα) gene polymorphisms with paranoid schizophrenia in a Polish population.

    Science.gov (United States)

    Paul-Samojedny, Monika; Owczarek, Aleksander; Kowalczyk, Małgorzata; Suchanek, Renata; Palacz, Marta; Kucia, Krzysztof; Fila-Daniłow, Anna; Borkowska, Paulina; Kowalski, Jan

    2013-01-01

    Numerous reports have brought attention to the potential role of cytokines in schizophrenia. The aim of the study was to determine whether polymorphisms of IL-2, IL-6, and TNFα genes are risk factors for development of paranoid schizophrenia in a Polish population. Promoter polymorphisms of IL-6 (rs1800795), TNFα (rs1800629), and IL-2 (rs2069762) genes in patients (N=115) and controls (N=135) were genotyped by PCR-RFLP and AS-PCR methods, respectively. Genotype TT and allele T for IL-2 polymorphism, and genotype AA and allele A for TNFα polymorphism were found to be significantly associated with paranoid schizophrenia. Similarly, haplotypes CTA and GTA increased the risk (4.4 times and 5.9 times, respectively) of schizophrenia. To reveal associations between Positive and Negative Symptom Scale subscales and age at onset of schizophrenia, the authors used a novel method called Grade Correspondence Analysis. This analysis revealed that patients with early age at onset have higher scores on the Negative and General subscales of PANSS, and, in that group of patients, haplotype CTA was the most represented. As far as is known, this analysis was used for the first time with reference to genetic data.

  3. Shockwaves increase T-cell proliferation and IL-2 expression through ATP release, P2X7 receptors, and FAK activation.

    Science.gov (United States)

    Yu, Tiecheng; Junger, Wolfgang G; Yuan, Changji; Jin, An; Zhao, Yi; Zheng, Xueqing; Zeng, Yanjun; Liu, Jianguo

    2010-03-01

    Shockwaves elicited by transient pressure disturbances are used to treat musculoskeletal disorders. Previous research has shown that shockwave treatment affects T-cell function, enhancing T-cell proliferation and IL-2 expression by activating p38 mitogen-activated protein kinase (MAPK) signaling. Here we investigated the signaling pathway by which shockwaves mediate p38 MAPK phosphorylation. We found that shockwaves at an intensity of 0.18 mJ/mm(2) induce the release of extracellular ATP from human Jurkat T-cells at least in part by affecting cell viability. ATP released into the extracellular space stimulates P2X7-type purinergic receptors that induce the activation of p38 MAPK and of focal adhesion kinase (FAK) by phosphorylation on residues Tyr397 and Tyr576/577. Elimination of released ATP with apyrase or inhibition of P2X7 receptors with the antagonists KN-62 or suramin significantly weakens FAK phosphorylation, p38 MAPK activation, IL-2 expression, and T-cell proliferation. Conversely, addition of exogenous ATP causes phosphorylation of FAK and p38 MAPK. Silencing of FAK expression also reduces these cell responses to shockwave treatment. We conclude that shockwaves enhance p38 MAPK activation, IL-2 expression, and T-cell proliferation via the release of cellular ATP and feedback mechanisms that involve P2X7 receptor activation and FAK phosphorylation.

  4. Clinical observation of serum IL-18, IL-10 and sIL-2R levels in patients with chronic hepatitis C pre- and post antiviral treatment

    Institute of Scientific and Technical Information of China (English)

    贾红宇; 杜杰; 朱思和; 马英骥; 蔡华枫

    2003-01-01

    Objective To discuss the roles of serum interleukin-18 (IL-18), interleukin-10 (IL-10) and soluble interleukin-2R (sIL-2R) in the pathogenesis of chronic hepatitis C and to observe the effects of interferon (IFN) on the above- mentioned serum cytokines. Methods The levels of above- mentioned cytokines were detected in 10 healthy individuals, 24 asymptomatic hepatitis virus C (HCV) carriers and 27 patients with chronic hepatitis C ( before and after IFN treatment) using enzyme linked immunosorbent assay (ELISA). Results The levels of the cytokines in patients with chronic hepatitis C are higher than in healthy people (P<0.05) and in asymptomatic HCV carriers(P<0.05). The values of the cytokines show a significant positive correlation to ALT (P<0.05). Levels of tested cytokines decreased observably after IFN treatment (P<0.05). The grades of the serum levels for sIL-2R and IL-10 before IFN treatment (from high to low) were categorized accordingly: non-response group> partial- response group >complete- response group (P<0.05). Conclusions The tested cytokines co-participate in the pathogenesis of chronic hepatitis C, and can be used to evaluate the effect of IFN on the immune state of organisms. Furthermore, sIL-2R and IL-10 are important for predicting the anti-viral efficacy of IFN.

  5. Monitoring of TNFR1, IL-2Rα, HGF, CCL8, IL-8 and IL-12p70 following HSCT and their role as GVHD biomarkers in paediatric patients.

    Science.gov (United States)

    Berger, M; Signorino, E; Muraro, M; Quarello, P; Biasin, E; Nesi, F; Vassallo, E; Fagioli, F

    2013-09-01

    No predictive factors are currently available to establish patient-specific GVHD risk. A panel of six serum cytokines (TNF receptor 1, IL-2 receptor alfa (IL-2Rα), hepatocyte growth factor (HGF), monocyte chemo-attractant protein-2, IL-8, IL-12p70) were monitored at established time points (days -1, +1, +7, +14, +21, +28 and +60) in 170 paediatric hematopoietic SCT (HSCT) recipients. We found that higher concentrations of IL-2Rα on days +14 and +21 together with HGF on days +14 and +21 were significantly associated at a higher probability of both grade II-IV GVHD (on day +14 it was: 60% vs 28%, P=0.007) and grade III-IV (on day +14 it was: 40% vs 15%, P=0.001). The higher IL-8 serum concentration on day +28 was associated with a lower probability of chronic GVHD being 4% vs 29% (P=0.01) for patients with higher vs lower IL-8 serum concentration. These findings were confirmed when the analysis was restricted to the the matched unrelated donor group. In conclusion, even if the serum cytokine levels were related to several variables associated with HSCT, we identified two cytokines as predictors of GVHD II-IV and III-IV, translating into a higher TRM risk (17% vs 3%, P=0.004).

  6. Effect of Long-term Inhalation of Glucocorticoids on the Level of Leptin, IL-13 and IL-2 in Bronchial Asthmatic Children%长期吸入糖皮质激素对支气管哮喘患者血清leptin、IL-13和IL-2水平的影响

    Institute of Scientific and Technical Information of China (English)

    潘炯伟

    2011-01-01

    目的:观察支气管哮喘患者血清leptin、IL-13和IL-2水平的变化并探讨长期吸入糖皮质激素后对支气管哮喘患者血清leptin、IL-13和IL-2的影响.方法:4采用酶联免疫吸附法(ELISA),分别检测70例支气管哮喘患者采用吸入糖皮质激素治疗前、治疗3、6、12个月后及60例对照者血清IL-13和IL-2水平;采用放射免疫分析血清leptin浓度.结果:支气管哮喘患者血清leptin、IL-13和IL-2水平显著高于正常对照组.吸入糖皮质激素治疗3个月后支气管哮喘患者血清leptin、IL-13和IL-2浓度与治疗前比较下降(P均<0.05),治疗6个月和12个月后显著低于治疗前(P均<0.01),且治疗12个月后各个炎症指标与对照组相比无显著性差异(P>0.05).结论:长期吸入糖皮质激素是治疗支气管哮喘的重要手段,其治疗作用与下调血清leptin、IL-13和IL-2水平有关.%Objective To determine the effect of long-term inhalation of glucocorticoids on the level of leptin, IL-13, and H-2 in bronchial asthmatic patient. Methods End/me-linked immunosorbent assay ( ELISA ) was used to detect the serum IL-13 and IL-2 level in 60 healthy persons ( normal control group ) and 70 bronchial asthma patients untreated and 3, 6, 12 months pest-treatment, meanwhile leptin was determined by radio immunoassay. Results The serum levels of leptin, IL-13, and IL-2 in were significantly increased in patient with bronchial asthma compared with that in the normal control group. The serum levels of leptin, IL-13, and IL 2 in children with asthma were clem'eased gradually after inhaling gineccortieoids for 3 months ( P < 0.05 ). The treatment of inhaled glucocortieoids for 6 and 12 months can attenuate the elevation of leptin, IL-13, and IL-2 compared with that before the treatment. Conclusion Long-term inhaled glucoeortieoid is an important means for asthma, and the effects are related to the decrease of level of leptin, IL-13, and IL-2.

  7. IL-2 induces beta2-integrin adhesion via a wortmannin/LY294002-sensitive, rapamycin-resistant pathway. Phosphorylation of a 125-kilodalton protein correlates with induction of adhesion, but not mitogenesis

    DEFF Research Database (Denmark)

    Nielsen, M; Svejgaard, A; Skov, S;

    1996-01-01

    beta2-integrin-dependent, homotypic adhesion in Ag-specific, human T cell lines. The IL-2 adhesion response is blocked by wortmannin and LY294002, inhibitors of phosphatidylinositol-3 (PI-3) kinase activity. In contrast, rapamycin strongly inhibits IL-2-induced proliferation without inhibiting IL-2......, and cytochalasin E almost completely inhibit cytokine-induced tyrosine phosphorylation of p125, whereas tyrosine phosphorylation of PI-3 kinase, Janus kinases, Stat3, Stat5, and other proteins is unaffected. In contrast, rapamycin has little effect on IL-2-induced phosphorylation of p125. Taken together......, these data suggest that 1) IL-2R ligation induces homotypic adhesion through a wortmannin/LY294002-sensitive, rapamycin-resistant pathway, 2) tyrosine kinases play a critical role in cytokine-induced adhesion, and 3) adhesion, but not mitogenesis, correlates with enhanced tyrosine phosphorylation...

  8. Intestinal colonization of IL-2 deficient mice with non-colitogenic B. vulgatus prevents DC maturation and T-cell polarization.

    Directory of Open Access Journals (Sweden)

    Martina Müller

    Full Text Available BACKGROUND: IL-2 deficient (IL-2(-/- mice mono-colonized with E. coli mpk develop colitis whereas IL-2(-/--mice mono-colonized with B. vulgatus mpk do not and are even protected from E. coli mpk induced colitis. METHODOLOGY/PRINCIPAL FINDINGS: We investigated if mono-colonization with E. coli mpk or B. vulgatus mpk differentially modulates distribution, activation and maturation of intestinal lamina propria (LP dendritic cells (DC. LP DC in mice mono-colonized with protective B. vulgatus mpk or co-colonized with E. coli mpk/B. vulgatus mpk featured a semi-mature LP DC phenotype (CD40(loCD80(loMHC-II(hi whereas mono-colonization with colitogenic E. coli mpk induced LP DC activation and maturation prior to onset of colitis. Accordingly, chemokine receptor (CCR 7 surface expression was more strikingly enhanced in mesenteric lymph node DC from E. coli mpk than B. vulgatus mpk mono- or co-colonized mice. Mature but not semi-mature LP DC promoted Th1 polarization. As B. vulgatus mpk promotes differentiation of semi-mature DC presumably by IL-6, mRNA and protein expression of IL-6 was investigated in LP DC. The data demonstrated that IL-6 mRNA and protein was increased in LP DC of B. vulgatus mpk as compared to E. coli mpk mono-colonized IL-2(-/--mice. The B. vulgatus mpk mediated suppression of CCR7 expression and DC migration was abolished in IL-6(-/--DC in vitro. CONCLUSIONS/SIGNIFICANCE: From this data we conclude that the B. vulgatus triggered IL-6 secretion by LP DC in absence of proinflammatory cytokines such as IL-12 or TNF-alpha induces a semi-mature LP DC phenotype, which might prevent T-cell activation and thereby the induction of colitis in IL-2(-/--mice. The data provide new evidence that IL-6 might act as an immune regulatory cytokine in the mucosa by targeting intestinal DC.

  9. Effect of alpha 2b interferon on inducement of mIL-2R and treatment of HCV in PBMC from patients with chronic viral hepatitis C

    Institute of Scientific and Technical Information of China (English)

    Jian Wang; Gui-Ju Xiang; Bing-Xiang Liu

    2003-01-01

    AIM: To study the level of membrane interleukin-2 receptor (mIL-2R) on surface of peripheral blood mononuclear cells (PBMC) and the therapeutic efficacy of alpha 2b interferon on the treatment of HCV-RNA in PBMC of patients with chronic hepatitis C and to compare the negative rates of HCV-RNA in PBMC, HCV-RNA and anti-HCV in serum.METHODS: Before and after treatment of alpha 2b interferon, the level of mIL-2R of patients with chronic hepatitis C was detected by biotin-streptavidin (BSA). The therapeutic group (26 cases) was treated with alpha 2b interferon (3 MU/d) and control therapeutic group (22 cases)was treated with routine drugs (VitC, aspartic acid). The total course of treatment with alpha 2b interferon and routine drug was six months and per course of the treatment was three months. The levels of HCV-RNA in PBMC, HCV-RNA and anti-HCV in serum were detected before and after a course of the treatment.RESULTS: Before and after treatment of alpha 2b interferon and routine drugs, the levels of mIL-2R in silence stage were (3.44±0.77)% and (2.95±0.72)%, the levels of mIL-2R in inducement stage were (33.62±3.95)% and (30.04±3.73)%. There was a significant difference between two groups (P<0.01-P<0.05). After treatment of alpha 2b interferon with 3 MU/d for two courses of the treatment,the total negative rates of HCV-RNA in the PBMC and HCVRNA, anti-HCV in serum were 42.31% (11/26), 57.69%(15/26), 65.38%(17/26) respectively. After the treatment of routine drug, the negative rates of HCV-RNA in PBMC and HCV-RNA, anti-HCV in serum were 13.64% (3/22),22.73% (5/22), 27.27% (6/22) respectively. There was high significant difference in the group treated with alpha 2b interferon and the group treated with routine drugs (P<0.01-P<0.05).CONCLUSION: The mIL-2R can be induced by alpha 2b interferon during the treatment. The alpha 2b interferon has a definite effect on the treatment of HCV-RNA in PBMC.The curative effect of alpha 2b interferon is better than that

  10. Genome wide transcriptional analysis of resting and IL2 activated human natural killer cells: gene expression signatures indicative of novel molecular signaling pathways

    Directory of Open Access Journals (Sweden)

    Schmitz Alexander

    2007-07-01

    Full Text Available Abstract Background Human natural killer (NK cells are the key contributors of innate immune response and the effector functions of these cells are enhanced by cytokines such as interleukine 2 (IL2. We utilized genome-wide transcriptional profiling to identify gene expression signatures and pathways in resting and IL2 activated NK cell isolated from peripheral blood of healthy donors. Results Gene expression profiling of resting NK cells showed high expression of a number of cytotoxic factors, cytokines, chemokines and inhibitory and activating surface NK receptors. Resting NK cells expressed many genes associated with cellular quiescence and also appeared to have an active TGFβ (TGFB1 signaling pathway. IL2 stimulation induced rapid downregulation of quiescence associated genes and upregulation of genes associated with cell cycle progression and proliferation. Numerous genes that may enhance immune function and responsiveness including activating receptors (DNAM1, KLRC1 and KLRC3, death receptor ligand (TNFSF6 (FASL and TRAIL, chemokine receptors (CX3CR1, CCR5 and CCR7, interleukin receptors (IL2RG, IL18RAB and IL27RA and members of secretory pathways (DEGS1, FKBP11, SSR3, SEC61G and SLC3A2 were upregulated. The expression profile suggested PI3K/AKT activation and NF-κB activation through multiple pathways (TLR/IL1R, TNF receptor induced and TCR-like possibly involving BCL10. Activation of NFAT signaling was supported by increased expression of many pathway members and downstream target genes. The transcription factor GATA3 was expressed in resting cells while T-BET was upregulated on activation concurrent with the change in cytokine expression profile. The importance of NK cells in innate immune response was also reflected by late increased expression of inflammatory chemotactic factors and receptors and molecules involved in adhesion and lymphocyte trafficking or migration. Conclusion This analysis allowed us to identify genes implicated in

  11. Supermagnetic Neutron Star Surprises Scientists, Forces Revision of Theories

    Science.gov (United States)

    2006-08-01

    magnetars because their magnetic fields are 100-1,000 times stronger than those of typical pulsars. It is the decay of those incredibly strong fields that powers their strange X-ray emission. "The magnetic field from a magnetar would make an aircraft carrier spin around and point north quicker than a compass needle moves on Earth," said David Helfand, of Columbia University. A magnetar's field is 1,000 trillion times stronger than Earth's, Helfand pointed out. The new object -- named XTE J1810-197 -- was first discovered by NASA's Rossi X-ray Timing Explorer when it emitted a strong burst of X-rays in 2003. While the X-rays were fading in 2004, Jules Halpern of Columbia University and collaborators identified the magnetar as a radio-wave emitter using the National Science Foundation's (NSF) Very Large Array (VLA) radio telescope in New Mexico. Any radio emission is highly unusual for a magnetar. Because magnetars had not been seen to regularly emit radio waves, the scientists presumed that the radio emission was caused by a cloud of particles thrown off the neutron star at the time of its X-ray outburst, an idea they soon would realize was wrong. With knowledge that the magnetar emitted some form of radio waves, Camilo and his colleagues observed it with the Parkes radio telescope in Australia in March and immediately detected astonishingly strong radio pulsations every 5.5 seconds, corresponding to the previously-determined rotation rate of the neutron star. As they continued to observe XTE J1810-197, the scientists got more surprises. Whereas most pulsars become weaker at higher radio frequencies, XTE J1810-197 does not, remaining a strong emitter at frequencies up to 140 GHz, the highest frequency ever detected from a radio pulsar. In addition, unlike normal pulsars, the object's radio emission fluctuates in strength from day to day, and the shape of the pulsations changes as well. These variations likely indicate that the magnetic fields around the pulsar are changing

  12. Chandra Finds Surprising Black Hole Activity In Galaxy Cluster

    Science.gov (United States)

    2002-09-01

    Scientists at the Carnegie Observatories in Pasadena, California, have uncovered six times the expected number of active, supermassive black holes in a single viewing of a cluster of galaxies, a finding that has profound implications for theories as to how old galaxies fuel the growth of their central black holes. The finding suggests that voracious, central black holes might be as common in old, red galaxies as they are in younger, blue galaxies, a surprise to many astronomers. The team made this discovery with NASA'S Chandra X-ray Observatory. They also used Carnegie's 6.5-meter Walter Baade Telescope at the Las Campanas Observatory in Chile for follow-up optical observations. "This changes our view of galaxy clusters as the retirement homes for old and quiet black holes," said Dr. Paul Martini, lead author on a paper describing the results that appears in the September 10 issue of The Astrophysical Journal Letters. "The question now is, how do these black holes produce bright X-ray sources, similar to what we see from much younger galaxies?" Typical of the black hole phenomenon, the cores of these active galaxies are luminous in X-ray radiation. Yet, they are obscured, and thus essentially undetectable in the radio, infrared and optical wavebands. "X rays can penetrate obscuring gas and dust as easily as they penetrate the soft tissue of the human body to look for broken bones," said co-author Dr. Dan Kelson. "So, with Chandra, we can peer through the dust and we have found that even ancient galaxies with 10-billion-year-old stars can have central black holes still actively pulling in copious amounts of interstellar gas. This activity has simply been hidden from us all this time. This means these galaxies aren't over the hill after all and our theories need to be revised." Scientists say that supermassive black holes -- having the mass of millions to billions of suns squeezed into a region about the size of our Solar System -- are the engines in the cores of

  13. Trait Anxiety Is Associated with Negative Interpretations When Resolving Valence Ambiguity of Surprised Faces.

    Science.gov (United States)

    Park, Gewnhi; Vasey, Michael W; Kim, Grace; Hu, Dixie D; Thayer, Julian F

    2016-01-01

    The current research examines whether trait anxiety is associated with negative interpretation bias when resolving valence ambiguity of surprised faces. To further isolate the neuro-cognitive mechanism, we presented angry, happy, and surprised faces at broad spatial frequency (BSF), high spatial frequency (HSF), and low spatial frequency (LSF) and asked participants to determine the valence of each face. High trait anxiety was associated with more negative interpretations of BSF (i.e., intact) surprised faces. However, the modulation of trait anxiety on the negative interpretation of surprised faces disappeared at HSF and LSF. The current study provides evidence that trait anxiety modulates negative interpretations of BSF surprised faces. However, the negative interpretation of LSF surprised faces appears to be a robust default response that occurs regardless of individual differences in trait anxiety.

  14. Trait anxiety is associated with negative interpretations when resolving valence ambiguity of surprised faces

    Directory of Open Access Journals (Sweden)

    Gewnhi Park

    2016-08-01

    Full Text Available The current research examines whether trait anxiety is associated with negative interpretation bias when resolving valence ambiguity of surprised faces. To further isolate the neuro-cognitive mechanism, we presented angry, happy, and surprised faces at broad, high, and low spatial frequency and asked participants to determine the valence of each face. High trait anxiety was associated with more negative interpretations of broad spatial frequency (i.e., intact surprised faces. However, the modulation of trait anxiety on the negative interpretation of surprised faces disappeared at high and low spatial frequencies. The current study provides evidence that trait anxiety modulates negative interpretations of broad spatial frequency surprised faces. However, the negative interpretation of low spatial frequency surprised faces appears to be a robust default response that occurs regardless of individual differences in trait anxiety.

  15. Effects of Surprisal and Locality on Danish Sentence Processing: An Eye-Tracking Investigation.

    Science.gov (United States)

    Balling, Laura Winther; Kizach, Johannes

    2017-03-22

    An eye-tracking experiment in Danish investigates two dominant accounts of sentence processing: locality-based theories that predict a processing advantage for sentences where the distance between the major syntactic heads is minimized, and the surprisal theory which predicts that processing time increases with big changes in the relative entropy of possible parses, sometimes leading to anti-locality effects. We consider both lexicalised surprisal, expressed in conditional trigram probabilities, and syntactic surprisal expressed in the manipulation of the expectedness of the second NP in Danish constructions with two postverbal NP-objects. An eye-tracking experiment showed a clear advantage for local syntactic relations, with only a marginal effect of lexicalised surprisal and no effect of syntactic surprisal. We conclude that surprisal has a relatively marginal effect, which may be clearest for verbs in verb-final languages, while locality is a robust predictor of sentence processing.

  16. Trait Anxiety Is Associated with Negative Interpretations When Resolving Valence Ambiguity of Surprised Faces

    OpenAIRE

    Gewnhi Park; Vasey, Michael W.; Grace Kim; Dixie D Hu; Thayer, Julian F

    2016-01-01

    The current research examines whether trait anxiety is associated with negative interpretation bias when resolving valence ambiguity of surprised faces. To further isolate the neuro-cognitive mechanism, we presented angry, happy, and surprised faces at broad, high, and low spatial frequency and asked participants to determine the valence of each face. High trait anxiety was associated with more negative interpretations of broad spatial frequency (i.e., intact) surprised faces. However, the mo...

  17. The study on pathogenesis, TNF-α and sIL-2R changes in acute Guillain-Barré syndrome%急性Guillain-Barré综合征外周血TNF-α及sIL-2R的变化及发病机制探讨

    Institute of Scientific and Technical Information of China (English)

    华耀松; 钟述猷

    2002-01-01

    目的探讨肿瘤坏死因子(tumor necrosis factor-α,TNF-α)及可溶性白介素2受体(solubleinterleukin-2 receptor,sIL-2R)在急性Guillain-Barré综合征(Guillain-Barré syndrome,GBS)免疫发病机制中的作用.方法采用双抗体夹心ELISA法,对30例急性GBS患者外周血TNF-α及sIL-2R水平进行检测,并与24例其他神经系统疾病患者及正常对照组进行比较.结果急性GBS患者外周血TNF-α及sIL-2R水平明显升高,与正常对照组及其他神经系统疾病组比较差异有显著性意义(P<0.01);且外周血TNF-α水平的明显增高与GBS的病情进展有关.结论急性GRS患者有多种细胞因子异常,TNF-α、sIL-2R可能参与了急性GBS的免疫发病机制过程.

  18. 脂质体介导IL-2、TNF-α联合基因转导体内抗肝细胞癌的实验研究%Combined IL-2 cDNA with TNF-α cDNA genetherapy for hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    李东复; 申吉子; 闫峻; 邵国光; 周晓琦; 杨春荣

    2003-01-01

    目的:探讨脂质体介导IL-2cDNA、TNF-αcDNA联合基因转导体内抗肿瘤效果.方法:建立裸鼠肝癌动物模型,在荷瘤部位将脂质体包裹的IL-2cDNA和TNF-αcDNA直接注入瘤体中,观察肿瘤大小变化,并检测此2种基因在肿瘤组织中的表达情况.结果:IL-2基因和TNF-α基因联合治疗组肿瘤生长明显受到抑制,抗肿瘤效果显著优于单纯治疗组和对照组.结论:IL-2和TNF-α基因联合治疗组对肿瘤生长抑制效果明显优于单纯治疗组与对照组,荷瘤鼠生存期明显延长(P<0.05).

  19. A Neural Mechanism for Surprise-related Interruptions of Visuospatial Working Memory.

    Science.gov (United States)

    Wessel, Jan R

    2016-11-30

    Surprising perceptual events recruit a fronto-basal ganglia mechanism for inhibition, which suppresses motor activity following surprise. A recent study found that this inhibitory mechanism also disrupts the maintenance of verbal working memory (WM) after surprising tones. However, it is unclear whether this same mechanism also relates to surprise-related interruptions of non-verbal WM. We tested this hypothesis using a change-detection task, in which surprising tones impaired visuospatial WM. Participants also performed a stop-signal task (SST). We used independent component analysis and single-trial scalp-electroencephalogram to test whether the same inhibitory mechanism that reflects motor inhibition in the SST relates to surprise-related visuospatial WM decrements, as was the case for verbal WM. As expected, surprising tones elicited activity of the inhibitory mechanism, and this activity correlated strongly with the trial-by-trial level of surprise. However, unlike for verbal WM, the activity of this mechanism was unrelated to visuospatial WM accuracy. Instead, inhibition-independent activity that immediately succeeded the inhibitory mechanism was increased when visuospatial WM was disrupted. This shows that surprise-related interruptions of visuospatial WM are not effected by the same inhibitory mechanism that interrupts verbal WM, and instead provides evidence for a 2-stage model of distraction.

  20. 胸腺五肽局部应用对口腔溃疡患者血清IL-2及SOD的影响%Effects of topical administration of thymopentin on the serum level of IL-2 and SOD in patients with recurrent oral aphthous ulcer

    Institute of Scientific and Technical Information of China (English)

    刘捷; 迟强; 栾中山; 杨志

    2013-01-01

    Objective:To investigate the effects of topical administration of thymopentin on the serum level of IL-2 and SOD in patients with recurrent oral aphthous ulcer(ROU).Methods:80 cases of ROU and 40 age-and sex-matched healthy controls were included in the study.All the cases were divided into two groups:40 were treated by topical administration of thymopentin and another 40 by Bingpeng powder.Ulcer healing and pain relief in the patients were observed.Serum IL-2 and SOD levels were measured before and after treatment.Results:The serum levels of IL-2 and SOD in thyonopentin treated patients were increased 3 days after treatment(P < 0.01),but lower than those in the healthy controls (P < 0.05).The serum levels of IL-2 and SOD in bingpeng powder treated patients were unchanged(P > 0.05).87.5% and 82.5% cases obtained pain relief and ulcer healing in thymopentin group,whereas 60% and 45% in bingpeng powder group,respectively(P < 0.01).Conclusion:Thymopentin is effective in the pain control and promotion of ROU healing,and the effects might be related to elevateion serum IL-2 and SOD.%目的:考察口腔溃疡患者应用胸腺五肽局部治疗后,血清白细胞介素-2(IL-2)和超氧化物歧化酶(SOD)的变化情况.方法:选择本院门诊确诊的口腔溃疡期患者80例,随机分为胸腺五肽治疗组40例,冰硼散治疗组40例.同时另选40例同期在年龄、性别方面差异无显著性的本院门诊健康体检者作为正常对照组.观察患者的溃疡愈合情况,记录疼痛缓解情况,测定各组在初诊和复诊时血清IL-2和SOD的含量.结果:胸腺五肽治疗3d后,血清IL-2和SOD有明显提高(P<0.01),但仍低于正常对照组.冰硼散组治疗前后患者血清IL-2和SOD水平无明显变化(P>0.05).胸腺五肽组疼痛缓解率和溃疡愈合率分别达到87.5%和82.5%,而冰硼散组分别为60%和45%.结论:胸腺五肽治疗口腔溃疡能够有效缓解疼痛和加速愈合,这可能与提高血清IL

  1. 腺性膀胱炎患者血清中细胞因子IL-2、IFN-γ、TNF-α的研究%Study of Cytokines in Sera of Patients with Cystitis Glandularis in IL-2,IFN- γ,TNF-α

    Institute of Scientific and Technical Information of China (English)

    崔应东; 胡述彬

    2014-01-01

    Objective:To investigate the role of the cytokines IL-2,IFN-γ,TNF-αin cystitis glandularis occurred. Method:Selected the author’s hospital treated by cystoscopy and biopsy was confirmed pathologically as cystitis gland sex as experimental group of 30 cases,alternate period health check-up 30 cases as control group,through the detection of the expression levels of two groups of patients with serum IL-2,IFN-γ,TNF-αcytokine,and expression level in the patients with cystitis glandularis after 3 months of treatment the serum levels of IL-2,IFN-γ,TNF-αcytokine,make statistical analysis. Result:Treatment group 28 cases effective,2 cases had no effect,the effective rate was 93.3%. Patients serum cytokine IL-2,IFN-gamma,TNF alpha were significantly higher than that of control group,the difference was statistically significant (P0.05).Conclusion:Cytokines in the gland sex cystitis plays an important role;cutting and bladder perfusion chemotherapy drugs in treatment of glandular cystitis method does not change cytokines in serum IL-2,IFN-γ, TNF-αlevel,patients need long-term follow-up.%目的:探讨细胞因子IL-2、IFN-γ、TNF-α在腺性膀胱炎发生中的作用。方法:选取笔者所在医院收治的通过膀胱镜检查及活组织病理检查证实为腺性膀胱炎的30例患者设为试验组,另选同期健康体检者30例设为对照组,通过检测两组患者血清中IL-2、IFN-γ、TNF-α细胞因子的表达水平,以及腺性膀胱炎患者治疗3个月后血清中IL-2、IFN-γ、TNF-α细胞因子的表达水平,做出统计分析。结果:试验组有效28例,无效2例,有效率93.3%。治疗前后试验组血清中细胞因子IL-2、IFN-γ、TNF-α均明显高于对照组,差异有统计学意义(P0.05)。结论:细胞因子在腺性膀胱炎的发生中起着重要作用;电切加化疗药物膀胱灌注治疗腺性膀胱炎的方法并不能改变患者血清中细胞因子IL-2、IFN-γ、TNF-α水平,患者需要长期随访。

  2. Serum IL-2, IL-6, IL-10 and TNF-α Levels in Patients with Vitiligo before and after Treatment%白癜风患者治疗前后血清IL-2、IL-6、IL-10和TNF-α水平

    Institute of Scientific and Technical Information of China (English)

    孙岩; 钱立

    2011-01-01

    目的:探讨白癜风患者治疗前后血清IL-2、IL-6、IL-10、和TNF-α水平及临床意义.方法:应用放射免疫分析法检测32例白癜风患者治疗前后血清IL-2、IL-6、IL-10和TNF-α水平,以35名健康体检者为对照.结果:白癜风患者在治疗前血清IL-6、IL-10、TNF-α水平非常显著地高于对照组(P<0.01),IL-2水平非常显著地低于对照组(P<0.01);经治疗3个月后与对照组比较仍有显著性差异(P<0.05),且血清IL-2水平与IL-6、IL-10、TNF-α水平呈负相关(r=-0.482 2、-0.501 8、-0.613 4.P<0.01).结论:白癜风患者存在自身免疫调节的异常,检测血清IL-2、IL-6、IL-10和TNF-α水平的变化对疾病的治疗和预后具有重要的临床价值.%Objective: To detect serum levels of IL-2, IL-6, IL-10, and TNF-a in patients with vitili-go and to investigate its clinical significance. Methods:Radioimmunoassay was adopted to detect serum levels of IL-2, IL-6, IL-10 and TNF-α of 32 patients with vitiligo before and after treatment. The results were compared with those of 35 healthy people. Results: Serum levels of IL-6, IL-10, TNF-a in vitiligo patients before treatment were significantly higher than those of healthy people ( P<0.01) , while IL-2 level was significantly lower than that of healthy people (P<0.01). After treatment for 3 months, the differences between the two groups were significant (P<0. 05 ) , and serum IL-2 level was negatively correlated with IL-6, IL-10 and TNF-a levels (r=-0.482 2, -0.5018, -0.613 4.P <0.01). Conclusion: Autoimmune regulation is abnormal in vitiligo patients. Detection of serum IL-2, IL-6, IL-10, IL-6 and TNF-a levels have important clinical value in treatment and prognosis of the disease.

  3. Clinical significance of the Changes of Serum Levels of IL-2,IL-6,IL-10,IL-18 and T cell subset in patients with chronic nephritis%慢性肾炎治疗前后血清IL-2、IL-6、IL-10、IL-18和T淋巴细胞亚群检测意义

    Institute of Scientific and Technical Information of China (English)

    刘薇娜; 鲍培玉; 蒋全

    2010-01-01

    目的 探讨慢性肾炎患者治疗前后血清IL-2、IL-6、IL-10、IL-18和T淋巴细胞亚群的变化.方法 分别应用放免法、ELISA法和单克隆抗体法对30例慢性肾炎患者治疗前后进行了血清IL-2、IL-6、IL-10、IL-18和T淋巴细胞亚群水平的检测,并与35名正常健康人作比较.结果 慢性肾炎患者在治疗前血清IL-2和CD4/CD8比值明显低于正常人组(P<0.05),而IL-6、IL-10和IL-18水平高于正常人组(P<0.01);经半年治疗后血清IL-2、IL-6、IL-10、IL-18和CD4/CD8与治疗前组比较差异有统计学意义(P<0.05).结论 检测慢性肾炎患者血清IL-2、IL-6、IL-10、IL-18和T淋巴细胞亚群水平对判断病情及其预后均具有一定的临床实用价值.

  4. Detection of Levels of IL-2/IL-10 and Promoting Th2 Molecular IL-4 in Peripheral Blood of Gestational Hypertension%妊娠高血压外周血中促Th2的细胞因子水平及IL-2/IL-10平衡的临床意义

    Institute of Scientific and Technical Information of China (English)

    肖文辉; 钟荣钟; 林洁; 彭耀金

    2011-01-01

    目的:检测妊娠高血压患者外周血中促Th2的分子IL-4、IL-2与IL-10的水平,探讨IL-2/IL-10在妊高症中的临床意义.方法:选择40例未妊娠妇女为对照组,30例正常妊娠妇女为妊娠组,28例妊娠高血压患者为妊娠高血压组,ELISA检测血清中IL-4、IL-2和IL-10的水平.结果:与对照组外周血中IL-4水平(0.53±0.04)pg/ml相比:正常妊娠组IL-4水平升高至(0.91±0.03)pg/ml(P<0.05),妊娠高血压组II-4水平(0.67±0.35)pg/ml升高但明显低于正常妊娠组(P<0.01).与对照组外周血中IL-2水平(0.41±0.05)pg/ml相比:正常妊娠组IL-2水平升高至(0.82±0.11)pg/ml(P<0.01);妊娠高血压组IL-2水平高达1.57±0.22(pg/ml)明显高于其它两组(P<0.01).妊娠高血压组外周血中IL-10水平明显低于正常妊娠组IL-10水平(P<0.01);妊娠高血压组外周血中IL-2/IL-10比值明显高于于对照组及正常妊娠组的比值.结论:妊娠高血压患者外周血中细胞因子IL-2和IL-10分泌异常且诱导Th2细胞产生的IL-4降低,打破Th1/Th2平衡,致使Th1型免疫反应增强,使早孕期滋养细胞受到免疫损伤以致侵入能力下降,导致妊娠期高血压疾病的发生.%Objective: To detect the levels of IL-4 and IL-2 and IL-10 in the patients with pregnancy-induced hypertension, and discuss the detection of IL-2/IL-10. Methods: Taking 40 cases of non-pregnant women as control group, 30 normal pregnant women as pregnancy group, 28 cases of pregnancy induced hypertension as pregnancy-induced hypertension group patients, we used ELISA to detect the levels of IL-4, IL-2 and IL-10 in their serum. Results: The levels of IL-4 in peripheral blood of pregnancy group was (0.91± 0.03) pg / ml, significantly higher than the level of IL-4 (0.53 ± 0.04) pg / ml in control group (P<0.05). The levels of IL-4 in peripheral blood of pregnancy-induced hypertension group was (0.67± 0.35) pg / ml, significantly lower than the IL-4 level in normal pregnancy group (P

  5. Generation of conditional knockout alleles for PRL-3.

    Science.gov (United States)

    Yan, Hong; Kong, Dong; Ge, Xiaomei; Gao, Xiang; Han, Xiao

    2011-11-01

    Phosphatase of regenerating liver-3 (PRL-3) is a member of the protein tyrosine phosphatase (PTP) superfamily and is highly expressed in cancer metastases. For better understanding of the role of PRL-3 in tumor metastasis, we applied a rapid and efficient method for generating PRL-3 floxed mice and investigated its phenotypes. A BAC retrieval strategy was applied to construct the PRL-3 conditional gene-targeting vector. Exon 4 was selected for deletion to generate a nonfunctional prematurely terminated short peptide as it will cause a frame-shift mutation. Conditional knockout PRL-3 mice were generated by using the Cre-loxP system and were validated by Southern blot and RT-PCR analysis. Further analysis revealed the phenotype characteristics of PRL-3 knockout mice and wildtype mice. In this study, we successfully constructed the PRL-3 conditional knockout mice, which will be helpful to clarify the roles of PRL-3 and the mechanisms in tumor metastasis.

  6. One-neutron knockout from Ne24-28 isotopes

    CERN Document Server

    Rodriguez-Tajes, C; Caamano, M; Faestermann, T; Cortina-Gil, D; Zhukov, M; Simon, H; Nilsson, T; Borge, M J G; Alvarez-Pol, H; Winkler, M; Prochazka, A; Nociforo, C; Weick, H; Kanungo, R; Perez-Loureiro, D; Kurtukian, T; Suemmerer, K; Eppinger, K; Perea, A; Chatillon, A; Maierbeck, P; Benlliure, J; Pascual-Izarra, C; Gernhaeuser, R; Geissel, H; Aumann, T; Kruecken, R; Larsson, K; Tengblad, O; Benjamim, E; Jonson, B; Casarejos, E

    2010-01-01

    One-neutron knockout reactions of Ne24-28 in a beryllium target have been studied in the Fragment Separator (FRS), at GSI. The results include inclusive one-neutron knockout cross-sections as well as longitudinal-momentum distributions of the knockout fragments. The ground-state structure of the neutron-rich neon isotopes was obtained from an analysis of the measured momentum distributions. The results indicate that the two heaviest isotopes, Ne-27 and Ne-28, are dominated by a configuration in which a s(1/2) neutron is coupled to an excited state of the Ne-26 and Ne-27 core, respectively. (C) 2010 Elsevier B.V. All rights reserved.

  7. Using engineered endonucleases to create knockout and knockin zebrafish models.

    Science.gov (United States)

    Bedell, Victoria M; Ekker, Stephen C

    2015-01-01

    Over the last few years, the technology to create targeted knockout and knockin zebrafish animals has exploded. We have gained the ability to create targeted knockouts through the use of zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats/CRISPR associated system (CRISPR/Cas). Furthermore, using the high-efficiency TALEN system, we were able to create knockin zebrafish using a single-stranded DNA (ssDNA) protocol described here. Through the use of these technologies, the zebrafish has become a valuable vertebrate model and an excellent bridge between the invertebrate and mammalian model systems for the study of human disease.

  8. Potent suppression of Kv1.3 potassium channel and IL-2 secretion by diphenyl phosphine oxide-1 in human T cells.

    Directory of Open Access Journals (Sweden)

    Ning Zhao

    Full Text Available Diphenyl phosphine oxide-1 (DPO-1 is a potent Kv1.5 channel inhibitor that has therapeutic potential for the treatment of atrial fibrillation. Many other Kv1.5 channel blockers also potently inhibit the Kv1.3 channel, but whether DPO-1 blocks Kv1.3 channels has not been investigated. The Kv1.3 channel is highly expressed in activated T cells, which is considered a favorable target for immunomodulation. Accordingly, we hypothesized that DPO-1 may exert immunosuppressive and anti-inflammatory effects by inhibiting Kv1.3 channel activity. In this study, DPO-1 blocked Kv1.3 current in a voltage-dependent and concentration-dependent manner, with IC₅₀ values of 2.58 µM in Jurkat cells and 3.11 µM in human peripheral blood T cells. DPO-1 also accelerated the inactivation rate and negatively shifted steady-state inactivation. Moreover, DPO-1 at 3 µM had no apparent effect on the Ca²⁺ activated potassium channel (K(Ca current in both Jurkat cells and human peripheral blood T cells. In Jurkat cells, pre-treatment with DPO-1 for 24 h decreased Kv1.3 current density, and protein expression by 48±6% and 60±9%, at 3 and 10 µM, respectively (both p<0.05. In addition, Ca²⁺ influx to Ca²⁺-depleted cells was blunted and IL-2 production was also reduced in activated Jurkat cells. IL-2 secretion was also inhibited by the Kv1.3 inhibitors margatoxin and charybdotoxin. Our results demonstrate for the first time that that DPO-1, at clinically relevant concentrations, blocks Kv1.3 channels, decreases Kv1.3 channel expression and suppresses IL-2 secretion. Therefore, DPO-1 may be a useful treatment strategy for immunologic disorders.

  9. Effect of a four-week exercise program on the secretion of IFN-γ, TNF-α, IL-2 and IL-6 cytokines in elite Taekwondo athletes.

    Science.gov (United States)

    Kaya, Oktay

    2016-09-01

    The aim of the present study was to examine how a 4-week exercise program affects the serum levels of certain cytokines in Taekwondo athletes. The study involved 10 elite male Taekwondo athletes (mean age, 20.67±0.24 years; mean weight, 65.45±1.69 kg) who were studying at the Physical Education and Sports High School of Selçuk University (Konya, Turkey) in June 2014. The subjects were involved in a Taekwondo exercise program on every weekday for 4 weeks. The subjects were also engaged in an exercise to exhaustion session twice; once before starting the 4-week exercise program and once upon completion of the program. Blood samples were collected from the subjects in four rounds: During rest, upon fatigue, and before and after the 4-week exercise program. These samples were analyzed to establish the serum levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin (IL)-2 and IL-6 using enzyme-linked immunosorbent assay test kits. Pre- and post-exercise program, the IFN-γ and TNF-α levels did not show any significant difference. When compared with the pre-exercise levels, serum IL-2 levels of the subjects were found to be elevated after the 4-week exercise program. The highest serum IL-6 values were established after the subjects were exercised to fatigue before the exercise program was initiated (P<0.05). The 4-week exercise program resulted in a decrease in IL-6 levels (P<0.05). The findings of the study indicate that a 4-week exercise program did not result in significant changes in IFN-γ and TNF-α levels, but led to an increase in IL-2 levels. The notable finding of the present study is that a 4-week exercise program reduces cellular immune functions and, thus, the levels of IL-6, which negatively influences performance.

  10. Improving Bacillus Calmette-Guérin (BCG) immunotherapy for bladder cancer by adding interleukin 2 (IL-2): a mathematical model.

    Science.gov (United States)

    Bunimovich-Mendrazitsky, Svetlana; Halachmi, Sarel; Kronik, Natalie

    2016-06-01

    One of the treatments offered to non-invasive bladder cancer patients is BCG instillations, using a well-established, time-honoured protocol. Some of the patients, however, do not respond to this protocol. To examine possible changes in the protocol, we provide a platform for in silico testing of alternative protocols for BCG instillations and combinations with IL-2, to be used by urologists in planning new treatment strategies for subpopulations of bladder cancer patients who may benefit from a personalized protocol. We use a systems biology approach to describe the BCG-tumour-immune interplay and translate it into a set of mathematical differential equations. The variables of the equation set are the number of tumour cells, bacteria cells, immune cells, and cytokines participating in the tumour-immune response. Relevant parameters that describe the system's dynamics are taken from a variety of independent literature, unrelated to the clinical trial results assessed by the model predictions. Model simulations use a clinically relevant range of initial tumour sizes (tumour volume) and tumour growth rates (tumour grade), representative of a virtual population of fifty patients. Our model successfully retrieved previous clinical results for BCG induction treatment and BCG maintenance therapy with a complete response (CR) rate of 82%. Furthermore, we designed alternative maintenance protocols, using IL-2 combinations with BCG, which improved success rates up to 86% and 100% of the patients, albeit without considering possible side effects. We have shown our simulation platform to be reliable by demonstrating its ability to retrieve published clinical trial results. We used this platform to predict the outcome of treatment combinations. Our results suggest that the subpopulation of non-responsive patients may benefit from an intensified combined BCG IL-2 maintenance treatment.

  11. TIM-3 Suppresses Anti-CD3/CD28-Induced TCR Activation and IL-2 Expression through the NFAT Signaling Pathway.

    Directory of Open Access Journals (Sweden)

    Brian Tomkowicz

    Full Text Available TIM-3 (T cell immunoglobulin and mucin-domain containing protein 3 is a member of the TIM family of proteins that is preferentially expressed on Th1 polarized CD4+ and CD8+ T cells. Recent studies indicate that TIM-3 serves as a negative regulator of T cell function (i.e. T cell dependent immune responses, proliferation, tolerance, and exhaustion. Despite having no recognizable inhibitory signaling motifs, the intracellular tail of TIM-3 is apparently indispensable for function. Specifically, the conserved residues Y265/Y272 and surrounding amino acids appear to be critical for function. Mechanistically, several studies suggest that TIM-3 can associate with interleukin inducible T cell kinase (ITK, the Src kinases Fyn and Lck, and the p85 phosphatidylinositol 3-kinase (PI3K adaptor protein to positively or negatively regulate IL-2 production via NF-κB/NFAT signaling pathways. To begin to address this discrepancy, we examined the effect of TIM-3 in two model systems. First, we generated several Jurkat T cell lines stably expressing human TIM-3 or murine CD28-ECD/human TIM-3 intracellular tail chimeras and examined the effects that TIM-3 exerts on T cell Receptor (TCR-mediated activation, cytokine secretion, promoter activity, and protein kinase association. In this model, our results demonstrate that TIM-3 inhibits several TCR-mediated phenotypes: i NF-kB/NFAT activation, ii CD69 expression, and iii suppression of IL-2 secretion. To confirm our Jurkat cell observations we developed a primary human CD8+ cell system that expresses endogenous levels of TIM-3. Upon TCR ligation, we observed the loss of NFAT reporter activity and IL-2 secretion, and identified the association of Src kinase Lck, and PLC-γ with TIM-3. Taken together, our results support the conclusion that TIM-3 is a negative regulator of TCR-function by attenuating activation signals mediated by CD3/CD28 co-stimulation.

  12. The stoichiometric production of IL-2 and IFN-γ mRNA defines memory T cells that can self-renew after adoptive transfer in humans.

    Science.gov (United States)

    Wang, Anran; Chandran, Smita; Shah, Syed A; Chiu, Yu; Paria, Biman C; Aghamolla, Tamara; Alvarez-Downing, Melissa M; Lee, Chyi-Chia Richard; Singh, Sanmeet; Li, Thomas; Dudley, Mark E; Restifo, Nicholas P; Rosenberg, Steven A; Kammula, Udai S

    2012-08-29

    Adoptive immunotherapy using ex vivo-expanded tumor-reactive lymphocytes can mediate durable cancer regression in selected melanoma patients. Analyses of these trials have associated the in vivo engraftment ability of the transferred cells with their antitumor efficacy. Thus, there is intensive clinical interest in the prospective isolation of tumor-specific T cells that can reliably persist after transfer. Animal studies have suggested that central memory CD8(+) T cells (T(CM)) have divergent capabilities including effector differentiation to target antigen and stem cell-like self-renewal that enable long-term survival after adoptive transfer. We sought to isolate human melanoma-specific T(CM) to define their in vivo fate and function after autologous therapeutic transfer to metastatic patients. To facilitate the high-throughput identification of these rare cells from patients, we report that T(CM) have a defined stoichiometric production of interleukin-2 (IL-2) and interferon-γ (IFN-γ) mRNA after antigen stimulation. Melanoma-specific T cells screened for high relative IL-2 production had a T(CM) phenotype and superior in vitro proliferative capacity compared to cells with low IL-2 production. To investigate in vivo effector function and self-renewal capability, we allowed melanoma-specific T(CM) to undergo in vitro expansion and differentiation into lytic effector clones and then adoptively transferred them back into their hosts. These clones targeted skin melanocytes in all five patients and persisted long term and reacquired parental T(CM) attributes in four patients after transfer. These findings demonstrate the favorable engraftment fitness for human T(CM)-derived clones, but further efforts to improve their antitumor efficacy are still necessary.

  13. Xenogeneic graft-versus-host-disease in NOD-scid IL-2Rγnull mice display a T-effector memory phenotype.

    Directory of Open Access Journals (Sweden)

    Niwa Ali

    Full Text Available The occurrence of Graft-versus-Host Disease (GvHD is a prevalent and potentially lethal complication that develops following hematopoietic stem cell transplantation. Humanized mouse models of xenogeneic-GvHD based upon immunodeficient strains injected with human peripheral blood mononuclear cells (PBMC; "Hu-PBMC mice" are important tools to study human immune function in vivo. The recent introduction of targeted deletions at the interleukin-2 common gamma chain (IL-2Rγ(null, notably the NOD-scid IL-2Rγ(null (NSG and BALB/c-Rag2(null IL-2Rγ(null (BRG mice, has led to improved human cell engraftment. Despite their widespread use, a comprehensive characterisation of engraftment and GvHD development in the Hu-PBMC NSG and BRG models has never been performed in parallel. We compared engrafted human lymphocyte populations in the peripheral blood, spleens, lymph nodes and bone marrow of these mice. Kinetics of engraftment differed between the two strains, in particular a significantly faster expansion of the human CD45(+ compartment and higher engraftment levels of CD3(+ T-cells were observed in NSG mice, which may explain the faster rate of GvHD development in this model. The pathogenesis of human GvHD involves anti-host effector cell reactivity and cutaneous tissue infiltration. Despite this, the presence of T-cell subsets and tissue homing markers has only recently been characterised in the peripheral blood of patients and has never been properly defined in Hu-PBMC models of GvHD. Engrafted human cells in NSG mice shows a prevalence of tissue homing cells with a T-effector memory (T(EM phenotype and high levels of cutaneous lymphocyte antigen (CLA expression. Characterization of Hu-PBMC mice provides a strong preclinical platform for the application of novel immunotherapies targeting T(EM-cell driven GvHD.

  14. Killer immunoglobulin-like receptor (KIR) and KIR-ligand genotype do not correlate with clinical outcome of renal cell carcinoma patients receiving high-dose IL2.

    Science.gov (United States)

    Wang, Wei; Erbe, Amy K; Gallenberger, Mikayla; Kim, KyungMann; Carmichael, Lakeesha; Hess, Dustin; Mendonca, Eneida A; Song, Yiqiang; Hank, Jacquelyn A; Cheng, Su-Chun; Signoretti, Sabina; Atkins, Michael; Carlson, Alexander; Weiss, Jonathan M; Mier, James; Panka, David; McDermott, David F; Sondel, Paul M

    2016-12-01

    NK cells play a role in many cancer immunotherapies. NK cell activity is tightly regulated by killer immunoglobulin-like receptor (KIR) and KIR-ligand interactions. Inhibitory KIR-ligands have been identified as HLA molecules, while activating KIR-ligands are largely unknown. Individuals that have not inherited the corresponding KIR-ligand for at least one inhibitory KIR gene are termed the "KIR-ligand missing" genotype, and they are thought to have a subset of NK cells that express inhibitory KIRs for which the corresponding KIR-ligand is missing on autologous tissue, and thus will not be inhibited through KIR-ligand recognition. In some settings where an anticancer immunotherapeutic effect is likely mediated by NK cells, individuals with a KIR-ligand missing genotype have shown improved clinical outcome compared to individuals with an "all KIR-ligands present" genotype. In addition, patients receiving hematopoietic stem cell transplants for leukemia may do better if their donor has more activating KIR genes (i.e., KIR haplotype-B). In a recent multi-institution clinical trial of patients with metastatic renal cell carcinoma receiving high-dose IL2 (HD-IL2), 25 % of patients showed a complete or partial tumor response to this therapy. We genotyped KIR and KIR-ligand genes for these patients (n = 107) and tested whether KIR/KIR-ligand genotypes correlated with patient clinical outcomes. In these analyses, we did not find any significant association of KIR/KIR-ligand genotype (either KIR-ligand missing or the presence of KIR haplotype-B) with patient outcome in response to the HD-IL2 therapy.

  15. Efficacy of fulguration combined with imiquimod cream on condyloma acuminatum, and the effect on immune functions and serums levels of IL-2 and IL-10.

    Science.gov (United States)

    Chen, Quan; Yang, Ridong; Gao, Aili; Zhong, Daoqing; Zhu, Huilan

    2017-07-01

    The objective of the present study was to investigate the clinical efficacy of high-frequency fulguration combined with 5% imiquimod cream for condyloma acuminatum (CA), and the effect on T cell immune function and serum levels of interleukin (IL)-2 and IL-10. We enrolled 112 patients with CA between January 2014 and January 2016. Patients were randomly divided into the control group (n=56) and observation group (n=56). The control group received high-frequency fulguration combined with intramuscular injection of Bacillus Calmette-Guérin polysaccharide nucleic acid, and the observation group received high-frequency fulguration combined with external application of 5% imiquimod cream. In both groups, the course of treatment lasted for 12 weeks, and the follow-up period was 6 months. Clinical efficacy was compared between the groups. The total effective rate in the observation group was higher than that in the control group (peffectiveness and recurrence rate between the two groups (p>0.05). After treatment, the levels of CD3(+) and CD4(+) cells, and CD4(+)/CD8(+) ratio in both groups were increased compared with those before treatment (p0.05); in both groups before and after treatment, there was no significant difference in the comparison of T cells (p>0.05). After treatment in both groups, the serum levels of IL-2 were increased, and the levels of IL-10 were decreased compared with those before treatment; the improvement in the observation group was superior to that in the control group (pcream for CA, which is correlated with enhanced immune functions of T cells, and improvements in the serum levels of IL-2 and IL-10.

  16. El factor de transferencia como inductor de la expresión de RNAm de IFN-γ e IL-2 en pollos vacunados contra influenza aviar

    Directory of Open Access Journals (Sweden)

    A Bravo-Blas

    2010-01-01

    Full Text Available La influenza aviar es una enfermedad de gran importancia económica para la industria avícola. En México sólo se ha reportado la cepa H5N2 de baja patogenicidad y ésta se controla mediante la vacunación con virus inactivado. Esta vacuna en emulsión reduce la presencia de signos, pero no la eliminación viral. Desde hace más de 50 años se ha informado acerca de la eficacia del Factor de Transferencia (FT como inmunomodulador en casos clínicos humanos y en menor cantidad en modelos animales. El objetivo de este trabajo fue el de establecer la dosis que produce un mayor porcentaje de expresión del RNAm de dos citocinas: IL-2 y de IFN-γ. Se diseñó un experimento para evidenciar la expresión del RNAm de estas dos citocinas en pollos previamente inoculados con FT específico para influenza aviar. En la primera fase se aplicaron 0,1, 1, y 10 unidades de FT a diferentes grupos de pollos, posteriormente se realizó la PCR a partir de tejido esplénico. En la segunda fase se aplicó el FT junto con la vacuna a tres nuevos grupos de pollos. Del experimento 1 solamente IL-2 tuvo un porcentaje mayor de positivos (58,33% con 1 unidad (P < 0,05. En cambio, en el experimento 2, con 1 unidad se obtuvo 75% de positivos para IL-2 (P < 0,05 y 100% para IFN-γ (P < 0,01. De estos resultados su puede concluir que al aplicar una unidad de FT (equivalente a 7,3 μg de proteína al inicio del experimento y 10 días después otra unidad de FT junto con la vacuna inactivada de IA se indujo la expresión del RNAm de IFN-γ e IL-2.

  17. Cyclosporin A suppresses the expression of the interleukin 2 gene by inhibiting the binding of lymphocyte-specific factors to the IL-2 enhancer.

    OpenAIRE

    Randak, C; Brabletz, T; Hergenröther, M; Sobotta, I; Serfling, E

    1990-01-01

    Cyclosporin A (CsA), a powerful immunosuppressive drug, inhibits the synthesis of lymphokines in T lymphocytes at the level of gene transcription. Using protein extracts from El4 lymphoma cells we show that the binding of lymphocyte-specific factors interacting with the two so-called purine boxes (Pu-boxes) of the interleukin 2 (IL-2) enhancer are missing in CsA-treated cells. The CsA-sensitive factors are newly synthesized upon induction. The most prominent factor consists of 45 kd polypepti...

  18. Surprisal-based comparison between a symbolic and a connectionist model of sentence processing

    NARCIS (Netherlands)

    Frank, S.L.; Taatgen, N.; van Rijn, H.

    2009-01-01

    The 'unlexicalized surprisal' of a word in sentence context is defined as the negative logarithm of the probability of the word's part-of-speech given the sequence of previous parts-of-speech of the sentence. Unlexicalized surprisal is known to correlate with word reading time. Here, it is shown

  19. The role of surprising events in a math game on proportional reasoning

    NARCIS (Netherlands)

    Wouters, P.; Oostendorp, van H.; Vrugte, ter J.; Jong, de T.; Vandercruysse, S.; Elen, J.

    2015-01-01

    This study examines whether surprising events can be used to stimulate students’ playful learning in a GBL environment in the domain of proportional reasoning. The assumed effect of surprise is that unexpected events interrupt an expectation and therefore triggers the player to evaluate the new situ

  20. Distinct medial temporal networks encode surprise during motivation by reward versus punishment.

    Science.gov (United States)

    Murty, Vishnu P; LaBar, Kevin S; Adcock, R Alison

    2016-10-01

    Adaptive motivated behavior requires predictive internal representations of the environment, and surprising events are indications for encoding new representations of the environment. The medial temporal lobe memory system, including the hippocampus and surrounding cortex, encodes surprising events and is influenced by motivational state. Because behavior reflects the goals of an individual, we investigated whether motivational valence (i.e., pursuing rewards versus avoiding punishments) also impacts neural and mnemonic encoding of surprising events. During functional magnetic resonance imaging (fMRI), participants encountered perceptually unexpected events either during the pursuit of rewards or avoidance of punishments. Despite similar levels of motivation across groups, reward and punishment facilitated the processing of surprising events in different medial temporal lobe regions. Whereas during reward motivation, perceptual surprises enhanced activation in the hippocampus, during punishment motivation surprises instead enhanced activation in parahippocampal cortex. Further, we found that reward motivation facilitated hippocampal coupling with ventromedial PFC, whereas punishment motivation facilitated parahippocampal cortical coupling with orbitofrontal cortex. Behaviorally, post-scan testing revealed that reward, but not punishment, motivation resulted in greater memory selectivity for surprising events encountered during goal pursuit. Together these findings demonstrate that neuromodulatory systems engaged by anticipation of reward and punishment target separate components of the medial temporal lobe, modulating medial temporal lobe sensitivity and connectivity. Thus, reward and punishment motivation yield distinct neural contexts for learning, with distinct consequences for how surprises are incorporated into predictive mnemonic models of the environment.

  1. 癌基因p21ras、raf和细胞外信号调节蛋白激酶参与刺激Jurkat细胞产生TNF-β和IL-2%Stimulation of TNF-β and IL-2 production by PMA/PHA requires p21ras, raf and ERK

    Institute of Scientific and Technical Information of China (English)

    黄铁生; 黄韵竹

    2001-01-01

    Objective To investigate whether the p21ras/ERK (MAPK) cascade is involved in regulating the production of TNF-β and IL-2 in Jurkat cells. Methods Cells were transiently transfected with a dominant negation construct of p21ras (ras15A or ras17N), raf (raf 1-130) or ERK1 (erk1K71R), or transforming p21ras (H-ras61L) or constitutively active raf (raf22W) using lipofectamine. Control cells received a plasmid carrying β-galactosidease. Transfectant cells were stimulated with PMA/PHA and released TNF-β and IL-2 quantitated by ELISA. Results In control cells, the production of TNF-β and IL-2 was approx. 2 fold by PMA/PHA stimulation (P<0.001), while transfection with a dominant negative mutant construct abrogated the effects of PMA/PHA. Transfection with a constitutively active mutant had no effect on basal production of TNF-β or IL-2, but all of the constitutively active mutants significantly enhanced the response of the cells to PMA/PHA (P<0.05). MEK1 inhibitor PD98059 inhibited the effects of PMA/PHA and active construct genes on ERK activities and cytokine production. Conclusion These data demonstrate that the p21ras-ERK cascade plays an important role in regulating the production of both TNF-β and IL-2 in Jurkat cells stimulated with PMA/PHA.%目的明确p21ras-细胞外信号调节蛋白激酶(the extracellular signal-regulated protein kinase, ERK)系列是否参与调节Jurkat细胞产生TNF-β和IL-2。方法用负向突变基因p21ras(ras17N或ras15A),raf-1(raf1~130)及ERK1(erk1K71R)或活性结构p21ras(H-ras61L)和raf(raf22W)转染细胞,以PMA/PHA刺激细胞,ELISA法检测细胞因子。结果 PMA/PHA刺激细胞产生较正常对照细胞约2倍的TNF-β和IL-2(P<0.001)。负向突变基因去除了PMA/PHA增加细胞因子分泌的作用。活性突变基因本身不影响TNF-β和IL-2产生,但明显增强细胞对PMA/PHA的应答(P<0.05)。结论 p21ras-ERK系列在调节Jurkat细胞在PMA/PHA刺激下产生TNF-β和IL-2中起重要的作用。

  2. 中药"凤香洗液"对伴HPV感染的CIN患者宫颈局部IL-2和IL-4的影响%Effects of traditional Chinese medicine"Fengxiang Lotion"on local cervical IL-2 and IL-4 in patients of cervical intraepithelial neoplasia with HPV infection

    Institute of Scientific and Technical Information of China (English)

    李小宁; 贺丰杰; 吉喆

    2015-01-01

    Objective To observe the effects of traditional Chinese medical compound"Fengxiang Lotion"on the local vaginal immune state for patients of cervical intraepithelial neoplasia (CIN) with human papillomavirus (HPV) infection.Methods Sixty patients with high risk HPV infection diagnosed with cervical biopsy using colpos-copy in the Affiliated Hospital of Shaanxi University of Chinese Medicine and Xi'an XD Group Hospital from July 2013 to February 2015 were selected in the study,which were divided into CINⅠand CINⅡgroup (n=30 each).Thirty healthy women coming for medical examination during the same period served as the control group.CINⅠgroup received Fengxiang Lotion for treatment,while the other two groups not.The levels of interleukin (IL)-2 and IL-4 in cervical-vaginal lavage solution,which were synthesized by type 1 and type 2 helper T cells respective-ly,were tested by ELISA.Results (1) IL-2 levels of CINⅠgroup and CINⅡgroup were significantly lower than that of the control group (P<0.01),while IL-4 levels of CINⅠgroup and CINⅡ group were significantly higher (P<0.05).The ratios of IL-2 to IL-4 in CINⅠgroup and CINⅡgroup were significantly lower than that of the con-trol group (P<0.05).What's more,all these changes was more significant in CINⅡgroup than CINⅠgroup (P<0.05).(2) In CINⅠgroup,the IL-2 level increased significantly after medication (P<0.05),while IL-4 decreased significantly (P<0.05),with the ratio of IL-2 to IL-4 increased significantly (P<0.01).Conclusion The IL-2 lev-els and IL-2/IL-4 ratio in CIN patients with HPV decreased,while IL-4 increased.These changes were consistent with the severity of CIN."Fengxiang Lotion"may block the progression of CIN through regulating the balance of Th1 and Th2.%目的 观察中药"凤香洗液"对伴有HPV感染的CINⅠ、CINⅡ患者阴道局部免疫状态的影响及治疗效果.方法 选取2013年7月至2015年2月于陕西中医学院附属医院、西安西电集团医院门诊就

  3. Dynamics of IL-2 and IL-7 levels during Highly active antiretroviral therapy and their significance%中国HIV感染者IL-2和IL-7参与高效抗反转录病毒治疗的抗病毒免疫反应及其在病毒控制中的作用

    Institute of Scientific and Technical Information of China (English)

    Diallo MA; 陈霞; 郑煜煌; 何艳; 贺波; 周华英; 谌资; 罗艳; 曾飔

    2012-01-01

    Objective The objective of this study was to investigate the course of certain common gamma cytokines ( IL-2 and IL-7 ) and their role on the control of the viral infection in a short term antiviral therapy.Methods A total of 35 adults with chronic HIV infection,responding to combined antiretroviral therapy (cART) guideline criteria were enrolled in this one year follow-up study.After signing an informed consent,20 ml blood were collected from each patient at base line,week 0,week 24 and week 48.1 ml serum collected from each patient was kept at -80 * C until use.Serum concentration of IL-2 and IL-7 was determined using ELISA kit from "ebioscience Beijing".CD4 and CD8 cells were counted and quantified using flux cytometry,and serum HIV RNA was quantified using real time PCR.Results All patients had a mean baseline IL-2 level [ (9.67 ± 2.6 ) pg/ml ]lower than the controls [ ( 27.36 ± 5.05 ) pg/ml ].After treatment for 48 weeks,IL-2 increased[ ( 19.8 ± 3.3 ) pg/ml ].However,the mean baseline 1L-7 [ ( 81.74± 20.47 ) pg/ml ]in patients was higher than controls [ ( 2.06 ± 1.52 ) pg/ml ].After treatment for 48 weeks,IL-7 decreased [ (8.36 ± 2.16)pg/ml ].IL-2 showed a significant increase and positive correlation with CD4 cells after HAART initiation (0week:R =0.21,P =0.063,24week:R =0.24,P =0.033,48week:R =0.19,P =0.103; IL-7 showed a significant decrease after HAART initiation but it did not show correlation with CD4 cells.We noted there was a negative correlation between IL-2 and CD4 count in HAART baseline (R =0.28,P =0.012 ),but no correlation between IL-7 and CD4 count from 6 month after HAART.IL-2 showed negative correlation with HIV RNA ( R =- 0.17,P =0.032),but IL-7 showed a relationship with the HIV RNA Conclusions The increase of IL-2 coupled with the decrease of IL-7 revealed a partial restoration of immune response during HAART.However,the absence of relationship with HIV RNA suggested that these cytokines might not be directly involved in the reduction

  4. IL2RG基因新突变致X-连锁重症联合免疫缺陷病二例及产前诊断研究%Mutation analyses and prenatal diagnosis in two families of X linked severe combined immunodeficiency caused by IL2RG gene novel mutation

    Institute of Scientific and Technical Information of China (English)

    孔祥东; 刘宁; 徐学聚; 吴庆华; 赵振华; 白巧玲; 孟静静

    2014-01-01

    目的 对2个X-连锁重症联合免疫缺陷病(X-SCID)家系进行致病基因突变分析及产前诊断.方法 收集2012年1月至2013年2月郑州大学第一附属医院就诊的2个X-SCID家系中患者及其家庭成员的外周血,提取基因组DNA,应用PCR扩增和直接测序方法对2个X-SCID家系成员进行白细胞介素2受体基因IL2RG基因测序,分析IL2RG基因外显子区和剪切区DNA序列改变情况,同时选择100名健康对照个体进行IL2RG基因序列分析.在确定每个家系基因型后,对家系1中的高危胎儿抽取绒毛进行产前诊断.对家系1中可疑女性进行携带者检测.结果 2个X-SCID家系分别发现1种IL2RG基因新突变.家系1中,患者及其母亲携带IL2RG基因c.361-363delGAG(p.E121del)突变;家系2中,先证者母亲携带IL2RG基因c.510-511insGAACT(p.W173X)杂合突变.c.361-363delGAG(p.E121del)和c.510-511 insGAACT(p.W173X)突变均为新发现的突变,100名健康个体X-SCID基因相应区域测序,未发现有上述同样序列改变.对明确致病突变的家系1中胎儿行孕早期产前诊断,胎儿为女性,未携带致病突变,家系1夫妇选择继续妊娠,胎儿娩出后随访结果与产前诊断结果一致.对家系1中可疑女性Ⅱ-3行携带者检测,证实为非携带者.结论 发现2个IL2RG基因新变异,IL2RG基因p.E121del和p.W173X突变是家系1和家系2患者的致病原因;有X-SCID生育史的夫妇再次生育时,应用基因测序技术行产前IL2RG基因突变分析可以有效地预防患儿出生,并且可进行可疑女性的携带者检测.%Objective To evaluate the diagnostic feasibility of mutation analysis and prenatal genetic diagnosis genetic analysis of IL2RG gene in two families with a birth history of X-linked severe combined immunodeficiency (X-SCID).Methods Blood samples of a male infant patient of X-SCID and his mother in family 1 and the parents of another deceased child with X-SCID in family 2 from January 2012 to February

  5. Generation of knockout rats with X-linked severe combined immunodeficiency (X-SCID using zinc-finger nucleases.

    Directory of Open Access Journals (Sweden)

    Tomoji Mashimo

    Full Text Available BACKGROUND: Although the rat is extensively used as a laboratory model, the inability to utilize germ line-competent rat embryonic stem (ES cells has been a major drawback for studies that aim to elucidate gene functions. Recently, zinc-finger nucleases (ZFNs were successfully used to create genome-specific double-stranded breaks and thereby induce targeted gene mutations in a wide variety of organisms including plants, drosophila, zebrafish, etc. METHODOLOGY/PRINCIPAL FINDINGS: We report here on ZFN-induced gene targeting of the rat interleukin 2 receptor gamma (Il2rg locus, where orthologous human and mouse mutations cause X-linked severe combined immune deficiency (X-SCID. Co-injection of mRNAs encoding custom-designed ZFNs into the pronucleus of fertilized oocytes yielded genetically modified offspring at rates greater than 20%, which possessed a wide variety of deletion/insertion mutations. ZFN-modified founders faithfully transmitted their genetic changes to the next generation along with the severe combined immune deficiency phenotype. CONCLUSIONS AND SIGNIFICANCE: The efficient and rapid generation of gene knockout rats shows that using ZFN technology is a new strategy for creating gene-targeted rat models of human diseases. In addition, the X-SCID rats that were established in this study will be valuable in vivo tools for evaluating drug treatment or gene therapy as well as model systems for examining the treatment of xenotransplanted malignancies.

  6. Generation of Knockout Rats with X-Linked Severe Combined Immunodeficiency (X-SCID) Using Zinc-Finger Nucleases

    Science.gov (United States)

    Mashimo, Tomoji; Takizawa, Akiko; Voigt, Birger; Yoshimi, Kazuto; Hiai, Hiroshi; Kuramoto, Takashi; Serikawa, Tadao

    2010-01-01

    Background Although the rat is extensively used as a laboratory model, the inability to utilize germ line-competent rat embryonic stem (ES) cells has been a major drawback for studies that aim to elucidate gene functions. Recently, zinc-finger nucleases (ZFNs) were successfully used to create genome-specific double-stranded breaks and thereby induce targeted gene mutations in a wide variety of organisms including plants, drosophila, zebrafish, etc. Methodology/Principal Findings We report here on ZFN-induced gene targeting of the rat interleukin 2 receptor gamma (Il2rg) locus, where orthologous human and mouse mutations cause X-linked severe combined immune deficiency (X-SCID). Co-injection of mRNAs encoding custom-designed ZFNs into the pronucleus of fertilized oocytes yielded genetically modified offspring at rates greater than 20%, which possessed a wide variety of deletion/insertion mutations. ZFN-modified founders faithfully transmitted their genetic changes to the next generation along with the severe combined immune deficiency phenotype. Conclusions and Significance The efficient and rapid generation of gene knockout rats shows that using ZFN technology is a new strategy for creating gene-targeted rat models of human diseases. In addition, the X-SCID rats that were established in this study will be valuable in vivo tools for evaluating drug treatment or gene therapy as well as model systems for examining the treatment of xenotransplanted malignancies. PMID:20111598

  7. Effect of Drug Sera from per os Da Cheng Qi(大承气) Granule on Production/Secretion of IL-2 by Intestinal Intraepithelial Lymphocytes of Mice%大承气颗粒药物血清对小鼠肠上皮内淋巴细胞产生/分泌IL-2的作用

    Institute of Scientific and Technical Information of China (English)

    方步武; 吴咸中; 来丽娜; 陈菲; 刘俊红; 李继坤; 王民宪; 崔志清; 林秀珍

    2005-01-01

    目的:探讨大承气颗粒药物血清对小鼠肠上皮内淋巴细胞产生/分泌白细胞介素-2(interleukin-2,IL-2)的作用.方法:以不同浓度的大承气颗粒剂灌胃大鼠后不同时间点于无菌条件下采取腹腔静脉血,制备药物血清;分离培养肠上皮内淋巴细胞(intestinal intraepithelial lymphocytes,IELs),以药物血清作用于IELs,设培养液对照、IEL对照、正常血清对照,采用放射免疫分析法测定IL-2.结果:不同浓度大承气颗粒的药物血清在多数时间点的作用明显强于培养液对照、IEL对照及正常大鼠血清对照.正常大鼠血清对照组与IEL对照组的IL-2水平很接近.同时间点的药物血清比较,在30 min和12 h时,4%大承气颗粒的药物血清作用强;在3 h时,40%大承气颗粒的作用最强.4%、20%大承气颗粒的药物血清使小鼠分泌IL-2的作用在1.5 h达峰值,在24 h出现第二个峰值;40%大承气颗粒药物血清使IEL分泌IL-2的峰值在3 h.结论:不同浓度的大承气颗粒制备的药物血清具有使IEL产生/分泌IL-2的作用;该作用涉及到药物本身和药物在体内的活性代谢物和/或其诱导的内源性活性物质的作用.

  8. 构建能转染人骨髓间充质干细胞的Ad5 GM-CSF-IL-2腺病毒载体*★%Construction of an adenoviral vector encoding Ad5GM-CSF-IL-2 in human bone marrow mesenchymal stem cells

    Institute of Scientific and Technical Information of China (English)

    张玉萍; 张璇; 郭智; 谭晓华

    2013-01-01

      背景:如何将树突状细胞和 T 细胞活化因子运送至肿瘤局部是有待解决的难题之一。利用人骨髓间充质干细胞具有肿瘤趋向性和低免疫原性的特性,将树突状细胞和 T 细胞活化因子导入骨髓间充质干细胞后运送至肿瘤局部表达可能是解决上述难题的方案之一。目的:构建共表达粒细胞-巨噬细胞集落刺激因子和白细胞介素2的5型腺病毒载体(Ad5 GM-CSF-IL-2),感染人骨髓间充质干细胞,检测粒细胞-巨噬细胞集落刺激因子和白细胞介素2的表达水平和持续时间,为体内活化树突状细胞和 T 细胞提供实验依据。方法:提取人外周血单个核细胞总 RNA,以此为模板用 RT-PCR 方法扩增粒细胞-巨噬细胞集落刺激因子和白细胞介素2基因 cDNA,PCR 扩增片段分别插入 pcDNA3.1/Myc-His(-)B 真核表达载体中,再利用脑心肌炎病毒内部核酸进入位点(IRES)序列,构建腺病毒载体穿梭质粒 pDC515 GM-CSF-IRES-IL-2。采用 AdMaxTM FLP 重组腺病毒载体体系,将穿梭质粒 pDC515 GM-CSF-IRES-IL-2与 pBGHfrt△E1,3 FLP 骨架质粒共转染至293细胞,通过重组酶位点特异性重组获得 Ad5 GM-CSF-IL-2。Ad5 GM-CSF-IL-2感染人骨髓间充质干细胞后经γ射线照射使其失去增殖能力,分别用粒细胞-巨噬细胞集落刺激因子和白细胞介素2 ELISA 试剂盒在不同的时间点检测细胞上清中粒细胞-巨噬细胞集落刺激因子和白细胞介素2蛋白的水平。结果与结论:经测序证实,克隆获得的粒细胞-巨噬细胞集落刺激因子、白细胞介素2的 cDNA 序列分别与 GenBank NM_000758(435 bp)和 GenBank NM_000586(462 bp)提供的序列完全一致。用AdMaxTM FLP 重组腺病毒载体可高效、快捷地获得所要包装的腺病毒载体,通过 IRES 连接粒细胞-巨噬细胞集落刺激因子和白细胞介素2两个基因,均获得高效表达。Ad5 GM-CSF-IL-2感染人骨

  9. Threshold Energies for Single Carbon Knockout from Polycyclic Aromatic Hydrocarbons

    CERN Document Server

    Stockett, M H; Chen, T; de Ruette, N; Giacomozzi, L; Wolf, M; Schmidt, H T; Zettergren, H; Cederquist, H

    2015-01-01

    We have measured absolute cross sections for ultrafast (fs) single-carbon knockout from Polycyclic Aromatic Hydrocarbon (PAH) cations as functions of He-PAH center-of-mass collision energy in the range 10-200 eV. Classical Molecular Dynamics (MD) simulations cover this range and extend up to 10$^5$ eV. The shapes of the knockout cross sections are well described by a simple analytical expression yielding experimental and MD threshold energies of $E_{th}^{Exp}=32.5\\pm 0.4$ eV and $E_{th}^{MD}=41.0\\pm 0.3$ eV, respectively. These are the first measurements of knockout threshold energies for molecules isolated \\emph{in vacuo}. We further deduce semi-empirical (SE) and MD displacement energies --- \\emph{i.e.} the energy transfers to the PAH molecules at the threshold energies for knockout --- of $T_{disp}^{SE}=23.3\\pm 0.3$ eV and $T_{disp}^{MD}=27.0\\pm 0.3$ eV. The semi-empirical results compare favorably with measured displacement energies for graphene $T_{disp}=23.6$ eV [Meyer \\emph{et al.} Phys. Rev Lett. \\tex...

  10. The mammalian gene function resource: The International Knockout Mouse Consortium

    NARCIS (Netherlands)

    A. Bradley (Allan); K. Anastassiadis (Konstantinos); A. Ayadi (Abdelkader); J.F. Battey (James); C. Bell (Cindy); M.-C. Birling (Marie-Christine); J. Bottomley (Joanna); S.D.M. Brown (Steve); F. Bürger (Friederike); C.J. Bult (Carol); W. Bushell (Wendy); F.S. Collins (Francis); C. Desaintes (Christian); B. Doe (Brendan); E. Aris (Economides); J.T. Eppig (Janan); R.H. Finnell (Richard); C. Fletcher (Colin); M. Fray (Martin); D. Frendewey (David); R.H. Friedel (Roland); F.G. Grosveld (Frank); J. Hansen; Y. Hérault (Yann); G. Hicks (Geoffrey); A. Hörlein (Andreas); C. Houghton (Catherine); M. Hrabé De Angelis (Martin); D. Huylebroeck (Danny); V. Iyer (Vivek); P.J. de Jong (Pieter); J.A. Kadin (James); C. Kaloff (Cornelia); K. Kennedy (Karen); M. Koutsourakis (Manousos); K.C. Kent Lloyd (K.); S. Marschall (Susan); J. Mason (Jeremy); C. McKerlie (Colin); M.P. McLeod (Michael); H. von Melchner (Harald); M. Moore (Matt); A.O. Mujica (Alejandro); A. Nagy (Andras); M. Nefedov (Mikhail); L.M. Nutter (Lauryl); G. Pavlovic (Guillaume); J.L. Peterson (Jane); I. Pollock; R. Ramirez-Solis (Ramiro); D.E. Rancourt (Derrick); M. Raspa (Marcello); J.E. Remacle (Jacques); M. Ringwald (Martin); B. Rosen (Barry); N. Rosenthal (Nadia); J. Rossant (Janet); P. Ruiz Noppinger (Patricia); S. Ryder; J.Z. Schick (Joel Zupicich); F. Schnütgen (Frank); C.J. Schofield (Christopher); C. Seisenberger (Claudia); M. Selloum (Mohammed); E.M. Simpson (Elizabeth); W.C. Skarnes (William); D. Smedley (Damian); W.L. Stanford (William); A. Francis Stewart (A.); K. Stone (Kevin); K. Swan (Kate); H. Tadepally (Hamsa); J.L. Teboul (Jean Louis); G.P. Tocchini-Valentini (Glauco); D. Valenzuela (David); A.P. West (Anthony); K.-I. Yamamura (Ken-Ichi); Y. Yoshinaga (Yuko); M. Wurst (Martin)

    2012-01-01

    textabstractIn 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed highthroughput gene trapping and, i

  11. Recoil proton tagged knockout reaction for {sup 8}He

    Energy Technology Data Exchange (ETDEWEB)

    Cao, Z.X. [School of Physics and State Key Laboratory of Nuclear Physics and Technology, Peking University, Beijing 100871 (China); Ye, Y.L., E-mail: yeyl@pku.edu.cn [School of Physics and State Key Laboratory of Nuclear Physics and Technology, Peking University, Beijing 100871 (China); Xiao, J.; Lv, L.H.; Jiang, D.X.; Zheng, T.; Hua, H.; Li, Z.H.; Li, X.Q.; Ge, Y.C.; Lou, J.L.; Qiao, R.; Li, Q.T.; You, H.B.; Chen, R.J.; Pang, D.Y. [School of Physics and State Key Laboratory of Nuclear Physics and Technology, Peking University, Beijing 100871 (China); Sakurai, H.; Otsu, H.; Nishimura, M.; Sakaguchi, S. [RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198 (Japan); and others

    2012-01-16

    We report for the first time the discrimination of the core fragment knockout and valence nucleon knockout reaction mechanisms at medium energy range, by the use of the recoil proton tagging technique. Intense {sup 8}He beams at 82.3 MeV/u were supplied by the RIPS beam line at RIKEN, and impinged on both hydrogen and carbon targets. Recoil protons were detected in coincidence with the forward moving core fragments and neutrons. The core fragment knockout mechanism is identified through the polar angle correlation and checked by various kinematics relations. This mechanism may be used to extract the cluster structure information of unstable nuclei. On the other hand, with the selection of the tagged valence nucleon knockout mechanism, a narrower peak of {sup 7}He ground state is obtained. The extracted neutron spectroscopic factor S{sub n}=0.512(18) is relatively smaller than the no-tagged one, and is in good agreement with the prediction of ab initio Green's function Monte Carlo calculations.

  12. The mammalian gene function resource: The International Knockout Mouse Consortium

    NARCIS (Netherlands)

    A. Bradley (Allan); K. Anastassiadis (Konstantinos); A. Ayadi (Abdelkader); J.F. Battey (James); C. Bell (Cindy); M.-C. Birling (Marie-Christine); J. Bottomley (Joanna); S.D.M. Brown (Steve); F. Bürger (Friederike); C.J. Bult (Carol); W. Bushell (Wendy); F.S. Collins (Francis); C. Desaintes (Christian); B. Doe (Brendan); E. Aris (Economides); J.T. Eppig (Janan); R.H. Finnell (Richard); C. Fletcher (Colin); M. Fray (Martin); D. Frendewey (David); R.H. Friedel (Roland); F.G. Grosveld (Frank); J. Hansen; Y. Hérault (Yann); G. Hicks (Geoffrey); A. Hörlein (Andreas); C. Houghton (Catherine); M. Hrabé De Angelis (Martin); D. Huylebroeck (Danny); V. Iyer (Vivek); P.J. de Jong (Pieter); J.A. Kadin (James); C. Kaloff (Cornelia); K. Kennedy (Karen); M. Koutsourakis (Manousos); K.C. Kent Lloyd (K.); S. Marschall (Susan); J. Mason (Jeremy); C. McKerlie (Colin); M.P. McLeod (Michael); H. von Melchner (Harald); M. Moore (Matt); A.O. Mujica (Alejandro); A. Nagy (Andras); M. Nefedov (Mikhail); L.M. Nutter (Lauryl); G. Pavlovic (Guillaume); J.L. Peterson (Jane); I. Pollock; R. Ramirez-Solis (Ramiro); D.E. Rancourt (Derrick); M. Raspa (Marcello); J.E. Remacle (Jacques); M. Ringwald (Martin); B. Rosen (Barry); N. Rosenthal (Nadia); J. Rossant (Janet); P. Ruiz Noppinger (Patricia); S. Ryder; J.Z. Schick (Joel Zupicich); F. Schnütgen (Frank); C.J. Schofield (Christopher); C. Seisenberger (Claudia); M. Selloum (Mohammed); E.M. Simpson (Elizabeth); W.C. Skarnes (William); D. Smedley (Damian); W.L. Stanford (William); A. Francis Stewart (A.); K. Stone (Kevin); K. Swan (Kate); H. Tadepally (Hamsa); J.L. Teboul (Jean Louis); G.P. Tocchini-Valentini (Glauco); D. Valenzuela (David); A.P. West (Anthony); K.-I. Yamamura (Ken-Ichi); Y. Yoshinaga (Yuko); M. Wurst (Martin)

    2012-01-01

    textabstractIn 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed highthroughput gene trapping and,

  13. The Computational Complexity of the Parallel Knock-Out Problem

    NARCIS (Netherlands)

    Broersma, H.J.; Johnson, M.; Paulusma, D.; Stewart, I.A.; Correa, J.R.; Hevia, A.; Kiwi, M.

    2006-01-01

    We consider computational complexity questions related to parallel knock-out schemes for graphs. In such schemes, in each round, each remaining vertex of a given graph eliminates exactly one of its neighbours. We show that the problem of whether, for a given graph, such a scheme can be found that el

  14. Blood Serum Levels of IL-2, IL-6, IL-8, TNF-α and IL-1β in Patients on Maintenance Hemodialysis

    Institute of Scientific and Technical Information of China (English)

    Jacek Rysz; Maciej Banach; Aleksandra Cialkowska-Rysz; Robert Stolarek; Marcin Barylski; Jaroslaw Drozdz; Piotr Okonski

    2006-01-01

    Cytokines are essential mediators of immune response and inflammatory reactions. Patients with chronic renal failure (CRF) commonly present with abnormalities of immune function related with impaired kidney function and the accumulation of uremic toxins in addition to bioincompatibility of dialyzer membranes. During a hemodialysis (HD) session, cytokines are released mainly by monocytes activated by endotoxin-type compounds in dialyzer fluid,complement factors and direct contact with dialyzer membrane. The study included 15 CRF patients, aged 36.4 ± 2.9 years, on regular HD maintenance therapy for mean 68 ± 10 months and 15 healthy controls. It was designed to assess serum levels of a panel of inflammatory cytokines: IL-1β, IL-2, IL-6, IL-8 and TNF-α in CRF patients on regular maintenance HD before, 20, 60 and 240 minutes of a single HD session in parallel with C-reactive protein (CRP) as an additional parameter. CRP concentration was increased in HD patients when compared with healthy controls. The concentrations of IL-1, IL-6, IL-8 and TNF-α were increased, whereas the serum level of IL-2 was not altered during a single HD session.

  15. Activation-induced expression of thymic shared antigen-1 on T lymphocytes and its inhibitory role for TCR-mediated IL-2 production.

    Science.gov (United States)

    Kosugi, A; Saitoh, S; Narumiya, S; Miyake, K; Hamaoka, T

    1994-12-01

    We have produced a hamster mAb, PRST1, which reacts with thymic shared Ag-1 (TSA-1), a product of the Ly6 gene family. By cross-blocking experiments, we found that TSA-1 is identical to stem cell Ag-2 (Sca-2). Using PRST1, the changes of TSA-1/Sca-2 expression on mature T cells during the activation process were analyzed. Although freshly isolated T cells did not express detectable TSA-1 on their cell surface, in vitro stimulation of T cells with concanavalin A induced a marked increase of surface TSA-1 expression. The increased expression of TSA-1 on T cells was detected from 12 h after stimulation and was associated with the increase of TSA-1 mRNA. In vivo injection of mice with staphylococcal enterotoxin B (SEB) resulted in the enhanced TSA-1 expression in splenic V beta 8+ T cells. This antigen-specific induction of TSA-1 expression in vivo preceded a detectable increase in numbers of V beta 8- T cells after SEB injection. Functionally, whereas anti-TSA-1 mAb was not mitogenic to T cells, it inhibited anti-CD3-induced IL-2 production by T cell hybridomas. These results indicate that TSA-1/Sca-2 is a unique marker for T cell activation and a signal through this molecule may have a negative feedback role to limit IL-2 production from activated T cells stimulated through the TCR.

  16. Generation of hematopoietic humanized mice in the newborn BALB/c-Rag2null Il2rγnull mouse model: a multivariable optimization approach.

    Science.gov (United States)

    Lang, Julie; Weiss, Nicholas; Freed, Brian M; Torres, Raul M; Pelanda, Roberta

    2011-07-01

    Hematopoietic humanized mice generated via transplantation of human hematopoietic stem cells (hHSCs) into immunodeficient mice are a valuable tool for studying development and function of the human immune system. This study was performed to generate a protocol that improves development and quality of humanized mice in the BALB/c-Rag2(null)Il2rγ(null) strain, testing route of injection, in vitro culture and freezing of hHSCs, types of cytokines in the culture, and co-injection of lineage-depleted CD34(-) cells. Specific hHSC culturing conditions and the addition of support cells were found to increase the frequency, and human hematopoietic chimerism, of humanized mice. The optimized protocol resulted in BALB/c-Rag2(null)Il2rγ(null) humanized mice displaying more consistent human hematopoietic and lymphoid engraftment. Thus, hematopoietic humanized mice generated on a BALB/c immunodeficient background represent a useful model to study the human immune system.

  17. Thermal ablation versus conventional regional hyperthermia has greater anti-tumor activity against melanoma in mice by upregulating CD4~+ cells and enhancing IL-2 secretion

    Institute of Scientific and Technical Information of China (English)

    Yingying Zhang; Wei Zhang; Cuanying Geng; Tongjun Lin; Xiaowen Wang; Lingyun Zhao; Jintian Tang

    2009-01-01

    To determine whether conventional hyperthermia (42-45℃) or ablation therapy (>50℃) achieves better synergistic effects on direct cytotoxicity and anti-tumor immunity,we compared the therapeutic effects of two hyperthermia temperatures,43 and 55℃,in terms of cytotoxicity and upregulation of immune functions in a mouse malignant melanoma model.Melanoma-bearing mice were treated by directly applying regional hyperthermia to the tumor nodule with a heating light at a temperature of 43℃ for 30 min or 55℃ for 10 min.The tumor growth curve and mice survival rate were observed.To investigate the hyperthermia-induced immunological response,peripheral blood CD4~+ and CD8~+ T cells and the serum IL-2 level were determined.Our results indicated that application of regional hyperthermia at the ablation temperature (such as 55℃) achieved better synergistic anti-tumor effects than did conventional hyperthermia (43℃).Significant increases in the number of peripheral blood CD4~+ T cells and the serum IL-2 level likely contributed to the underlying mechanism.

  18. Expression of avian influenza haemagglutinin (H5) and chicken interleukin 2 (chIL-2) under control of the ptcB promoter in Lactococcus lactis.

    Science.gov (United States)

    Szatraj, Katarzyna; Szczepankowska, Agnieszka K; Sączyńska, Violetta; Florys, Katarzyna; Gromadzka, Beata; Łepek, Krzysztof; Płucienniczak, Grażyna; Szewczyk, Bogusław; Zagórski-Ostoja, Włodzimierz; Bardowski, Jacek

    2014-01-01

    Gram-positive and nonpathogenic lactic acid bacteria (LAB) are considered to be promising candidates for the development of new, safe systems of heterologous protein expression. Recombinant LAB has been shown to induce specific local and systemic immune response against selected pathogens, and could be a good alternative to classical attenuated carriers. The main goal of our study was to express the avian influenza haemagglutinin (H5) and chicken interleukin 2 (chIL-2) in Lactococcus lactis. Results of this study were anticipated to lead to construction of lactococcal strain(s) with potential vaccine properties against the avian influenza A (H5N1) virus. Expression of the cloned H5 gene, its His-tagged variant and chIL-2 gene, under the control of the ptcB gene promoter was attested by RT-PCR on transcriptional level and Western or dot blot analysis on translational level, demonstrating that system can be an attractive solution for production of heterologous proteins. The results of the preliminary animal trial conducted in mice are a promising step toward development of a vaccine against avian bird flu using Lactococcus lactis cells as antigen carriers.

  19. IFN-γ, IL-2, IP-10, and MIG as Biomarkers of Exposure to Leishmania spp., and of Cure in Human Visceral Leishmaniasis

    Directory of Open Access Journals (Sweden)

    Ana V. Ibarra-Meneses

    2017-05-01

    Full Text Available New biomarkers are needed for monitoring the effectiveness of treatment for visceral leishmaniasis (VL. They might also improve the detection of the asymptomatic population in Leishmania-endemic areas. This paper examines the IL-2, IFN-γ, IFN-γ-induced protein 10 (IP-10, and monokine-induced-by-IFN-γ (MIG levels in whole blood—stimulated in vitro with soluble Leishmania antigen (SLA—taken from asymptomatic individuals and patients treated for VL living in a post-outbreak (Leishmania infantum area in Spain, and in an endemic (Leishmania donovani area of Bangladesh. IP-10 was found to be an accurate global marker of asymptomatic subjects with positive cellular/humoral tests, while MIG was found to be a better marker of contact with L. donovani than IL-2 but no for those with L. infantum. Determining IP-10, MIG, and IFN-γ levels proved useful in monitoring the cellular immune response following treatment for active disease caused by L. infantum.

  20. The Ikaros transcription factor regulates responsiveness to IL-12 and expression of IL-2 receptor alpha in mature, activated CD8 T cells.

    Directory of Open Access Journals (Sweden)

    Eric T Clambey

    Full Text Available The Ikaros family of transcription factors is critical for normal T cell development while limiting malignant transformation. Mature CD8 T cells express multiple Ikaros family members, yet little is known about their function in this context. To test the functions of this gene family, we used retroviral transduction to express a naturally occurring, dominant negative (DN isoform of Ikaros in activated CD8 T cells. Notably, expression of DN Ikaros profoundly enhanced the competitive advantage of activated CD8 T cells cultured in IL-12, such that by 6 days of culture, DN Ikaros-transduced cells were 100-fold more abundant than control cells. Expression of a DN isoform of Helios, a related Ikaros-family transcription factor, conferred a similar advantage to transduced cells in IL-12. While DN Ikaros-transduced cells had higher expression of the IL-2 receptor alpha chain, DN Ikaros-transduced cells achieved their competitive advantage through an IL-2 independent mechanism. Finally, the competitive advantage of DN Ikaros-transduced cells was manifested in vivo, following adoptive transfer of transduced cells. These data identify the Ikaros family of transcription factors as regulators of cytokine responsiveness in activated CD8 T cells, and suggest a role for this family in influencing effector and memory CD8 T cell differentiation.

  1. A New IL-2RG Gene Mutation in an X-linked SCID Identified through TREC/KREC Screening: a Case Report

    Directory of Open Access Journals (Sweden)

    Maryam Nourizadeh

    2015-10-01

    Full Text Available Severe combined immunodeficiency (SCID represents a rare group of primary immunodeficiency disorders (PIDs, with known or unknown genetic alterations. Here, we report a new interleukin 2 receptor, gamma chain (IL-2RG mutation in an Iranian SCID newborn.The patient was a 6-day old boy with a family history of PID. The child was screened using a molecular-based analysis for the assessment of T cell receptor excision circles (TRECs and kappa-deleting recombination excision circles (KRECs. Moreover, a complete immunological evaluation and gene sequencing was performed.Results showed undetectable TREC but a high level of KREC copy numbers. Flowcytometric data indicated low numbers of T and NK cells, but elevated number of B cells. A novel substitution in IL2RG: c.675 C>A, leading to p.225 Ser>Arg was found. Based on the functional analysis, the mutation is predicted to be damaging. The patient was diagnosed as a T B+ NK X-linked SCID.

  2. Effects of acupuncture and moxibustion on the IL2-IFN-NKC regulatory network and its relative network MФ-IL1-Th

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective The tumor-bearing (S37) mice were used to study the effects of acupuncture and moxibustion on relative network of IL2-IFN-NKC regulatory network. Methods After puncturing and (or) igniting the acupoints of Dazhui (Du 14) and Houhai(Du 1), we observed its effects on MФ,IL1 ,Th and tumor S37 by means of MФ devouring neutral red test,MTT colorimetry and Anti-L3T4 McAb-SPA rosetle test simultaneously. Results The phagocytic power of MФ in the mice's abdomen,the amount of IL1 and percentage of L3T4 increased obviously,compared to that of the control group;excepted the acupuncture group ,the other two experimental groups had the obvious inhibition to the tumor S37. In addition,the IL1 content increased remarkably in acumoxi group and moxibustion group than in acupuncture group. The percentage of L3T4 increased remarkably in acumoxi group than that in acupuncture group. Conclusion Applying both acupuncture and moxibustion at points of Dazhui (Du 14) and Houhai (Du 1) can make positive regulation on the relative MФ-IL1-Th network of IL2-IFNNKC regulatory network and has anti-tumor effect. The moxibustion also has the similar effects.

  3. Cyclosporin A suppresses the expression of the interleukin 2 gene by inhibiting the binding of lymphocyte-specific factors to the IL-2 enhancer.

    Science.gov (United States)

    Randak, C; Brabletz, T; Hergenröther, M; Sobotta, I; Serfling, E

    1990-08-01

    Cyclosporin A (CsA), a powerful immunosuppressive drug, inhibits the synthesis of lymphokines in T lymphocytes at the level of gene transcription. Using protein extracts from El4 lymphoma cells we show that the binding of lymphocyte-specific factors interacting with the two so-called purine boxes (Pu-boxes) of the interleukin 2 (IL-2) enhancer are missing in CsA-treated cells. The CsA-sensitive factors are newly synthesized upon induction. The most prominent factor consists of 45 kd polypeptides and contacts both Pu-boxes at the two central G residues within the identical core sequence AAGAGGAAAA. The CsA-mediated suppression of factor binding to the Pu-boxes correlates well with functional studies in which the inducible, T cell-restricted proto-enhancer activity of Pu-boxes was selectively repressed by CsA. These observations support the conclusion that the suppression of factor binding to the Pu-boxes by CsA impairs the activity of IL-2 and of further lymphokine genes, thereby inhibiting the synthesis of lymphokines in T lymphocytes.

  4. 奥硝唑治疗滴虫性阴道炎的疗效及细胞因子IL-2、IL-8和IL-13的变化%Clinical efficacy of ornidazole for treatment of trichomonas vaginitis and the changes of IL-2, IL-8, and IL-13

    Institute of Scientific and Technical Information of China (English)

    牛义贵

    2012-01-01

    Objective; To study the clinical efficacy of ornidazole for treatment of trichomonas vaginitis and the effect on interleukin-2 (IL-2), IL-8, and IL - 13 in vaginal secretions before and after treatment. Methods; The patients with trichomonas vaginitis were divided into observation group and control group according to the sequence of on admission, 70 patients in each group, the patients in observation group were treated with ornidazole and the patients in control group were treated with metronidazole; the curative effects in the two groups were evaluated, and the changes of IL ?2, IL-8, and IL ?13 levels in vaginal lavage fluid before and after treatment were detected. Results: The curative effect in observation group at seven days after treatment was superior to that in control group, the total effective rates in the two groups were 94. 28% and 85. 71% , respectively, there was statistically significant difference between the two groups (P< 0. 05 ) . After treatment, the levels of IL - 2, IL - 8 , and IL - 13 in vaginal lavage fluid in the two groups decreased, the decreasing amplitude in observation group was significantly higher than that in control group. Conclusion; The curative effect of ornidazole for treatment of trichomonas vaginitis is dominant. Ornidazole can reduce the levels of IL - 2, IL - 8 , and IL - 13 in vaginal secretions effectively and improve vaginal microenvironment, which can be used for clinical treatment extensively.%目的:研究奥硝唑治疗滴虫性阴道炎的疗效及其对治疗前后患者阴道分泌物中细胞因子IL-2、IL-8和IL-13的影响.方法:将滴虫性阴道炎患者按就诊顺序分为观察组和对照组各70例,观察组使用奥硝唑治疗,对照组使用甲硝唑治疗,评价治疗的效果并检测治疗前后阴道灌洗液中IL-2、IL-8和IL-13的变化.结果:服药7天后,观察组的治疗效果优于对照组,总有效率分别为94.28%和85.71%,差异有统计学意义(P<0.05).两组患者治疗后阴道灌洗液中的IL

  5. IL-2, IFN-γ, IL-4、 IL-6 Expression in Peri-implant Gingival Crevicular Fluid and Clinical Significance%种植体周围炎龈沟液中IL-2、 IFN-γ、IL-4、IL-6的表达及临床意义

    Institute of Scientific and Technical Information of China (English)

    郦兴

    2015-01-01

    目的 探讨探讨白细胞介素2、4、6(IL-2、IL-4、IL-6)、干扰素γ(IFN-γ)在种植体周围炎龈沟液(GCF)中的表达及意义.方法 选择2011年6月~2014年6月50例种植体周围炎患者为研究对象.另选择健康种植体患者50例和健康人群50例为对照组.统计3组探诊深度(PD)、龈沟出血指数(SBI)、IL-2、IFN-γ、IL-4、IL-6水平.结果 种植体周围炎组PD、SBI、GCF均高于健康种植体组和对照组,差异有统计学意义(P<0.01);但健康种植体组和对照组PD、SBI、GCF差异无统计学意义(P>0.05);种植体周围炎组IL-2、IFN-γ水平低于健康种植体组和对照组(P<0.01),健康种植体组IL-2、IFN-γ水平低于对照组(P<0.05),种植体周围炎组IL-4、IL-6水平高于健康种植体组和对照组(P<0.01),健康种植体组IL-4、IL-6水平高于对照组(P<0.05);≥60岁组IL-2、IFN-γ水平低于<60岁组(P<0.01),≥60岁组IL-4、IL-6水平高于<60岁组(P<0.01);种植体周围炎患者GCF中IL-2与IFN-γ呈正相关(r=4.267,P=0.016),与IL-4、IL-6分别呈负相关(r=4.352、4.615,P=0.005、0.002),IFN-γ与IL-4、IL-6分别呈负相关(r=4.322、4.603,P=0.009、0.005),IL-4,IL-6呈正相关(r=4.065,P=0.019).结论 种植体周围炎患者IL-4、IL-6高表达,IL-2、IFN-γ低表达,IL-2、IFN-γ、IL-4、IL-6的表达与种植体周围炎患者性别无关,与种植体周围炎患者的年龄有关.

  6. 过敏性哮喘患者外周血IL-2、IL-4、IL-6和IL-8水平的变化%Change of the Level of IL-2, IL-4, IL-6 and IL-8 of Irritability Asthma Patients

    Institute of Scientific and Technical Information of China (English)

    王爱华; 李全新

    2000-01-01

    为了观察白细胞介素在哮喘发病中的作用,该文分别对哮喘发作期20例 ,缓解期12例患者及正常对照组10例进行了血清IL-2、IL-4、IL-6和IL-8的测定,结果发现 ,发作期患者血清IL-2水平下降,而IL-4、IL-6和IL-8水平均增高,缓解期均恢复至正常水平.提示这些细胞因子在哮喘发病过程中起着重要作用.

  7. DETECTION OF PBMC T CELL SUBSETS AND mIL-2R OF THE PERSONS INFECTED BY CRYPTOSPORIDIUM PARVUM BY USING THE SYSTEM OF BSA%应用BSA系统检测隐孢子虫感染者外周血T细胞亚群及mIL-2R

    Institute of Scientific and Technical Information of China (English)

    许礼发; 李朝品; 张荣波; 王晓秋

    2004-01-01

    Objective To explore the changes of cellular immune function in the persons infected by Cryptosporidium parvum .MethodsThe system of biotin streptavidin (BSA) was used to detect T cell subsets and membrane interleukin 2 receptor (mIL 2R) in peripheral blood mononuclear cell (PBMC) of the persons infected byC. parvum . ResultsThe positive rates of CD3+,CD4+,CD8+ and CD4+/CD8+ in the persons in whose stoolsC. parvum oocysts were found were (54.77±7.33)%,(38.17±7.52)%,(30.64±5.87)% and 1.28±0.72 respectively,and the level of mIL 2R in induction period was (32.15±2.42)%. It could be concluded that the positive rates of CD3+,CD4+,CD8+ and CD4+/CD8+ in the persons in whose stoolsC. parvum oocysts were found were significantly different from those with noC. parvum oocysts were found (P <0.05~0.01). The level of mIL 2R in induction period was significantly different from which in resting period (P <0.05~0.01).ConclusionIn the persons infected byC. parvum,cellular immunity participates in resisting the parasite,and T cell subsets and mIL 2R play an important role.%目的探讨隐孢子虫感染者机体细胞免疫功能的变化. 方法采用生物素-链霉亲和素(Biotin-Streptavidin , BSA)法对卵囊阳性患者分别进行外周血T细胞亚群、膜白介素-2受体(mIL-2R)检测. 结果隐孢子虫卵囊阳性者的CD3+、CD4+、CD8+百分率和CD4+/CD8+比值分别为(54.77±7.33)%、(38.17±7.52)%、(30.64±5.87)% 和1.28±0.72,诱导期mIL-2R表达水平为(32.15±2.42)%,两者分别与卵囊阴性者及静息期mIL-2R相比,差异有显著性(P<0.05~0.01). 结论隐孢子虫感染者引起细胞免疫功能的变化,T细胞亚群、mIL-2R在抗隐孢子虫感染中起重要作用.

  8. 姜黄素对戊四氮致癫大鼠海马区 IL-2和IL-6表达水平的影响%Effect of the curcumin on expression of IL-2 and IL-6 of hippocampus in pentyle-netetrazol-induced epilepsy in rats

    Institute of Scientific and Technical Information of China (English)

    董伟; 严建维; 谈巧玲; 叶森

    2016-01-01

    Objective To investigate the mechanism of anti-epileptic effect of the curcumin .Methods The SD rats were injected intraperitoneally with pentylenetetrazol kindling 25 .0 mg/kg to induce a rat epilepsy model .All of the treatments were performed once a day continuously for 28 days .The rats in blank group and model group received 5 ml of normal saline .The rats in the high and low curcumin group were given 200 mg/kg and 100 mg/kg of curcumin once a day ,respectively .The rats in the sodium valproate (VPA) group were given 400 mg/kg of VPA once a day by gavage .After treatment ,the seizures level was recorded by using the Racine′s six point grading scale ,and the expression of IL-2 and IL-6 of hippocampus were detected by the enzyme linked immunoassay (ELISA) .Results The seizures level was reduced by curcumin in epileptic rats .The ex-pressions of IL-2 and IL-6 of the model group were significantly higher than those of the blank group (P0 .05) . Conclusion The curcumin can reduce the seizure level in rats ,it shows some anti-epileptic effets and dose-dependently ,which may be through down-regulating the expression of IL-2 and IL-6 in hippocampus .%目的:探讨姜黄素抗癫的作用机制。方法取健康成年雄性SD大鼠,连续腹腔注射戊四氮,诱发大鼠点燃致癫模型。空白组和模型组灌予生理盐水5 ml ,1次/d ,连续28 d。低剂量和高剂量姜黄素组分别灌予姜黄素100 mg/kg和200 mg/kg ,1次/d ,连续28 d;丙戊酸钠组灌予丙戊酸钠400 mg/kg ,1次/d ,连续28 d。治疗结束后,按照Racine的6级评分标准,观察癫大鼠发作等级变化,用酶联免疫法(ELISA)检测海马区IL-2和IL-6表达水平的变化。结果姜黄素组的癫大鼠惊厥发作等级降低。模型组IL-2和IL-6高表达,比空白组呈显著升高(P<0.05)。与模型组比较,姜黄素组大鼠海马区IL-2和IL-6的表达明显降低( P<0.05);与低剂量姜黄素组

  9. Effects of Alcohol Extracts of Typhonium Gigantewm Engl. on the Serum IL-2 and TNF-alpha Levels of H22 Liver Cancer-bearing Mice%独角莲醇提液对H22肝癌荷瘤小鼠血清IL-2和TNF-α水平的影响

    Institute of Scientific and Technical Information of China (English)

    黄展; 辛华; 江旭东; 欧芹; 孙国志

    2013-01-01

    目的:探讨独角莲醇提液对H22肝癌荷瘤小鼠血清IL-2和TNF-α水平的影响。方法建立体内H22肝癌荷瘤小鼠的模型,采用灌胃法给予其100mg·kg-1·d-1独角莲醇提液,以生理盐水灌胃和5-FU腹腔注射作为对照,连续10d,停药后第2天摘取小鼠眼球取血后断髓处死,取出胸腺、脾脏称重,计算小鼠的胸腺重量指数、脾脏重量指数,采用ELISA法检测小鼠血清中细胞因子白介素-2(IL-2)、肿瘤坏死因子-α(TNF-α)的水平。结果与生理盐水灌胃的H22肝癌荷瘤小鼠比较,5-FU腹腔注射和独角莲醇提液灌胃处理的H22荷瘤鼠血清中细胞因子IL-2、TNF-α水平明显升高;但胸腺重量指数、脾脏重量指数显著下降,差异均具有统计学意义(P<0.05)。结论独角莲醇提液可提高H22荷瘤鼠的血清IL-2和TNF-α水平。%Objective To explore the effects of alcohol extracts of Typhonium giganteum Engl. on the serum IL-2 and TNF-alpha levels of H22 liver cancer-bearing mice. Methods The models of in vivo H22 cancer bearing mice were established, and 10 mice were lavaged with 100 mg·kg-1·d-1 of alcohol extracts of Typhonium giganteum Engl., and another 10 had intra-peritoneal injection of 5-FU, and the remaining 10 had lavage of saline and were taken as control, for 10 days. On the 2nd day after drug discontinuation, the mice were pulpotomy executed after being taken blood from eyes, and then the thymus, spleen were removed, weighed and calculated. The serum interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-α) levels were detected by ELISA. Results Compared with the mice lavaged by saline, the serum IL-2 and TNF-αlevels of mice with intra-peritoneal injection of 5-FU and those with Typhonium giganteum Engl. alcohol extracts significantly increased, but their thymus weight index, spleen weight index both decreased (P<0.05). Differences all had statistical significance. Conclusion The alcohol

  10. Treatment of diffuse large B cell lymphoma with combined thymic peptide- enhanced autologous cvtokine induced killer cells and IL-2 in aged patients%含胸腺肽免疫增强的自体CIK细胞联合IL-2方案治疗高龄弥漫大B细胞淋巴瘤

    Institute of Scientific and Technical Information of China (English)

    杨洋; 陈云燕; 张文英; 刘洋; 王瑶; 代汉仁; 韩为东; 张峰; 姚善谦; 杨波; 脱帅; 卢学春; 朱宏丽; 脱朝伟; 蔡力力; 迟小华; 于睿莉

    2012-01-01

    目的 评价含胸腺肽免疫增强的自体CIK细胞联合IL-2(TCIL-2)方案治疗高龄弥漫大B细胞淋巴瘤的有效性和安全性.方法 采集预先接受胸腺五肽免疫增强治疗的4例高龄弥漫大B细胞淋巴瘤(DLBCL)患者外周血单个核细胞,在体外经干扰素-γ(IFN-γ)、白介素-2(IL-2)、抗CD3单克隆抗体诱导成CIK细胞,回输细胞数为2×109-3×109个,回输后应用IL-2 100mU/d,皮下注射,连续10d.28d为1个周期,共完成24个周期的自体CIK细胞输注.观察治疗前后细胞免疫功能、肿瘤相关生物学指标变化.结果 2例接受8个周期的CIK细胞输注,2例接受4个周期的输注,回输后所有患者未出现不良反应.CIK细胞治疗后CD3+、CD3+CD8+、CDTCD56+细胞比例明显升高(P<0.05),β2微球蛋白水平显著下降(P<0.05).3例达完全缓解,1例完成8周期的CIK细胞输注后一度达良好的部分缓解,但最终因急性心肌梗死和淋巴瘤持续进展而死亡.结论 自体CIK细胞联合IL-2治疗高龄弥漫大B细胞淋巴瘤安全有效.%Objective To assess the efficiency and safety of combined thymic peptide-enhanced autologous cytokine induced killer (CIK) cells and IL-2 in treatment of diffuse large B cell lymphoma in aged patients. Methods Peripheral blood mononuclear cells (PBMC) were collected from 4 aged patients with diffuse large B cell lymphoma. CIK cells were induced with in vitro interferon gamma (IFN- γ), IL-2 and anti-CD3 monoclonal antibody (mAb). Immune function of the cells and tumor-related biological indexes of the patients were observed after 2 x 10'-3 x 109 autologous CIK cells were re-transfused into the patients each time and IL-2 l00mU/d was subcutaneously injected for 10 days, 28 days a cycle for 24 cycles. Results Two patients received 8 cycles of CIK cells transfusion and 2 patients received 4 cycles of CIK cells transfusion. No adverse reaction occurred in them. The number of CD3+, CD3+CD8+ and CD3+CD56+ was significantly

  11. Previously seen and expected stimuli elicit surprise in the context of visual search.

    Science.gov (United States)

    Retell, James D; Becker, Stefanie I; Remington, Roger W

    2016-04-01

    In the context of visual search, surprise is the phenomenon by which a previously unseen and unexpected stimulus exogenously attracts spatial attention. Capture by such a stimulus occurs, by definition, independent of task goals and is thought to be dependent on the extent to which the stimulus deviates from expectations. However, the relative contributions of prior-exposure and explicit knowledge of an unexpected event to the surprise response have not yet been systematically investigated. Here observers searched for a specific color while ignoring irrelevant cues of different colors presented prior to the target display. After a brief familiarization period, we presented an irrelevant motion cue to elicit surprise. Across conditions we varied prior exposure to the motion stimulus - seen versus unseen - and top-down expectations of occurrence - expected versus unexpected - to assess the extent to which each of these factors contributes to surprise. We found no attenuation of the surprise response when observers were pre-exposed to the motion cue and or had explicit knowledge of its occurrence. Our results show that it is neither sufficient nor necessary that a stimulus be new and unannounced to elicit surprise and suggest that the expectations that determine the surprise response are highly context specific.

  12. A Statistical Analysis of the Relationship between Harmonic Surprise and Preference in Popular Music.

    Science.gov (United States)

    Miles, Scott A; Rosen, David S; Grzywacz, Norberto M

    2017-01-01

    Studies have shown that some musical pieces may preferentially activate reward centers in the brain. Less is known, however, about the structural aspects of music that are associated with this activation. Based on the music cognition literature, we propose two hypotheses for why some musical pieces are preferred over others. The first, the Absolute-Surprise Hypothesis, states that unexpected events in music directly lead to pleasure. The second, the Contrastive-Surprise Hypothesis, proposes that the juxtaposition of unexpected events and subsequent expected events leads to an overall rewarding response. We tested these hypotheses within the framework of information theory, using the measure of "surprise." This information-theoretic variable mathematically describes how improbable an event is given a known distribution. We performed a statistical investigation of surprise in the harmonic structure of songs within a representative corpus of Western popular music, namely, the McGill Billboard Project corpus. We found that chords of songs in the top quartile of the Billboard chart showed greater average surprise than those in the bottom quartile. We also found that the different sections within top-quartile songs varied more in their average surprise than the sections within bottom-quartile songs. The results of this study are consistent with both the Absolute- and Contrastive-Surprise Hypotheses. Although these hypotheses seem contradictory to one another, we cannot yet discard the possibility that both absolute and contrastive types of surprise play roles in the enjoyment of popular music. We call this possibility the Hybrid-Surprise Hypothesis. The results of this statistical investigation have implications for both music cognition and the human neural mechanisms of esthetic judgments.

  13. The "Goldilocks Effect" in Cystic Fibrosis: identification of a lung phenotype in the cftr knockout and heterozygous mouse

    Directory of Open Access Journals (Sweden)

    Bates Jason HT

    2004-07-01

    Full Text Available Abstract Background Cystic Fibrosis is a pleiotropic disease in humans with primary morbidity and mortality associated with a lung disease phenotype. However, knockout in the mouse of cftr, the gene whose mutant alleles are responsible for cystic fibrosis, has previously failed to produce a readily, quantifiable lung phenotype. Results Using measurements of pulmonary mechanics, a definitive lung phenotype was demonstrated in the cftr-/- mouse. Lungs showed decreased compliance and increased airway resistance in young animals as compared to cftr+/+ littermates. These changes were noted in animals less than 60 days old, prior to any long term inflammatory effects that might occur, and are consistent with structural differences in the cftr-/- lungs. Surprisingly, the cftr+/- animals exhibited a lung phenotype distinct from either the homozygous normal or knockout genotypes. The heterozygous mice showed increased lung compliance and decreased airway resistance when compared to either homozygous phenotype, suggesting a heterozygous advantage that might explain the high frequency of this mutation in certain populations. Conclusions In the mouse the gene dosage of cftr results in distinct differences in pulmonary mechanics of the adult. Distinct phenotypes were demonstrated in each genotype, cftr-/-, cftr +/-, and cftr+/+. These results are consistent with a developmental role for CFTR in the lung.

  14. October Surprises.

    Science.gov (United States)

    2016-10-01

    Ushered in with the rampage of Hurricane Matthew, later days brightened in this month that has often been harbinger of both good and bad news for Cuba and the world. Hurricane Matthew ripped through Eastern Cuba, devastating the historic town of Baracoa (Cuba's first capital, founded in 1511) and the village of Maisí, where the morning sun first rises over Cuban territory. Wind and flood leveled hundreds of homes, brought down the power grid and destroyed crops. Yet there was no loss of human life, unlike in neighboring Haiti and other countries in Matthew's path, and unlike in Cuba in 1963, when Hurricane Flora caused more than 1200 deaths. In Haiti, efforts of health workers-including hundreds of Haitian graduates from Cuba's Latin American Medical School and 600 Cuban health professionals already there-were bolstered by dozens of specially trained Cuban disaster medical personnel in the wake of the storm.

  15. Surprising Resists

    Science.gov (United States)

    Morton, Stephie

    2007-01-01

    In this article, the author discusses an art adventure with her third, fourth, and fifth grade enrichment kids to the Fort Collins Museum of Contemporary Art in Colorado. The author demonstrates and teaches her students how to use the art tissue paper and oil pastel complementing the creative spirit of the Jaune Quick-to-See Smith work presented…

  16. MsrA knockout mouse exhibits abnormal behavior and brain dopamine levels.

    Science.gov (United States)

    Oien, Derek B; Osterhaus, Greg L; Latif, Shaheen A; Pinkston, Jonathan W; Fulks, Jenny; Johnson, Michael; Fowler, Stephen C; Moskovitz, Jackob

    2008-07-15

    Oxidative stress can cause methionine oxidation that has been implicated in various proteins malfunctions, if not adequately reduced by the methionine sulfoxide reductase system. Recent evidence has found oxidized methionine residues in neurodegenerative conditions. Previously, we have described elevated levels of brain pathologies and an abnormal walking pattern in the methionine sulfoxide reductase A knockout (MsrA(-/-)) mouse. Here we show that MsrA(-/-) mice have compromised complex task learning capabilities relative to wild-type mice. Likewise, MsrA(-/-) mice exhibit lower locomotor activity and altered gait that exacerbated with age. Furthermore, MsrA(-/-) mice were less responsive to amphetamine treatment. Consequently, brain dopamine levels were determined. Surprisingly, relative to wild-type mice, MsrA(-/-) brains contained significantly higher levels of dopamine up to 12 months of age, while lower levels of dopamine were observed at 16 months of age. Moreover, striatal regions of MsrA(-/-) mice showed an increase of dopamine release parallel to observed dopamine levels. Similarly, the expression pattern of tyrosine hydroxylase activating protein correlated with the age-dependent dopamine levels. Thus, it is suggested that dopamine regulation and signaling pathways are impaired in MsrA(-/-) mice, which may contribute to their abnormal behavior. These observations may be relevant to age-related neurological diseases associated with oxidative stress.

  17. The MsrA knockout mouse exhibits abnormal behavior and brain dopamine levels

    Science.gov (United States)

    Oien, Derek B.; Osterhaus, Greg L.; Latif, Shaheen A.; Pinkston, Jonathan W.; Fulks, Jenny; Johnson, Michael; Fowler, Stephen C.; Moskovitz, Jackob

    2008-01-01

    Oxidative stress can cause methionine oxidation that has been implicated in various proteins malfunctions, if not adequately reduced by the methionine sulfoxide reductase system. Recent evidence has found oxidized methionine residues in neurodegenerative conditions. Previously, we have described elevated levels of brain pathologies and an abnormal walking pattern in the methionine sulfoxide reductase A knockout (MsrA−/−) mouse. Here we show that MsrA−/− mice have compromised complex task learning capabilities relative to wild-type mice. Likewise, MsrA−/− mice exhibit lower locomotor activity and altered gait that exacerbated with age. Furthermore, MsrA−/− mice were less responsive to amphetamine treatment. Consequently, brain dopamine levels were determined. Surprisingly, relative to wild-type mice, MsrA−/− brains contained significantly higher levels of dopamine up to 12 months of age, while lower level of dopamine was observed at 16 months of age. Moreover, striatal regions of MsrA−/− mice showed an increase of dopamine release parallel to observed dopamine levels. Similarly, the expression pattern of tyrosine hydroxylase activating protein correlated with the age-dependent dopamine levels. Thus, it is suggested that dopamine regulation and signaling pathway are impaired in MsrA−/− mice, which may contribute to their abnormal bio-behavior. These observations may be relevant to age-related neurological diseases associated with oxidative stress. PMID:18466776

  18. Analysis of Cytokines (IL-2, IL-8, IL-10) in the Expressed Prostatic Secretions of Chronic Prostatitis%慢性前列腺炎患者前列腺液中IL-2、IL-8及IL-10水平分析

    Institute of Scientific and Technical Information of China (English)

    段志国; 杨为民

    2005-01-01

    目的: 检测慢性前列腺炎(CP)患者前列腺液中细胞因子IL-2、IL-8及IL-10的水平,探讨这些细胞因子对CP发病机制及诊断方面的价值. 方法: 采用双抗体夹心ELISA法测定31例CP患者前列腺液中IL-2、IL-8及IL-10的水平,并以10例健康男性为对照.对每例患者进行两杯法尿液细菌培养、前列腺常规检查和美国国立卫生院前列腺炎症状指数评分(NIH-CPSI).按NIH分类法将31例CP患者分为3型:Ⅱ型5例,ⅢA型13例,ⅢB型13例. 结果: CP组与对照组比较,前列腺液IL-8含量显著升高(P0.05). 结论: 前列腺液中IL-2、IL-8及IL-10在CP的发病过程中起重要作用,是诊断CP有价值的指标.

  19. 性病患者58例血清IL-2、IL-6和IL-8水平的检测及其临床意义

    Institute of Scientific and Technical Information of China (English)

    高英举

    2002-01-01

    目的探讨血清白细胞介素-2(IL-2)、白细胞介素-6(IL-6),白细胞介素-8(IL-8)在性病患者血清中水平及临床意义.方法应用双抗体夹心EliSA法检测了58例性病患者血清中IL-2、IL-6和IL-8水平.结果 58例性病患者血清中,IL-2、IL-6、IL-8水平分别为(6.4±3.2) ng/ml、(0.15±0.06) ng/ml、(0.34±0.13) ng/ml、而IL-8则显著高于正常人组(P<0.01),其中IL-2、IL-6则明显低于正常人组(P<0.01).结论性病患者的发生与发展与IL-2、IL-6降低和IL-8升高密切相关,检测IL-2、IL-6和IL-8血清水平有助于性病的判断和治疗的选择.

  20. Zinc finger nuclease mediated knockout of ADP-dependent glucokinase in cancer cell lines: effects on cell survival and mitochondrial oxidative metabolism.

    Directory of Open Access Journals (Sweden)

    Susan Richter

    Full Text Available Zinc finger nucleases (ZFN are powerful tools for editing genes in cells. Here we use ZFNs to interrogate the biological function of ADPGK, which encodes an ADP-dependent glucokinase (ADPGK, in human tumour cell lines. The hypothesis we tested is that ADPGK utilises ADP to phosphorylate glucose under conditions where ATP becomes limiting, such as hypoxia. We characterised two ZFN knockout clones in each of two lines (H460 and HCT116. All four clones had frameshift mutations in all alleles at the target site in exon 1 of ADPGK, and were ADPGK-null by immunoblotting. ADPGK knockout had little or no effect on cell proliferation, but compromised the ability of H460 cells to survive siRNA silencing of hexokinase-2 under oxic conditions, with clonogenic survival falling from 21±3% for the parental line to 6.4±0.8% (p = 0.002 and 4.3±0.8% (p = 0.001 for the two knockouts. A similar increased sensitivity to clonogenic cell killing was observed under anoxia. No such changes were found when ADPGK was knocked out in HCT116 cells, for which the parental line was less sensitive than H460 to anoxia and to hexokinase-2 silencing. While knockout of ADPGK in HCT116 cells caused few changes in global gene expression, knockout of ADPGK in H460 cells caused notable up-regulation of mRNAs encoding cell adhesion proteins. Surprisingly, we could discern no consistent effect on glycolysis as measured by glucose consumpti