A prospective randomized evaluation of the prophylactic use of low-dose dopamine in cancer patients receiving interleukin-2.

Science.gov (United States)

Cormier, J N; Hurst, R; Vasselli, J; Lee, D; Kim, C J; McKee, M; Venzon, D; White, D; Marincola, F M; Rosenberg, S A

1997-07-01

The administration of high-dose interleukin-2 (IL-2) causes tumor regression in 17-25% of patients with metastatic melanoma or renal cell carcinoma. Renal dysfunction is a common dose-limiting toxicity of IL-2 administration, limiting 26% of treatment cycles. We have conducted a prospective randomized trial to evaluate whether the prophylactic administration of low-dose dopamine (2 mg/kg/min) can minimize renal toxicity and thus affect the amount of IL-2 administered. Forty-two patients were randomly assigned to receive systemic high-dose IL-2 with standard supportive measures (group A = 21 patients) or with the addition of prophylactic dopamine (group B = 21 patients) at 2 mg/kg/min. For patients in group B, dopamine was instituted 1 h before the initiation of IL-2 administration and was discontinued 6-12 h after the maximum number of doses of IL-2 were given. There was no difference in the amount of IL-2 administered for each course of therapy for groups A and B. Despite differences in urine flow (milliliters per kilogram per day), fluid balance (liters per day), and overall weight gain, prophylactic low-dose dopamine did not significantly alter maximum plasma urea or creatinine levels in group B when compared with the control group (group A). The overall toxicity profile considering all grade 3 and 4 toxicities for patients in groups A and B was comparable. Thus, there is no evidence to support the routine use of prophylactic low-dose dopamine in patients receiving high-dose IL-2.

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

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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.

A Pilot Study of IL2 in Drug-Resistant Idiopathic Nephrotic Syndrome.

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Alice Bonanni

Full Text Available Tregs infusion reverts proteinuria and reduces renal lesions in most animal models of nephrotic syndrome (i.e. Buffalo/Mna, Adriamycin, Promycin, LPS. IL2 up-regulates Tregs and may be an alternative to cell-therapy in this setting. To evaluate a potential role of IL2 as Tregs inducer and proteinuria lowering agent in human nephrotic syndrome we treated 5 nephrotic patients with 6 monthly cycles of low-dose IL2 (1x106 U/m2 first month, 1.5x106 U/m2 following months. The study cohort consisted of 5 children (all boys, 11–17 years resistant to all the available treatments (i.e. steroids, calcineurin inhibitors, mycophenolate, Rituximab. Participants had Focal Segmental Glomerulosclerosis (3 cases or Minimal Change Nephropathy (2 cases. IL2 was safe in all but one patient who had an acute asthma attack after the first IL2 dose and did not receive further doses. Circulating Tregs were stably increased (>10% during the whole study period in 2 cases while were only partially modified in the other two children who started with very low levels and partially responded to single IL2 Proteinuria and renal function were not modified by IL2 at any phase of the study. We concluded that low-dose IL2 given in monthly pulses is safe and modifies the levels of circulating Tregs. This drug may not be able to lower proteinuria or affect renal function in children with idiopathic nephrotic syndrome. We were unable to reproduce in humans the effects of IL2 described in rats and mice reducing de facto the interest on this drug in nephrotic syndrome.ClinicalTrials.gov NCT02455908.

Glucocorticoids inhibit the proliferation of IL-2-dependent T cell clones

International Nuclear Information System (INIS)

Fresno, M.; Redondo, J.M.; Lopez-Rivas, A.

1986-01-01

It has been shown that glucocorticoids inhibit mitogen or antigen-induced lymphocyte proliferation by decreasing the production of interleukin-2 (IL-2). They have studied the effect of dexamethasone (Dx) on the proliferation of IL-2-dependent T cell clones. They have found that preincubation of these clones with Dx inhibits ( 3 H) thymidine incorporation and cell proliferation in a dose-dependent manner (ID 50 % 5 x 10 -10 M). The inhibition of DNA synthesis by Dx was dependent on the concentration of IL-2. High concentration of IL-2 reversed completely this inhibition. The action of Dx seems to be mediated through the induction of a protein since the simultaneous presence of cycloheximide and Dx prevented the inhibitory effect of the latter. Moreover, dialyzed conditioned medium of Dx treated cells inhibited DNA synthesis by T cell clones. The biochemical characterization of this protein is in progress

Requirements for growth and IL-10 expression of highly purified human T regulatory cells

OpenAIRE

Bonacci, Benedetta; Edwards, Brandon; Jia, Shuang; Williams, Calvin; Hessner, Martin J.; Gauld, Stephen; Verbsky, James

2012-01-01

Human regulatory T cells (TR) cells have potential for the treatment of a variety of immune mediated diseases but the anergic phenotype of these cells makes them difficult to expand in vitro. We have examined the requirements for growth and cytokine expression from highly purified human TR cells, and correlated these findings with the signal transduction events of these cells. We demonstrate that these cells do not proliferate or secrete IL-10 even in the presence of high doses of IL-2. Stimu...

A BCR/ABL-hIL-2 DNA Vaccine Enhances the Immune Responses in BALB/c Mice

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Yanan Qin

2013-01-01

Full Text Available The use of a DNA vaccine encoding the BCR/ABL fusion gene is thought to be a promising approach for patients with chronic myeloid leukemia (CML to eradicate minimal residual disease after treatment with chemotherapy or targeted therapy. In this study, our strategy employs genetic technology to create a DNA vaccine encoding the BCR/ABL fusion and human interleukin-2 (hIL-2 genes. The successfully constructed plasmids BCR/ABL-pIRES-hIL-2, BCR/ABL-pIRES, and pIRES-hIL-2 were delivered intramuscularly to BALB/c mice at 14-day intervals for three cycles. The transcription and expression of the BCR/ABL and hIL-2 genes were found in the injected muscle tissues. The interferon-γ (IFN-γ serum levels were increased, and the splenic CD4+/CD8+ T cell ratio was significantly decreased in the BCR/ABL-pIRES-hIL-2-injected mice. Furthermore, specific antibodies against K562 cells could be detected by indirect immunofluorescence. These results indicate that a DNA vaccine containing BCR/ABL and hIL-2 together may elicit increased in vivo humoral and cellular immune responses in BALB/c mice.

IL33 Is a Stomach Alarmin That Initiates a Skewed Th2 Response to Injury and InfectionSummary

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Jon N. Buzzelli

2015-03-01

Full Text Available Background & Aims: Interleukin (IL33 is a recently described alarmin that is highly expressed in the gastric mucosa and potently activates Th2 immunity. It may play a pivotal role during Helicobacter pylori infection. Here, we delineate the role of IL33 in the normal gastric mucosa and in response to gastropathy. Methods: IL33 expression was evaluated in mice and human biopsy specimens infected with H pylori and in mice after dosing with aspirin. IL33 expression was localized in the gastric mucosa using immunofluorescence. Mice were given 1 or 7 daily doses of recombinant IL33 (1 μg/dose, and the stomach and the spleen responses were quantified morphologically, by flow cytometry and using quantitative reverse-transcription polymerase chain reaction and immunoblotting. Results: In mice, the IL33 protein was localized to the nucleus of a subpopulation of surface mucus cells, and co-localized with the surface mucus cell markers Ulex Europaeus 1 (UEA1, and Mucin 5AC (Muc5AC. A small proportion of IL33-positive epithelial cells also were Ki-67 positive. IL33 and its receptor Interleukin 1 receptor-like 1 (ST2 were increased 4-fold after acute (1-day H pylori infection, however, this increase was not apparent after 7 days and IL33 expression was reduced 2-fold after 2 months. Similarly, human biopsy specimens positive for H pylori had a reduced IL33 expression. Chronic IL33 treatment in mice caused systemic activation of innate lymphoid cell 2 and polarization of macrophages to the M2 phenotype. In the stomach, IL33-treated mice developed transmural inflammation and mucous metaplasia that was mediated by Th2/signal transducer and activator of transcription 3 signaling. Rag-1-/- mice, lacking mature lymphocytes, were protected from IL33-induced gastric pathology. Conclusions: IL33 is highly expressed in the gastric mucosa and promotes the activation of T helper 2–cytokine–expressing cells. The loss of IL33 expression after prolonged H

Carbon monoxide releasing molecule-2 ameliorates IL-1β-induced IL-8 in human gastric cancer cells

International Nuclear Information System (INIS)

Lian, Sen; Xia, Yong; Ung, Trong Thuan; Khoi, Pham Ngoc; Yoon, Hyun Joong; Kim, Nam Ho; Kim, Kyung Keun; Jung, Young Do

2016-01-01

Carbon monoxide (CO), a byproduct of heme oxygenase (HO), presents antioxidant, anti-inflammatory, and anti-tumor properties. Accumulating evidence supports that interleukin (IL)-8 contribute to the vascularity of human gastric cancer. However, the inhibition of IL-8 expression by CO is yet to be elucidated. Here, we utilized CO releasing molecule-2 (CORM-2) to investigate the effect of CO on IL-1β-induced IL-8 expression and the underlying molecular mechanisms in human gastric cancer AGS cells. CORM-2 dose-dependently suppressed IL-1β-induced IL-8 mRNA and protein expression as well as IL-8 promoter activity. IL-1β induced the translocation of p47 phox to activate reactive oxygen species (ROS)-producing NADPH oxidase (NOX). Moreover, IL-1β activated MAPKs (Erk1/2, JNK1/2, and p38 MAPK) and promoted nuclear factor (NF)-kB and activator protein (AP)-1 binding activities. Pharmacological inhibition and mutagenesis studies indicated that NOX, ROS, Erk1/2, and p38 MAPK are involved in IL-1β-induced IL-8 expression. Transient transfection of deletion mutant constructs of the IL-8 promoter in cells suggested that NF-kB and AP-1 are critical for IL-1β-induced IL-8 transcription. NOX-derived ROS and MAPKs (Erk1/2 and p38 MAPK) functioned as upstream activators of NF-κB and AP-1, respectively. CORM-2 pretreatment significantly mitigated IL-1β-induced activation of ROS/NF-kB and Erk1/2/AP-1 cascades, blocking IL-8 expression and thus significantly reducing endothelial cell proliferation in the tumor microenvironment.

Eradication of Human Hepatic and Pulmonary Melanoma Metastases in SCID Mice by Antibody--Interleukin 2 Fusion Proteins

Science.gov (United States)

Becker, Jurgen C.; Pancook, James D.; Gillies, Stephen D.; Mendelsohn, John; Reisfeld, Ralph A.

1996-04-01

Antibody--cytokine fusion proteins combine the unique targeting ability of antibodies with the multifunctional activity of cytokines. Here, we demonstrate the therapeutic efficacy of such constructs for the treatment of hepatic and pulmonary metastases of different melanoma cell lines. Two antibody--interleukin 2 (IL-2) fusion proteins, ch225-IL2 and ch14.18-IL2, constructed by fusion of a synthetic sequence coding for human IL-2 to the carboxyl end of the Cγ 1 gene of the corresponding antibodies, were tested for their therapeutic efficacy against xenografted human melanoma in vivo. Tumorspecific fusion proteins completely inhibited the growth of hepatic and pulmonary metastases in C.B-17 scid/scid mice previously reconstituted with human lymphokine-activated killer cells, whereas treatment with combinations of the corresponding antibodies plus recombinant IL-2 only reduced the tumor load. Even when treatment with fusion proteins was delayed up to 8 days after inoculation of tumor cells, it still resulted in complete eradication of micrometastases that were established at that time point. Selection of tumor cell lines expressing or lacking the targeted antigen of the administered fusion protein proved the specificity of the observed antitumor effect. Biodistribution analysis demonstrated that the tumorspecific fusion protein accumulated not only in subcutaneous tumors but also in lungs and livers affected with micrometastases. Survival times of animals treated with the fusion protein were more than doubled as compared to those treated with the combination of the corresponding antibody plus IL-2. Our data demonstrate that an immunotherapeutic approach using cytokines targeted by antibodies to tumor sites has potent effects against disseminated human melanoma.

Clinical trial of combination therapy using systemic interleukin-2 infusion and low-dose tumor irradiation for advanced hepatocellular carcinoma

International Nuclear Information System (INIS)

Tsuchida, Tetsuo; Hiragushi, Junji; Asano, Yoshihide

1995-01-01

Although recent progress in surgical techniques and interventional radiology enables patients with hepatocellular carcinoma (HCC) to survive longer, there are still many who cannot receive them due to disease progression. We are currently investigating the therapeutic efficacy of the combination of systemic recombinant interleukin-2 (IL-2) administration and local tumor irradiation for HCC patients in the advanced stage. First, the results of the basic experiment to analyze the optimal dose and timing of IL-2 infusion were demonstrated. Intensive administration of high-dose IL-2 caused acute death, whereas intermittent low-dose IL-2 administration resulted in complete tumor regression followed by the acquisition of tumor-specific immunity. Our data suggested that the tumor-bearing state increased the responsiveness to IL-2 treatment, and that an excessively high-dose regimen is not prerequisite for the optimal IL-2 treatment. With regard to the effectiveness of radiotherapy for HCC, human hepatoma cells exhibited apoptotic death when hepatoma cells were cocultured with LAK cells, or were irradiated in vitro with relatively low-dose irradiation. These results suggested the possible synergistic effect of killer cells and low-dose irradiation. Finally, we presented six eligible cases of advanced HCC treated by combination therapy of IL-2 infusion and local low-dose tumor irradiation. Direct anti-tumor effects were one CR, one MR, two NC, and two PD. One CR case and a NC case have survived now for longer than 40 months. In all cases, NK cell activity increased prominently, and side effects wee mild flu-like symptoms except macroscopic hematuria and moderate VLS-like symptoms in two cases in which therapy was continued for longer than 2 years. Hepatic reserve function like prothrombin time or hepaplastic time improved. The apparent clinical effectiveness of the combination therapy presented here might give promising hints for a new therapeutic strategy for HCC. (author)

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 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...

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 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...

Differential Role of Rapamycin in Epidermis-Induced IL-15-IGF-1 Secretion via Activation of Akt/mTORC2.

Science.gov (United States)

Bai, Yang; Xu, Rui; Zhang, Xueyuan; Zhang, Xiaorong; Hu, Xiaohong; Li, Yashu; Li, Haisheng; Liu, Meixi; Huang, Zhenggen; Yan, Rongshuai; He, Weifeng; Luo, Gaoxing; Wu, Jun

2017-01-01

Backgroud/Aims: The effects of rapamycin (RPM) on wound healing have been previously studied. However, reciprocal contradictory data have been reported, and the underlying mechanism remains unclear. This study aims to uncover differential role of RPM in regulation of wound healing and explore the possible mechanism. C57BL/6J mice and epidermal cells were treated with different doses of RPM. The wound re-epithelialization was observed by hematoxylin and eosin (HE) staining. The expression of IL-15 and IGF-1 were detected by immunohistochemistry and quantitative real-time PCR. Epidermal cell survival was determined by CCK-8 assays. Moreover, the mTORC1 and mTORC2 pathway were examined by western blot analysis. This study showed that differential doses of RPM could lead to separate consequences in epidermis. Histological analyses showed that low-dose RPM promoted wound healing, and enhanced the expression of IL-15 and IGF-1. Furthermore, western blot analysis showed that the effect of low-dose RPM in epidermis were not through mTORC1 pathway. Instead, activation of the Akt/mTORC2 pathway was involved in low-dose RPM-induced IL-15 and IGF-1 production in epidermis, while high-dose RPM inhibited the expression of IL-15 and IGF-1 and the activity of mTORC1 and mTORC2 pathway. This study for the first time demonstrated that RPM-mediated wound healing was dose-dependent. © 2017 The Author(s). Published by S. Karger AG, Basel.

Fourteen-day high-dose esomeprazole, amoxicillin and metronidazole as third-line treatment for Helicobacter pylori infection.

Science.gov (United States)

Puig, Ignasi; González-Santiago, Jesús M; Molina-Infante, Javier; Barrio, Jesús; Herranz, Maria Teresa; Algaba, Alicia; Castro, Manuel; Gisbert, Javier P; Calvet, Xavier

2017-09-01

The efficacy of currently recommended third-line therapies for Helicobacter pylori is suboptimal, even that of culture-guided treatments. Resistance to multiple antibiotics is the major factor related to treatment failure. The aim of this study was to evaluate the effectiveness and safety of a 14-day therapy using high-dose of amoxicillin, metronidazole and esomeprazole. Multicenter open-label study as a register in routine clinical practice in patients with two previous failures of eradication therapy. A triple therapy with esomeprazole 40 mg b.d., amoxicillin 1 g t.d.s and metronidazole 500 mg t.d.s for 2 weeks was administered as a third-line therapy after a first treatment including clarithromycin and a second treatment including a quinolone. Helicobacter pylori status was determined by either histology or 13 C-UBT both before and after treatment. A total of 68 patients were included in this study. An interim analysis showed that only three out of eight patients who had received metronidazole in previous eradication regimens were cured (37%, 95% CI 8-75); as a result, after this interim analysis only metronidazole-naïve patients were included. The ITT eradication rate in metronidazole-naive patients was 64% (95% CI 51-76). Adverse events occurred in 58% of patients, all of them mild-to-moderate. Two patients (3%) did not complete >90% of the treatment because of side effects. No severe adverse events occurred. Cure rates of this 14-day schedule using high-dose esomeprazole, amoxicillin and metronidazole as a third-line eradication regimen were suboptimal, especially in patients who had received metronidazole in previous failed eradication regimens. © 2017 John Wiley & Sons Ltd.

THE INFLUENCE OF POLYMORPHISM IN THE INFLAMMATORY GENES IL-1, ß IL-6, IL-10, PPAR?2 AND COX-2 IN PATIENTS WITH MULTIPLE MYELOMA UNDERGOING AUTOLOGOUS BONE MARROW TRANSPLANTATION

DEFF Research Database (Denmark)

Vangsted, Annette; Klausen, Tobias W.; Gimsing, Peter

2007-01-01

in genes involved in the inflammatory response in 348 patients undergoing high dose treatment followed by autologous tem cell transplantation. We found that the polymorphism in IL-1ß T-31C significantly influence overall survival (p=0.02). Homozygous carriers of the variant C-allele had a significantly...

A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors

International Nuclear Information System (INIS)

Connor, Joseph P; Henslee-Downey, Jean; Kramer, Daniel; Neugebauer, Roland; Stupp, Roger; Cristea, Mihaela C; Lewis, Nancy L; Lewis, Lionel D; Komarnitsky, Philip B; Mattiacci, Maria R; Felder, Mildred; Stewart, Sarah; Harter, Josephine

2013-01-01

Humanized KS-interleukin-2 (huKS-IL2), an immunocytokine with specificity for epithelial cell adhesion molecule (EpCAM), has demonstrated favorable tolerability and immunologic activity as a single agent. Phase 1b study in patients with EpCAM-positive advanced solid tumors to determine the maximum tolerated dose (MTD) and safety profile of huKS-IL2 in combination with low-dose cyclophosphamide. Treatment consisted of cyclophosphamide (300 mg/m 2 on day 1), and escalating doses of huKS-IL2 (0.5–4.0 mg/m 2 IV continuous infusion over 4 hours) on days 2, 3, and 4 of each 21-day cycle. Safety, pharmacokinetic profile, immunogenicity, anti-tumor and biologic activity were evaluated. Twenty-seven patients were treated for up to 6 cycles; 26 were evaluable for response. The MTD of huKS-IL2 in combination with 300 mg/m 2 cyclophosphamide was 3.0 mg/m 2 . At higher doses, myelosuppression was dose-limiting. Transient lymphopenia was the most common grade 3/4 adverse event (AE). Other significant AEs included hypotension, hypophosphatemia, and increase in serum creatinine. All patients recovered from these AEs. The huKS-IL2 exposure was dose-dependent, but not dose-proportional, accumulation was negligible, and elimination half-life and systemic clearance were independent of dose and time. Most patients had a transient immune response to huKS-IL2. Immunologic activity was observed at all doses. Ten patients (38%) had stable disease as best response, lasting for ≥ 4 cycles in 3 patients. The combination of huKS-IL2 with low-dose cyclophosphamide was well tolerated. Although no objective responses were observed, the combination showed evidence of immunologic activity and 3 patients showed stable disease for ≥ 4 cycles.

Asian longhorned beetle (ALB) Anoplophora gabripennis: advancements in the eradication program

Science.gov (United States)

Christine Markham; Joe Gittleman; Tom Denholm; Clint. McFarland

2011-01-01

Current detections of Asian longhorned beetle (ALB): August 1996--Brooklyn, NY, later detected on Long Island and in other parts of New York City; July 1998--Chicago, IL; October 2002--Jersey City, NJ; August 2004--Carteret, NJ; August 2008--Worcester, MA. Declared eradication of ALB infestations: April 2008--Chicago, IL, and Jersey City, NJ. Currently regulated for...

Effect of IL-2 on recovery of proliferation ability of irradiated T lymphocytes

International Nuclear Information System (INIS)

Wang Ninghai; Zhang Lansheng

1989-01-01

3 H-thymidine incorporation assay was used to evaluated the proliferation ability of normal human peripheral blood T lymphocytes irradiated with or without exogenous IL-2 by 60 Co γ-ray at various doses after exposure to 1, 2.5, 5, 10, 20 and 40 Gy γ-ray, the DNA synthesis is blocked. It indicated IL-2 has damage effect on the proliferation ability of T cells. 3 H-thymidine incorporation rate in cells decreases with increasing dose of irradiation. Incorporation of 3 H-Tdk in irradiated groups in the dose range of 1 to 40 Gy was compared with that in the control group. The incorporation rate 3 H-TdR in these irradiated groups is 27 to 82 % of that in control group. The inhibition of lymphocyte proliferation was partially enhanced by adding IL-2, but the inhibiting effect on proliferation of human peripheral blood lymphocytes exposed to irradiation at more than 10 Gy is not reversible

Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis.

Science.gov (United States)

Hainzl, Eva; Stockinger, Silvia; Rauch, Isabella; Heider, Susanne; Berry, David; Lassnig, Caroline; Schwab, Clarissa; Rosebrock, Felix; Milinovich, Gabriel; Schlederer, Michaela; Wagner, Michael; Schleper, Christa; Loy, Alexander; Urich, Tim; Kenner, Lukas; Han, Xiaonan; Decker, Thomas; Strobl, Birgit; Müller, Mathias

2015-11-15

In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2(-/-) mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22-STAT3 target genes is reduced in IECs from healthy and colitic Tyk2(-/-) mice. Experiments with conditional Tyk2(-/-) mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22-Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22-dependent colitis was confirmed in Citrobacter rodentium-induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3. Copyright © 2015 by The American Association of Immunologists, Inc.

TRAF2 regulates peripheral CD8(+) T-cell and NKT-cell homeostasis by modulating sensitivity to IL-15.

Science.gov (United States)

Villanueva, Jeanette E; Malle, Elisabeth K; Gardam, Sandra; Silveira, Pablo A; Zammit, Nathan W; Walters, Stacey N; Brink, Robert; Grey, Shane T

2015-06-01

In this study, a critical and novel role for TNF receptor (TNFR) associated factor 2 (TRAF2) is elucidated for peripheral CD8(+) T-cell and NKT-cell homeostasis. Mice deficient in TRAF2 only in their T cells (TRAF2TKO) show ∼40% reduction in effector memory and ∼50% reduction in naïve CD8(+) T-cell subsets. IL-15-dependent populations were reduced further, as TRAF2TKO mice displayed a marked ∼70% reduction in central memory CD8(+) CD44(hi) CD122(+) T cells and ∼80% decrease in NKT cells. TRAF2TKO CD8(+) CD44(hi) T cells exhibited impaired dose-dependent proliferation to exogenous IL-15. In contrast, TRAF2TKO CD8(+) T cells proliferated normally to anti-CD3 and TRAF2TKO CD8(+) CD44(hi) T cells exhibited normal proliferation to exogenous IL-2. TRAF2TKO CD8(+) T cells expressed normal levels of IL-15-associated receptors and possessed functional IL-15-mediated STAT5 phosphorylation, however TRAF2 deletion caused increased AKT activation. Loss of CD8(+) CD44(hi) CD122(+) and NKT cells was mechanistically linked to an inability to respond to IL-15. The reduced CD8(+) CD44(hi) CD122(+) T-cell and NKT-cell populations in TRAF2TKO mice were rescued in the presence of high dose IL-15 by IL-15/IL-15Rα complex administration. These studies demonstrate a critical role for TRAF2 in the maintenance of peripheral CD8(+) CD44(hi) CD122(+) T-cell and NKT-cell homeostasis by modulating sensitivity to T-cell intrinsic growth factors such as IL-15. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

Clinical significance of determination of semen plasma IL-2, IL-6, IL-8 and TNF-α contents in infertile males

International Nuclear Information System (INIS)

Sun Baoyi; Li Jun; Zhang Jiyun

2004-01-01

Objective: To explore the influence of high semen plasma contents of the cytokines (IL-2, IL-6, IL-8, TNF-α) on male fertility. Methods: Semen plasma levels of IL-2, IL-6, IL-8, and TNF-α were determined with RIA in 126 infertile and 20 fertile males. Results: Semen plasma contents of the 4 cytokines in infertile subjects were significantly higher than those in fertile ones (p 4/HP, n=15) had significantly higher contents of cytokines than those without leucocytospermia (WBC<4/HP, n=111). Besides, TNF-α contents in subjects with lower sperm activity and less motility rate as well as IL-8 contents in subjects with less sperm motility rate were both significantly higher than those in subjects with more normal sperms (p<0.01, p<0.05). Conclusion: High semen plasma cytokines contents represent existing local infection and enhanced auto-immune status, both damaging to sperms. Infertility would be the inevitable consequence. Monitoring of changes of the cytokine contents should be a part of fertility studies

IL-2/anti-IL-2 mAb immunocomplexes: A renascence of IL-2 in cancer immunotherapy?

Czech Academy of Sciences Publication Activity Database

Tomala, Jakub; Kovář, Marek

2016-01-01

Roč. 5, č. 3 (2016), e1102829 ISSN 2162-402X R&D Projects: GA ČR GA13-12885S; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61388971 Keywords : Anti-IL-2 mAb * cancer immunotherapy * IL-2 Subject RIV: EE - Microbiology, Virology Impact factor: 7.719, year: 2016

Effects of Shugan Jieyuling self-made on behavior and levels of serum IL-2, IL-6 and cortisol in depression models

International Nuclear Information System (INIS)

Li Qiubo; Yao Di; Zhang Ping; Li Youtian; Xu Dan; Jiang Sailin; Xu Caiyun

2005-01-01

Objective: To study the effects of Shugan Jieyuling self-made (SJSM) on behavior, levels of serum IL-2, IL-6 and cortisol in depression model mice. Methods: The adult mice separately raised and treated with chronic unpredictable middle stress stimulus were used to establish depression models. The curative effect of SJSM was observed in depression model mice. The changes of weight and behavior were detected in a period. Radioimmunoassay (RIA) was used to examine the contents of serum IL-2, IL-6 and cortisol levels. Results: The increased weights of the depression model mice were declined compared with the normal mice before administration. The mental state and behavior of the depression mice were changed. The mice were starling, dreadful, helpless and immobile. At the same time the contents of serum IL-2, IL-6 and cortisol were obviously lower than those of the normal mice. SJSM (large and low doses) and Baiyoujie changed the increased weights and behaviors of the depression after administration for 21 d. The mental state was meliorated simultaneously, and the serum IL-2, IL-6 and cortisol levels in the depression model mice were decreased significantly compared with normal mice. Conclusion: The levels of serum IL-2, IL-6 and cortisol may be the guideline for the diagnosis of depression disease. SJSM can obviously improve both the symptoms of the depression models and the levels of serum IL-2, IL-6 and cortisol. (authors)

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

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

2015-01-01

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

Strengthening the partnership between routine immunization and the global polio eradication initiative to achieve eradication and assure sustainability.

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Abdelwahab, Jalaa; Dietz, Vance; Eggers, Rudolf; Maher, Christopher; Olaniran, Marianne; Sandhu, Hardeep; Vandelaer, Jos

2014-11-01

Since the launch of the Global Polio Eradication Initiative (GPEI) in 1988, the number of polio endemic countries has declined from 125 to 3 in 2013. Despite this remarkable achievement, ongoing circulation of wild poliovirus in polio-endemic countries and the increase in the number of circulating vaccine-derived poliovirus cases, especially those caused by type 2, is a cause for concern. The Polio Eradication and Endgame Strategic Plan 2013-2018 (PEESP) was developed and includes 4 objectives: detection and interruption of poliovirus transmission, containment and certification, legacy planning, and a renewed emphasis on strengthening routine immunization (RI) programs. This is critical for the phased withdrawal of oral poliovirus vaccine, beginning with the type 2 component, and the introduction of a single dose of inactivated polio vaccine into RI programs. This objective has inspired renewed consideration of how the GPEI and RI programs can mutually benefit one another, how the infrastructure from the GPEI can be used to strengthen RI, and how a strengthened RI can facilitate polio eradication. The PEESP is the first GPEI strategic plan that places strong and clear emphasis on the necessity of improving RI to achieve and sustain global polio eradication. Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

A single 2 g oral dose of extended-release azithromycin for treatment of gonococcal urethritis.

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Yasuda, Mitsuru; Ito, Shin; Kido, Akira; Hamano, Kiminari; Uchijima, Yutaka; Uwatoko, Noriyasu; Kusuyama, Hiroyuki; Watanabe, Akiko; Miyamura, Ryuzou; Miyata, Kazutoyo; Deguchi, Takashi

2014-11-01

We treated gonococcal urethritis in men with a single 2 g dose of azithromycin extended-release formulation (azithromycin-SR) to determine its microbiological outcomes and tolerability. We enrolled 189 Japanese men with gonococcal urethritis between April 2009 and December 2013. The patients were given a single 2 g dose of azithromycin-SR. Microbiological efficacy was evaluated by the results of the post-treatment molecular testing of Neisseria gonorrhoeae. MIC testing was performed only for pretreatment isolates of N. gonorrhoeae collected from the patients. We evaluated 130 patients for microbiological outcomes. Of these patients, 122 (93.8%) were judged to be microbiologically cured on the basis of negative test results. All isolates for which the azithromycin MICs were ≤0.25 mg/L were eradicated, whereas 5 of 12 isolates for which the MICs were 1 mg/L persisted after the treatment. Forty-six adverse events occurred in 41 patients. However, all adverse events were classified as mild. The eradication rate of N. gonorrhoeae was 93.8% in men with gonococcal urethritis treated with a single 2 g dose of azithromycin-SR. The breakpoint MIC of a 2 g dose of azithromycin-SR for gonococcal urethritis associated with clinical treatment failures appeared to be 1 mg/L. With regard to side effects of higher doses of azithromycin, the 2 g dose of azithromycin-SR appeared to improve tolerability. However, the widespread use of a high-dose regimen of azithromycin might lead to the development of further resistance to azithromycin. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients

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Ellebaek Eva

2012-08-01

Full Text Available Abstract Background Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL, in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections. Methods This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625 including patients with metastatic melanoma, PS ≤1, age Results Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3–4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months, 2 patients had stable disease (4 and 5 months and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission. Conclusion Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.

Influence of IL28B polymorphisms on response to a lower-than-standard dose peg-IFN-α 2a for genotype 3 chronic hepatitis C in HIV-coinfected patients.

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Luis F López-Cortés

Full Text Available Data on which to base definitive recommendations on the doses and duration of therapy for genotype 3 HCV/HIV-coinfected patients are scarce. We evaluated the efficacy of a lower peginterferon-α 2a dose and a shorter duration of therapy than the current standard of care in genotype 3 HCV/HIV-coinfected patients.Pilot, open-label, single arm clinical trial which involved 58 Caucasian HCV/HIV-coinfected patients who received weekly 135 µg peginterferon-α 2a plus ribavirin 400 mg twice daily during 20 weeks after attaining undetectable viremia. The relationships between baseline patient-related variables, including IL28B genotype, plasma HCV-RNA, ribavirin dose/kg, peginterferon-α 2a and ribavirin levels with virological responses were analyzed. Only 4 patients showed lack of response and 5 patients dropped out due to adverse events related to the study medication. Overall, sustained virologic response (SVR rates were 58.3% by intention-to-treat and 71.4% by per protocol analysis, respectively. Among patients with rapid virologic response (RVR, SVR and relapses rates were 92.6% and 7.4%, respectively. No relationships were observed between viral responses and ribavirin dose/kg, peginterferon-α 2a concentrations, ribavirin levels or rs129679860 genotype.Weekly 135 µg pegIFN-α 2a could be as effective as the standard 180 µg dose, with a very low incidence of severe adverse events. A 24-week treatment duration appears to be appropriate in patients achieving RVR, but extending treatment up to just 20 weeks beyond negativization of viremia is associated with a high relapse rate in those patients not achieving RVR. There was no influence of IL28B genotype on the virological responses.ClinicalTrials.gov NCT00553930.

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

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Todd, John A.; Porter, Linsey; Smyth, Deborah J.; Rainbow, Daniel B.; Ferreira, Ricardo C.; Yang, Jennie H.; Bell, Charles J. M.; Schuilenburg, Helen; Challis, Ben; Clarke, Pamela; Coleman, Gillian; Dawson, Sarah; Goymer, Donna; Kennet, Jane; Brown, Judy; Greatorex, Jane; Goodfellow, Ian; Evans, Mark; Mander, Adrian P.; Bond, Simon; Wicker, Linda S.

2016-01-01

Background Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. Methods and Findings To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = −0

Modulation of pulmonary fibrosis by IL-13Rα2.

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Lumsden, Robert V; Worrell, Julie C; Boylan, Denise; Walsh, Sinead M; Cramton, Jennifer; Counihan, Ian; O'Beirne, Sarah; Medina, Maria Fe; Gauldie, Jack; Fabre, Aurelie; Donnelly, Seamas C; Kane, Rosemary; Keane, Michael P

2015-04-01

Pulmonary fibrosis is a progressive and fatal disease that involves the remodeling of the distal airspace and the lung parenchyma, which results in compromised gas exchange. The median survival time once diagnosed is less than three years. Interleukin (IL)-13 has been shown to play a role in a number of inflammatory and fibrotic diseases. IL-13 modulates its effector functions via a complex receptor system that includes the IL-4 receptor (R) α, IL-13Rα1, and the IL-13Rα2. IL-13Rα1 binds IL-13 with low affinity, yet, when it forms a complex with IL-4α, it binds with much higher affinity, inducing the effector functions of IL-13. IL-13Rα2 binds IL-13 with high affinity but has a short cytoplasmic tail and has been shown to act as a nonsignaling decoy receptor. Transfection of fibroblasts and epithelial cells with IL-13Rα2 inhibited the IL-13 induction of soluble collagen, TGF-β, and CCL17. Adenoviral overexpression of IL-13Rα2 in the lung reduced bleomycin-induced fibrosis. Our work shows that overexpression of IL-13Rα2 inhibits the IL-13 induction of fibrotic markers in vitro and inhibits bleomycin-induced pulmonary fibrosis. In summary our study highlights the antifibrotic nature of IL-13Ra2. Copyright © 2015 the American Physiological Society.

Effects of overexpression of IL-1 receptor-associated kinase on NFkappaB activation, IL-2 production and stress-activated protein kinases in the murine T cell line EL4.

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Knop, J; Wesche, H; Lang, D; Martin, M U

1998-10-01

The association and activation of the IL-1 receptor-associated protein kinase (IRAK) to the IL-1 receptor complex is one of the earliest events detectable in IL-1 signal transduction. We generated permanent clones of the murine T cell line EL4 6.1 overexpressing human (h)IRAK to evaluate the role of this kinase in IL-1 signaling. Overexpression of hIRAK enhanced IL-1-stimulated activation of the transcription factor NFkappaB, whereas a truncated form (N-IRAK) specifically inhibited IL-1-dependent NFkappaB activity. In clones stably overexpressing hIRAK a weak constitutive activation of NFkappaB correlated with a low basal IL-2 production which was enhanced in an IL-1-dependent manner. Compared to the parental cell line the dose-response curve of IL-1-induced IL-2 production was shifted in both potency and efficacy. These results demonstrate that IRAK directly triggers NFkappaB-mediated gene expression in EL4 cells. Qualitatively different effects were observed for the IL-1-induced activation of stress-activated protein (SAP) kinases: permanent overexpression of IRAK did not affect the dose dependence but prolonged the kinetics of IL-1-induced activation of SAP kinases, suggesting that this signaling branch may be regulated by distinct mechanisms.

Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2 receptor agonist for cancer immunotherapy.

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Deborah Charych

Full Text Available Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2 protein bound by multiple releasable polyethylene glycol (PEG chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR-214 is a biologic prodrug. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated-IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs. Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR-214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action.

Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy.

Science.gov (United States)

Charych, Deborah; Khalili, Samira; Dixit, Vidula; Kirk, Peter; Chang, Thomas; Langowski, John; Rubas, Werner; Doberstein, Stephen K; Eldon, Michael; Hoch, Ute; Zalevsky, Jonathan

2017-01-01

Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2) protein bound by multiple releasable polyethylene glycol (PEG) chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR-214 is a biologic prodrug. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated-IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α) subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs). Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR-214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action.

Closely related glycosylation patterns of recombinant human IL-2 expressed in a CHO cell line and natural IL-2

International Nuclear Information System (INIS)

Vita, N.; Magazin, M.; Marchese, E.; Lupker, J.; Ferrara, P.

1990-01-01

We report here the study of the glycosylation pattern of human recombinant (r) IL2 expressed in a Chinese hamster ovary (CHO) cell line. The human rIL2 secreted by this high-producing recombinant CHO cell line was metabolically radiolabelled with [35S]-methionine, or with [3H]-glucosamine and [3H]-galactose, purified to homogeneity, and then characterized. The electrophoretic analysis of the [35S]-methionine-labelled proteins present in the culture medium of the CHO cell line showed that the rIL2 represents approximately 12% of the total secreted proteins. Furthermore, pulse-chase experiments showed that the glycosylated rIL2 is synthesized and secreted within 30 min. The point of attachment and the structure of the carbohydrate moiety of the rIL2 was determined by: amino-terminal sequencing and fingerprint analysis of the 3H-labelled rIL2, mass spectroscopy of the amino-terminal tryptic octapeptide, and carbohydrate analysis after enzymatic (Vibrio cholerae neuraminidase and Aspergillus oryzae beta-galactosidase) or sulfuric acid hydrolysis. The results indicate that the recombinant protein possesses a sugar moiety O-linked to the threonine residue at position 3 of the polypeptide chain, and that sialic acid, galactose and N-acetyl galactosamine are components of this carbohydrate moiety. Taken together these results suggest that the recombinant molecule is identical to natural IL2

[The role of Sabin inactivated poliovirus vaccine in the final phase of global polio eradication].

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Dong, S Z; Zhu, W B

2016-12-06

Global polio eradication has entered its final phase, but still faces enormous challenges. The Polio Eradication and Endgame Strategic Plan (2013-2018) set the target for making the world polio-free by 2018. Meanwhile, the World Heath Organization Global Action Plan (GAP Ⅲ) recommended that polioviruses be stored under strict conditions after eradication of the wild poliovirus. At least one dose of inactivated poliovirus vaccine (IPV) would be required for each newborn baby in the world to ensure successful completion of the final strategy and GAP Ⅲ. The Sabin IPV has a high production safety and low production cost, compared with the wild-virus IPV and, therefore, can play an important role in the final stage of global polio eradication.

Chronic IL-6 Administration Desensitizes IL-6 Response in Liver, Causes Hyperleptinemia and Aggravates Steatosis in Diet-Induced-Obese Mice

DEFF Research Database (Denmark)

Gavito, Ana Luisa; Bautista, Dolores; Suarez, Juan

2016-01-01

High-fat diet-induced obesity (DIO) is associated with fatty liver and elevated IL-6 circulating levels. IL-6 administration in rodents has yielded contradictory results regarding its effects on steatosis progression. In some models of fatty liver disease, high doses of human IL-6 ameliorate the ...

Direct regulation of IL-2 by curcumin.

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Oh, Jin-Gyo; Hwang, Da-Jeong; Heo, Tae-Hwe

2018-01-01

Interleukin-2 (IL-2) is a crucial growth factor for both regulatory and effector T cells. Thus, IL-2 plays a critical role in the stimulation and suppression of immune responses. Recently, anti-IL-2 antibodies (Abs) have been shown to possess strong IL-2 modulatory activities by affecting the interaction between IL-2 and IL-2 receptors. In this study, we screened an herbal library to identify a compound that regulates IL-2, which resulted in the identification of curcumin as a direct binder and inhibitor of IL-2. Curcumin is a phytochemical with well-known anti-cancer properties. In this study, curcumin mimicked or altered the binding pattern of anti-IL-2 Abs against IL-2 and remarkably inhibited the interaction of recombinant IL-2 with the IL-2 receptor α, CD25. Interestingly, curcumin neutralized the biological activities of IL-2 both in vitro and in vivo. In this report, we elucidated the unsolved mechanism of the anti-cancer effect of curcumin by identifying IL-2 as a direct molecular target. Curcumin, as a small molecule IL-2 modulator, has the potential to be used to treat IL-2 related pathologic conditions. Copyright © 2017 Elsevier Inc. All rights reserved.

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

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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.

Peak {sup 14}CO{sub 2} excretion, symptoms and eradication of H.Pylori (HP) in patients with duodenal ulcer (DU)

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Batholomeusz, F.D.L.; Bellon, M. [Royal Adelaide Hospital, Adelaide, SA (Australia). Department of Nuclear Medicine

1997-12-01

Full text: Many factors including drug efficacy, compliance and antibiotic resistance may influence HP eradication rates. The {sup 14}C urea breath test is a sensitive method of confirming HP colonisation and eradication. The aim was to study the relationships between the peak {sup 14}CO{sub 2} counts on the breath test prior to treatment, smoking and HP eradication, and to assess if persistent or recurrent symptoms implied failure of eradication. 117 patients with DU and HP colonisation proved on biopsy or rapid urease test who underwent {sup 14}C urea breath tests at least one month after eradication treatment was ceased were studied (69 male, 48 female, mean age 41, range 26-87 y). Questionnaire assessment of treatment regimen, smoking history and dyspeptic symptoms was made at the time of the breath test. A sub-group of 43 patients who had pre- and post-treatment breath tests was studied to assess if high peak {sup 14}CO{sub 2} counts on the pre-treatment breath test related to treatment success. The mean peak initial {sup 14}CO{sub 2} excretion in those who were treated successfully was 4187 (+ 472) counts/min and for failures 4817 (+739) counts/min (p 0.24). Dyspeptic symptoms were present in 36% of patients treated successfully and 37% where treatment failed. The eradication rate for the 56 smokers was 75 per cent, and the 61 non-smokers 83%. (p>0.2) High {sup 14}CO{sub 2} excretion on the initial {sup 14}C urea breath test and smoking are not associated with a significantly lower rate of HP eradication and the presence of dyspepsia is not a good indicator of persistent infection

High IL-17E and low IL-17C dermal expression identifies a fibrosis-specific motif common to morphea and systemic sclerosis.

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Paola Adele Lonati

Full Text Available BACKGROUND: High interleukin (IL-17A levels are characteristically found in the skin of systemic sclerosis (SSc individuals. Our aim was to investigate whether the dermal expression of IL-17A and related IL-17 family members (i.e. IL-17C, IL-17E and IL-17F could distinguish fibrotic from healthy skin and could show similarities in SSc and morphea, two disorders with presumed distinct pathogenesis, but characterized by skin fibrosis. METHODS: Biopsies were obtained from the involved skin of 14 SSc, 5 morphea and 8 healthy donors (HD undergoing plastic surgery. Immunohistochemistry/immunofluorescence techniques were coupled to a semi-automated imaging quantification approach to determine the presence of the IL-17 family members in the skin. The in vitro effects induced by the IL-17 family members on fibroblasts from normal and SSc individuals were assessed by ELISA and RIA. RESULTS: Positive cells for each of the IL-17 isoforms investigated were present in the dermis of all the individuals tested, though with variable frequencies. SSc individuals had increased frequency of IL-17A+ (p = 0.0237 and decreased frequency of IL-17F+ (p = 0.0127 and IL-17C+ cells (p = 0.0008 when compared to HD. Similarly, morphea individuals had less frequent IL-17C+ cells (p = 0.0186 in their skin but showed similar number of IL-17A+ and IL-17F+ cells when compared to HD. Finally, IL-17E+ cells were more numerous in morphea (p = 0.0109 and tended to be more frequent in SSc than in HD. Fibroblast production of IL-6, MMP-1 and MCP-1 was enhanced in a dose-dependent manner in the presence of IL-17E and IL-17F, but not in the presence of IL-17C. None of the cytokine tested had significant effect on type I collagen production. Of interest, in SSc the frequency of both IL-17A and IL-17F positive cells increased with disease duration. CONCLUSIONS: The frequency of IL-17A and IL-17F distinguish SSc to morphea individuals while dermal expression of IL-17C (low and IL-17E (high

Clinical significance of the changes of serum levels of the rheumatoid activity markers IL-2, sIL-2R, HA and VEGF

International Nuclear Information System (INIS)

Bao Yong; Long Wubin; Yu Ke; Zeng Ying; Liu Deying

2004-01-01

Objective: To explore the relationship between rheumatoid activity and serum levels of the cytokines interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R), hyaluronic acid (HA), vascular endothelial growth factor (VEGF) in patients with rheumatoid arthritis. Methods: Serum IL-2, HA(with RIA) and sIL-2R, VEGF (with ELISA) levels were determined in 30 controls, 30 patients with active rheumatoid arthritis and 30 patients with rheumatoid arthritis in remission. Sensitivity and specificity for each marker were analyzed. Results: In patients with active rheumatoid arthritis, the serum levels of sIL-2R, HA, VEGF were significantly higher and serum levels of IL-2 significantly lower than those in patients in remission and controls (p<0.01). Determination of VEGF levels possessed the highest specificity (93.3%) and also a high sensitivity (93.3% as well). Conclusion: Determination of the serum levels of any of these markers was valuable for monitoring the activity of the rheumatoid process. It is more desirable to take measurements of VEGF levels due to its highest specificity

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

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Gabardi, Steven; Catella, Jennifer; Martin, Spencer T; Perrone, Ronald; Chandraker, Anil; Magee, Colm C; McDevitt-Potter, Lisa M

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. The first patient is a 52-year-old female with a history of intolerance to calcineurin inhibitors (CNIs) and sirolimus. Following her second transplant, the patient received mycophenolate mofetil 100 mg twice daily, a tapering corticosteroid regimen (initial dose of methylprednisolone 500 mg tapered over 1 week to prednisone 30 mg/day), and biweekly intravenous daclizumab 1-1.2 mg/kg/dose; 33 months after transplant the IL-2RA was changed to intravenous basiliximab 40 mg once a month. At 40 months after transplant, the patient continued to have stable renal function (estimated glomerular filtration rate 48 mL/min/1.73 m²) with excellent tolerability. The second patient is a 59-year-old female also intolerant to CNIs and sirolimus who required intermittent maintenance therapy with intravenous basiliximab 20 mg/dose. Despite an initial rejection episode, the patient tolerated more than 2 years of basiliximab therapy with good renal function (estimated glomerular filtration rate 103 months after transplant 69 mL/min/1.73 m²) and no adverse events. The IL-2RAs basiliximab and daclizumab possess several characteristics of ideal maintenance immunosuppressive agents (ie, nondepleting, long half-lives, limited adverse events). Based on a MEDLINE search (through December 31, 2010) using the search terms basiliximab, daclizumab, organ transplant, immunosuppression, and/or maintenance immunosuppression, and an advanced search in the published abstracts from the American Transplant Congress and World Transplant Congress (2000-2010), it appears that IL-2RAs have been used successfully as short-term therapy in both renal and extrarenal transplant recipients to allow for renal recovery following CNI-induced nephrotoxicity. In heart transplant recipients, the IL-2

Virulence factor genotypes of Helicobacter pylori affect cure rates of eradication therapy.

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Sugimoto, Mitsushige; Yamaoka, Yoshio

2009-01-01

The cure rates of Helicobacter pylori infection by using a combination of a proton pump inhibitor (PPI) and antimicrobial agents are mainly influenced by bacterial susceptibility to antimicrobial agents and the magnitude of acid inhibition during the treatment. Currently used empirical triple therapies do not reliably produce a > or =80% cure rate on an intention-to-treat basis. Therefore, tailored regimens based on relevant microbiological findings and pharmacogenomics are recommended for attaining an acceptable > or =95% cure rate. Recently, virulence factors of H. pylori, such as cagA and vacA, are reported to be major factors determining the cure rates. Individuals infected with strains with cagA-negative and vacA s2 genotypes have significantly increased risk of eradication failure of H. pylori infection. These virulence factors enhance gastric mucosal inflammation and are associated with the development of peptic ulcer and gastric cancer. H. pylori virulence factors induce proinflammatory cytokines, such as interleukin (IL)-1, IL-8, and tumor necrosis factor (TNF)- which influence mucosal inflammation and/or gastric acid secretion. When physicians select an H. pylori eradication regimen with an acceptable cure rate, they might need to consider H. pylori virulence factors, especially cagA and vacA.

High-dose MeV electron irradiation of Si-SiO2 structures implanted with high doses Si+

Science.gov (United States)

Kaschieva, S.; Angelov, Ch; Dmitriev, S. N.

2018-03-01

The influence was studied of 22-MeV electron irradiation on Si-SiO2 structures implanted with high-fluence Si+ ions. Our earlier works demonstrated that Si redistribution is observed in Si+-ion-implanted Si-SiO2 structures (after MeV electron irradiation) only in the case when ion implantation is carried out with a higher fluence (1016 cm-2). We focused our attention on the interaction of high-dose MeV electron irradiation (6.0×1016 cm-2) with n-Si-SiO2 structures implanted with Si+ ions (fluence 5.4×1016 cm-2 of the same order magnitude). The redistribution of both oxygen and silicon atoms in the implanted Si-SiO2 samples after MeV electron irradiation was studied by Rutherford back-scattering (RBS) spectroscopy in combination with a channeling technique (RBS/C). Our results demonstrated that the redistribution of oxygen and silicon atoms in the implanted samples reaches saturation after these high doses of MeV electron irradiation. The transformation of amorphous SiO2 surface into crystalline Si nanostructures (after MeV electron irradiation) was evidenced by atomic force microscopy (AFM). Silicon nanocrystals are formed on the SiO2 surface after MeV electron irradiation. The shape and number of the Si nanocrystals on the SiO2 surface depend on the MeV electron irradiation, while their size increases with the dose. The mean Si nanocrystals height is 16-20 nm after irradiation with MeV electrons at the dose of 6.0×1016 cm-2.

Preclinical evaluation of IL2-based immunocytokines supports their use in combination with dacarbazine, paclitaxel and TNF-based immunotherapy.

Science.gov (United States)

Pretto, Francesca; Elia, Giuliano; Castioni, Nadia; Neri, Dario

2014-09-01

Antibody-cytokine fusion proteins ("immunocytokines") represent a promising class of armed antibody products, which allow the selective delivery of potent pro-inflammatory payloads at the tumor site. The antibody-based selective delivery of interleukin-2 (IL2) is particularly attractive for the treatment of metastatic melanoma, an indication for which this cytokine received marketing approval from the US Food and drug administration. We used the K1735M2 immunocompetent syngeneic model of murine melanoma to study the therapeutic activity of F8-IL2, an immunocytokine based on the F8 antibody in diabody format, fused to human IL2. F8-IL2 was shown to selectively localize at the tumor site in vivo, following intravenous administration, and to mediate tumor growth retardation, which was potentiated by the combination with paclitaxel or dacarbazine. Combination treatment led to a substantially more effective tumor growth inhibition, compared to the cytotoxic drugs used as single agents, without additional toxicity. Analysis of the immune infiltrate revealed a significant accumulation of CD4(+) T cells 24 h after the administration of the combination. The fusion proteins F8-IL2 and L19-IL2, specific to the alternatively spliced extra domain A and extra domain B of fibronectin respectively, were also studied in combination with tumor necrosis factor (TNF)-based immunocytokines. The combination treatment was superior to the action of the individual immunocytokines and was able to eradicate neoplastic lesions after a single intratumoral injection, a procedure that is being clinically used for the treatment of Stage IIIC melanoma. Collectively, these data reinforce the rationale for the use of IL2-based immunocytokines in combination with cytotoxic agents or TNF-based immunotherapy for the treatment of melanoma patients.

Phase I Trial of Anti-PSMA Designer CAR-T Cells in Prostate Cancer: Possible Role for Interacting Interleukin 2-T Cell Pharmacodynamics as a Determinant of Clinical Response.

Science.gov (United States)

Junghans, Richard P; Ma, Qiangzhong; Rathore, Ritesh; Gomes, Erica M; Bais, Anthony J; Lo, Agnes S Y; Abedi, Mehrdad; Davies, Robin A; Cabral, Howard J; Al-Homsi, A Samer; Cohen, Stephen I

2016-10-01

Chimeric antigen receptor (CAR)-modified "designer" T cells (dTc, CAR-T) against PSMA selectively target antigen-expressing cells in vitro and eliminate tumors in vivo. Interleukin 2 (IL2), widely used in adoptive therapies, was proven essential in animal models for dTc to eradicate established solid tumors. Patients under-went chemotherapy condi-tion-ing, followed by dTc dosing under a Phase I escalation with continuous infusion low dose IL2 (LDI). A target of dTc escalation was to achieve ≥20% engraftment of infused activated T cells. Six patients enrolled with doses prepared of whom five were treated. Patients received 10(9) or 10(10) autologous T cells, achieving expansions of 20-560-fold over 2 weeks and engraftments of 5-56%. Pharmacokinetic and pharmacodynamic analyses established the impact of conditioning to promote expansion and engraftment of the infused T cells. Unexpectedly, administered IL2 was depleted up to 20-fold with high engraftments of activated T cells (aTc) in an inverse correlation (P < 0.01). Clinically, no anti-PSMA toxicities were noted, and no anti-CAR reactivities were detected post-treatment. Two-of-five patients achieved clinical partial responses (PR), with PSA declines of 50% and 70% and PSA delays of 78 and 150 days, plus a minor response in a third patient. Responses were unrelated to dose size (P = 0.6), instead correlating inversely with engraftment (P = 0.06) and directly with plasma IL2 (P = 0.03), suggesting insufficient IL2 with our LDI protocol to support dTc anti-tumor activity under optimal (high) dTc engraftments. Under a Phase I dose escalation in prostate cancer, a 20% engraftment target was met or exceeded in three subjects with adequate safety, leading to study conclusion. Clinical responses were obtained but were suggested to be restrained by low plasma IL2 when depleted by high levels of engrafted activated T cells. This report presents a unique example of how the pharmaco-dynamics of "drug

Structure of IL-22 Bound to Its High-Affinity IL-22R1 Chain

Energy Technology Data Exchange (ETDEWEB)

Jones, B.C.; Logsdon, N.J.; Walter, M.R. (UAB)

2008-09-29

IL-22 is an IL-10 family cytokine that initiates innate immune responses against bacterial pathogens and contributes to immune disease. IL-22 biological activity is initiated by binding to a cell-surface complex composed of IL-22R1 and IL-10R2 receptor chains and further regulated by interactions with a soluble binding protein, IL-22BP, which shares sequence similarity with an extracellular region of IL-22R1 (sIL-22R1). IL-22R1 also pairs with the IL-20R2 chain to induce IL-20 and IL-24 signaling. To define the molecular basis of these diverse interactions, we have determined the structure of the IL-22/sIL-22R1 complex. The structure, combined with homology modeling and surface plasmon resonance studies, defines the molecular basis for the distinct affinities and specificities of IL-22 and IL-10 receptor chains that regulate cellular targeting and signal transduction to elicit effective immune responses.

Immunotherapy of human cancer with lak cells and IL-2

International Nuclear Information System (INIS)

Choi, Kyu Chul; Nam, Sang Yun; Ha, Youn Mun; Choi, Yong Mook

1988-01-01

The effects of adoptive immunotherapy with LAK cells and/or IL-2 were evaluated in 18 patients with advanced cancer for whom standard therapy had proved ineffective, from Jul. 1985 to Jan. 1988. Six patients were treated with LAK cells only, 4 patients treated with continuous IV infusion of IL-2 alone, and 8 patients treated with LAK cells plus IL-2. In a patient with hepatoma LAK cells and IL-2 were infused by selective catheterization to a branch of hepatic artery, in a patient with gastric cancer complicated by cancer peritonities LAK cells and IL-2 were infused to peritoneal cavity, and in a patient with renal cell carcinoma HLA-matched allogeneic LAK cells from 2 siblings were infused intravenously(8 times, total 2.49 X 10 10 cells). In the patient with gastric cancer who was treated by peritoneal infusion, LAK cells were induced from mononuclear cells obtained from ascites. Of 17 evaluable patients, 1(5.9%) had complete response(CR), 1(5.9%) had partial response (PR), 4(23.5%) had minimal responses(Min R), and 2(11.8%) had mixed responses(Mix R). Especially, of 7 evaluable patients treated with LAK cells plus IL-2, 1(14.3%) had CR, 1(14.3%) had PR, and 3(42.9%) had Min R. CR with relapse-free survival for 19 months was observed in a lung cancer (squamous cell carcinoma). PR was observed in a lung cancer, and Min R were observed in 2 hepatomas, 1 gastric cancer and 1 neuroblastoma. In 3 pediatric patients (3 to 7 years old) continuous infusion of IL-2 in dose-escalation mode were studied. They were able to tolerate 4,000,000 KH u/M 2 /day for 7 days of IL-2(1 KH u=1.1 BRMP u). Most of adult patients well tolerated 2,000,000 KH u/M 2 /day for 5 days of IL-2 in mode of continuous IV infusion. Most common side effects were chills and fever which could be prevented or minimized by premedication of antihistamine, indomethacin and acetaminophen, and IV infusion of demerol. Serious side effects were complicated by capillary leak syndrome which showed hypotension

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.

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

Purification, crystallization and preliminary X-ray diffraction analysis of the IL-20-IL-20R1-IL-20R2 complex

Energy Technology Data Exchange (ETDEWEB)

Logsdon, Naomi J.; Allen, Christopher E.; Rajashankar, Kanagalaghatta R.; Walter, Mark R. (Cornell); (UAB)

2012-02-08

Interleukin-20 (IL-20) is an IL-10-family cytokine that regulates innate and adaptive immunity in skin and other tissues. In addition to protecting the host from various external pathogens, dysregulated IL-20 signaling has been shown to contribute to the pathogenesis of human psoriasis. IL-20 signals through two cell-surface receptor heterodimers, IL-20R1-IL-20R2 and IL-22R1-IL-20R2. In this report, crystals of the IL-20-IL-20R1-IL-20R2 ternary complex have been grown from polyethylene glycol solutions. The crystals belonged to space group P4{sub 1}2{sub 1}2 or P4{sub 3}2{sub 1}2, with unit-cell parameters a = 111, c = 135 {angstrom}, and diffracted X-rays to 3 {angstrom} resolution. The crystallographic asymmetric unit contains one IL-20-IL-20R1-IL-20R2 complex, corresponding to a solvent content of approximately 54%.

Global Polio Eradication - Way Ahead.

Science.gov (United States)

Bahl, Sunil; Bhatnagar, Pankaj; Sutter, Roland W; Roesel, Sigrun; Zaffran, Michel

2018-02-01

In 1988, the World Health Assembly resolved to eradicate poliomyelitis by the year 2000. Although substantial progress was achieved by 2000, global polio eradication proved elusive. In India, the goal was accomplished in 2011, and the entire South-East Asia Region was certified as polio-free in 2014. The year 2016 marks the lowest wild poliovirus type 1 case count ever, the lowest number of polio-endemic countries (Afghanistan, Nigeria and Pakistan), the maintenance of wild poliovirus type 2 eradication, and the continued absence of wild poliovirus type 3 detection since 2012. The year also marks the Global Polio Eradication Initiative (GPEI) moving into the post-cessation of Sabin type 2, after the effort of globally synchronized withdrawal of Sabin type 2 poliovirus in April 2016. Sustained efforts will be needed to ensure polio eradication is accomplished, to overcome the access and security issues, and continue to improve the quality and reach of field operations. After that, surveillance (the "eyes and ears") will move further to the center stage. Sensitive surveillance will monitor the withdrawal of all Sabin polioviruses, and with facility containment, constitute the cornerstones for eventual global certification of wild poliovirus eradication. An emergency response capacity is essential to institute timely control measures should polio still re-emerge. Simultaneously, the public health community needs to determine whether and how to apply the polio-funded infrastructure to other priorities (after the GPEI funding has stopped). Eradication is the primary goal, but securing eradication will require continued efforts, dedicated resources, and a firm commitment by the global public health community.

[Effects of canine IL-2 and IL-7 genes on enhancing immunogenicity of canine parvovirus VP2 gene vaccine in mice].

Science.gov (United States)

Chen, Huihui; Zhong, Fei; Li, Xiujin; Wang, Lu; Sun, Yan; Neng, Changai; Zhang, Kao; Li, Wenyan; Wen, Jiexia

2012-11-04

To investigate the effects of canine interleukin-2 (cIL-2) and cIL-7 genes on enhancing the immunogenicity of canine parvovirus (CPV) VP2 DNA vaccine. The bicistronic vectors of cIL-2 and cIL-7 genes were constructed using the eukaryotic expression vector containing internal ribosome entry site (IRES). The cIL-2/ cIL-7 dicistronic vector plus previously constructed vectors, including CPV VP2 DNA vaccine vector, cIL-2 vector and cIL-7 vector, were used to co-immunize mice with different combinations, consisting of VP2 alone, VP2 + cIL-2, VP2 + cIL-7 and VP2 + cIL-2/cIL-7. The VP2-specific antibody levels in immunized mice were measured by ELISA at different time post-immunization. The proliferation indices and interferon-gamma expression were measured by lymphocyte proliferation assay and ELISA, respectively. The cIL-2/cIL-7 bicistronic vector was correct and could mediate cIL-2 and cIL-7 gene expression in eukaryotic cells. Immunization results revealed that the antibody titers and the neutralizing antibody levels of the mice co-immunized with VP2 + cIL-7/cIL-2 vectors were significantly higher than that with either VP2 + cIL-2 vectors or VP2 + cIL-7 vectors (P vaccine.

An optimized clarithromycin-free 14-day triple therapy for Helicobacter pylori eradication achieves high cure rates in Uruguay.

Science.gov (United States)

Dacoll, Cristina; Sánchez-Delgado, Jordi; Balter, Henia; Pazos, Ximena; Di Pace, María; Sandoya, Gabriela; Cohen, Henry; Calvet, Xavier

Strong acid inhibition increases cure rates with triple therapy and 14-day are more effective than 7-day treatments. The combination of amoxicillin plus metronidazole at full doses has been shown to overcome metronidazole resistance and to achieve good eradication rates even in patients harboring resistant strains. No previous studies have been reported in Latin-America with this optimized triple-therapy scheme. The aim of the present study was to assess the eradication rate and tolerance of a new first-line treatment regimen associating strong acid inhibition, amoxicillin and metronidazole. Patients from the Clínica de Gastroenterología of the Hospital de Clínicas (Montevideo, Uruguay) were included. Hp status was mainly assessed by at least one of the following: histologyor urea breath test (UBT). A 14-day treatment was prescribed comprising esomeprazole 40mg twice a day plus amoxicillin 1g and metronidazole 500mg, both three times a day. H. pylori cure was assessed by UBT. Forty-one patients were enrolled. Mean age was 53.3±13 years and 17.1% of patients were male. Main indications for treatment were: functional dyspepsia (27.5%), gastritis (45%), gastric or duodenal erosions (20%), gastric ulcer (5%) and intestinal metaplasia (2.5%). H. pylori eradication was achieved in 33 of the 37 patients who returned for follow-up. Eradication rates were 80.5% (95% CI: 68.4-92.6) by intention-to-treat (ITT) analysis and 89.2% (95% CI; 79.2-99.2) per protocol (PP). No major side effects were reported; 26 patients (65.8%) complained of mild side effects (nausea, diarrhea and headache). Cure rates of this triple therapy including esomeprazole, amoxicillin and metronidazole were 81% per ITT and the treatment was well tolerated. These optimal results with a simple clarithromycin-free triple therapy are better than described for standard triple therapy but there is still room for improvement to reach the desired target of 90% per ITT. Copyright © 2017 Elsevier España, S

Synergy between an antiangiogenic integrin αv antagonist and an antibody–cytokine fusion protein eradicates spontaneous tumor metastases

OpenAIRE

Lode, Holger N.; Moehler, Thomas; Xiang, Rong; Jonczyk, Alfred; Gillies, Stephen D.; Cheresh, David A.; Reisfeld, Ralph A.

1999-01-01

The suppression and eradication of primary tumors and distant metastases is a major goal of alternative treatment strategies for cancer, such as inhibition of angiogenesis and targeted immunotherapy. We report here a synergy between two novel monotherapies directed against vascular and tumor compartments, respectively, a tumor vasculature-specific antiangiogenic integrin αv antagonist and tumor-specific antibody–interleukin 2 (IL-2) fusion proteins. Simultaneous an...

Immunogenicity and safety of a novel monovalent high-dose inactivated poliovirus type 2 vaccine in infants: a comparative, observer-blind, randomised, controlled trial.

Science.gov (United States)

Sáez-Llorens, Xavier; Clemens, Ralf; Leroux-Roels, Geert; Jimeno, José; Clemens, Sue Ann Costa; Weldon, William C; Oberste, M Steven; Molina, Natanael; Bandyopadhyay, Ananda S

2016-03-01

Following the proposed worldwide switch from trivalent oral poliovirus vaccine (tOPV) to bivalent types 1 and 3 OPV (bOPV) in 2016, inactivated poliovirus vaccine (IPV) will be the only source of protection against poliovirus type 2. With most countries opting for one dose of IPV in routine immunisation schedules during this transition because of cost and manufacturing constraints, optimisation of protection against all poliovirus types will be a priority of the global eradication programme. We assessed the immunogenicity and safety of a novel monovalent high-dose inactivated poliovirus type 2 vaccine (mIPV2HD) in infants. This observer-blind, comparative, randomised controlled trial was done in a single centre in Panama. We enrolled healthy infants who had not received any previous vaccination against poliovirus. Infants were randomly assigned (1:1) by computer-generated randomisation sequence to receive a single dose of either mIPV2HD or standard trivalent IPV given concurrently with a third dose of bOPV at 14 weeks of age. At 18 weeks, all infants were challenged with one dose of monovalent type 2 OPV (mOPV2). Primary endpoints were seroconversion and median antibody titres to type 2 poliovirus 4 weeks after vaccination with mIPV2HD or IPV; and safety (as determined by the proportion and nature of serious adverse events and important medical events for 8 weeks after vaccination). The primary immunogenicity analyses included all participants for whom a post-vaccination blood sample was available. All randomised participants were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02111135. Between April 14 and May 9, 2014, 233 children were enrolled and randomly assigned to receive mIPV2HD (117 infants) or IPV (116 infants). 4 weeks after vaccination with mIPV2HD or IPV, seroconversion to poliovirus type 2 was recorded in 107 (93·0%, 95% CI 86·8-96·9) of 115 infants in the mIPV2HD group compared with 86 (74·8%, 65·8

Eradicating hepatitis C virus ameliorates insulin resistance without change in adipose depots.

Science.gov (United States)

Milner, K-L; Jenkins, A B; Trenell, M; Tid-Ang, J; Samocha-Bonet, D; Weltman, M; Xu, A; George, J; Chisholm, D J

2014-05-01

Chronic hepatitis C (CHC) is associated with lipid-related changes and insulin resistance; the latter predicts response to antiviral therapy, liver disease progression and the risk of diabetes. We sought to determine whether insulin sensitivity improves following CHC viral eradication after antiviral therapy and whether this is accompanied by changes in fat depots or adipokine levels. We compared 8 normoglycaemic men with CHC (genotype 1 or 3) before and at least 6 months post viral eradication and 15 hepatitis C antibody negative controls using an intravenous glucose tolerance test and two-step hyperinsulinaemic-euglycaemic clamp with [6,6-(2) H2 ] glucose to assess peripheral and hepatic insulin sensitivity. Magnetic resonance imaging and spectroscopy quantified abdominal fat compartments, liver and intramyocellular lipid. Peripheral insulin sensitivity improved (glucose infusion rate during high-dose insulin increased from 10.1 ± 1.6 to 12 ± 2.1 mg/kg/min/, P = 0.025), with no change in hepatic insulin response following successful viral eradication, without any accompanying change in muscle, liver or abdominal fat depots. There was corresponding improvement in incremental glycaemic response to intravenous glucose (pretreatment: 62.1 ± 8.3 vs post-treatment: 56.1 ± 8.5 mm, P = 0.008). Insulin sensitivity after viral clearance was comparable to matched controls without CHC. Post therapy, liver enzyme levels decreased but, interestingly, levels of glucagon, fatty acid-binding protein and lipocalin-2 remained elevated. Eradication of the hepatitis C virus improves insulin sensitivity without alteration in fat depots, adipokine or glucagon levels, consistent with a direct link of the virus with insulin resistance. © 2013 John Wiley & Sons Ltd.

IL-2 and IL-15 regulate CD154 expression on activated CD4 T cells

DEFF Research Database (Denmark)

Skov, S; Bonyhadi, M; Odum, Niels

2000-01-01

The cellular and humoral immune system is critically dependent upon CD40-CD154 (CD40 ligand) interactions between CD40 expressed on B cells, macrophages, and dendritic cells, and CD154 expressed primarily on CD4 T cells. Previous studies have shown that CD154 is transiently expressed on CD4 T cells...... after T cell receptor engagement in vitro. However, we found that stimulation of PBLs with maximal CD28 costimulation, using beads coupled to Abs against CD3 and CD28, led to a very prolonged expression of CD154 on CD4 cells (>4 days) that was dependent upon autocrine IL-2 production. Previously...... activated CD4 T cells could respond to IL-2, or the related cytokine IL-15, by de novo CD154 production and expression without requiring an additional signal from CD3 and CD28. These results provide evidence that CD28 costimulation of CD4 T cells, through autocrine IL-2 production, maintains high levels...

Study on the changes of serum IL-2, IL-6, IL-8 and TNF levels in patients with diabetic nephrosis

International Nuclear Information System (INIS)

Qin Wenjing

2005-01-01

Objective: To investigate the changes of serum IL-2, IL-6, IL-8 and TNF levels in patients with diabetic nephrosis. Methods: Serum IL-2, IL-6, IL-8 and TNF levels were measured with RIA in 38 patients with diabetic nephrosis and 36 controls. Results: Serum levels of IL-6, IL-8 and TNF were significantly higher in patients with diabetic nephrosis than those in controls (P<0.01), but serum IL-2 levels were significantly lower in the patients (P<0.01). Conclusion: These cytokines participated in the pathogenesis of diabetic nephrosis. Monitoring the changes of their serum levels was helpful for the management of the disease. (authors)

Fasting induces IL-1 resistance and free fatty acid-mediated up-regulation of IL-1R2 and IL-1RA

Directory of Open Access Journals (Sweden)

jenifer j joesting

2014-07-01

Full Text Available Objective: Weight loss is a near societal obsession and many diet programs use significant calorie restriction (CR including fasting/short term starvation to generate rapid effects. Fasting is also a well-recognized cause of immunosuppression especially within the innate immune system. In this study, we sought to determine if the IL-1 arm of the neuroimmune system was down-regulated by a 24 hr fast and how fasting might generate this effect. Design: Mice were allowed ad libitum access to food or had food withheld for 24 hrs. Expression of the endogenous IL-1 antagonists IL-1 receptor type 2 (IL-1R2 and IL-1 receptor antagonist (IL-1RA were determined as were sickness behaviors before and after IL-1 administration.Results: Fasting markedly increased gene expression of IL-1R2 (83-fold in adipose tissue, 9.5-fold in liver and IL-1RA (68-fold in liver. Fasted mice were protected from IL-1-induced weight loss, hypoglycemia, loss of locomotor and social anxiety. These protections were coupled to a large positive interaction of fasting and IL-1 on IL-1R2 gene expression in adipose tissue and liver (2.6-fold and 1.6-fold, respectively. Fasting not only increased IL-1RA and IL-1R2 protein 2.5-fold and 3.2-fold, respectively, in liver; but also increased IL-1R2 1.8-fold in adipose tissue. Fasting, in turn, triggered a 2.4-fold increase in plasma free-fatty acids (FFAs and a 2.1-fold increase in plasma corticosterone. Inhibition, of glucocorticoid action with mifepristone did not impact fasting-dependent IL-1R2 or IL-1RA gene expression. Administration of the FFA, palmitate, to mice increased liver IL-1R2 and IL-1RA gene expression by 14-fold and 11-fold, respectively. Conclusion: These findings indicate that fasting augments expression of endogenous IL-1 antagonists inducing IL-1 resistance. Fasting-induced increases in plasma FFAs appears to be a signal that drives immunosuppression during fasting/short term starvation.

Clinical significance of changes of levels of serum IL-2, IL-8, IL-10 and gastrin in patients with chronic eczema

International Nuclear Information System (INIS)

Huang Haifeng; Bi Mingye; Shi Hejian

2009-01-01

Objective: To study the significance of changes of serum IL-2, IL-8, IL-10 and Gastrin levels in patients with chronic eczema. Methods: Serum levels of IL-2, IL-8, IL-10 and Gastrin were determined with RIA in 30 patients with chronic eczema and 30 controls. Results: The levels of serum IL-2 were significantly lower in the eczema patients than those in controls (P 0.05). Both serum IL-10 and Gastrin levels were significantly higher in the patients than those in controls (P<0.01). Conclusion: Determination of serum IL-2, IL-8, IL-10 and Gastrin levels in patients with chronic eczema would be of help in monitoring the disease process and outcome prediction. (authors)

Is there enough vaccine to eradicate measles? An integrated analysis of measles-containing vaccine supply and demand.

Science.gov (United States)

Smith, Graegar; Michelson, Joshua; Singh, Rohit; Dabbagh, Alya; Hoekstra, Edward; van den Ent, Maya; Mallya, Apoorva

2011-07-01

Responding to regional advancements in combating measles, the World Health Organization in May 2008 called for an assessment of the feasibility of measles eradication, including whether sufficient vaccine supply exists. Interviews with international health officials and vaccine-makers provided data for a detailed model of worldwide demand and supply for measles-containing vaccine (MCV). The study projected global MCV demand through 2025 with and without a global eradication goal. The study found that 5.2 billion MCV doses must be administered during 2010-2025 to maintain current measles programs, and 5.9 billion doses would likely be needed with a 2020 eradication goal; in the most intensive scenario, demand could increase to 7.5 billion doses. These volumes are within existing and planned MCV-manufacturing capacity, although there are risks. In some markets, capacity is concentrated: Supply-chain disruptions could reduce supply or increase prices. Mitigation strategies could include stockpiling, long-term contracts, and further coordination with manufacturers. © The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved.

[Dental status and efficacy of Helicobacter pylori eradication].

Science.gov (United States)

Namiot, D B; Namiot, Z; Kemona, A; Gołebiewska, M

2001-04-01

Beside stomach Helicobacter pylori can colonize the oral cavity. One may think, therefore, that if H. pylori persists the eradication therapy in the oral cavity, it could infect the stomach again. Since in the oral cavity H. pylori occurs most frequently in a dental plaque gathering on teeth, the aim of the study was to investigate whether the natural teeth status is important for the efficacy of H. pylori eradication. The study was conducted on 45 peptic ulcer patients with natural teeth. They were eradicated with one of two regimens: 1/OAT-omeprazole (2 x 20 mg), amoxicillin (2 x 1000 mg), tinidazole (2 x 500 mg) (14-day course), 2/OAC-omeprazole (2 x 20 mg), amoxicillin (2 x 1000 mg), clarithromycin (2 x 250 mg) (7-day course). Dentistry examination was performed 4-6 weeks after the end of eradication therapy and consisted of determination of the number of teeth, caries index, dental treatment index, plaque index, and periodontal index. It was found that in successfully eradicated patients with OAT regimen, the number of teeth was higher and caries index lower than in those whose eradication therapy was unsuccessful; 24.8 +/- 5.2 vs 15.5 +/- 8.6 (p caries index were not associated with the efficacy of H. pylori eradication in OAC treated group. Irrespectively of the eradication regimen used, OAT or OAC, dental treatment index, plaque index, and periodontal index were not associated with the efficacy of H. pylori eradication. It is concluded that the natural teeth status may have influence on the outcome of H. pylori eradication. One should remember about this prescribing drugs for H. pylori eradication.

Biological Feasibility of Measles Eradication

Science.gov (United States)

Strebel, Peter

2011-01-01

Recent progress in reducing global measles mortality has renewed interest in measles eradication. Three biological criteria are deemed important for disease eradication: (1) humans are the sole pathogen reservoir; (2) accurate diagnostic tests exist; and (3) an effective, practical intervention is available at reasonable cost. Interruption of transmission in large geographical areas for prolonged periods further supports the feasibility of eradication. Measles is thought by many experts to meet these criteria: no nonhuman reservoir is known to exist, accurate diagnostic tests are available, and attenuated measles vaccines are effective and immunogenic. Measles has been eliminated in large geographical areas, including the Americas. Measles eradication is biologically feasible. The challenges for measles eradication will be logistical, political, and financial. PMID:21666201

Association analysis of IL10, TNF-α and IL23R-IL12RB2 SNPs with Behçet's disease risk in Western Algeria

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Ouahiba eKhaib Dit Naib

2013-10-01

Full Text Available Objective: We have conducted the first study of the association of interleukin (IL-10, tumor necrosis factor alpha (TNF-α and IL23R-IL12RB2 regionSNPswith Behçet's disease (BD in Western Algeria. Methods: A total of 51 BD patients and 96 unrelated controls from West region of Algeria were genotyped by direct sequencing for 11 SNPs including 2 SNPsfrom the IL10 promoter [c.-819T>C (rs1800871, c.-592A>C (rs1800872], 6 SNPs from the TNF-α promoter [c.-1211T>C (rs1799964, c.-1043C>A (rs1800630, c.-1037C>T (rs1799724, c.-556G>A (rs1800750, c.-488G>A (rs1800629 and c.-418G>A (rs361525], and 3 SNPs from the IL23R-IL12RB2 region [g.67747415A>C (rs12119179, g.67740092G>A (rs11209032 and g.67760140T>C (rs924080]. Results: The minor alleles c.-819T and c.-592A were significantly associated with BD (OR= 2.18; 95% CI 1.28-3.73, p = 0.003; whereas, there was weaker association between TNF-αpromoter SNPs or IL23R-IL12RB2 region and disease risk.Conclusion: Unlike the TNF-αand the IL23R-IL12RB2 region SNPs, the two IL10 SNPs were strongly associated with BD. The -819T, and -592A alleles and the -819TT, -819CT, and -592AA and -592CA genotypes seem to be highly involved in the risk of developing of BD in the population of Western Algeria.

Low-Dose Radiation Promotes Dendritic Cell Migration and IL-12 Production via the ATM/NF-KappaB Pathway.

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Yu, Nan; Wang, Sinian; Song, Xiujun; Gao, Ling; Li, Wei; Yu, Huijie; Zhou, Chuanchuan; Wang, Zhenxia; Li, Fengsheng; Jiang, Qisheng

2018-04-01

For dendritic cells (DCs) to initiate an immune response, their ability to migrate and to produce interleukin-12 (IL-12) is crucial. It has been previously shown that low-dose radiation (LDR) promoted IL-12 production by DCs, resulting in increased DC activity that contributed to LDR hormesis in the immune system. However, the molecular mechanism of LDR-induced IL-12 production, as well as the effect of LDR on DC migration capacity require further elucidation. Using the JAWSII immortalized mouse dendritic cell line, we showed that in vitro X-ray irradiation (0.2 Gy) of DCs significantly increased DC migration and IL-12 production, and upregulated CCR7. The neutralizing antibody against CCR7 has been shown to abolish LDR-enhanced DC migration, demonstrating that CCR7 mediates LDR-promoting DC migration. We identified nuclear factor kappaB (NF-κB) as the central signaling pathway that mediated LDR-enhanced expression of IL-12 and CCR7 based on findings that 0.2 Gy X-ray irradiation activated NF-κB, showing increased nuclear p65 translocation and NF-κB DNA-binding activity, while an NF-κB inhibitor blocked LDR-enhanced expression of IL-12 and CCR7, as well as DC migration. Finally, we demonstrated that 0.2 Gy X-ray irradiation promoted ATM phosphorylation and reactive oxygen species generation; however, only the ATM inhibitor abolished the LDR-induced NF-κB-mediated expression of IL-12 and CCR7. Altogether, our data show that exposure to LDR resulted in a hormetic effect on DCs regarding CCR7-mediated migration and IL-12 production by activating the ATM/NF-κB pathway.

The Role of High Dose Interleukin-2 in the Era of Targeted Therapy.

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Gills, Jessie; Parker, William P; Pate, Scott; Niu, Sida; Van Veldhuizen, Peter; Mirza, Moben; Holzbeierlein, Jeffery M; Lee, Eugene K

2017-09-01

We assessed survival outcomes following high dose interleukin-2 in a contemporary cohort of patients during the era of targeted agents. We retrospectively reviewed the records of patients with metastatic renal cell carcinoma treated with high dose interleukin-2 between July 2007 and September 2014. Clinicopathological data were abstracted and patient response to therapy was based on RECIST (Response Evaluation Criteria In Solid Tumors), version 1.1 criteria. The Kaplan-Meier method was used to estimate progression-free and overall survival in the entire cohort, the response to high dose interleukin-2 in regard to previous targeted agent therapy and the response to the targeted agent in relation to the response to high dose interleukin-2. We identified 92 patients, of whom 87 had documentation of a response to high dose interleukin-2. Median overall survival was 34.4 months from the initiation of high dose interleukin-2 therapy in the entire cohort. Patients who received targeted therapy before high dose interleukin-2 had overall survival (median 34.4 and 30.0 months, p = 0.88) and progression-free survival (median 1.5 and 1.7 months, p = 0.8) similar to those in patients who received no prior therapy, respectively. Additionally, patients with a complete or partial response to high dose interleukin-2 had similar outcomes for subsequent targeted agents compared to patients whose best response was stable or progressive disease (median overall survival 30.1 vs 25.4 months, p = 0.4). Our data demonstrate that patient responses to high dose interleukin-2 and to targeted agents before and after receiving high dose interleukin-2 are independent. As such, carefully selected patients should be offered high dose interleukin-2 for the possibility of a complete and durable response without the fear of limiting the treatment benefit of targeted agents. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

IL-1 family members IL-18 and IL-33 upregulate the inflammatory potential of differentiated human Th1 and Th2 cultures

DEFF Research Database (Denmark)

Blom, Lars; Poulsen, Lars K.

2012-01-01

The IL-1 family members IL-1ß, IL-18, and IL-33 are potent cytokines in relationship to amplifying the CD4(+) T cell cytokine production. To evaluate their impact on in vitro-differentiated human Th1 and Th2 cultures, such cultures were established from naive T cells, purified from healthy blood...... donors, and reactivated in the presence of IL-1ß, IL-18, or IL-33. Interestingly, we observe modifying responses in Th1 and Th2 cultures induced by IL-18 or IL-33 but not by IL-1ß, both contributing to amplify production of IL-5, IL-13, and IFN-¿. IL-18 or IL-33 stimulation of Th1 cultures resulted...... in increased IFN-¿ and IL-13 production concurrent with reduced IL-10 gene transcription and secretion even though Th1 cultures, in contrast to IL-18Ra, had low ST2L expression. Furthermore, adding IL-18 to Th1 cultures promoted Tbet mRNA expression and production. Th2 cultures stimulated with IL-18 or IL-33...

Effects of low priming dose irradiation on cell cycle arrest of HepG2 cells caused by high dose irradiation

International Nuclear Information System (INIS)

Xia Jingguang; Jin Xiaodong; Chinese Academy of Sciences, Beijing; Li Wenjian; Wang Jufang; Guo Chuanling; Gao Qingxiang

2005-01-01

Human hepatoma cells hepG2 were irradiated twice by 60 Co γ-rays with a priming dose of 5 cGy and a higher dose of 3 Gy performed 4h or 8h after the low dose irradiation. Effects of the priming dose irradiation on cell cycle arrest caused by high dose were examined with flow cytometry. Cells in G 2 /M phase accumulated temporarily after the 5 cGy irradiation, and proliferation of tumor cells was promoted significantly by the low dose irradiation. After the 3 Gy irradiation, G 2 phase arrest occurred, and S phase delayed temporally. In comparison with 3 kGy irradiation only, the priming dose delivered 4h prior to the high dose irradiation facilitated accumulation of hepG2 cells in G 2 /M phase, whereas the priming dose delivered 8h prior to the high dose irradiation helped the cells to overcome G 2 arrest. It was concluded that effects of the priming dose treatment on cell cycle arrest caused by high dose irradiation were dependent on time interval between the two irradiations. (authors)

The role of genetic variation across IL-1β, IL-2, IL-6, and BDNF in antipsychotic-induced weight gain.

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Fonseka, Trehani M; Tiwari, Arun K; Gonçalves, Vanessa F; Lieberman, Jeffrey A; Meltzer, Herbert Y; Goldstein, Benjamin I; Kennedy, James L; Kennedy, Sidney H; Müller, Daniel J

2015-01-01

Antipsychotics with high weight gain-inducing propensities influence the expression of immune and neurotrophin genes, which have been independently related to obesity indices. Thus, we investigated whether variants in the genes encoding interleukin (IL)-1β, IL-2, and IL-6 and brain-derived neurotrophic factor (BDNF) Val66Met are associated with antipsychotic-induced weight gain (AIWG). Nineteen polymorphisms were genotyped using Taqman(®) assays in 188 schizophrenia patients on antipsychotic treatment for up to 14 weeks. Mean weight change (%) from baseline was compared across genotypic groups using analysis of covariance (ANCOVA). Epistatic effects between cytokine polymorphisms and BDNF Val66Met were tested using Model-Based Multifactor Dimensionality Reduction. In European patients, IL-1β rs16944*GA (P = 0.013, Pcorrected = 0.182), IL-1β rs1143634*G (P = 0.001, Pcorrected = 0.014), and BDNF Val66Met (Val/Val, P = 0.004, Pcorrected = 0.056) were associated with greater AIWG, as were IL-1β rs4849127*A (P = 0.049, Pcorrected = 0.784), and IL-1β rs16944*GA (P = 0.012, Pcorrected = 0.192) in African Americans. BDNF Val66Met interacted with both IL-1β rs13032029 (Val/Met+ TT, PPerm = 0.029), and IL-6 rs2069837 (Val/Val+ AA, PPerm = 0.021) in Europeans, in addition to IL-1β rs16944 (Val/Val+ GA, PPerm = 0.006) in African Americans. SNPs across IL-1β and BDNF Val66Met may influence AIWG. Replication of these findings in larger, independent samples is warranted.

Increasing the biological activity of IL-2 and IL-15 through complexing with anti-IL-2 mAbs and Il-15Ralfa-Fc chimera

Czech Academy of Sciences Publication Activity Database

Votavová, Petra; Tomala, Jakub; Kovář, Marek

2014-01-01

Roč. 195, č. 1 (2014), s. 1-10 ISSN 0165-2478 R&D Projects: GA ČR GAP301/11/0325; GA MŠk(CZ) ED1.1.00/02.0109; GA ČR GA13-12885S Institutional support: RVO:61388971 Keywords : IL-2 * IL-15 * chimera Subject RIV: EC - Immunology Impact factor: 2.512, year: 2014

Safety and immunogenicity of an HIV-1 gag DNA vaccine with or without IL-12 and/or IL-15 plasmid cytokine adjuvant in healthy, HIV-1 uninfected adults.

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Spyros A Kalams

Full Text Available DNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques.We performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37 DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug IL-12 DNA. However, after three doses, 44.4% (4/9 of vaccinees receiving gag DNA and intermediate dose (500 ug of IL-12 DNA demonstrated a detectable cellular immune response.This combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity.Clinicaltrials.gov NCT00115960 NCT00111605.

Immunogenicity to poliovirus type 2 following two doses of fractional intradermal inactivated poliovirus vaccine: A novel dose sparing immunization schedule.

Science.gov (United States)

Anand, Abhijeet; Molodecky, Natalie A; Pallansch, Mark A; Sutter, Roland W

2017-05-19

The polio eradication endgame strategic plan calls for the sequential removal of Sabin poliovirus serotypes from the trivalent oral poliovirus vaccine (tOPV), starting with type 2, and the introduction of ≥1 dose of inactivated poliovirus vaccine (IPV), to maintain an immunity base against poliovirus type 2. The global removal of oral poliovirus type 2 was successfully implemented in May 2016. However, IPV supply constraints has prevented introduction in 21 countries and led to complete stock-out in >20 countries. We conducted a literature review and contacted corresponding authors of recent studies with fractional-dose IPV (fIPV), one-fifth of intramuscular dose administered intradermally, to conduct additional type 2 immunogenicity analyses of two fIPV doses compared with one full-dose IPV. Four studies were identified that assessed immunogenicity of two fIPV doses compared to one full-dose IPV. Two fractional doses are more immunogenic than 1 full-dose, with type 2 seroconversion rates improving between absolute 19-42% (median: 37%, pvaccine compared to one full-dose IPV. In response to the current IPV shortage, a schedule of two fIPV doses at ages 6 and 14weekshas been endorsed by technical oversight committees and has been introduced in some affected countries. Copyright © 2017. Published by Elsevier Ltd.

High dose per fraction dosimetry of small fields with Gafchromic EBT2 film

International Nuclear Information System (INIS)

Hardcastle, Nicholas; Basavatia, Amar; Bayliss, Adam; Tome, Wolfgang A.

2011-01-01

Purpose: Small field dosimetry is prone to uncertainties due to the lack of electronic equilibrium and the use of the correct detector size relative to the field size measured. It also exhibits higher sensitivity to setup errors as well as large variation in output with field size and shape. Radiochromic film is an attractive method for reference dosimetry in small fields due to its ability to provide 2D dose measurements while having minimal impact on the dose distribution. Gafchromic EBT2 has a dose range of up to 40 Gy; therefore, it could potentially be useful for high dose reference dosimetry with high spatial resolution. This is a requirement in stereotactic radiosurgery deliveries, which deliver high doses per fraction to small targets. Methods: Targets of 4 mm and 12 mm diameters were treated to a minimum peripheral dose of 21 Gy prescribed to 80% of the maximum dose in one fraction. Target doses were measured with EBT2 film (both targets) and an ion chamber (12 mm target only). Measured doses were compared with planned dose distributions using profiles through the target and minimum peripheral dose coverage. Results: The measured target doses and isodose coverage agreed with the planned dose within ±1 standard deviation of three measurements, which were 2.13% and 2.5% for the 4 mm and 12 mm targets, respectively. Conclusions: EBT2 film is a feasible dosimeter for high dose per fraction reference 2D dosimetry.

IL-15 augments TCR-induced CD4+ T cell expansion in vitro by inhibiting the suppressive function of CD25 High CD4+ T cells.

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Tom L Van Belle

Full Text Available Due to its critical role in NK cell differentiation and CD8(+ T cell homeostasis, the importance of IL-15 is more firmly established for cytolytic effectors of the immune system than for CD4(+ T cells. The increased levels of IL-15 found in several CD4(+ T cell-driven (auto- immune diseases prompted us to examine how IL-15 influences murine CD4(+ T cell responses to low dose TCR-stimulation in vitro. We show that IL-15 exerts growth factor activity on both CD4(+ and CD8(+ T cells in a TCR-dependent and Cyclosporin A-sensitive manner. In CD4(+ T cells, IL-15 augmented initial IL-2-dependent expansion and once IL-15Rα was upregulated, IL-15 sustained the TCR-induced expression of IL-2/15Rβ, supporting proliferation independently of secreted IL-2. Moreover, IL-15 counteracts CD4(+ T cell suppression by a gradually expanding CD25(HighCD4(+ T cell subset that expresses Foxp3 and originates from CD4(+CD25(+ Tregs. These in vitro data suggest that IL-15 may dramatically strengthen the T cell response to suboptimal TCR-triggering by overcoming an activation threshold set by Treg that might create a risk for autoimmune pathology.

Cloning and characterization of two duplicated interleukin-17A/F2 genes in common carp (Cyprinus carpio L.): Transcripts expression and bioactivity of recombinant IL-17A/F2.

Science.gov (United States)

Li, Hongxia; Yu, Juhua; Li, Jianlin; Tang, Yongkai; Yu, Fan; Zhou, Jie; Yu, Wenjuan

2016-04-01

Interleukin-17 (IL-17) plays an important role in inflammation and host defense in mammals. In this study, we identified two duplicated IL-17A/F2 genes in the common carp (Cyprinus carpio) (ccIL-17A/F2a and ccIL-17A/F2b), putative encoded proteins contain 140 amino acids (aa) with conserved IL-17 family motifs. Expression analysis revealed high constitutive expression of ccIL-17A/F2s in mucosal tissues, including gill, skin and intestine, their expression could be induced by Aeromonas hydrophila, suggesting a potential role in mucosal immunity. Recombinant ccIL-17A/F2a protein (rccIL-17A/F2a) produced in Escherichia coli could induce the expression of proinflammatory cytokines (IL-1β) and the antimicrobial peptides S100A1, S100A10a and S100A10b in the primary kidney in a dose- and time-dependent manner. Above findings suggest that ccIL-17A/F2 plays an important role in both proinflammatory and innate immunity. Two duplicated ccIL-17A/F2s showed different expression level with ccIL-17A/F2a higher than b, comparison of two 5' regulatory regions indicated the length from anticipated promoter to transcriptional start site (TSS) and putative transcription factor binding site (TFBS) were different. Promoter activity of ccIL-17A/F2a was 2.5 times of ccIL-17A/F2b which consistent with expression results of two genes. These suggest mutations in 5'regulatory region contributed to the differentiation of duplicated genes. To our knowledge, this is the first report to analyze 5'regulatory region of piscine IL-17 family genes. Copyright © 2016 Elsevier Ltd. All rights reserved.

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; Ellebæk, Eva

2016-01-01

PURPOSE: Adoptive cell transfer therapy (ACT) based on autologous tumor-infiltrating lymphocytes (TIL) has achieved impressive clinical results in several phase I and II trials performed outside of Europe. Although transient, the toxicities associated with high-dose (HD) bolus IL2 classically...

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.

Intrathymic radioresistant stem cells follow an IL-2/IL-2R pathway during thymic regeneration after sublethal irradiation

International Nuclear Information System (INIS)

Zuniga-Pfluecker, J.C.K.; Kruisbeek, A.M.

1990-01-01

Sublethally irradiated mice undergo thymic regeneration which follows a phenotypic pattern of events similar to that observed during normal fetal development. Thymic regeneration after irradiation is the product of a limited pool of intrathymic radioresistant stem cells undergoing simultaneous differentiation. We show that in this model of T cell development, thymic regeneration follows a pathway in which the IL-2R is transiently expressed on CD4-/CD8- cells. IL-2R expression occurred during the exponential growth period of thymic regeneration, and IL-2R blocking prevented this explosive growth. Flow cytometry analysis revealed that the IL-2R blockade affected primarily the development of the immature CD3-/CD4-/CD8- (triple negative) cells and their ability to generate CD3+/CD4+/CD8+ or CD3+/CD4+/CD8- and CD3+/CD4-/CD8+ thymocytes. Thus, our findings demonstrate that blocking of the IL-2R resulted in an arrest in proliferation and differentiation by intrathymic radioresistant stem cells, indicating that the IL-2/IL-2R pathway is necessary for the expansion of immature triple negative T cells

Expression of fusion IL2-B7.1(IgV+C) and effects on T lymphocytes.

Science.gov (United States)

Kong, Linghong; Li, Yaochen; Yang, Ye; Li, Kangsheng

2007-12-01

The search for an effective immunotherapeutic treatment for tumors is an important area of cancer research. To prepare a more effective form of the bifunctional fusion protein IL2-B7.1(IgV+C) and analyze its effect on the stimulation of T lymphocyte proliferation, we used DNAStar 5.03 software to predict the structural diversity and biochemical character of IL2-B7.1(IgV+C). We then prepared fusion protein IL2-B7.1(IgV+C) by establishing its prokaryotic expression system, and tested its effect on the stimulation of T lymphocytes in vitro. The results indicated that IL2-B7.1(IgV+C) correctly formed a secondary structure in which both IL2 and B7.1(IgV+C) maintained their original hydrophilicity and epitopes. Western blot analysis revealed that IL2-B7.1(IgV+C) was efficiently expressed. Our analysis of CTLL-2 and T-cell proliferation showed that recombinant human (rh) IL2-B7.1(IgV+C) exerted the combined stimulating effects of both rhIL2 and rh B7.1(IgV+C) on cell proliferation, and that these effects could be blocked by adding either anti-IL2 or anti-B7.1 monoclonal antibodies. A >2-fold increase in [3H]TdR incorporation compared with that of cells treated with recombinant protein IL2, or B7.1(IgV+C) alone, revealed that rhIL2-B7.1(IgV+C) had dose-dependent synergetic effects on T-cell activation in the presence of anti-CD3 monoclonal antibody. We concluded that the augmented potency of rhIL2-B7.1(IgV+C) resulted in a stronger stimulation of T-cell proliferation than either rhB7.1(IgV+C) or rhIL2 alone.

Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose Interleukin-2: evaluation of biomarkers of immunologic and therapeutic response.

Science.gov (United States)

Ridolfi, Laura; de Rosa, Francesco; Ridolfi, Ruggero; Gentili, Giorgia; Valmorri, Linda; Scarpi, Emanuela; Parisi, Elisabetta; Romeo, Antonino; Guidoboni, Massimo

2014-09-23

Tumor cells killed by radiation therapy (RT) are a potentially good source of antigens for dendritic cell (DC) uptake and presentation to T-cells. RT upregulates cell death receptors such as Fas/CD95 and MHC-I, induces the expression of co-stimulatory molecules on tumor cells, and promotes production of pro-inflammatory cytokines. High-dose interleukin-2 (HD-IL-2) bolus has been shown to obtain objective response rates ranging from 15% to 17% in patients with metastatic melanoma or renal cell carcinoma (RCC), with 6% to 8% of cases experiencing a durable complete response. However, HD-IL-2 is also associated with severe side-effects; if it is to remain a component of the curative treatment strategy in patients with metastatic melanoma or RCC, its therapeutic efficacy must be improved and patients who are most likely to benefit from treatment must be identified a priori. We designed a clinical study combining immunomodulating RT and HD-IL-2 to evaluate their clinical and immunological efficacy and to explore the predictive and prognostic value of 1) tumor-specific immune response and 2) serum levels of proangiogenic cytokines. The primary endpoint of this proof-of-principle phase II study is immune response. Secondary endpoints are the identification of biomarkers potentially predictive of response, toxicity, response rate and overall survival. Three daily doses of booster radiotherapy (XRT) at 6-12 Gy will be administered to at least one metastatic field on days -3 to -1 before the first and third cycle. Treatment with IL-2 (dose 18 MIU/m2/day by continuous IV infusion for 72 hours) will start on day +1 and will be repeated every 3 weeks for up to 4 cycles and then every 4 weeks for a further 2 cycles. Immune response against tumor antigens expressed by melanoma and/or RCC will be evaluated during treatment. Circulating immune effectors and regulators, e.g. cytotoxic T lymphocytes and regulatory T cells, as well as serum levels of proangiogenic

Polarized Th2 like cells, in the absence of Th0 cells, are responsible for lymphocyte produced IL-4 in high IgE-producer schistosomiasis patients

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Soares-Silveira Alda

2002-07-01

Full Text Available Abstract Background Human resistance to re-infection with S. mansoni is correlated with high levels of anti-soluble adult worm antigens (SWAP IgE. Although it has been shown that IL-4 and IL-5 are crucial in establishing IgE responses in vitro, the active in vivo production of these cytokines by T cells, and the degree of polarization of Th2 vs. Th0 in human schistosomiasis is not known. To address this question, we determined the frequency of IL-4 and IFN-γ or IL-5 and IL-2 producing lymphocytes from schistosomiasis patients with high or low levels of IgE anti-SWAP. Results Our analysis showed that high and low IgE-producers responded equally to schistosomiasis antigens as determined by proliferation. Moreover, patients from both groups displayed similar percentages of circulating lymphocytes. However, high IgE-producers had an increased percentage of activated CD4+ T cells as compared to the low IgE-producers. Moreover, intracellular cytokine analysis, after short-term stimulation with anti-CD3/CD28 mAbs, showed that IgE high-producers display an increase in the percentage of T lymphocytes expressing IL-4 and IL-5 as compared to IgE low-responders. A coordinate control of the frequency of IL-4 and IL-5 producing lymphocytes in IgE high, but not IgE low-responders, was observed. Conclusions High IgE phenotype human schistosomiasis patients exhibit a coordinate regulation of IL-4 and IL-5 producing cells and the lymphocyte derived IL-4 comes from true polarized Th2 like cells, in the absence of measurable Th0 cells as measured by co-production of IL-4 and IFN-γ.

The Use of Highly Sensitive Detection Methods for Eradication of Plasmodium

DEFF Research Database (Denmark)

Hede, Marianne Smedegaard; Knudsen, Birgitta R.

2017-01-01

The key to a successful malaria eradication program is highly efficient detection of Plasmodium infected people followed by appropriate treatment to avoid spreading of the parasite. We will discuss some of the demands that such a detection method needs to fulfill and review some of the advantages...... and disadvantages of currently available detection methods...

Aloin Inhibits Interleukin (IL)-1β-Stimulated IL-8 Production in KB Cells.

Science.gov (United States)

Na, Hee Sam; Song, Yu Ri; Kim, Seyeon; Heo, Jun-Young; Chung, Hae-Young; Chung, Jin

2016-06-01

Interleukin (IL)-1β, which is elevated in oral diseases including gingivitis, stimulates epithelial cells to produce IL-8 and perpetuate inflammatory responses. This study investigates stimulatory effects of salivary IL-1β in IL-8 production and determines if aloin inhibits IL-1β-stimulated IL-8 production in epithelial cells. Saliva was collected from volunteers to determine IL-1β and IL-8 levels. Samples from volunteers were divided into two groups: those with low and those with high IL-1β levels. KB cells were stimulated with IL-1β or saliva with or without IL-1 receptor agonist or specific mitogen-activated protein kinase (MAPK) inhibitors. IL-8 production was measured by enzyme-linked immunosorbent assay (ELISA). MAPK protein expression involved in IL-1β-induced IL-8 secretion was detected by Western blot. KB cells were pretreated with aloin, and its effect on IL-1β-induced IL-8 production was examined by ELISA and Western blot analysis. Saliva with high IL-1β strongly stimulated IL-8 production in KB cells, and IL-1 receptor agonist significantly inhibited IL-8 production. Low IL-1β-containing saliva did not increase IL-8 production. IL-1β treatment of KB cells induced activation of MAPK signaling molecules as well as nuclear factor-kappa B. IL-1β-induced IL-8 production was decreased by p38 and extracellular signal-regulated kinase (ERK) inhibitor treatment. Aloin pretreatment inhibited IL-1β-induced IL-8 production in a dose-dependent manner and inhibited activation of the p38 and ERK signaling pathway. Finally, aloin pretreatment also inhibited saliva-induced IL-8 production. Results indicated that IL-1β in saliva stimulates epithelial cells to produce IL-8 and that aloin effectively inhibits salivary IL-1β-induced IL-8 production by mitigating the p38 and ERK pathway. Therefore, aloin may be a good candidate for modulating oral inflammatory diseases.

Effect of high-dose intravenous vitamin C on inflammation in cancer patients

Directory of Open Access Journals (Sweden)

Mikirova Nina

2012-09-01

Full Text Available Abstract Background An inflammatory component is present in the microenvironment of most neoplastic tissues. Inflammation and elevated C-reactive protein (CRP are associated with poor prognosis and decreased survival in many types of cancer. Vitamin C has been suggested as having both a preventative and therapeutic role in a number of pathologies when administered at much higher-than-recommended dietary allowance levels. Since in vitro studies demonstrated inhibition of pro-inflammatory pathways by millimolar concentrations of vitamin C, we decided to analyze the effects of high dose IVC therapy in suppression of inflammation in cancer patients. Methods 45 patients with prostate cancer, breast cancer, bladder cancer, pancreatic cancer, lung cancer, thyroid cancer, skin cancer and B-cell lymphoma were treated at the Riordan Clinic by high doses of vitamin C (7.5 g -50 g after standard treatments by conventional methods. CRP and tumor markers were measured in serum or heparin-plasma as a routine analysis. In addition, serum samples were collected before and after the IVCs for the cytokine kit tests. Results According to our data positive response to treatment, which was demonstrated by measurements of C- reactive protein, was found in 75% of patients and progression of the inflammation in 25% of patients. IVC treatments on all aggressive stage cancer patients showed the poor response of treatment. There was correlation between tumor markers (PSA, CEA, CA27.29 and CA15-3 and changes in the levels of C-reactive protein. Our test of the effect of IVC on pro-inflammatory cytokines demonstrated that inflammation cytokines IL-1α, IL-2, IL-8, TNF-α, chemokine eotaxin and CRP were reduced significantly after treatments. Conclusions The high dose intravenous ascorbic acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients. In our study, we found that modulation of inflammation by IVC correlated with decreases

Seasonal influenza A/H3N2 virus infection and IL-1Β, IL-10, IL-17, and IL-28 polymorphisms in Iranian population.

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Rogo, Lawal Dahiru; Rezaei, Farhad; Marashi, Seyed Mahdi; Yekaninejad, Mir Saeed; Naseri, Maryam; Ghavami, Nastaran; Mokhtari-Azad, Talat

2016-12-01

Increased blood cytokines is the main immunopathological process that were attributed to severe clinical outcomes in cases of influenza A/H3N2 virus infection. The study was aimed to investigate the polymorphisms of IL-1β, IL-10, IL-17, and IL-28 genes to find the possibility of their association with the clinical outcome of influenza A/H3N2 virus infection among the infected patients in Iran. This is a Case-Control study in which influenza A/H3N2 virus positive confirmed with real-time PCR were the cases. DNA samples from groups were genotyped for polymorphisms in rs16944 (IL-1β), rs1800872 (IL-10), rs2275913 (IL-17), and rs8099917 (IL-28). Confidence interval (95%CI) and Odds ratio (OR) were calculated. IL-17 rs2275913 (GG and AG) were associated with risk of infection with that were statistically significant (P rs16944) (GG) was associated with reduced risk of infection (P < 0.01, OR = 0.46). Genotype GG and GT of IL-10 (rs1800872) were associated with increased risk of infection with influenza A/H3N2 virus (P < 0.05, OR = 2.04-2.58). In addition, IL-28 (rs8099917) genotypes GG (P < 0.05, OR = 0.49) and TG (P < 0.05, OR = 0.59) were associated with reduced risk of ILI symptom while genotype TT (P < 0.01, OR = 4.31) was associated with increased risk of ILI symptom. The results of this study demonstrated that polymorphisms of genes involved in the inflammatory and anti-inflammatory process affect the outcome of disease caused by influenza A/H3N2 virus. Thorough insight on host immune response at the time of influenza A virus infection is required to ensure adequate patient care in the case of feature outbreaks. J. Med. Virol. 88:2078-2084, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Association study of IL10 and IL23R-IL12RB2 in Iranian patients with Behçet's disease.

Science.gov (United States)

Xavier, Joana M; Shahram, Farhad; Davatchi, Fereydoun; Rosa, Alexandra; Crespo, Jorge; Abdollahi, Bahar Sadeghi; Nadji, Abdolhadi; Jesus, Gorete; Barcelos, Filipe; Patto, José Vaz; Shafiee, Niloofar Mojarad; Ghaderibarim, Fahmida; Oliveira, Sofia A

2012-08-01

Independent replication of the findings from genome-wide association studies (GWAS) remains the gold standard for results validation. Our aim was to test the association of Behçet's disease (BD) with the interleukin-10 gene (IL10) and the IL-23 receptor-IL-12 receptor β2 (IL23R-IL12RB2) locus, each of which has been previously identified as a risk factor for BD in 2 different GWAS. Six haplotype-tagging single-nucleotide polymorphisms (SNPs) in IL10 and 42 in IL23R-IL12RB2 were genotyped in 973 Iranian patients with BD and 637 non-BD controls. Population stratification was assessed using a panel of 86 ancestry-informative markers. Subtle evidence of population stratification was found in our data set. In IL10, rs1518111 was nominally associated with BD before and after adjustment for population stratification (odds ratio [OR] for T allele 1.20, 95% confidence interval [95% CI] 1.02-1.40, unadjusted P [P(unadj) ] = 2.53 × 10(-2) ; adjusted P [P(adj) ] = 1.43 × 10(-2) ), and rs1554286 demonstrated a trend toward association (P(unadj) = 6.14 × 10(-2) ; P(adj) = 3.21 × 10(-2) ). Six SNPs in IL23R-IL12RB2 were found to be associated with BD after Bonferroni correction for multiple testing, the most significant of which were rs17375018 (OR for G allele 1.51, 95% CI 1.27-1.78, P(unadj) = 1.93 × 10(-6) ), rs7517847 (OR for T allele 1.48, 95% CI 1.26-1.74, P(unadj) = 1.23 × 10(-6) ), and rs924080 (OR for T allele 1.29, 95% CI 1.20-1.39, P = 1.78 × 10(-5) ). SNPs rs10489629, rs1343151, and rs1495965 were also significantly associated with BD in all tests performed. Results of meta-analyses of our data combined with data from other populations further confirmed the role of rs1518111, rs17375018, rs7517847, and rs924080 in the risk of BD, but no epistatic interactions between IL10 and IL23R-IL12RB2 were detected. Results of imputation analysis highlighted the importance of IL23R regulatory regions in the susceptibility to BD. These findings independently confirm

Western hemisphere leading the way in disease eradication.

Science.gov (United States)

1997-08-01

National immunization programs in the Americas are fine examples of what mankind can achieve through the appropriate use of technology, global collaboration, and political will for the benefit of all. Over the past 20 years, Western Hemisphere countries have led the world in the war against vaccine-preventable infectious diseases. In September 1985, the 31st Meeting of the Pan American Health Organization's (PAHO) Directing Council established the goal of eradicating the indigenous transmission of wild poliovirus from all countries of the Americas by 1990. Investigations of more than 4000 stool specimens by 1991 identified wild poliovirus transmission in only Colombia and Peru. In September 1994, and following an extensive review of surveillance information, key polio surveillance indicators and laboratory results throughout the region, the International Commission for the Certification of Poliomyelitis Eradication (ICCPE) declared that transmission of wild poliovirus had been interrupted in the Americas. PAHO's recommended measles vaccination strategy has led to the interruption of measles transmission in major geographic areas of the Americas, but the disease still circulates freely elsewhere in the world. Cases of neonatal tetanus (NNT) continue to decline due to PAHO's recommended strategy of vaccinating women of childbearing age with at least 2 doses of tetanus toxoid vaccine, especially in high-risk areas for the disease. NNT is endemic in 16 countries in the Americas.

Can probiotics improve efficiency and safety profile of triple Helicobacter pylori eradication therapy? A prospective randomized study

Directory of Open Access Journals (Sweden)

Grgov Saša

2016-01-01

Full Text Available Background/Aim. Some studies suggest the benefit of applying different probiotic strains in combination with antibiotics in the eradication of Helicobacter pylori (H. pylori infection. The aim of this study was to evaluate the effect of co-administration of multiple probiotic strains with triple H. pylori eradication therapy. Methods. This prospective study included 167 patients with dyspeptic symptoms and chronic gastritis who were diagnosed with H. pylori infection and randomized into two groups. The group I of 77 patients underwent triple eradication therapy, for 7 days, with lansoprazole, 2 × 30 mg half an hour before the meal, amoxicillin 2 × 1.000 mg per 12 hours and clarithromycin 2 × 500 mg per 12 hours. After the 7th day of the therapy, lansoprazole continued at a dose of 30 mg for half an hour before breakfast for 4 weeks. The group II of 90 patients received the same treatment as the patients of the group I, with the addition of the probiotic cultures in the form of a capsule comprising Lactobacillus Rosell-52, Lactobacillus Rosell-11, Bifidobacterium Rosell-1755 and Saccharomyces boulardii, since the beginning of eradication for 4 weeks. Eradication of H. pylori infection control was performed 8 weeks after the therapy by rapid urease test and histopathologic evaluation of endoscopic biopsies or by stool antigen test for H. pylori. Results. Eradication of H. pylori infection was achieved in 93.3% of the patients who received probiotics with eradication therapy and in 81.8% of patients who were only on eradication therapy without probiotics. The difference in eradication success was statistically significant, (p < 0.05. The incidence of adverse effects of eradication therapy was higher in the group of patients who were not on probiotic (28.6% than in the group that received probiotic (17.7%, but the difference was not statistically significant. Conclusion. Multiple probiotic strains addition to triple eradication therapy of H

Poverty eradication in a carbon constrained world

OpenAIRE

Hubacek, Klaus; Baiocchi, Giovanni; Feng, Kuishuang; Patwardhan, Anand

2017-01-01

The UN Framework Convention on Climate Change aims to keep warming below 2 °C while recognizing developing countries’ right to eradicate extreme poverty. Poverty eradication is also the first of the Sustainable Development Goals. This paper investigates potential consequences for climate targets of achieving poverty eradication. We find that eradicating extreme poverty, i.e., moving people to an income above $1.9 purchasing power parity (PPP) a day, does not jeopardize the climate target even...

IL-2 absorption affects IFN-gamma and IL-5, but not IL-4 producing memory T cells in double color cytokine ELISPOT assays.

Science.gov (United States)

Quast, Stefan; Zhang, Wenji; Shive, Carey; Kovalovski, Damian; Ott, Patrick A; Herzog, Bernhard A; Boehm, Bernhard O; Tary-Lehmann, Magdalena; Karulin, Alexey Y; Lehmann, Paul V

2005-09-01

Cytokine assays are gaining increasing importance for human immune monitoring because they reliably detect antigen-specific T cells in primary PBMC, even at low clonal sizes. Double color ELISPOT assays permit the simultaneous visualization of cells producing two different cytokines. Permitting the simultaneous assessment of type 1 and 2 immunity and due to the limited numbers of PBMC available from human study subjects, double color assays should be particularly attractive for clinical trials. Since the performance of double color assays has not yet been validated, we set out to compare them to single color measurements. Testing the recall antigen-induced cytokine response of PBMC, we found that double color assays regularly provided lower numbers of IFN-gamma and IL-5 spots than single color measurements when IL-2 detection was part of the double color assay. We showed that the inhibitory effect resulted from IL-2 absorption and could be overcome by either antibody free preactivation cultures or by inclusion of anti-CD28 antibody. In contrast, the simultaneous detection of IL-2 did not affect the numbers of IL-4 spots. Therefore, unlike IL-2/IL-4 and IFN-gamma/IL-5 assays, IL-2/IFN-gamma, and IL-2/IL-5 assays require compensation for the IL-2 capture to provide accurate numbers for the frequencies of cytokine producing memory T cells.

Interleukin-1 is required for cancer eradication mediated by tumor-specific Th1 cells.

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Haabeth, Ole Audun Werner; Lorvik, Kristina Berg; Yagita, Hideo; Bogen, Bjarne; Corthay, Alexandre

The role of inflammation in cancer is controversial as both tumor-promoting and tumor-suppressive aspects of inflammation have been reported. In particular, it has been shown that pro-inflammatory cytokines, like interleukin-1α (IL-1α), IL-1β, IL-6, and tumor necrosis factor α (TNFα), may either promote or suppress cancer. However, the cellular and molecular basis underlying these opposing outcomes remains enigmatic. Using mouse models for myeloma and lymphoma, we have recently reported that inflammation driven by tumor-specific T helper 1 (Th1) cells conferred protection against B-cell cancer and that interferon-γ (IFN-γ) was essential for this process. Here, we have investigated the contribution of several inflammatory mediators. Myeloma eradication by Th1 cells was not affected by inhibition of TNF-α, TNF-related weak inducer of apoptosis (TWEAK), or TNF-related apoptosis-inducing ligand (TRAIL). In contrast, cancer elimination by tumor-specific Th1 cells was severely impaired by the in vivo neutralization of both IL-1α and IL-1β (collectively named IL-1) with IL-1 receptor antagonist (IL-1Ra). The antitumor functions of tumor-specific Th1 cells and tumor-infiltrating macrophages were both affected by IL-1 neutralization. Secretion of the Th1-derived cytokines IL-2 and IFN-γ at the incipient tumor site was severely reduced by IL-1 blockade. Moreover, IL-1 was shown to synergize with IFN-γ for induction of tumoricidal activity in tumor-infiltrating macrophages. This synergy between IL-1 and IFN-γ may explain how inflammation, when driven by tumor-specific Th1 cells, represses rather than promotes cancer. Collectively, the data reveal a central role of inflammation, and more specifically of the canonical pro-inflammatory cytokine IL-1, in enhancing Th1-mediated immunity against cancer.

Poverty eradication in a carbon constrained world.

Science.gov (United States)

Hubacek, Klaus; Baiocchi, Giovanni; Feng, Kuishuang; Patwardhan, Anand

2017-10-24

The UN Framework Convention on Climate Change aims to keep warming below 2 °C while recognizing developing countries' right to eradicate extreme poverty. Poverty eradication is also the first of the Sustainable Development Goals. This paper investigates potential consequences for climate targets of achieving poverty eradication. We find that eradicating extreme poverty, i.e., moving people to an income above $1.9 purchasing power parity (PPP) a day, does not jeopardize the climate target even in the absence of climate policies and with current technologies. On the other hand, bringing everybody to a still modest expenditure level of at least $2.97 PPP would have long-term consequences on achieving emission targets. Compared to the reference mitigation pathway, eradicating extreme poverty increases the effort by 2.8% whereas bringing everybody to at least $2.97 PPP would increase the required mitigation rate by 27%. Given that the top 10% global income earners are responsible for 36% of the current carbon footprint of households; the discourse should address income distribution and the carbon intensity of lifestyles.

Dosimetric systems of high dose, dose rate and dose uniformity in food and medical products

International Nuclear Information System (INIS)

Vargas, J.; Vivanco, M.; Castro, E.

2014-08-01

In the Instituto Peruano de Energia Nuclear (IPEN) we use the chemical dosimetry Astm-E-1026 Fricke as a standard dosimetric system of reference and different routine dosimetric systems of high doses, according to the applied doses to obtain the desired effects in the treated products and the doses range determined for each type of dosimeter. Fricke dosimetry is a chemical dosimeter in aqueous solution indicating the absorbed dose by means an increase in absorbance at a specific wavelength. A calibrated spectrophotometer with controlled temperature is used to measure absorbance. The adsorbed dose range should cover from 20 to 400 Gy, the Fricke solution is extremely sensitive to organic impurities, to traces of metal ions, in preparing chemical products of reactive grade must be used and the water purity is very important. Using the referential standard dosimetric system Fricke, was determined to March 5, 2013, using the referential standard dosimetric system Astm-1026 Fricke, were irradiated in triplicate Fricke dosimeters, to 5 irradiation times (20; 30; 40; 50 and 60 seconds) and by linear regression, the dose rate of 5.400648 kGy /h was determined in the central point of the irradiation chamber (irradiator Gamma cell 220 Excel), applying the decay formula, was compared with the obtained results by manufacturers by means the same dosimetric system in the year of its manufacture, being this to the date 5.44691 kGy /h, with an error rate of 0.85. After considering that the dosimetric solution responds to the results, we proceeded to the irradiation of a sample of 200 g of cereal instant food, 2 dosimeters were placed at the lateral ends of the central position to maximum dose and 2 dosimeters in upper and lower ends as minimum dose, they were applied same irradiation times; for statistical analysis, the maximum dose rate was 6.1006 kGy /h and the minimum dose rate of 5.2185 kGy /h; with a dose uniformity of 1.16. In medical material of micro pulverized bone for

Increase of Circulating CD4(+)CD25(high)Foxp3(+) Regulatory T Cells in Patients With Metastatic Renal Cell Carcinoma During Treatment With Dendritic Cell Vaccination and Low-Dose Interleukin-2

DEFF Research Database (Denmark)

Berntsen, Annika; Brimnes, M.K.; Straten, P.T.

2010-01-01

Regulatory T cells (Treg) play an important role in the maintenance of immune tolerance and may be one of the obstacles of successful tumor immunotherapy. In this study, we analyzed the impact of administration of dendritic cell (DC) vaccination in combination with low-dose interleukin (IL)-2...... in patients with metastatic renal cell carcinoma on the frequency of CD4(+) CD25(high)Foxp3(+) Treg cells in peripheral blood. We found that the treatment increased the frequency of Treg cells more than 7-fold compared with pretreatment levels (P cells decreased when patients...... had been off IL-2 treatment for only 8 days, but remained higher than pretreatment levels. A functional assay showed that isolated Treg cells were capable of inhibiting proliferation of responder cells. Also, in vitro studies showed that coculture of mature DCs, autologous T cells and IL-2 leads...

Eradication versus control for poliomyelitis: an economic analysis.

Science.gov (United States)

Thompson, Kimberly M; Tebbens, Radboud J Duintjer

2007-04-21

Worldwide eradication of wild polioviruses is likely to yield substantial health and financial benefits, provided we finish the job. Challenges in the four endemic areas combined with continuing demands for financial resources for eradication have led some to question the goal of eradication and to suggest switching to a policy of control. We developed a dynamic model, based on modelling of the currently endemic areas in India, to show the importance of maintaining and increasing the immunisation intensity to complete eradication and to illustrate how policies based on perception about high short-term costs or cost-effectiveness ratios without consideration of long-term benefits could undermine any eradication effort. An extended model assesses the economic implications and disease burden of a change in policy from eradication to control. Our results suggest that the intensity of immunisation must be increased to achieve eradication, and that even small decreases in intensity could lead to large outbreaks. This finding implies the need to pay even higher short-run costs than are currently being spent, which will further exacerbate concerns about continued investment in interventions with high perceived cost-effectiveness ratios. We show that a wavering commitment leads to a failure to eradicate, greater cumulative costs, and a much larger number of cases. We further show that as long as it is technically achievable, eradication offers both lower cumulative costs and cases than control, even with the costs of achieving eradication exceeding several billion dollars more. A low-cost control policy that relies only on routine immunisation for 20 years with discounted costs of more than $3500 million could lead to roughly 200 000 expected paralytic poliomyelitis cases every year in low-income countries, whereas a low-case control policy that keeps the number of cases at about 1500 per year could cost around $10 000 million discounted over the 20 years. Focusing on the

Counterbalancing of TH2-driven allergic airway inflammation by IL-12 does not require IL-10.

Science.gov (United States)

Tournoy, K G; Kips, J C; Pauwels, R A

2001-03-01

Asthma is characterized by allergen-induced airway inflammation orchestrated by TH2 cells. The TH1-promoting cytokine IL-12 is capable of inhibiting the TH2-driven allergen-induced airway changes in mice and is therefore regarded as an interesting strategy for treating asthma. The antiallergic effects of IL-12 are only partially dependent of IFN-gamma. Because IL-12 is a potent inducer of the anti-inflammatory cytokine IL-10, the aim of the present study was to investigate in vivo whether the antiallergic effects of IL-12 are mediated through IL-10. C57BL/6J-IL-10 knock-out (IL-10(-/-)) mice were sensitized intraperitoneally to ovalbumin (OVA) and subsequently exposed from day 14 to day 21 to aerosolized OVA (1%). IL-12 was administered intraperitoneally during sensitization, subsequent OVA exposure, or both. IL-12 inhibited the OVA-induced airway eosinophilia, despite the absence of IL-10. Moreover, a shift from a TH2 inflammatory pattern toward a TH1 reaction was observed, with concomitant pronounced mononuclear peribronchial inflammation after IL-12 treatment. Allergen-specific IgE synthesis was completely suppressed only when IL-12 was administered along with the allergen sensitization. Furthermore, treating the animals with IL-12 at the time of the secondary allergen challenge resulted not only in a significant suppression of the airway responsiveness but also in an important IFN-gamma-associated toxicity. These results indicate that IL-12 is able to inhibit allergen-induced airway changes, even in the absence of IL-10. In addition, our results raise concerns regarding the redirection of TH2 inflammation by TH1-inducing therapies because treatment with IL-12 resulted not only in a disappearance of the TH2 inflammation but also in a TH1-driven inflammatory pulmonary pathology.

Changes of serum IL-2, IL-4, IL-10 and IFN-γ levels after treatment with 131I-17-allylamino-17-demethoxygeldanamycin in VX2 rabbit models

International Nuclear Information System (INIS)

Gao Wen; Liu Lu; Zhou Yun

2007-01-01

Objective: To study the influence of 131 I-17-allylamino-17-demethoxygeldanamycin( 131 I-17-AAG) therapy on immune function in VX2 rabbit models with transplanted liver cancer. Methods: Serum IL-2, IL-4, IL-10 and IFN-γ levels were measured with RIA in 8 VX2 rabbit models with transplanted liver cancer 1-2 weeks after 10mCi 131 I-17-AAG treatment as well as in 8 controls rabbits (models with tumor but without treatment). Results: 1 week after 10mCi 131 I treatment, the serum IL - 2 and IFN-γ levels were significantly lower in the treated rabbits than those in controls (P 0.05). Serum IL-4 and IL-10 levels in the treated rabbits (both at 1 and 2 week) were not significantly different from those in controls (P>0.05). Conclusion: 131 I-17-AAG treatment had transient effects on cellular immunity with no influence on humoral immunity. As a whole, it is a safe to treat VX2 rabbit models with this preparation. (authors)

Interaction of 2-Gy Equivalent Dose and Margin Status in Perioperative High-Dose-Rate Brachytherapy

International Nuclear Information System (INIS)

Martinez-Monge, Rafael; Cambeiro, Mauricio; Moreno, Marta; Gaztanaga, Miren; San Julian, Mikel; Alcalde, Juan; Jurado, Matias

2011-01-01

Purpose: To determine patient, tumor, and treatment factors predictive of local control (LC) in a series of patients treated with either perioperative high-dose-rate brachytherapy (PHDRB) alone (Group 1) or with PHDRB combined with external-beam radiotherapy (EBRT) (Group 2). Patient and Methods: Patients (n = 312) enrolled in several PHDRB prospective Phase I-II studies conducted at the Clinica Universidad de Navarra were analyzed. Treatment with PHDRB alone, mainly because of prior irradiation, was used in 126 patients to total doses of 32 Gy/8 b.i.d. or 40 Gy/10 b.i.d. treatments after R0 or R1 resections. Treatment with PHDRB plus EBRT was used in 186 patients to total doses of 16 Gy/4 b.i.d. or 24 Gy/6 b.i.d. treatments after R0 or R1 resections along with 45 Gy of EBRT with or without concomitant chemotherapy. Results: No dose-margin interaction was observed in Group 1 patients. In Group 2 patients there was a significant interaction between margin status and 2-Gy equivalent (Eq2Gy) dose (p = 0.002): (1) patients with negative margins had 9-year LC of 95.7% at Eq2Gy = 62.9Gy; (2) patients with close margins of >1 mm had 9-year LC of 92.4% at Eq2Gy = 72.2Gy, and (3) patients with positive/close <1-mm margins had 9-year LC of 68.0% at Eq2Gy = 72.2Gy. Conclusions: Two-gray equivalent doses ≥70 Gy may compensate the effect of close margins ≥1 mm but do not counterbalance the detrimental effect of unfavorable (positive/close <1 mm) resection margins. No dose-margin interaction is observed in patients treated at lower Eq2Gy doses ≤50 Gy with PHDRB alone.

Conditional IL-2 gene deletion: consequences for T cell proliferation

Directory of Open Access Journals (Sweden)

Kendall A Smith

2012-05-01

Full Text Available To explore the role of interleukin-2 (IL-2 in T cell proliferation, and to circumvent the IL-2 deficiency autoimmune syndrome of conventional il2 gene deletion, mice were created to allow conditional il2 gene deletion when treated with the estrogen analogue, tamoxifen (TAM as adults. Splenocytes from four different mouse strains, C57Bl/6 wild type (WT, conventional IL-2 (-/-, TAM-treated Cre recombinase negative (Cre-/IL2fl/fl, and Cre+/IL-2fl/fl (Cre+, were activated with anti-CD3 and anti-CD28, and monitored for CD4+ and CD8+ T cell lymphocyte blastogenesis, aerobic glycolysis, BrdU incorporation into newly synthesized DNA, and CFSE dye dilution to monitor cell division. IL-2 production was monitored by quantitative ELISA and multiple additional cytokines were monitored by protein-bead arrays. Splenocytes from conventional IL-2 (-/- and TAM-treated Cre+ mice resulted in undetectable IL-2 production, so that both strains were IL-2 deficient. As monitored by flow cytometry, activated CD4+ and CD8+ T cells from WT, Cre+ and Cre- mice all underwent blastogenesis, whereas far fewer cells from conventional IL-2 (-/- mice did so. By comparison, only cells from IL-2 sufficient WT and Cre- switched to aerobic glycolysis as evidenced by a drop in media pH. Blastogenesis was mirrored by BrdU incorporation and CFSE dye dilution by CD4+ and CD8+ T cells from WT, Cre+ and Cre- mice, which were all equivalent, while proliferation of cells from conventional IL-2 (-/- mice was compromised. Splenocytes from IL-2 deficient conventional IL-2 (-/- mice produced low or undetectable other γc-chain cytokines (IL-4, IL-7, IL-9, IL-13, IL-15, and IL-21, whereas production of these γc-chain cytokines from IL-2-deficient conditional IL-2 (-/- Cre+ mice were comparable with WT and Cre- mice. These results indicate that CD4+ and CD8+ T cell blastogenesis cannot be attributable to IL-2 alone, but a switch to aerobic glycolysis is attributable to IL-2, and proliferation

Augmentation of natural cytotoxicity by chronic low-dose ionizing radiation in murine natural killer cells primed by IL-2

International Nuclear Information System (INIS)

Sonn, Chung-Hee; Choi, Jong-Rip; Kim, Tae-Jin

2012-01-01

The possible beneficial effects of chronic low-dose irradiation (LDR) and its mechanism of action in a variety of pathophysiological processes such as cancer are a subject of intense investigation. While animal studies involving long-term exposure to LDR have yielded encouraging results, the influence of LDR at the cellular level has been less well defined. We reasoned that since natural killer (NK) cells constitute an early responder to exogenous stress, NK cells may reveal sentinel alterations in function upon exposure to LDR. When purified NK cells received LDR at 4.2 mGy/h for a total of 0.2 Gy in vitro, no significant difference in cell viability was observed. Likewise, no functional changes were detected in LDR-exposed NK cells, demonstrating that LDR alone was insufficient to generate changes at the cellular level. Nonetheless, significant augmentation of cytotoxic, but not proliferative, function was detected when NK cells were stimulated with low-dose IL-2 prior to irradiation. This enhancement of NK cytotoxicity was not due to alterations in NK-activating receptors, NK1.1, NKG2D, CD69 and 2B4, or changes in the rate of early or late apoptosis. Therefore, LDR, in the presence of suboptimal cytokine levels, can facilitate anti-tumor cytotoxicity of NK cells without influencing cellular proliferation or apoptosis. Whether these results translate to in vivo consequences remains to be seen; however, our data provide initial evidence that exposure to LDR can lead to subtle immune-enhancing effects on NK cells and may explain, in part, the functional basis underlying, diverse beneficial effects seen in the animals chronically exposed to LDR. (author)

cagA Status and Eradication Treatment Outcome of Anti-Helicobacter pylori Triple Therapies in Patients with Nonulcer Dyspepsia

Science.gov (United States)

Broutet, Nathalie; Marais, Armelle; Lamouliatte, Hervé; de Mascarel, Antoine; Samoyeau, Roland; Salamon, Roger; Mégraud, Francis

2001-01-01

The differences in eradication rates reported in clinical trials aiming to cure Helicobacter pylori infection cannot be entirely explained by the type of regimen, bacterial resistance, or lack of compliance. Using data from a clinical trial, a logistic regression model was constructed to determine whether cagA status, assessed by PCR, affects the outcome of eradication. Resistance to clarithromycin (10% of the strains) predicted failure perfectly. In the model (n = 156), a cagA-lacking strain (odds ratio [OR] = 2.2; 95% confidence interval [CI], (1.1 to 4.7), tobacco smoking OR = 3.1; 95% CI, 1.3 to 7.0), and a double dose of proton pump inhibitor in the treatment regimen (OR = 0.3; 95% CI, 0.2 to 0.7) were associated with the treatment outcome. The exact role of cagA in the outcome of H. pylori eradication therapy has not been explored. However, the type of histological lesions which it causes in the gastric mucosa may be implicated. Regardless of the mechanism involved, cagA status is a good predictive marker of eradication outcome. PMID:11283049

Structural Characterisation Reveals Mechanism of IL-13-Neutralising Monoclonal Antibody Tralokinumab as Inhibition of Binding to IL-13Rα1 and IL-13Rα2.

Science.gov (United States)

Popovic, B; Breed, J; Rees, D G; Gardener, M J; Vinall, L M K; Kemp, B; Spooner, J; Keen, J; Minter, R; Uddin, F; Colice, G; Wilkinson, T; Vaughan, T; May, R D

2017-01-20

Interleukin (IL)-13 is a pleiotropic T helper type 2 cytokine frequently associated with asthma and atopic dermatitis. IL-13-mediated signalling is initiated by binding to IL-13Rα1, which then recruits IL-4Rα to form a heterodimeric receptor complex. IL-13 also binds to IL-13Rα2, considered as either a decoy or a key mediator of fibrosis. IL-13-neutralising antibodies act by preventing IL-13 binding to IL-13Rα1, IL-4Rα and/or IL-13Rα2. Tralokinumab (CAT-354) is an IL-13-neutralising human IgG4 monoclonal antibody that has shown clinical benefit in patients with asthma. To decipher how tralokinumab inhibits the effects of IL-13, we determined the structure of tralokinumab Fab in complex with human IL-13 to 2 Å resolution. The structure analysis reveals that tralokinumab prevents IL-13 from binding to both IL-13Rα1 and IL-13Rα2. This is supported by biochemical ligand-receptor interaction assay data. The tralokinumab epitope is mainly composed of residues in helices D and A of IL-13. It is mostly light chain complementarity-determining regions that are driving paratope interactions; the variable light complementarity-determining region 2 plays a key role by providing residue contacts for a network of hydrogen bonds and a salt bridge in the core of binding. The key residues within the paratope contributing to binding were identified as Asp50, Asp51, Ser30 and Lys31. This study demonstrates that tralokinumab prevents the IL-13 pharmacodynamic effect by binding to IL-13 helices A and D, thus preventing IL-13 from interacting with IL-13Rα1 and IL-13Rα2. Copyright © 2016 AstraZeneca. Published by Elsevier Ltd.. All rights reserved.

Interactions between Diet, Lifestyle and IL10, IL1B, and PTGS2/COX-2 Gene Polymorphisms in Relation to Risk of Colorectal Cancer in a Prospective Danish Case-Cohort Study

DEFF Research Database (Denmark)

Andersen, Vibeke; Holst, René; Kopp, Tine Iskov

2013-01-01

Genetically determined low COX-2 and high IL-1β activity were associated with increased risk of CRC in this northern Caucasian cohort. Furthermore, interactions were found between IL10, IL1b, and PTGS2 and diet and lifestyle factors in relation to CRC. The present study demonstrates that gene...

Clinical significance of determination of changes of serum EMAb, IL-2, IL-2R and VEGF levels in patients with endometriosis

International Nuclear Information System (INIS)

Min Jieyan

2009-01-01

Objective: To investigate the relationship between the progress of the disease process and changes of serum antiendome-trium antibody (EMAb), interleukin-2 (IL-2), interleukin-2 receptor (IL-2R) and vascular endothelial growth factor (VEGF) levels in patients with endometriosis. Methods: Serum EMAb (with ELISA) and VEGF, IL-2, IL-2R (with RIA) levels were measured in 45 patients with endometriosis both before and after treatment as well as in 35 controls. Results: Before treatment with integrated traditional and western medicine, the positive rate of serum EMAb were significantly higher in patients with endometriosis than that in the controls (P 0.05). Conclusion: Determination of changes of serum EMAb, IL-2, IL-2R and VEGF levels in patients with endometriosis were helpful for assessment of the progress of disease process and outcome prediction. (authors)

India's Research Contributions Towards Polio Eradication (1965-2015).

Science.gov (United States)

John, T Jacob

2016-08-07

Pioneering research has been conducted in India during the past five decades, comprehensively covering epidemiology of poliovirus infection and of polio, efficacy and effectiveness of oral and inactivated polio vaccines (OPV, IPV) as well as pathogenesis of wild and vaccine polioviruses. It was estimated, based on epidemiology data, that India had a very heavy burden of polio, with average 500-1000 cases per day. Prevention was an urgent need, but OPV showed unacceptably low vaccine efficacy (VE) for poliovirus types 1 and 3. Having learned that response to sequential doses followed arithmetic pattern and not prime-boost principle, multiple doses were tested and found to be a simple intervention to increase VE. Eventually this knowledge became critical for polio eradication. Indian research demonstrated that monovalent OPV (mOPV) had nearly three timed higher VE than trivalent OPV (tOPV). Eventually, mOPV type 1 became essential to interrupt wild type 1 infection in many locations where the VE of tOPV was very low. Indian research pointed to the epidemiologic importance of direct person-to-person spread of wild polio viruses and the need and potential of IPV to prevent and control polio. Research on vaccine responses led to the understanding that OPV would become wild-like through back mutations and to the definition of eradication as interrupting transmission of both wild and vaccine-derived polioviruses. By asking and answering the right questions insequence, Indian polio research presaged and guided polio eradication.

Probiotics as an adjuvant treatment in Helicobacter pylori eradication therapy.

Science.gov (United States)

Zhu, Xin Yan; Liu, Fei

2017-04-01

Over 80% of individuals infected with Helicobacter pylori (H. pylori) are asymptomatic. Increased resistance to antibiotics and decreased compliance to the therapeutic regimens have led to the failure of eradication therapy. Probiotics, with direct and indirect inhibitory effects on H. pylori in both animal models and clinical trials, have recently been used as a supplementary treatment in H. pylori eradication therapy. Probiotics have been considered useful because of the improvements in H. pylori eradication rates and therapy-related side effects although treatment outcomes using probiotics are controversial due to the heterogeneity of species, strains, doses and therapeutic duration of probiotics. Thus, despite the positive role of probiotics, several factors need to be further considered during their applications. Moreover, adverse events of probiotic use need to be noted. Further investigations into the safety of adjuvant probiotics to H. pylori eradication therapy are required. © 2017 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Expression of TNF, IL-17A, IL-4 and IL-10 cytokines in irradiated peripheral blood mononuclear cells 'In vitro'

International Nuclear Information System (INIS)

Amaral, Ademir de Jesus; Leite, Lidía Lúcia Bezerra; Nascimento, Ayala Gomes do; Diniz, Ewerton Clementino; Silva, Gicielne Freitas da; Fernandes, Thiago de Salazar e; Silva, Edvane Borges da; Cavalcanti, Mariana Brayner; Veras, Robson Cavalcante; Medeiros, Isac Almeida de

2017-01-01

The aim of the present study was to determine and to compare the profile of cytokines produced by non-irradiated and irradiated peripheral blood mononuclear cells (PBMCs) and the possible application of this analysis as a biomarker of individual radiosensitivity. For this, peripheral blood (PB) samples were collected from seven healthy volunteers, and each sample divided in two aliquots: one aliquot was irradiated with a dose of 2 Gy (from a 6MV Linear Accelerator) and while the other one was kept non irradiated. All PBMCs were cultured in RPMI 1640 supplemented with 10% Bovine Fetal Serum for 48 hours at 37°C and 5% CO2. The cytokines TNF, IL-17A, IL-4 and IL-10 were measured by flow cytometry. Wilcoxon test was performed with the level of significance of 95%. In the irradiated samples it was observed a slight increase of the median of the level of cytokines TNF, IL-4 and IL-10 (from 1040.9 to 1196.1 pg/mL, from 127.3 to 138 pg/mL, and from 99.9 to 120.8 pg/mL, respectively) and a slight decrease in median of cytokines IL- 17A (from 841.1 to 799.4 pg/mL). In addition to this evidence, there was a high inter-individual variability of cytokine concentrations in response to irradiation. It was observed that some individuals are more responsive to the expression of some inflammatory proteins after exposure to X-rays. Although further studies are necessary, the hypothesis that raises is that these biomarkers could be predictor of future individual responses to ionizing radiation exposure. (author)

T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production.

Science.gov (United States)

Zhu, Jinfang

2015-09-01

Interleukin-4 (IL-4), IL-5 and IL-13, the signature cytokines that are produced during type 2 immune responses, are critical for protective immunity against infections of extracellular parasites and are responsible for asthma and many other allergic inflammatory diseases. Although many immune cell types within the myeloid lineage compartment including basophils, eosinophils and mast cells are capable of producing at least one of these cytokines, the production of these "type 2 immune response-related" cytokines by lymphoid lineages, CD4 T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) in particular, are the central events during type 2 immune responses. In this review, I will focus on the signaling pathways and key molecules that determine the differentiation of naïve CD4 T cells into Th2 cells, and how the expression of Th2 cytokines, especially IL-4 and IL-13, is regulated in Th2 cells. The similarities and differences in the differentiation of Th2 cells, IL-4-producing T follicular helper (Tfh) cells and ILC2s as well as their relationships will also be discussed. Published by Elsevier Ltd.

T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production

Science.gov (United States)

Zhu, Jinfang

2015-01-01

Interleukin-4 (IL-4), IL-5 and IL-13, the signature cytokines that are produced during type 2 immune responses, are critical for protective immunity against infections of extracellular parasites and are responsible for asthma and many other allergic inflammatory diseases. Although many immune cell types within the myeloid lineage compartment including basophils, eosinophils and mast cells are capable of producing at least one of these cytokines, the production of these “type 2 immune response-related” cytokines by lymphoid lineages, CD4 T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) in particular, are the central events during type 2 immune responses. In this review, I will focus on the signaling pathways and key molecules that determine the differentiation of naïve CD4 T cells into Th2 cells, and how the expression of Th2 cytokines, especially IL-4 and IL-13, is regulated in Th2 cells. The similarities and differences in the differentiation of Th2 cells, IL-4-producing T follicular helper (Tfh) cells and ILC2s as well as their relationships will also be discussed. PMID:26044597

Malaria eradication: the economic, financial and institutional challenge.

Science.gov (United States)

Mills, Anne; Lubell, Yoel; Hanson, Kara

2008-12-11

Malaria eradication raises many economic, financial and institutional challenges. This paper reviews these challenges, drawing on evidence from previous efforts to eradicate malaria, with a special focus on resource-poor settings; summarizes more recent evidence on the challenges, drawing on the literature on the difficulties of scaling-up malaria control and strengthening health systems more broadly; and explores the implications of these bodies of evidence for the current call for elimination and intensified control. Economic analyses dating from the eradication era, and more recent analyses, suggest that, in general, the benefits of malaria control outweigh the costs, though few studies have looked at the relative returns to eradication versus long-term control. Estimates of financial costs are scanty and difficult to compare. In the 1960s, the consolidation phase appeared to cost less than $1 per capita and, in 1988, was estimated to be $2.31 per capita (both in 2006 prices). More recent estimates for high coverage of control measures suggest a per capita cost of several dollars. Institutional challenges faced by malaria eradication included limits to the rule of law (a major problem where malaria was concentrated in border areas with movement of people associated with illegal activities), the existence and performance of local implementing structures, and political sustainability at national and global levels. Recent analyses of the constraints to scaling-up malaria control, together with the historical evidence, are used to discuss the economic, financial and institutional challenges that face the renewed call for eradication and intensified control. The paper concludes by identifying a research agenda covering: issues of the allocative efficiency of malaria eradication, especially using macro-economic modelling to estimate the benefits and costs of malaria eradication and intensified control, and studies of the links between malaria control and economic

Malaria eradication: the economic, financial and institutional challenge

Directory of Open Access Journals (Sweden)

Hanson Kara

2008-12-01

Full Text Available Abstract Malaria eradication raises many economic, financial and institutional challenges. This paper reviews these challenges, drawing on evidence from previous efforts to eradicate malaria, with a special focus on resource-poor settings; summarizes more recent evidence on the challenges, drawing on the literature on the difficulties of scaling-up malaria control and strengthening health systems more broadly; and explores the implications of these bodies of evidence for the current call for elimination and intensified control. Economic analyses dating from the eradication era, and more recent analyses, suggest that, in general, the benefits of malaria control outweigh the costs, though few studies have looked at the relative returns to eradication versus long-term control. Estimates of financial costs are scanty and difficult to compare. In the 1960s, the consolidation phase appeared to cost less than $1 per capita and, in 1988, was estimated to be $2.31 per capita (both in 2006 prices. More recent estimates for high coverage of control measures suggest a per capita cost of several dollars. Institutional challenges faced by malaria eradication included limits to the rule of law (a major problem where malaria was concentrated in border areas with movement of people associated with illegal activities, the existence and performance of local implementing structures, and political sustainability at national and global levels. Recent analyses of the constraints to scaling-up malaria control, together with the historical evidence, are used to discuss the economic, financial and institutional challenges that face the renewed call for eradication and intensified control. The paper concludes by identifying a research agenda covering: ∘ issues of the allocative efficiency of malaria eradication, especially using macro-economic modelling to estimate the benefits and costs of malaria eradication and intensified control, and studies of the links between

Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and interleukin 2 (IL-2) expression in the murine T-cell line, EL4.IL-2.

Science.gov (United States)

Condie, R; Herring, A; Koh, W S; Lee, M; Kaminski, N E

1996-05-31

Cannabinoid receptors negatively regulate adenylate cyclase through a pertussis toxin-sensitive GTP-binding protein. In the present studies, signaling via the adenylate cyclase/cAMP pathway was investigated in the murine thymoma-derived T-cell line, EL4.IL-2. Northern analysis of EL4.IL-2 cells identified the presence of 4-kilobase CB2 but not CB1 receptor-subtype mRNA transcripts. Southern analysis of genomic DNA digests for the CB2 receptor demonstrated identical banding patterns for EL4.IL-2 cells and mouse-derived DNA, both of which were dissimilar to DNA isolated from rat. Treatment of EL4.IL-2 cells with either cannabinol or Delta9-THC disrupted the adenylate cyclase signaling cascade by inhibiting forskolin-stimulated cAMP accumulation which consequently led to a decrease in protein kinase A activity and the binding of transcription factors to a CRE consensus sequence. Likewise, an inhibition of phorbol 12-myristate 13-acetate (PMA)/ionomycin-induced interleukin 2 (IL-2) protein secretion, which correlated to decreased IL-2 gene transcription, was induced by both cannabinol and Delta9-THC. Further, cannabinoid treatment also decreased PMA/ionomycin-induced nuclear factor binding to the AP-1 proximal site of the IL-2 promoter. Conversely, forskolin enhanced PMA/ionomycin-induced AP-1 binding. These findings suggest that inhibition of signal transduction via the adenylate cyclase/cAMP pathway induces T-cell dysfunction which leads to a diminution in IL-2 gene transcription.

Three-Dimensional Conformal Radiotherapy in Prostate Cancer Patients: Rise in Interleukin 6 (IL-6) but not IL-2, IL-4, IL-5, Tumor Necrosis Factor-{alpha}, MIP-1-{alpha}, and LIF Levels

Energy Technology Data Exchange (ETDEWEB)

Oliveira Lopes, Carlos [Universidade do Vale do Paraiba, Centro de Oncologia Radioterapica do Vale do Paraiba, Universidade do Vale do Paraiba Instituto de Pesquisa e Desenvolvimento, Universidade do Vale do Paraiba, Sao Jose dos Campos, Sao Paulo (Brazil); Callera, Fernando, E-mail: fcallera@gmail.com [Centro de Hematologia Onco-hematologia e Transplantes de Medula Ossea do Vale do Paraiba, Sao Paulo (Brazil)

2012-03-15

Purpose: To investigate the effect of radiotherapy (RT) on serum levels of interleukin-2 (IL-2), IL-4, IL-5, IL-6, tumor necrosis factor alpha (TNF-{alpha}), macrophage inflammatory protein-1-alpha (MIP-1-{alpha}) and leukemia inhibitory factor (LIF) in patients with prostate cancer. Methods and Materials: Forty eight patients with prostate cancer received three-dimensional conformal blocking radiation therapy with a linear accelerator. IL-2, IL-4, IL-5, IL-6, TNF-{alpha}, MIP-1-{alpha}, and LIF levels were measured by the related immunoassay kit 1 day before the beginning of RT and during RT at days 15 and 30. Results: The mean IL-2 values were elevated before and during the RT in contrast with those of IL-4, IL-5, IL-6, TNF-{alpha}, MIP-1-{alpha}, and LIF, which were within the normal range under the same conditions. Regarding markers IL-2, IL-4, IL-5, TNF-{alpha}, MIP-1-{alpha}, and LIF, comparisons among the three groups (before treatment and 15 and 30 days during RT) did not show significant differences. Although values were within the normal range, there was a significant rise in IL-6 levels at day 15 of RT (p = 0.0049) and a decline at day 30 to levels that were similar to those observed before RT. Conclusions: IL-6 appeared to peak after 15 days of RT before returning to pre-RT levels. In contrast, IL-2, IL-4, IL-5, TNF-{alpha}, MIP-1-{alpha}, and LIF levels were not sensitive to irradiation. The increased levels of IL-6 following RT without the concurrent elevation of other cytokines involved in the acute phase reaction did not suggest a classical inflammatory response to radiation exposure. Further studies should be designed to elucidate the role of IL-6 levels in patients with prostate cancer treated with RT.

Expression of TNF, IL-17A, IL-4 and IL-10 cytokines in irradiated peripheral blood mononuclear cells 'In vitro'; Expressão das citocinas TNF, IL-17A, IL-4 e IL-10 em células mononucleares do sangue periférico irradiadas 'in vitro'

Energy Technology Data Exchange (ETDEWEB)

Amaral, Ademir de Jesus; Leite, Lidía Lúcia Bezerra; Nascimento, Ayala Gomes do; Diniz, Ewerton Clementino; Silva, Gicielne Freitas da; Fernandes, Thiago de Salazar e; Silva, Edvane Borges da; Cavalcanti, Mariana Brayner, E-mail: maribrayner@yahoo.com.br [Universidade Federal de Pernambuco (GERAR/DEN/UFPE), Recife, PE (Brazil). Grupo de Estudos em Radioproteção e Radioecologia; Dantas, Samuel César [Instituto de Medicina Integrada Prof. Antônio Figueira (IMIP), PE (Brazil); Veras, Robson Cavalcante; Medeiros, Isac Almeida de [Universidade Federal da Paraiba (DCF/UFPB), PB (Brazil). Departamento de Ciências Farmacêuticas

2017-07-01

The aim of the present study was to determine and to compare the profile of cytokines produced by non-irradiated and irradiated peripheral blood mononuclear cells (PBMCs) and the possible application of this analysis as a biomarker of individual radiosensitivity. For this, peripheral blood (PB) samples were collected from seven healthy volunteers, and each sample divided in two aliquots: one aliquot was irradiated with a dose of 2 Gy (from a 6MV Linear Accelerator) and while the other one was kept non irradiated. All PBMCs were cultured in RPMI 1640 supplemented with 10% Bovine Fetal Serum for 48 hours at 37°C and 5% CO2. The cytokines TNF, IL-17A, IL-4 and IL-10 were measured by flow cytometry. Wilcoxon test was performed with the level of significance of 95%. In the irradiated samples it was observed a slight increase of the median of the level of cytokines TNF, IL-4 and IL-10 (from 1040.9 to 1196.1 pg/mL, from 127.3 to 138 pg/mL, and from 99.9 to 120.8 pg/mL, respectively) and a slight decrease in median of cytokines IL- 17A (from 841.1 to 799.4 pg/mL). In addition to this evidence, there was a high inter-individual variability of cytokine concentrations in response to irradiation. It was observed that some individuals are more responsive to the expression of some inflammatory proteins after exposure to X-rays. Although further studies are necessary, the hypothesis that raises is that these biomarkers could be predictor of future individual responses to ionizing radiation exposure. (author)

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.

Macrophages as IL-25/IL-33-responsive cells play an important role in the induction of type 2 immunity.

Directory of Open Access Journals (Sweden)

Zhonghan Yang

Full Text Available Type 2 immunity is essential for host protection against nematode infection but is detrimental in allergic inflammation or asthma. There is a major research focus on the effector molecules and specific cell types involved in the initiation of type 2 immunity. Recent work has implicated an important role of epithelial-derived cytokines, IL-25 and IL-33, acting on innate immune cells that are believed to be the initial sources of type 2 cytokines IL-4/IL-5/IL-13. The identities of the cell types that mediate the effects of IL-25/IL-33, however, remain to be fully elucidated. In the present study, we demonstrate that macrophages as IL-25/IL-33-responsive cells play an important role in inducing type 2 immunity using both in vitro and in vivo approaches. Macrophages produced type 2 cytokines IL-5 and IL-13 in response to the stimulation of IL-25/IL-33 in vitro, or were the IL-13-producing cells in mice administrated with exogenous IL-33 or infected with Heligmosomoides bakeri. In addition, IL-33 induced alternative activation of macrophages primarily through autocrine IL-13 activating the IL-4Rα-STAT6 pathway. Moreover, depletion of macrophages attenuated the IL-25/IL-33-induced type 2 immunity in mice, while adoptive transfer of IL-33-activated macrophages into mice with a chronic Heligmosomoides bakeri infection induced worm expulsion accompanied by a potent type 2 protective immune response. Thus, macrophages represent a unique population of the innate immune cells pivotal to type 2 immunity and a potential therapeutic target in controlling type 2 immunity-mediated inflammatory pathologies.

[Cytokines and malaria. A study of TNF-alpha, IL1-beta, IL6 and IL2R in 28 patients].

Science.gov (United States)

Nicolas, P; Hovette, P; Merouze, F; Touze, J E; Martet, G

1994-01-01

Authors have studied TNF alpha, IL1 bêta, IL6 and RIL2s in 28 malaria illness patients. Increased levels of TNF, IL1 bêta and RIL2s in serum, are observed on admission to hospital. These cytokine levels are decreased, eight days later, after patients are treated. In discussion, TNF levels as a prognosis component is evocated.

Clinical significance of determination of changes of serum IL-2, sIL-2R and TGF-β levels in patients with Graves' ophthalmopathy

International Nuclear Information System (INIS)

Li Han

2009-01-01

Objective: To study the relationship between progress of the disease and the changes of serum IL-2, sIL-2R and TGF-β levels in patients with Graves' ophthalmopathy. Methods: Serum TGF-β(with RIA) and IL-2, sIL-2R(with ELISA) levels were determined in 30 patients with Graves' ophthalmopathy both before and after six months' treatment with prednisonlone as well as in 30 controls. Results: The serum IL-2 levels in the patients before treatment were significantly lower than those in controls (P 0.05). Both serum sIL-2R and TGF-β levels in the patients before treatment were significantly higher than those in controls (P<0.01). After treatment, the levels dropped markedly, but still remained significantly higher than those in controls (P<0.05 and P<0.01). Conclusion: Determination of changes of serum IL-2, sIL-2R and TGF-β levels in patients with Graves' ophthalmopathy might be helpful for outcome prediction. (authors)

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...... chronic LCMV infection. Furthermore, in MHC class II-deficient mice, which only transiently control LCMV infection, IL-2-producing CD8+ T cells are initially generated, but by 4 weeks after infection this subset has nearly disappeared. Eventually the capacity to produce IFN-gamma also becomes impaired...

Safety and immunogenicity of Salmonella typhimurium expressing C-terminal truncated human IL-2 in a murine model

Directory of Open Access Journals (Sweden)

Brent Sorenson

2010-03-01

Full Text Available Brent Sorenson, Kaysie Banton, Lance Augustin, Sean Barnett, Karen McCulloch, Joshua Dorn, Natalie Frykman, Arnold Leonard, Daniel SaltzmanDepartment of Surgery, University of Minnesota Medical School, Minneapolis, MN, USAAbstract: Salmonella enterica serovar Typhimurium preferentially colonizes tumors in vivo and has proven to be an effective biologic vector. The attenuated S. enterica Typhimurium strain χ4550 was engineered to express truncated human interleukin-2 and renamed SalpIL2. Previously, we observed that a single oral administration of SalpIL2 reduced tumor number and volume, while significantly increasing local and systemic natural killer (NK cell populations in an experimental metastasis model. Here we report that in nontumor-bearing mice, a single oral dose of SalpIL2 resulted in increased splenic cytotoxic T and NK cell populations that returned to control levels by 4 weeks post oral administration. Though SalpIL2 was detected in mouse tissues for up to 10 weeks, no prolonged alterations in peripheral blood serum chemistry or complete blood cell counts were observed. Similarly, comparative histopathological analysis of tissues revealed no significant increase in pyogranulomas in SalpIL2-treated animals with respect to saline controls. In Rag-1 knockout mice, which have severely impaired B and T cell function, SalpIL2 reduced growth of hepatic metastases. Furthermore, SalpIL2 altered expression of several proinflammatory cytokines and chemokines in the serum of mice with pulmonary osteosarcoma metastases. These data further suggest that SalpIL2 is avirulent and induces a cell-mediated antitumor response.Keywords: Salmonella Typhimurium, natural killer cells, interleukin-2

Chimera of IL-2 Linked to Light Chain of anti-IL-2 mAb Mimics IL-2/anti-IL-2 mAb Complexes Both Structurally and Functionally

Czech Academy of Sciences Publication Activity Database

Tomala, Jakub; Kovářová, Jiřina; Kabešová, Martina; Votavová, Petra; Chmelová, Helena; Dvořáková, Barbora; Říhová, Blanka; Kovář, Marek

2013-01-01

Roč. 8, č. 5 (2013), s. 871-876 ISSN 1554-8929 R&D Projects: GA ČR GAP301/11/0325 Institutional support: RVO:61388971 Keywords : IN-VIVO EXPANSION * IL-2 * ANTIBODY Subject RIV: CE - Biochemistry Impact factor: 5.356, year: 2013

Alteration of cytokine profiles in mice exposed to chronic low-dose ionizing radiation

Energy Technology Data Exchange (ETDEWEB)

Shin, Suk Chul [Radiation Health Research Institute, Korea Hydro and Nuclear Power Co., Ltd., 388-1, Ssangmun-dong, Dobong-gu, Seoul 132-703 (Korea, Republic of); Lee, Kyung-Mi [Global Research Lab, BAERI Institute, Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-705 (Korea, Republic of); Kang, Yu Mi [Radiation Health Research Institute, Korea Hydro and Nuclear Power Co., Ltd., 388-1, Ssangmun-dong, Dobong-gu, Seoul 132-703 (Korea, Republic of); Kim, Kwanghee [Global Research Lab, BAERI Institute, Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-705 (Korea, Republic of); Kim, Cha Soon; Yang, Kwang Hee; Jin, Young-Woo [Radiation Health Research Institute, Korea Hydro and Nuclear Power Co., Ltd., 388-1, Ssangmun-dong, Dobong-gu, Seoul 132-703 (Korea, Republic of); Kim, Chong Soon [Department of Nuclear Medicine, Haeundae Paik Hospital, Inje University, Busan 612-030 (Korea, Republic of); Kim, Hee Sun, E-mail: hskimdvm@khnp.co.kr [Radiation Health Research Institute, Korea Hydro and Nuclear Power Co., Ltd., 388-1, Ssangmun-dong, Dobong-gu, Seoul 132-703 (Korea, Republic of)

2010-07-09

While a high-dose of ionizing radiation is generally harmful and causes damage to living organisms, a low-dose of radiation has been shown to be beneficial in a variety of animal models. To understand the basis for the effect of low-dose radiation in vivo, we examined the cellular and immunological changes evoked in mice exposed to low-dose radiation at very low (0.7 mGy/h) and low (3.95 mGy/h) dose rate for the total dose of 0.2 and 2 Gy, respectively. Mice exposed to low-dose radiation, either at very low- or low-dose rate, demonstrated normal range of body weight and complete blood counts. Likewise, the number and percentage of peripheral lymphocyte populations, CD4{sup +} T, CD8{sup +} T, B, or NK cells, stayed unchanged following irradiation. Nonetheless, the sera from these mice exhibited elevated levels of IL-3, IL-4, leptin, MCP-1, MCP-5, MIP-1{alpha}, thrombopoietin, and VEGF along with slight reduction of IL-12p70, IL-13, IL-17, and IFN-{gamma}. This pattern of cytokine release suggests the stimulation of innate immunity facilitating myeloid differentiation and activation while suppressing pro-inflammatory responses and promoting differentiation of naive T cells into T-helper 2, not T-helper 1, types. Collectively, our data highlight the subtle changes of cytokine milieu by chronic low-dose {gamma}-radiation, which may be associated with the functional benefits observed in various experimental models.

Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation.

Science.gov (United States)

Gupta, Mamta; Han, Jing Jing; Stenson, Mary; Maurer, Matthew; Wellik, Linda; Hu, Guangzhen; Ziesmer, Steve; Dogan, Ahmet; Witzig, Thomas E

2012-03-22

Cytokines are deregulated in cancers and can contribute to tumor growth. In patients with diffuse large-cell lymphoma (DLBCL), we observed higher levels of JAK/STAT pathway-related serum cytokines (ie, IL-6, IL-10, epidermal growth factor, and IL-2) compared with controls. Of these, only IL-10 activated the JAK2 pathway in lymphoma cells in vitro. Patients with high serum IL-10 had shorter event-free survival (EFS) than patients with low levels (P > .01) and high IL-10 was correlated with high lactase dehydrogenase (P = .0085) and higher International Prognostic Index scores (P = .01). To explore the mechanism by which IL-10 may contribute to an inferior EFS, we investigated the effect of IL-10 on the JAK2 pathway and found that the IL-10/IL-10 receptor complex up-regulated JAK2 signaling. Neutralizing Ab to IL-10 inhibited constitutive and IL-10-induced JAK2/STAT3 phosphorylation. JAK2 inhibition dephosphorylated JAK2 and STAT3 and caused an inhibitory effect on phospho-JAK2-positive DLBCL cells; there was a minimal effect on phospho-JAK2-negative cells. Apoptosis induced by JAK2 inhibition was dependent on inhibition of autocrine IL-10 and c-myc expression and independent of Bcl-2 family expression. These results provide the rationale for testing JAK2 inhibitors in DLBCL patients, and indicate that serum IL-10 may be a biomarker to identify patients more likely to respond to JAK2-targeted therapy.

The effect of three-monthly albendazole treatment on Th2 responses: Differential effects on IgE and IL-5.

Science.gov (United States)

de Ruiter, K; Tahapary, D L; Wammes, L J; Wiria, A E; Hamid, F; van Lieshout, L; Smit, J W A; Houwing-Duistermaat, J J; Sartono, E; Supali, T; Yazdanbakhsh, M

2017-06-01

Helminth parasites induce a strong Th2 response, characterized by high levels of IgE and elevated signature cytokines such as IL-5. As many global deworming programmes are underway, there is concern that this might lead to emergence of Th1-mediated pathologies when the counterbalancing helminth-induced Th2 response is absent. Therefore, we assessed the effect of deworming on Th2-mediated responses in a household-clustered randomized controlled trial in Indonesia. Total plasma IgE and whole-blood IL-5 responses to mitogen phytohaemagglutinin (PHA) were measured in 1494 and 682 subjects, respectively, at baseline, 9 and 21 months after three-monthly single-dose treatment with albendazole or placebo. Anthelmintic treatment did not result in complete removal of helminth infections in the community. However, treatment significantly decreased IgE levels in albendazole- compared to placebo-treated subjects. IL-5 responses to PHA were not significantly affected by anthelmintic treatment and tended to increase in albendazole-treated subjects, indicating that intensive treatment of helminth parasites has different outcomes on B-cell (IgE levels) and T-cell (IL-5) responses. The data shows that 2 years of deworming can have differential effects on responses typified as Th2-mediated, which needs to be taken into account when examining the impact of helminths on noncommunicable diseases. © 2017 John Wiley & Sons Ltd.

The eradication of tapeworms in pork and beef carcasses by irradiation

International Nuclear Information System (INIS)

Verster, A.; Du Plessis, T.A.; Heever, L.W. Van Den.

1977-01-01

The aim of this investigation was to determine the potential role that the γ irradiation of carcasses infested with pork and beef tape worms can play in the eradication of these parasites. Irradiated cysticerci were examined to determine the effect of various radiation doses on the evagination of the cysticerci. Such irradiated cysticerci were also fed to hamsters in order to study the effect of the treatment on their infectivity and the longevity of the resulting tapeworms. The results showed that carcasses infested with cysticercosis can be rendered fit for human consumption by exposing them to radiation doses of 20 to 60 krad. Irradiation at these low doses does not affect the taste of the meat, and, moreover, enhances its shelf life. The low irradiation doses required, together with the possibility of high irradiator utilization, favours the economy of such radiation processing and could lead to appreciable monetary savings as compared to present freezing techniques. (author)

Associations of vascular endothelial growth factor (VEGF gene and cytokine (IL-1B, IL-4, IL-6, IL-10, TNFA genes combinations with type 2 diabetes mellitus in women

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Vladimir Iosifovich Konenkov

2012-09-01

Full Text Available Aim. To study the association between vascular endothelial growth factor (VEGF and cytokine (IL1B, IL4, IL6, IL10 and TNFAgene polymorphism combinations with type 2 diabetes mellitus (T2DM in women. Materials and methods. 374 Caucasian women without carbohydrate metabolism disorders from 23 to 68 years of age and 212 womenwith T2DM from 28 to 69 years of age were included in the study. The combinations of polymorphism А-2578С, С+936Т in VEGFgene with polymorphism in IL1B С-31Т, IL4 С-590Т, IL6 G-174C, IL10 A-592C and А-1082G, TNFA А-238G, A-308G and A-863Cwere studied. Results. Analysis revealed 52 combined genetic variations with different rate of occurrence between diabetic and control groups(р

The Effects of Low Dose Irradiation on Inflammatory Response Proteins in a 3D Reconstituted Human Skin Tissue Model

Energy Technology Data Exchange (ETDEWEB)

Varnum, Susan M.; Springer, David L.; Chaffee, Mary E.; Lien, Katie A.; Webb-Robertson, Bobbie-Jo M.; Waters, Katrina M.; Sacksteder, Colette A.

2012-12-01

Skin responses to moderate and high doses of ionizing radiation include the induction of DNA repair, apoptosis, and stress response pathways. Additionally, numerous studies indicate that radiation exposure leads to inflammatory responses in skin cells and tissue. However, the inflammatory response of skin tissue to low dose radiation (<10 cGy) is poorly understood. In order to address this, we have utilized a reconstituted human skin tissue model (MatTek EpiDerm FT) and assessed changes in 23 cytokines twenty-four and forty eight hours following treatment of skin with either 3 or 10 cGy low-dose of radiation. Three cytokines, IFN-γ, IL-2, MIP-1α, were significantly altered in response to low dose radiation. In contrast, seven cytokines were significantly altered in response to a high radiation dose of 200 cGy (IL-2, IL-10, IL-13, IFN-γ, MIP-1α, TNF α, and VEGF) or the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (G-CSF, GM-CSF, IL-1α, IL-8, MIP-1α, MIP-1β, RANTES). Additionally, radiation induced inflammation appears to have a distinct cytokine response relative to the non-radiation induced stressor, TPA. Overall, these results indicate that there are subtle changes in the inflammatory protein levels following exposure to low dose radiation and this response is a sub-set of what is seen following a high dose in a human skin tissue model.

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

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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.

WHO Polio Eradication Program: Problems and Solutions

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S. M. Kharit

2016-01-01

Full Text Available In 2013 WHO re-evaluated its main goals of the polio eradication program. A modernization program was accepted with regard to the National vaccination calendars worldwide which includes a step-by-step refusal from the living polio vaccine (OPV and a total transition to the inactivated polio vaccine (IPV starting in 2019. Because of the total eradication of the polio type 2 virus, as an intermediate step the 3-valence OPV was substituted with the 2-valence OPV, which does not contain the type 2 polio virus, in April 2016. The aim of the article is to present the history of polio prevention and to state the reasons for the adoption of 3rd edition of the Global Polio Eradication Initiative. The new approaches were defined for eradication of wild polio virus type 1 and vaccine related strains. A new strategy for global switch to inactivated polio vaccine by 2019 was suggested.

Systemic Th17/IL-17A response appears prior to hippocampal neurodegeneration in rats exposed to low doses of ozone.

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Solleiro-Villavicencio, H; Rivas-Arancibia, S

2017-06-03

Exposure to low doses of O 3 leads to a state of oxidative stress. Some studies show that oxidative stress can modulate both the CNS and systemic inflammation, which are important factors in the development of Alzheimer disease (AD). This study aims to evaluate changes in the frequency of Th17-like cells (CD3 + CD4 + IL-17A + ), the concentration of IL-17A in peripheral blood, and hippocampal immunoreactivity to IL-17A in rats exposed to low doses of O 3 . One hundred eight male Wistar rats were randomly assigned to 6 groups (n=18) receiving the following treatments: control (O 3 free) or O 3 exposure (0.25ppm, 4hours daily) over 7, 15, 30, 60, and 90 days. Twelve animals from each group were decapitated and a peripheral blood sample was taken to isolate plasma and mononuclear cells. Plasma IL-17A was quantified using LUMINEX, while Th17-like cells were counted using flow cytometry. The remaining 6 rats were deeply anaesthetised and underwent transcardial perfusion for immunohistological study of the hippocampus. Results show that exposure to O 3 over 7 days resulted in a significant increase in the frequency of Th17-like cells and levels of IL-17A in peripheral blood. However, levels of Th17/IL-17A in peripheral blood were lower at day 15 of exposure. We also observed increased IL-17A in the hippocampus beginning at 30 days of exposure. These results indicate that O 3 induces a short-term, systemic Th17-like/IL-17A effect and an increase of IL-17A in the hippocampal tissue during the chronic neurodegenerative process. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Recombinant Newcastle disease virus (NDV/Anh-IL-2 expressing human IL-2 as a potential candidate for suppresses growth of hepatoma therapy

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Yunzhou Wu

2016-09-01

Full Text Available Newcastle disease virus (NDV have shown oncolytic therapeutic efficacy in preclinical study and are currently approved for clinical trials. NDV Anhinga strain which is a mesogenic strain should be classified as lytic strain and has a therapeutic efficacy in hepatocellular cancer. In this study, we evaluated the capacity of NDV Anhinga strain to elicit immune reaction in vivo and the possibility for using as a vaccine vector for expressing tumor therapeutic factors. Interleukin-2 (IL-2 could boost the immune response against the tumor cells. Therefore, we use NDV Anhinga strain as backbone to construct a recombinant virus (NDV/Anh-IL-2 expressing IL-2. The virus growth curve showed that the production of recombinant NDV/Anh-IL-2 was slightly delayed compared to the wild type. The NDV/Anh-IL-2 strain could express soluble IL-2 and effectively inhibit the growth of hepatocellular carcinoma in vivo. 60 days post-treatment, mice which were completely cured by previous treatment were well protected when rechallenged with the same tumor cell. From the H&E-stained sections, intense infiltration of lymphocyte was observed in the NDV Anhinga strain treated group, especially in NDV/Anh-IL-2 group. The NDV Anhinga strain could not only kill the tumor directly, but could also elicit immune reaction and a potent immunological memory when killing tumor in vivo. In conclusion, the Anhinga strain could be an effective vector for tumor therapy; the recombinant NDV/Anh-IL-2 strain expressing soluble IL-2 is a promising candidate for hepatoma therapy.

Effects of low dose X-ray irradiation on antigen presentation and IL-12 secretion in human dendritic cells in vitro

International Nuclear Information System (INIS)

Yan Peng; Jiang Qisheng; Li Fengsheng; He Rui; Wang Cuilan; Li Xiao

2012-01-01

Objective: To explore the effects of low dose X-ray irradiation on the ability of antigen presentation and IL-12 secretion in human dendritic cells that had been cultured for different time in vitro. Methods: The human peripheral blood mononuclear cells (PBMC) were collected and differentiated to dendritic cells (DCs) by rhGM-CSF and rhIL-4 treatment in vitro. The DCs were divided into 3 groups, group A: DCs were cultured for 2 d and then irradiated with 0.05, 0.1, 0.2 and 0.5 Gy X-rays; group B: DCs were cultured for 6 d and then irradiated as above; group C:DCs were cultured without irradiation.At 8 d of cell culture, the DCs were applied to activate T cells and CCK-8 was used to detect MLR (mixed lymphocyte reaction), and the antigen presentation ability of DCs was evaluated. MTT assay was also used to test the cell-killing effect of the activated T-cells on A549 cells. IL-12 in the culture medium of DCs was detected by ELISA. Results: After irradiation with 0.2 and 0.5 Gy X-rays, the antigen presentation ability of DCs was decreased in group A (t=2.79 and 3.71, P<0.05), but significantly increased in group B (t=3.60 and 3.11, P<0.05). The ability of the T cell activation was detected and the proliferation of A549 cells was slightly inhibited by the DCs in group A (t=2.89 and 2.91, P<0.05), but was obviously inhibited by the DCs in group B (t=2.91 and 2.82, P<0.05). Meanwhile,the level of IL-12 was dramatically decreased in group A (t=4.44 and 6.93, P<0.05), but was increased in group B (t=3.51 and 4.12, P<0.05). Conclusions: The abilities of antigen presentation and proliferation inhibition of DCs could be down-regulated by low dose (<0.5 Gy) of X-ray irradiation at the early stage of DCs, but was up-regulated at the late stage of DCs culture. (authors)

Induction of regulatory T cells by high-dose gp96 suppresses murine liver immune hyperactivation.

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Xinghui Li

Full Text Available Immunization with high-dose heat shock protein gp96, an endoplasmic reticulum counterpart of the Hsp90 family, significantly enhances regulatory T cell (Treg frequency and suppressive function. Here, we examined the potential role and mechanism of gp96 in regulating immune-mediated hepatic injury in mice. High-dose gp96 immunization elicited rapid and long-lasting protection of mice against concanavalin A (Con A-and anti-CD137-induced liver injury, as evidenced by decreased alanine aminotransaminase (ALT levels, hepatic necrosis, serum pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-6, and number of IFN-γ (+ CD4(+ and IFN-γ (+ CD8(+ T cells in the spleen and liver. In contrast, CD4(+CD25(+Foxp3(+ Treg frequency and suppressive function were both increased, and the protective effect of gp96 could be generated by adoptive transfer of Treg cells from gp96-immunized mice. In vitro co-culture experiments demonstrated that gp96 stimulation enhanced Treg proliferation and suppressive function, and up-regulation of Foxp3, IL-10, and TGF-β1 induced by gp96 was dependent on TLR2- and TLR4-mediated NF-κB activation. Our work shows that activation of Tregs by high-dose gp96 immunization protects against Con A- and anti-CD137-induced T cell-hepatitis and provides therapeutic potential for the development of a gp96-based anti-immune hyperactivation vaccine against immune-mediated liver destruction.

High Antigen Dose Is Detrimental to Post-Exposure Vaccine Protection against Tuberculosis.

Science.gov (United States)

Billeskov, Rolf; Lindenstrøm, Thomas; Woodworth, Joshua; Vilaplana, Cristina; Cardona, Pere-Joan; Cassidy, Joseph P; Mortensen, Rasmus; Agger, Else Marie; Andersen, Peter

2017-01-01

Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB), causes 1.8M deaths annually. The current vaccine, BCG, has failed to eradicate TB leaving 25% of the world's population with latent Mtb infection (LTBI), and 5-10% of these people will reactivate and develop active TB. An efficient therapeutic vaccine targeting LTBI could have an enormous impact on global TB incidence, and could be an important aid in fighting multidrug resistance, which is increasing globally. Here we show in a mouse model using the H56 (Ag85B-ESAT-6-Rv2660) TB vaccine candidate that post-exposure, but not preventive, vaccine protection requires low vaccine antigen doses for optimal protection. Loss of protection from high dose post-exposure vaccination was not associated with a loss of overall vaccine response magnitude, but rather with greater differentiation and lower functional avidity of vaccine-specific CD4 T cells. High vaccine antigen dose also led to a decreased ability of vaccine-specific CD4 T cells to home into the Mtb-infected lung parenchyma, a recently discovered important feature of T cell protection in mice. These results underscore the importance of T cell quality rather than magnitude in TB-vaccine protection, and the significant role that antigen dosing plays in vaccine-mediated protection.

Low-dose Norfloxacin-treated leptospires induce less IL-1β release in J774A.1 cells following discrepant leptospiral gene expression.

Science.gov (United States)

Cao, Yongguo; Xie, Xufeng; Zhang, Wenlong; Wu, Dianjun; Tu, Changchun

2018-06-01

Currently, accumulating evidence is challenging subtherapeutic therapy. Low-dose Norfloxacin (Nor) has been reported to suppress the immune response and worsen leptospirosis. In this study, we investigated the influence of low-dose Nor (0.03 μg/ml, 0.06 μg/ml, 0.125 μg/ml) on leptospiral gene expression and analyzed the immunomodulatory effects of low-dose Nor-treated leptospires in J774A.1 cells. To study the expression profiles of low-dose Nor-treated leptospires, we chose LipL71/LipL21 as reference genes determined by the geNorm applet in this experiment. The results showed that low-dose Nor up-regulated the expression of FlaB and inhibited the expression of 16S rRNA, LipL32, LipL41, Loa22, KdpA, and KdpB compared with the untreated leptospires. These results indicated that low-dose Nor could regulate leptospiral gene expression. Using RT-PCR, the gene expression of IL-1β and TNF-α in J774A.1 cells was detected. Nor-treated leptospires induced higher expression levels of both IL-1β and TNF-α. However, when analyzed by ELISA, the release of mature IL-1β was reduced compared with that observed in cells induced with no Nor-treated leptospires, although the TNF-α protein level showed no significant change. Our study indicated that the gene expression of leptospires could be modulated by low-dose Nor, which induced less IL-1β release in J774A.1 cells. Copyright © 2018 Elsevier Ltd. All rights reserved.

Staphylococcus epidermidis polysaccharide intercellular adhesin induces IL-8 expression in human astrocytes via a mechanism involving TLR2.

LENUS (Irish Health Repository)

Stevens, Niall T

2009-03-01

Staphylococcus epidermidis is an opportunistic biofilm-forming pathogen associated with neurosurgical device-related meningitis. Expression of the polysaccharide intercellular adhesin (PIA) on its surface promotes S. epidermidis biofilm formation. Here we investigated the pro-inflammatory properties of PIA against primary and transformed human astrocytes. PIA induced IL-8 expression in a dose- and\\/or time-dependent manner from U373 MG cells and primary normal human astrocytes. This effect was inhibited by depletion of N-acetyl-beta-d-glucosamine polymer from the PIA preparation with Lycopersicon esculentum lectin or sodium meta-periodate. Expression of dominant-negative versions of the TLR2 and TLR4 adaptor proteins MyD88 and Mal in U373 MG cells inhibited PIA-induced IL-8 production. Blocking IL-1 had no effect. PIA failed to induce IL-8 production from HEK293 cells stably expressing TLR4. However, in U373 MG cells which express TLR2, neutralization of TLR2 impaired PIA-induced IL-8 production. In addition to IL-8, PIA also induced expression of other cytokines from U373 MG cells including IL-6 and MCP-1. These data implicate PIA as an important immunogenic component of the S. epidermidis biofilm that can regulate pro-inflammatory cytokine production from human astrocytes, in part, via TLR2.

Adjuvant immunotherapy of feline injection-site sarcomas with the recombinant canarypox virus expressing feline interleukine-2 evaluated in a controlled monocentric clinical trial when used in association with surgery and brachytherapy

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D. Jas

2015-01-01

Full Text Available The objective of this randomised, controlled, parallel-group monocentric clinical trial was to assess the efficacy (at low and high dose and the safety (at high dose of a recombinant canarypox virus (ALVAC® expressing feline interleukin 2 (IL-2. ALVAC IL-2 was administered to cats as an adjunct treatment of feline fibrosarcoma in complement to surgery and brachytherapy (reference treatment. Seventy-one cats with a first occurrence of feline fibrosarcoma were referred to the Veterinary Oncology Centre for post-surgical radiotherapy. They were randomly assigned to three treatment groups: reference treatment group (23 cats, ALVAC IL-2 low dose group (25 cats and ALVAC IL-2 high dose group (23 cats. Two dosages of ALVAC IL-2 were used to assess both safety (high dose and efficacy (high and low doses. The treatment consisted of six consecutive doses of ALVAC IL-2 administered subcutaneously at the tumour site on Day 0 (one day before brachytherapy treatment, Day 7, Day 14, Day 21, Day 35 and Day 49. All cats were evaluated for relapse (i.e. local tumour recurrence and/or metastasis every three months for at least one year (ALVAC IL-2 high dose group or two years (reference treatment and ALVAC IL-2 low dose groups by complete physical examination and regular CT scans. ALVAC IL-2 treatment was well tolerated and adverse effects were limited to mild local reactions. ALVAC IL-2 treatment resulted in a significant longer median time to relapse (>730 days in the ALVAC IL-2 low dose group than in the reference treatment group (287 days, and a significant reduction of the risk of relapse by 56% at one year (ALVAC IL-2 treatment groups versus reference treatment group and 65% at two years (ALVAC IL-2 low dose treatment group versus reference treatment group.

Simultaneous Effect of High-Intensity Interval Training (HIIT and Consumption of Flaxseed on Serum Levels of TNF-α and IL1β in Rats

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Khademi Y.

2017-12-01

Full Text Available Aims The high concentration of Interleukin-1 beta (IL-1β and Tumor Necrosis Factor- α (TNF-α is an important risk factor for developing cardiovascular disease. The purpose of this study was to investigate the simultaneous effect of High-Intensity Interval Training (HIIT and the use of flaxseed oil with different doses on the serum levels of TNF-α and IL1β in rats. Materials & Methods In this experimental study, 30 Wistar rats were randomly divided into six groups: control, training, 10mg/kg supplement, 30mg/kg supplement, training with 10mg/kg supplement and training with 30mg/kg supplement. The groups performed High- Intensity Interval Training (HIIT for 10 weeks and received flaxseed oil extracts. Data were analyzed by one way ANOVA and LSD post hoc test. Findings Serum levels of IL1β in the training group and training groups with doses of 10 and 30mg/kg of extract were significantly lower than the control group. Serum levels of IL1β in the training group with 30mg/kg of extract, was significantly lower than group with 10mg/ kg of extract. Also, serum levels of TNF-α in the training group, training groups with doses of 10 and 30mg/kg of extract and group with 30mg/kg of extract were significantly lower than the control group. Serum levels of TNF-α in the training group with 30mg/kg of extract were significantly lower than other groups (p<0.05. Conclusion High-Intensity Interval Training (HIIT and consumption of flaxseed oil for 10 weeks have interactive effects on reduction of serum levels of TNF-α and IL-1β in rats.

IL-4 enhances IL-10 production in Th1 cells: implications for Th1 and Th2 regulation.

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Mitchell, Ruth E; Hassan, Masriana; Burton, Bronwen R; Britton, Graham; Hill, Elaine V; Verhagen, Johan; Wraith, David C

2017-09-12

IL-10 is an immunomodulatory cytokine with a critical role in limiting inflammation in immune-mediated pathologies. The mechanisms leading to IL-10 expression by CD4 + T cells are being elucidated, with several cytokines implicated. We explored the effect of IL-4 on the natural phenomenon of IL-10 production by a chronically stimulated antigen-specific population of differentiated Th1 cells. In vitro, IL-4 blockade inhibited while addition of exogenous IL-4 to Th1 cultures enhanced IL-10 production. In the in vivo setting of peptide immunotherapy leading to a chronically stimulated Th1 phenotype, lack of IL-4Rα inhibited the induction of IL-10. Exploring the interplay of Th1 and Th2 cells through co-culture, Th2-derived IL-4 promoted IL-10 expression by Th1 cultures, reducing their pathogenicity in vivo. Co-culture led to upregulated c-Maf expression with no decrease in the proportion of T-bet + cells in these cultures. Addition of IL-4 also reduced the encephalitogenic capacity of Th1 cultures. These data demonstrate that IL-4 contributes to IL-10 production and that Th2 cells modulate Th1 cultures towards a self-regulatory phenotype, contributing to the cross-regulation of Th1 and Th2 cells. These findings are important in the context of Th1 driven diseases since they reveal how the Th1 phenotype and function can be modulated by IL-4.

Human, recombinant interleukin-2 induces in vitro histamine release in a dose-dependent manner

DEFF Research Database (Denmark)

Nielsen, Hans Jørgen; Petersen, L J; Skov, P S

1995-01-01

significantly in the supernatant from cells stimulated by rIL-2 in a dose-dependent manner both in patients and volunteers. Total cell-bound histamine was 49.3 +/- 4.1 ng/ml in patients compared to 78.5 +/- 7.7 ng/ml in volunteers (p ... was significantly enhanced in cancer patients compared to volunteers (*p manner in both cancer patients and volunteers. This may in part explain the severe toxicity observed during high...

The MHV68 M2 protein drives IL-10 dependent B cell proliferation and differentiation.

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Andrea M Siegel

2008-04-01

Full Text Available Murine gammaherpesvirus 68 (MHV68 establishes long-term latency in memory B cells similar to the human gammaherpesvirus Epstein Barr Virus (EBV. EBV encodes an interleukin-10 (IL-10 homolog and modulates cellular IL-10 expression; however, the role of IL-10 in the establishment and/or maintenance of chronic EBV infection remains unclear. Notably, MHV68 does not encode an IL-10 homolog, but virus infection has been shown to result in elevated serum IL-10 levels in wild-type mice, and IL-10 deficiency results in decreased establishment of virus latency. Here we show that a unique MHV68 latency-associated gene product, the M2 protein, is required for the elevated serum IL-10 levels observed at 2 weeks post-infection. Furthermore, M2 protein expression in primary murine B cells drives high level IL-10 expression along with increased secretion of IL-2, IL-6, and MIP-1alpha. M2 expression was also shown to significantly augment LPS driven survival and proliferation of primary murine B cells. The latter was dependent on IL-10 expression as demonstrated by the failure of IL10-/- B cells to proliferate in response to M2 protein expression and rescue of M2-associated proliferation by addition of recombinant murine IL-10. M2 protein expression in primary B cells also led to upregulated surface expression of the high affinity IL-2 receptor (CD25 and the activation marker GL7, along with down-regulated surface expression of B220, MHC II, and sIgD. The cells retained CD19 and sIgG expression, suggesting differentiation to a pre-plasma memory B cell phenotype. These observations are consistent with previous analyses of M2-null MHV68 mutants that have suggested a role for the M2 protein in expansion and differentiation of MHV68 latently infected B cells-perhaps facilitating the establishment of virus latency in memory B cells. Thus, while the M2 protein is unique to MHV68, analysis of M2 function has revealed an important role for IL-10 in MHV68 pathogenesis

The MHV68 M2 protein drives IL-10 dependent B cell proliferation and differentiation.

Science.gov (United States)

Siegel, Andrea M; Herskowitz, Jeremy H; Speck, Samuel H

2008-04-04

Murine gammaherpesvirus 68 (MHV68) establishes long-term latency in memory B cells similar to the human gammaherpesvirus Epstein Barr Virus (EBV). EBV encodes an interleukin-10 (IL-10) homolog and modulates cellular IL-10 expression; however, the role of IL-10 in the establishment and/or maintenance of chronic EBV infection remains unclear. Notably, MHV68 does not encode an IL-10 homolog, but virus infection has been shown to result in elevated serum IL-10 levels in wild-type mice, and IL-10 deficiency results in decreased establishment of virus latency. Here we show that a unique MHV68 latency-associated gene product, the M2 protein, is required for the elevated serum IL-10 levels observed at 2 weeks post-infection. Furthermore, M2 protein expression in primary murine B cells drives high level IL-10 expression along with increased secretion of IL-2, IL-6, and MIP-1alpha. M2 expression was also shown to significantly augment LPS driven survival and proliferation of primary murine B cells. The latter was dependent on IL-10 expression as demonstrated by the failure of IL10-/- B cells to proliferate in response to M2 protein expression and rescue of M2-associated proliferation by addition of recombinant murine IL-10. M2 protein expression in primary B cells also led to upregulated surface expression of the high affinity IL-2 receptor (CD25) and the activation marker GL7, along with down-regulated surface expression of B220, MHC II, and sIgD. The cells retained CD19 and sIgG expression, suggesting differentiation to a pre-plasma memory B cell phenotype. These observations are consistent with previous analyses of M2-null MHV68 mutants that have suggested a role for the M2 protein in expansion and differentiation of MHV68 latently infected B cells-perhaps facilitating the establishment of virus latency in memory B cells. Thus, while the M2 protein is unique to MHV68, analysis of M2 function has revealed an important role for IL-10 in MHV68 pathogenesis-identifying a

Association of the polymorphisms of the IL-1B, IL-1RN, IL-10 and p53 genes with risk of gastric cancer in a population of high risk of Costa Rica

International Nuclear Information System (INIS)

Alpizar Alpizar, Wagner

2004-01-01

Factors that increase the risk to develop gastric cancer are studied: associated factors to diet, nitrous compounds endogenous formation, genetic predisposition, infection by Helicobacter pylori and polymorphic mixes pickles in the cut out gen of p53 tumour. Also it describes like Helicobacter pylori causes inflammation and its magnitude depends of the reaction mechanisms of the innkeeper in answer to the pathogen. The study aim was to determined the association of polymorphisms of the IL-1B, IL-IRN, IL-10 and p53 genes with the gastric cancer and gastric harms in a population of high risk in Costa Rica. Blood samples of 58 patients diagnosed with gastric cancer were analysed, 99 people with no suspicions of gastric cancer according to the diagnosis by x-Ray (contrast double gastroduodenal series), 41 patients histologically classified as I and II groups in a accordance with the Japanese classification. The analyses was carried out from DNA extracted of leucocytes. Association of the polymorphisms IL-1B-31, IL-1B-511, IL-10-592, IL-10-819 and IL-10-1082 were not found with risk to develop gastric cancer in the studied population. For IL-IB+3954, it was determined that the people with the heterozygote genotype for the T allele present more risk to develop gastric cancer (OR 3.7; IC 95% 1.34-10.2; p=0.007). For the polymorphism of IL-IRN gene it was observed that heterozygote genotype carrier people for the allele 2, present more risk to develop the illness (OR 2.94; IC 1.09-7.93; p=0.03). The allele frequencies that have been related with increase of the pro inflammatory answer are higher in the total population studied here than in other populations. According with the got results it will be necessary to carry out studies with more size of sample, with representative samples of the Costa Rican population and with samples of regions of low and high risk. (author) [es

Non-technical constraints to eradication: the Italian experience.

Science.gov (United States)

Moda, Giuliana

2006-02-25

Although technical constraints to eradication of bovine tuberculosis are well-recognised, non-technical constraints can also delay progress towards eradication, leading to inefficiency and increased programme costs. This paper seeks to analyse the main non-technical constraints that can interfere with the successful implementation of tuberculosis eradication plans, based on experiences from an area of high tuberculosis prevalence in Regione Piemonte, Italy. The main social and economic constraints faced in the past 20 years are reviewed, including a social reluctance to recognise the importance of seeking eradication as the goal of disease control, effective communication of technical issues, the training and the organization of veterinary services, the relationship between the regional authority and farmers and their representatives, and data management and epidemiological reporting. The paper analyses and discusses the solutions that were applied in Regione Piemonte and the benefits that were obtained. Tuberculosis eradication plans are one of the most difficult tasks of the Veterinary Animal Health Services, and non-technical constraints must be considered when progress towards eradication is less than expected. Organizational and managerial resources can help to overcome social or economic obstacles, provided the veterinary profession is willing to address technical, but also non-technical, constraints to eradication.

Ketamine, as adjuvant analgesics for patients with refractory cancer pain, does affect IL-2/IFN-γ expression of T cells in vitro?

Science.gov (United States)

Zhou, Naibao; Fu, Zhijian; Li, Hao; Wang, Kaiguo

2017-01-01

Abstract Background: Ketamine has been used as an analgesic adjuvant with morphine in the treatment of refractory cancer pain recently. But both morphine and ketamine have been reported to produce a number of immunomodulatory effects. The current study was performed to assess whether the concentration of ketamine, as adjuvant analgesics for patient with refractory cancer pain, was related to its effect on T cells interleukin-2 (IL-2)/interferon-γ (IFN-γ) expression in vitro. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood of patients with refractory cancer pain over a Ficoll-Hypaque density gradient. T cells were isolated from by positive selection using anti-CD3 beads. T cells were then treated with vehicle (C group), morphine (200 ng/mL, M group), morphine (200 ng/mL), and different dose of ketamine (100, 200, 1000 ng/mL; MK1, MK5, MK10 group) for 24 hours before stimulation with anti-CD3 and anti-CD28. Then supernatant IL-2 and IFN-γ protein analysis, quantitative reverse transcription polymerase chain reaction (RT-PCR) for IL-2 and IFN-γ were done. Results: There were no significant difference of supernatant IL-2 and IFN-γ among C group, M group, and MK1 group, but the mRNA of M group and MK1 group were decreased compared with C group (P ketamine dose-dependently suppressed IL-2 and IFN-γ of activated T lymphocyte of patients with refractory cancer pain in vitro, but the inhibitory action of low dose ketamine could be neglected. PMID:28422864

Co-immunotherapy with interleukin-2 and taurolidine for progressive metastatic melanoma.

LENUS (Irish Health Repository)

O'Brien, G C

2012-02-03

BACKGROUND: Recombinant interleukin-2(rIL-2) therapy in metastatic melanoma is limited by toxicities, particularly vascular leak syndrome(VLS). Taurolidine potentiates the anti-neoplastic effects of IL-2 while reducing its associated endothelial cell dysfunction in experimental settings. We hypothesized that co-administration of rIL-2 with taurolidine could enhance tolerability without weakening effectiveness. METHODS: Eleven patients with progressive metastatic melanoma received high-dose rIL-2 with co-infusion of taurolidine. Patients were monitored for the development of toxicities and evidence of response. RESULTS: Ten patients tolerated twenty-nine courses of high-dose rIL-2 without dose-reduction. Most toxicities were low-grade. No patient developed VLS. Seven patients died from disease progression. Two had complete clinical and radiological responses to treatment. Two patients remain alive despite evidence of disease progression a mean of 17.5 months after diagnosing metastatic disease. CONCLUSION: Co-administration of taurolidine with high-dose rIL-2 in stage IV melanoma patients appears to greatly enhance the tolerability of this regime without diminishing its therapeutic value.

Clinical value of determination of changes of serum Gas, IL-2, IL-10 and IL-18 levels after transfusion of Red blood cells in patients with peptic ulcer

International Nuclear Information System (INIS)

Liu Tingting; Li Xinghua

2011-01-01

Objective: To investigation the changes of serum Gas, IL-2, IL-10 and IL-18 contents after transfusion of red blood cells in patients with peptic ulcer. Methods: Serum Gas, IL-2, IL-10 (with RIA), serum IL-18 (with ELISA) levels were measured in 31 patients with peptic ulcer and 35 controls. Results: Before transfusion,the serum IL-2 level in the patients was significantly lower than that in controls (P 0.05). Conclusion: Detection of serum Gas, IL-2, IL-10 and IL-18 levels is clinically useful for monitoring progress and favourable prognosis of patients with peptic ulcer possess important clinical value. (authors)

Clinical significance of determination of changes of EPS IL-1β, IL-2, IL-10 and LDH5/LDH1 levels in patients with chronic prostatitis

International Nuclear Information System (INIS)

Chen Yongchang

2009-01-01

Objective: To investigate the clinical significance of the changes of expressed prostatic secretion IL-1β, IL-2, IL-10 and LDH5/LDH1 levels in patients with chronic prostatitis. Methods: Expressed prostatic secretion IL-1β, IL-2, IL-10 (with Radioimmunoassay) and LDH5/LDH1 (with cellulose acetate membrane electrophoresis) levels were determined in 32 patients with chronic prostatitis and 35 controls. These 32 patients were of 3 groups: 1)chronic bacterial prostatitis (CBP, n=10) 2) chronic pelvic pain syndrome IIIA (CPPS IIIA n=9) 3) CPPSIIIB n=13. Results: Expressed prostatic secretion levels of IL-1β, IL-2 and LDH5/LDH1 were significantly higher in patients with chronic bacterial prostatitis (CBP) groups than those in controls (all P 0.05). But the expressed prostatic secretion levels of IL-10 were still significantly lower in patients with chronic nonbacterial prostatitis, chronic pelvic pain syndrome(CPPSIIIB) groups than those in controls (all P<0.05). Conclusion: There were changes of expressed prostatic secretion IL-1β, IL-2, IL-10 and LDH5/LDH1 levels in patients with chronic prostatitis. Combined determination of the expressed prostatic secretion 4 markers levels is valuable for the diagnosis of chronic prostatitis and CPPSIII and for differentiation of CPPSIII types. (authors)

IL-33 and IgE stimulate mast cell production of IL-2 and regulatory T cell expansion in allergic dermatitis.

Science.gov (United States)

Salamon, P; Shefler, I; Moshkovits, I; Munitz, A; Horwitz Klotzman, D; Mekori, Y A; Hershko, A Y

2017-11-01

We have previously shown that mast cells (MCs) suppress chronic allergic dermatitis in mice. The underlying mechanism involves MC-derived IL-2, which supports regulatory T cell (Treg) response at the site of inflammation. However, it is not clear what are the factors that drive MCs to produce IL-2. To understand the mechanisms that lead to IL-2 production from MCs in chronic allergic dermatitis. Isolated murine bone marrow-derived MCs (BMMCs) were incubated with various stimulators, and IL-2 production was assessed by RT-PCR and ELISA. The response of signalling pathways was evaluated by MAPK inhibitors and Western blot analysis. The effect of MC-IL-2 on Tregs was studied by incubation of splenic T cells with conditioned media obtained from activated BMMCs. Dermatitis was elicited by repeated exposures of mouse ears to oxazolone. MCs in mouse and human skin samples were evaluated by immunostaining. BMMCs released IL-2 in response to IL-33, and IL-2 production was further enhanced by concomitant FcεRI activation. The effect of IL-33 was mediated by activation of the MAPK family members. IL-2 in conditioned media from IL-33 and IgE-stimulated BMMCs led to considerable expansion of Tregs in vitro. IL-33 levels were elevated in oxazolone-challenged ears along with increased numbers of IL-2-expressing MCs. Human skin with chronic inflammation also contained IL-2-expressing MCs that colocalized with IL-33 staining in the dermis. IL-33, in collaboration with IgE, is critical for MC-IL-2 production in allergic skin disease, thus leading to Treg stimulation and suppression of allergic dermatitis. © 2017 John Wiley & Sons Ltd.

Role of the multichain IL-2 receptor complex in the control of normal and malignant T-cell proliferation

International Nuclear Information System (INIS)

Waldmann, T.A.

1987-01-01

Antigen-induced activation of resting T-cells induces the synthesis of interleukin-2 (IL-2), as well as the expression of specific cell surface receptors for this lymphokine. There are at least two forms of the cellular receptors for IL-2, one with a very high affinity and the other with a lower affinity. The authors have identified two IL-2 binding peptides, a 55-kd peptide reactive with the anti-Tac monoclonal antibody, and a novel 75-kd non-Tac IL-2 binding peptide. Cell lines bearing either the p55, Tac, or the p75 peptide along manifested low-affinity IL-2 binding, whereas cell lines bearing both peptides manifested both high- and low-affinity receptors. Fusion of cell membranes from low-affinity IL-2 binding cells bearing the Tac peptide alone with membranes from a cell line bearing the p75 peptide alone generates hybrid membranes bearing high-affinity receptors. They propose a multichain model for the high-affinity IL-2 receptor in which both the Tac and the p75 IL-2 binding peptides are associated in a receptor complex. In contrast to resting T-cells, human T-cell lymphotropic virus I-associated adult T-cell leukemia cells constitutively express large numbers of IL-2 receptors. Because IL-2 receptors are present on the malignant T-cells but not on normal resting cells, clinical trials have been initiated in which patients with adult T-cell leukemia are being treated with either unmodified or toxin-conjugated forms of anti-Tac monoclonal antibody directed toward this growth factor receptor. Cross-linking studies were done using [ 125 I] IL-2

Diagnostic value of combined determination of serum and chest fluid adenosine deaminase (ADA), IL-2, IL-6, IL-10 contents for differentiation of tuberculous from malignant pleural effusion

International Nuclear Information System (INIS)

Wu Jiaming; Wang Limin

2005-01-01

Objective: To investigate the possible diagnostic value of combined determination of serum and chest fluid contents of ADA, IL-2, IL-6, IL-10 in patients with tuberculous and malignant pleural effusion. Methods: Serum and chest fluid ADA (with biochemical method), IL-2, IL-6, IL-10 (with ELISA) contents were measured in 56 patients with tuberculosis pleural effusion, 53 patients with malignant effusion and 30 controls (in serum only). The receiving operative characteristic (ROC) curve for each parameter was analyzed for study of respective area under curse (Auc). Results: The serum IL-6 levels in both groups of patients were significantly higher than those in the controls (P<0.05). The chest fluid contents of ADA, IL-2, IL-6 and IL-10 in patients with tuberculous effusion were all significantly higher than those in patients with malignancies (P<0.05). The Auc in the ROC was largest in the case of ADA, followed by IL-10, IL-6 with IL-2 the least. Conclusion: Determination of chest fluid ADA, IL-2, IL-6, IL-10 contents was helpful in the differentiation of tuberculous from malignant pleural effusion. Combined determination of chest fluid ADA and IL-10 provided the highest accuracy rate for differentional diagnosis. (authors)

Study on the changes of serum IL-2, IL-6 and TNF-α levels in patients with psoriasis

International Nuclear Information System (INIS)

Xie Chuntao

2007-01-01

Objective: To investigate the changes of serum IL-2, IL-6 and TNF-α levels in patients with psoriasis. Methods: Serum IL-2, IL-6 and TNF-α levels were measured with KIA in 38 patients with psoriasis and 35 controls. Results: Serum levels of IL-6 and TNF-α were significantly higher in patients with psoriasis than those in controls (P<0.01), but serum IL-2 levels were significantly lower (P<0.01). Conclusion: These cytokines participated in the pathogenesis of psoriasis. Monitoring the changes of their serum levels was helpful for the management of the diseases. (authors)

Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17

DEFF Research Database (Denmark)

Muñoz, Melba; Heimesaat, Markus M; Danker, Kerstin

2009-01-01

Peroral infection with Toxoplasma gondii leads to the development of small intestinal inflammation dependent on Th1 cytokines. The role of Th17 cells in ileitis is unknown. We report interleukin (IL)-23-mediated gelatinase A (matrixmetalloproteinase [MMP]-2) up-regulation in the ileum of infected...... mice. MMP-2 deficiency as well as therapeutic or prophylactic selective gelatinase blockage protected mice from the development of T. gondii-induced immunopathology. Moreover, IL-23-dependent up-regulation of IL-22 was essential for the development of ileitis, whereas IL-17 was down...

Wild and vaccine-derived poliovirus circulation, and implications for polio eradication.

Science.gov (United States)

Lopalco, P L

2017-02-01

Polio cases due to wild virus are reported by only three countries in the world. Poliovirus type 2 has been globally eradicated and the last detection of poliovirus type 3 dates to November 2012. Poliovirus type 1 remains the only circulating wild strain; between January and September 2016 it caused 26 cases (nine in Afghanistan, 14 in Pakistan, three in Nigeria). The use of oral polio vaccine (OPV) has been the key to success in the eradication effort. However, paradoxically, moving towards global polio eradication, the burden caused by vaccine-derived polioviruses (VDPVs) becomes increasingly important. In this paper circulation of both wild virus and VDPVs is reviewed and implications for the polio eradication endgame are discussed. Between April and May 2016 OPV2 cessation has been implemented globally, in a coordinated switch from trivalent OPV to bivalent OPV. In order to decrease the risk for cVDPV2 re-emergence inactivated polio vaccine (IPV) has been introduced in the routine vaccine schedule of all countries. The likelihood of re-emergence of cVDPVs should markedly decrease with time after OPV cessation, but silent circulation of polioviruses cannot be ruled out even a long time after cessation. For this reason, immunity levels against polioviruses should be kept as high as possible in the population by the use of IPV, and both clinical and environmental surveillance should be maintained at a high level.

Changes of serum IL-1 and sIL-2R levels after intravenous photo-coagulation in patients with varicose greater saphenous vein

International Nuclear Information System (INIS)

Han Li'na; Gu Ying; Liu Fanguang

2004-01-01

Objective: To determine the changes of serum interleukin 2 (IL-2) and soluble interleukin 2 receptor (sIL-2R) levels in patients with varicose greater saphenous vein after intravenous photocoagulation. Methods: Fifty patients with varicose greater saphenous vein were divided into two groups (mild and severe) according to their clinical symptoms. Serum IL-2 and sIL-2R levels were determined with RIA and ELISA respectively in these patients and 30 controls. Results: Serum levels of IL-2 and sIL-2R in patients of the mild group were about the same as those in the controls. In patients of the severe group, levels of IL-2 decreased and levels of sIL-2R increased significantly. After photocoagulation, the IL-2 levels dropped at first but gradually rose; the reverse was true for the sIL-2R levels. The final levels of IL-2 and sIL-2R approached those before treatment in the mild group. In the severe group, the final IL-2 levels were higher and sIL-2R levels lower than those before photocoagulation. Conclusion: Determination of serum IL-2 and sIL-2R levels revealed information about the immune status of the patients and could be applied for judgement of the treatment effect

Economic analysis of the global polio eradication initiative.

Science.gov (United States)

Duintjer Tebbens, Radboud J; Pallansch, Mark A; Cochi, Stephen L; Wassilak, Steven G F; Linkins, Jennifer; Sutter, Roland W; Aylward, R Bruce; Thompson, Kimberly M

2010-12-16

The global polio eradication initiative (GPEI), which started in 1988, represents the single largest, internationally coordinated public health project to date. Completion remains within reach, with type 2 wild polioviruses apparently eradicated since 1999 and fewer than 2000 annual paralytic poliomyelitis cases of wild types 1 and 3 reported since then. This economic analysis of the GPEI reflects the status of the program as of February 2010, including full consideration of post-eradication policies. For the GPEI intervention, we consider the actual pre-eradication experience to date followed by two distinct potential future post-eradication vaccination policies. We estimate GPEI costs based on actual and projected expenditures and poliomyelitis incidence using reported numbers corrected for underreporting and model projections. For the comparator, which assumes only routine vaccination for polio historically and into the future (i.e., no GPEI), we estimate poliomyelitis incidence using a dynamic infection transmission model and costs based on numbers of vaccinated children. Cost-effectiveness ratios for the GPEI vs. only routine vaccination qualify as highly cost-effective based on standard criteria. We estimate incremental net benefits of the GPEI between 1988 and 2035 of approximately 40-50 billion dollars (2008 US dollars; 1988 net present values). Despite the high costs of achieving eradication in low-income countries, low-income countries account for approximately 85% of the total net benefits generated by the GPEI in the base case analysis. The total economic costs saved per prevented paralytic poliomyelitis case drive the incremental net benefits, which become positive even if we estimate the loss in productivity as a result of disability as below the recommended value of one year in average per-capita gross national income per disability-adjusted life year saved. Sensitivity analysis suggests that the finding of positive net benefits of the GPEI remains

Assessment of Helicobacter pylori eradication by virgin olive oil.

Science.gov (United States)

Castro, Manuel; Romero, Concepción; de Castro, Antonio; Vargas, Julio; Medina, Eduardo; Millán, Raquel; Brenes, Manuel

2012-08-01

 A recent study conducted by Medina et al. disclosed that virgin olive oil has a bactericidal effect in vitro against Helicobacter pylori because of its contents of certain phenolic compounds with dialdehydic structures. We carried out two clinical trials to evaluate the effect of virgin olive oil on H. pylori-infected individuals.  Two different pilot studies were performed with 60 H. pylori-infected adults. In the first study, thirty subjects who tested positive for H. pylori received 30 g of washed virgin olive oil for 14 days, and after 1 month, the patients took 30 g of unwashed virgin olive oil for another 14 days. In a second study, a group of 30 subjects received 30 g of a different virgin olive oil for 14 days. Helicobacter pylori-infection status was checked by the urea breath test.  Helicobacter pylori was eradicated in 8 of 30 individuals when microorganism status was checked after 4-6 weeks from the first clinical intervention although 12 of 30 individuals did not show H. pylori infection at 24-72 hour of the last oil dose. Eradication rates were 27 and 40% by intention to treat and per protocol, respectively. Moreover, only 3 of 30 individuals were H. pylori negative after 4-6 weeks from the second clinical intervention but 5 of 30 were negative at 24-72 hour of the last oil dose. Eradication rates were 10 and 11% by intention to treat and per protocol, respectively. It must also be noted that 13 subjects withdrew from the studies because of taste and nausea drawbacks.  The administration of virgin olive oil showed moderate effectiveness in eradicating H. pylori. Further studies are needed to confirm these findings, especially with longer periods, different administration conditions, and several types of olive oils. © 2012 Blackwell Publishing Ltd.

Eradication of dracunculiasis from Pakistan.

Science.gov (United States)

Hopkins, D R; Azam, M; Ruiz-Tiben, E; Kappus, K D

1995-09-02

In 1986 the World Health Organization targeted dracunculiasis (Guinea-worm disease), which seriously impairs socioeconomic development in 16 African countries, India, Pakistan, and Yemen, to be eradicated globally. The target date for eradication by the end of 1995 was established in 1991. Pakistan eradicated dracunculiasis from the country in October, 1993, after a national campaign which began in 1987 with a nationwide village-by-village search for cases. The infection, which is transmitted by drinking water from ponds containing infected water fleas, was eradicated by using health education, cloth filters, and the cyclopsicide, temephos; and in the later stages, by case containment. Methods pioneered in Pakistan's National Guinea Worm Eradication Program are now being applied in remaining endemic countries.

IL-1Ra: its role in rheumatoid arthritis

Directory of Open Access Journals (Sweden)

M. Cutolo

2011-09-01

Full Text Available Interleukin-1 (IL-1 is one of the pivotal cytokines in initiating and driving the processes of rheumatoid arthritis (RA, and the body’s natural response, IL-1 receptor antagonist (IL-1Ra, has been shown conclusively to block its effects. IL-1 mediate several clinical symptoms of the inflammatory reaction (i.e. fever, pain, sleep disturbances. IL-1 is considered a key mediator in RA joint damage because of its greater capacity (greater than TNF of increasing matrix degradation by inducing the production of MMPs and PGE2 in synovial cells, as well by its role as mediator of bone and cartilage destruction. In addition, IL-1 decreases the repair process by suppressing matrix synthesis and shows a strong synergism with TNF in inducing many inflammatory genes at both local and systemic level. The induced endogenous production of IL-1Ra, in presence of the RA synovitis, is too low to contrast the high affinity of IL-1 for the cell receptors. Therefore, IL-1Ra presence should result in very effective prevention of IL-1 signal transduction particularly in the inflammatory site. In laboratory and animal studies inhibition of IL-1 by either antibodies to IL-1 or IL-1Ra proved beneficial to the outcome. IL-1Ra is a member of the IL-1 superfamily. The effects of different DMARDs on IL-1Ra levels in RA patients support the important role that selected anticytokine treatments might exert in the pathophysiology of the disease. However, since anti TNFα therapy it is not effective in all RA patients, nor does it fully control the arthritic process in affected joints of good responders and complete TNF suppression should be avoided, the combined treatment with intermediate doses of TNF and IL-1 blockers, reaching synergistic suppression of arthritis, seems warranted in RA.

Clarithromycin highly-loaded gastro-floating fine granules prepared by high-shear melt granulation can enhance the efficacy of Helicobacter pylori eradication.

Science.gov (United States)

Aoki, Hajime; Iwao, Yasunori; Mizoguchi, Midori; Noguchi, Shuji; Itai, Shigeru

2015-05-01

In an effort to develop a new gastro-retentive drug delivery system (GRDDS) without a large amount of additives, 75% clarithromycin (CAM) loaded fine granules were prepared with three different hydrophobic binders by high-shear melt granulation and their properties were evaluated. Granules containing the higher hydrophobic binder showed sustained drug release and were able to float over 24h. The synchrotron X-ray CT measurement indicated that both the high hydrophobicity of the binder and the void space inside the granules might be involved in their buoyancy. In an in vivo experiment, the floating granules more effectively eradicated Helicobacter pylori than a CAM suspension by remaining in the stomach for a longer period. In short, CAM highly-loaded gastro-floating fine granules can enhance the eradication efficiency of H. pylori compared with CAM alone. Copyright © 2015 Elsevier B.V. All rights reserved.

Dynamic monitoring of serum IFN-γ, IL-2, and IL-6 contents in patients with Graves' disease

International Nuclear Information System (INIS)

Zou Jianwen; Li Weiguo

2006-01-01

Objective: To investigate the possible role of cytokines (IFN-γ, IL-2, IL-6) in the pathogenesis of Graves' disease. Methods: Serum FT 3 , FT 4 , TSH (with CLIA), IL-2, IL-6 (with RIA) and IFN-γ (with ELISA) contents were measured in the following subjects: (1) 42 patients with Graves' disease before any treatment, (2) 40 patients in remission after successful treatment with antithyroid drugs (ATD), (3) 25 patients in relapse (around 6 months after cessation of two years' ATD treatment, (4) 40 controls. Results: The serum IFN-γ and IL-6 contents in the patients before treatment and patients in relapse were significantly higher than those in the controls (P 3 , FT 4 levels while the serum IL-2 contents were linearly negatively correlated with FT 3 , FT 4 levels before treatment. Conclusion: Contents of these cytokines fluctuated dynamically along with the status of Graves' disease and might be related to the pathogenesis in some way. (authors)

Role of IL-1 beta and COX2 in silica-induced IL-6 release and loss of pneumocytes in co-cultures.

Science.gov (United States)

Herseth, Jan I; Refsnes, Magne; Låg, Marit; Schwarze, Per E

2009-10-01

The pro-inflammatory cytokines IL-1 beta, TNF-alpha and IL-6 are of great importance in the development of silica-induced lung damage and repair. In this study we investigated the role of IL-1 beta, TNF-alpha and COX2 in silica-induced regulation of IL-6 release and pneumocyte loss in various mono- and co-cultures of monocytes, pneumocytes and endothelial cells. All co-cultures with monocytes, and especially cultures including endothelial cells, showed an increase of silica-induced release of IL-6 compared to the respective monocultures. Treatment with the antagonist IL-1 ra strongly decreased IL-1 beta and IL-6 release in contact co-cultures of monocytes and pneumocytes. COX2 up-regulation by silica and IL-1 beta was eliminated by IL-1 ra. Inhibition of COX2 markedly reduced both IL-1 beta and IL-6 release. IL-1 ra was more effective than COX2-inhibition in reduction of IL-6, but not of IL-1 beta. Silica-induced pneumocyte loss was reduced by IL-1 beta, but this effect was not counteracted by the IL-1 receptor antagonist. Our findings suggest that silica-induced IL-6 release from pneumocytes is mainly mediated via IL-1 beta release from the monocytes, via both COX2-dependent and -independent pathways. Notably, COX2-derived mediators seem crucial for a positive feed-back regulation of IL-1 beta release from the monocytes. In contrast to silica-induced IL-6, the reduction in pneumocyte loss by IL-1 beta does not seem to be regulated through an IL-1R1-dependent mechanism.

High Antigen Dose Is Detrimental to Post-Exposure Vaccine Protection against Tuberculosis

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Rolf Billeskov

2018-01-01

Full Text Available Mycobacterium tuberculosis (Mtb, the etiologic agent of tuberculosis (TB, causes 1.8M deaths annually. The current vaccine, BCG, has failed to eradicate TB leaving 25% of the world’s population with latent Mtb infection (LTBI, and 5–10% of these people will reactivate and develop active TB. An efficient therapeutic vaccine targeting LTBI could have an enormous impact on global TB incidence, and could be an important aid in fighting multidrug resistance, which is increasing globally. Here we show in a mouse model using the H56 (Ag85B-ESAT-6-Rv2660 TB vaccine candidate that post-exposure, but not preventive, vaccine protection requires low vaccine antigen doses for optimal protection. Loss of protection from high dose post-exposure vaccination was not associated with a loss of overall vaccine response magnitude, but rather with greater differentiation and lower functional avidity of vaccine-specific CD4 T cells. High vaccine antigen dose also led to a decreased ability of vaccine-specific CD4 T cells to home into the Mtb-infected lung parenchyma, a recently discovered important feature of T cell protection in mice. These results underscore the importance of T cell quality rather than magnitude in TB-vaccine protection, and the significant role that antigen dosing plays in vaccine-mediated protection.

Staphylococcus aureus induces IL-8 expression through its lipoproteins in the human intestinal epithelial cell, Caco-2.

Science.gov (United States)

Kang, Seok-Seong; Noh, Su Young; Park, Ok-Jin; Yun, Cheol-Heui; Han, Seung Hyun

2015-09-01

Staphylococcus aureus can cause the intestinal inflammatory diseases. However, little is known about the molecular mechanism of S. aureus infection in the intestine. In the present study, we investigated whether S. aureus could stimulate human intestinal epithelial cells triggering inflammation. When the human intestinal epithelial cell-line, Caco-2, and the primary colon cells were stimulated with ethanol-inactivated S. aureus, IL-8 expression was induced in a dose-dependent manner. The inactivated S. aureus preferentially stimulated Toll-like receptor (TLR) 2 rather than TLR4. Lipoproteins, lipoteichoic acid (LTA), and peptidoglycan (PGN) are considered as potential TLR2 ligands of S. aureus. Interestingly, S aureus lipoproteins and Pam2CSK4 mimicking Gram-positive bacterial lipoproteins, but not LTA and PGN of S. aureus, significantly induced IL-8 expression in Caco-2 cells. Furthermore, lipoprotein-deficient S. aureus mutant strain failed to induce IL-8 production. Collectively, these results suggest that S. aureus stimulates the human intestinal epithelial cells to induce the chemokine IL-8 production through its lipoproteins, potentially contributing the development of intestinal inflammation. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

Directory of Open Access Journals (Sweden)

Ilona Hromadnikova

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

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

Science.gov (United States)

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

2016-01-01

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

Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses

International Nuclear Information System (INIS)

Choudhury, Sreetama; Gupta, Payal; Ghosh, Sayan; Mukherjee, Sudeshna; Chakraborty, Priyanka; Chatterji, Urmi; Chattopadhyay, Sreya

2016-01-01

Highlights: • We for the first time explicitly show that arsenic exposure causes morphological damage to the thymus and results in heightened death of thymocytes. • Our data suggests that arsenic-induced apoptosis occurs due to increase in cellular oxidative and nitrosative stress. • We have for the first time established a non-classical role of NF-κB, correlating it with increase in FoxP3 expression. • The % of CD4+ CD25+ T cells were high and expression of FoxP3 has also increased at higher doses of arsenic indicating an nTreg bias. - Abstract: Arsenic contamination of drinking water is a matter of global concern. Arsenic intake impairs immune responses and leads to a variety of pathological conditions including cancer. In order to understand the intricate tuning of immune responses elicited by chronic exposure to arsenic, a mouse model was established by subjecting mice to different environmentally relevant concentrations of arsenic in drinking water for 30 days. Detailed study of the thymus, a primary immune organ, revealed arsenic-mediated tissue damage in both histological specimens and scanning electron micrographs. Analysis of molecular markers of apoptosis by Western blot revealed a dose-dependent activation of the apoptotic cascade. Enzymatic assays supported oxidative stress as an instigator of cell death. Interestingly, assessment of inflammatory responses revealed disparity in the NF-κB/IL-6/STAT3 axis, where it was found that in animals consuming higher amounts of arsenic NF-κB activation did not lead to the classical IL-6 upregulation response. This deviation from the canonical pathway was accompanied with a significant rise in numbers of CD4+ CD25+ FoxP3 expressing cells in the thymus. The cytokine profile of the animals exposed to higher doses of arsenic also indicated an immune-suppressed milieu, thus validating that arsenic shapes the immune environment in context to its dose of exposure and that at higher doses it leads to immune

Effect of long-term inhalation of glucocorticoids on the level of leptin, IL-13 and IL-2 in bronchial asthmatic children

International Nuclear Information System (INIS)

Pan Jiongwei

2011-01-01

Objective: To determine the effect of long-term inhalation of glucocorticoids on the level of leptin, IL-13, and IL-2 in bronchial asthmatic patient. Methods: Enzyme-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 post-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 decreased gradually after inhaling glucocorticoids for 3 months (P<0.05). The treatment of inhaled glucocorticoids 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 glucocorticoid is an important means for asthma, and the effects are related to the decrease of level of leptin, IL-13, and IL-2. (authors)

Biological dose estimation for accidental supra-high dose gamma-ray exposure

International Nuclear Information System (INIS)

Chen, Y.; Yan, X.K.; Du, J.; Wang, Z.D.; Zhang, X.Q.; Zeng, F.G.; Zhou, P.K.

2011-01-01

To correctly estimate the biological dose of victims accidentally exposed to a very high dose of 60 Co gamma-ray, a new dose-effect curve of chromosomal dicentrics/multicentrics and rings in the supra-high dose range was established. Peripheral blood from two healthy men was irradiated in vitro with doses of 60 Co gamma-rays ranging from 6 to 22 Gy at a dose rate of 2.0 Gy/min. Lymphocytes were concentrated, cultured and harvested at 52 h, 68 h and 72 h. The numbers of dic + r were counted. The dose-effect curves were established and validated using comparisons with doses from the Tokai-mura accident and were then applied to two victims of supra-high dose exposure accident. The results indicated that there were no significant differences in chromosome aberration frequency among the different culture times from 52 h to 72 h. The 6-22 Gy dose-effect curve was fitted to a linear quadratic model Y = -2.269 + 0.776D - 7.868 x l0 -3 D 2 . Using this mathematic model, the dose estimates were similar to data from Tokai-mura which were estimated by PCC ring. Whole body average doses of 9.7 Gy and 18.1 Gy for two victims in the Jining accident were satisfactorily given. We established and successfully applied a new dose-effect curve of chromosomal dicentrics plus ring (dic + r) after 6-22 Gy γ-irradiation from a supra-high dose 60 Co gamma-ray accident.

The role of interleukin-8 (IL-8) and IL-8 receptors in platinum response in high grade serous ovarian carcinoma.

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Stronach, Euan A; Cunnea, Paula; Turner, Christina; Guney, Tankut; Aiyappa, Radhika; Jeyapalan, Senthuran; de Sousa, Camila H; Browne, Alacoque; Magdy, Nesreen; Studd, James B; Sriraksa, Ruethairat; Gabra, Hani; El-Bahrawy, Mona

2015-10-13

Platinum based drugs are the cornerstone of chemotherapy for ovarian cancer, however the development of chemoresistance hinders its success. IL-8 is involved in regulating several pro-survival pathways in cancer. We studied the expression of IL-8 and IL-8 receptors in platinum sensitive and resistant cell lines. Using qRT-PCR and immunohistochemistry, both platinum sensitive (PEA1, PEO14) and resistant (PEA2, PEO23) show increased expression of IL-8 and IL-8 receptors. IL-8RA shows nuclear and cytoplasmic expression, whilst IL-8RB is present solely in the cytoplasm. Knockdown of IL-8 increased sensitivity to cisplatin in platinum sensitive and reversed platinum resistance in resistant cell lines, decreased the expression of anti-apoptotic Bcl-2 and decreased inhibitory phosphorylation of pro-apoptotic Bad. IL-8 receptor antagonist treatment also enhanced platinum sensitivity. Nuclear localisation of IL-8RA was only detected in platinum resistant tumours. Inhibition of IL-8 signalling can enhance response in platinum sensitive and resistant disease. Nuclear IL-8RA may have potential as a biomarker of resistant disease.

Repletion of zinc in zinc-deficient cells strongly up-regulates IL-1β-induced IL-2 production in T-cells.

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Daaboul, Doha; Rosenkranz, Eva; Uciechowski, Peter; Rink, Lothar

2012-10-01

Mild zinc deficiency in humans negatively affects IL-2 production resulting in declined percentages of cytolytic T cells and decreased NK cell lytic activity, which enhances the susceptibility to infections and malignancies. T-cell activation is critically regulated by zinc and the normal physiological zinc level in T-cells slightly lies below the optimal concentration for T-cell functions. A further reduction in zinc level leads to T-cell dysfunction and autoreactivity, whereas high zinc concentrations (100 μM) were shown to inhibit interleukin-1 (IL-1)-induced IL-1 receptor kinase (IRAK) activation. In this study, we investigated the molecular mechanism by which zinc regulates the IL-1β-induced IL-2 expression in T-cells. Zinc supplementation to zinc-deficient T-cells increased intracellular zinc levels by altering the expression of zinc transporters, particularly Zip10 and Zip12. A zinc signal was observed in the murine T-cell line EL-4 6.1 after 1 h of stimulation with IL-1β, measured by specific zinc sensors FluoZin-3 and ZinPyr-1. This signal is required for the phosphorylation of MAPK p38 and NF-κB subunit p65, which triggers the transcription of IL-2 and strongly increases its production. These results indicate that short-term zinc supplementation to zinc-deficient T-cells leads to a fast rise in zinc levels which subsequently enhance cytokine production. In conclusion, low and excessive zinc levels might be equally problematic for zinc-deficient subjects, and stabilized zinc levels seem to be essential to avoid negative concentration-dependent zinc effects on T-cell activation.

High-dose myeloablative versus conventional low-dose radioimmunotherapy (RIT) of mantle cell lymphoma (MCL) with the chimeric anti-CD20 antibody C2B8

International Nuclear Information System (INIS)

Behr, T.M.; Gotthardt, M.; Schipperm, M.L.; Gratz, S.; Behe, M.P.; Brittinger, G.; Woermann, B.; Becker, W.

2002-01-01

CD20 has been used as target molecule for low-dose as well as high-dose, myeloablative RIT of B-cell NHL. MCL is an especially aggressive, prognostically unfavorable form of B-cell NHL. The aim of this study was to investigate whether high-dose, myeloablative RIT with the 131 I-labeled chimeric anti-CD20 antibody C2B8 (rituxan, Mabthera, Roche) may be therapeutically more effective than conventional low-dose therapy in MCL. A total of twelve patients with chemorefractory or relapsed mantle cell lymphoma were studied so far (all of them having relapsed after high-dose chemotherapy, seven of them combined with 12 Gy TBI). A diagnostic-dosimetric study was performed with 10 mCi of 131 I-C2B8 at a protein dose of 2.5 mg/kg. In case of splenic pooling, the protein dose was increased until a more 'favorable' biodistribution was obtained. Therapy was performed with conventional (30-75 mCi; n=4) or myeloablative activities (261-515 mCi; n=8) of 131 I-C2B8 at the previously optimized protein dose, aiming at whole-body doses of ≤ 0.8 Gy (for low-dose RIT) or lung doses of ≤ 27 Gy (for high-dose RIT). Clinical follow-up was obtained for up to 42 months. Overall, in 11 patients the 2.5 mg/kg protein dose was used, whereas in one patient with marked splenomegaly, 10 mg/kg were necessary to overcome the splenic antigenic sink. In the high-dose patients, non-hematologic toxicity was restricted to mild to moderate nausea, fever, transient bilirubin or liver enzyme elevations. Despite thyroid blocking, 6/8 high-dose (in contrast to 0/4 low-dose) patients developed hypothyroidism, requiring thyroxine substitution at 6-18 months after RIT. The response rate in the low-dose arm was only 1(PR)/4, whereas 7/8 high-dose patients experienced complete and the remainder a partial remission. 6 high-dose patients are still in CR (one of them relapsed locally at 3 months, one systemically at 26 months after RIT), and 7 are still alive for up to 42+ months. In contrast to low-dose therapy

Endgame for polio eradication? Options for overcoming social and political factors in the progress to eradicating polio.

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Ganapathiraju, Pavan V; Morssink, Christiaan B; Plumb, James

2015-01-01

In 1988, the Global Polio Eradication Initiative (GPEI) was launched with the goal of eradicating polio by the year 2000. After 25 years, several dynamics still challenge this large public health campaign with new cases of polio being reported annually. We examine the roots of this initiative to eradicate polio, its scope, the successes and setbacks during the last 25 years and reflect on the current state of affairs. We examine the social and political factors that are barriers to polio eradication. Options are discussed for solving the current impasse of polio eradication: using force, respecting individual freedoms and gaining support from those vulnerable to fundamentalist 'propaganda'. The travails of the GPEI indicate the need for expanding the Convention on the Rights of the Child to address situations of war and civic strife. Such a cultural and structural reference will provide the basis for global stakeholders to engage belligerent local actors whose local political conflicts are barriers to the eradication of polio. Disregard for these actors will result in stagnation of polio eradication policy, delaying eradication beyond 2018.

Transgenic Expression of IL15 Improves Antiglioma Activity of IL13Rα2-CAR T Cells but Results in Antigen Loss Variants.

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Krenciute, Giedre; Prinzing, Brooke L; Yi, Zhongzhen; Wu, Meng-Fen; Liu, Hao; Dotti, Gianpietro; Balyasnikova, Irina V; Gottschalk, Stephen

2017-07-01

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen receptors (CAR) is an attractive approach to improve outcomes. Although CAR T cells targeting GBM antigens, such as IL13 receptor subunit α2 (IL13Rα2), HER2, and EGFR variant III (EGFRvIII), have had antitumor activity in preclinical models, early-phase clinical testing has demonstrated limited antiglioma activity. Transgenic expression of IL15 is an appealing strategy to enhance CAR T-cell effector function. We tested this approach in our IL13Rα2-positive glioma model in which limited IL13Rα2-CAR T-cell persistence results in recurrence of antigen-positive gliomas. T cells were genetically modified with retroviral vectors encoding IL13Rα2-CARs or IL15 (IL13Rα2-CAR.IL15 T cells). IL13Rα2-CAR.IL15 T cells recognized glioma cells in an antigen-dependent fashion, had greater proliferative capacity, and produced more cytokines after repeated stimulations in comparison with IL13Rα2-CAR T cells. No autonomous IL13Rα2-CAR.IL15 T-cell proliferation was observed; however, IL15 expression increased IL13Rα2-CAR T-cell viability in the absence of exogenous cytokines or antigen. In vivo , IL13Rα2-CAR.IL15 T cells persisted longer and had greater antiglioma activity than IL13Rα2-CAR T cells, resulting in a survival advantage. Gliomas recurring after 40 days after T-cell injection had downregulated IL13Rα2 expression, indicating that antigen loss variants occur in the setting of improved T-cell persistence. Thus, CAR T cells for GBM should not only be genetically modified to improve their proliferation and persistence, but also to target multiple antigens. Summary: Glioblastoma responds imperfectly to immunotherapy. Transgenic expression of IL15 in T cells expressing CARs improved their proliferative capacity, persistence, and cytokine production. The emergence of antigen

Recommendations of 2nd National Consultative Meeting of Indian Academy of Pediatrics (IAP) on polio eradication and improvement of routine immunization.

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Vashishtha, Vipin M; Kalra, Ajay; John, T Jacob; Thacker, Naveen; Agarwal, R K

2008-05-01

Persistence of intense wild poliovirus (WPV) transmission, particularly type 3 in northern India necessitated the Indian Academy of Pediatrics (IAP) to convene a National Consultative Meeting to review its earlier recommendations on polio eradication and improvement of routine immunization. More than thirty experts were invited and intense deliberations were held over two days to draw consensus statements on various issues related with polio eradication. To review the ongoing strategy, identify the existing challenges, and suggest modifications to the current strategy for eradication of poliomyelitis in India. IAP reiterates its support to ongoing efforts on polio eradication but demand some flexibility in the strategy. The immediate challenges identified include persistent WPV type 1 transmission in Uttar Pradesh (UP) and Bihar, intense type 3 transmission also in UP and Bihar, and maintaining polio-free status of all other states. Circulating vaccine derived poliovirus (cVDPV), particularly type 2, was identified as a great future threat. Neglect of routine immunization (RI), poor efficacy of oral polio vaccine (OPV), operational issues, and inadequate uptake of OPV in the 2 endemic states are the main reasons of failure to interrupt transmission of WPV 1 and 3. However, for the first time in history the intensity of WPV 1 circulation is very low in western UP. IAP suggests that high-quality, uniform and consistent performance of supplementary immunization activities (SIAs) in all districts of western UP, particularly using mOPV1(monovalent OPV1) should be maintained to avoid reestablishment of circulation of type 1 poliovirus. A judicious mix of mOPV1 and mOPV3, given sequentially or even simultaneously (after validating the efficacies) will be necessary to address the upsurge of WPV3. Re-establishing routine immunization should be the foremost priority. IAP strongly recommends to Government of India (GOI) to take urgent measures to attain coverage of a minimum

IL6 gene promoter polymorphisms and type 2 diabetes

DEFF Research Database (Denmark)

Huth, Cornelia; Heid, Iris M; Vollmert, Caren

2006-01-01

Several lines of evidence indicate a causal role of the cytokine interleukin (IL)-6 in the development of type 2 diabetes in humans. Two common polymorphisms in the promoter of the IL-6 encoding gene IL6, -174G>C (rs1800795) and -573G>C (rs1800796), have been investigated for association with type...... 2 diabetes in numerous studies but with results that have been largely equivocal. To clarify the relationship between the two IL6 variants and type 2 diabetes, we analyzed individual data on >20,000 participants from 21 published and unpublished studies. Collected data represent eight different...... countries, making this the largest association analysis for type 2 diabetes reported to date. The GC and CC genotypes of IL6 -174G>C were associated with a decreased risk of type 2 diabetes (odds ratio 0.91, P = 0.037), corresponding to a risk modification of nearly 9%. No evidence for association was found...

ERAD-dependent control of the Wnt secretory factor Evi.

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Glaeser, Kathrin; Urban, Manuela; Fenech, Emma; Voloshanenko, Oksana; Kranz, Dominique; Lari, Federica; Christianson, John C; Boutros, Michael

2018-02-15

Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of β-catenin by the ubiquitin-proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)-associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP-dependent manner. Ubiquitination of Evi involves the E2-conjugating enzyme UBE2J2 and the E3-ligase CGRRF1. Furthermore, we show that a triaging complex of Porcn and VCP determines whether Evi enters the secretory or the ERAD pathway. In this way, ERAD-dependent control of Evi availability impacts the scale of Wnt protein secretion by adjusting the amount of Evi to meet the requirement of Wnt protein export. As Wnt and Evi protein levels are often dysregulated in cancer, targeting regulatory ERAD components might be a useful approach for therapeutic interventions. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

IL-2 induction of IL-1 beta mRNA expression in monocytes. Regulation by agents that block second messenger pathways

DEFF Research Database (Denmark)

Kovacs, E J; Brock, B; Varesio, L

1989-01-01

We have previously shown that in mixed cultures of PBL incubation with human rIL-2 induces the rapid expression of IL-1 alpha and IL-1 beta mRNA. Because studies have demonstrated that IL-2R can be expressed on the surface of human peripheral blood monocytes, we chose to investigate whether IL-1 ...

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

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

2015-01-01

This data article presents the first large-scale quantitative phosphoproteomics dataset generated to decipher the signaling networks initiated by IL-2 and IL-15 in T-lymphocytes. Data was collected by combining immunoprecipitation of tyrosine phosphorylated proteins and TiO2-based phosphopeptide...

Targeting HIV latency: pharmacologic strategies toward eradication

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Xing, Sifei; Siliciano, Robert F.

2013-01-01

The latent reservoir for HIV-1 in resting CD4+ T cells remains a major barrier to HIV-1 eradication, even though highly active antiretroviral therapy (HAART) can successfully reduce plasma HIV-1 levels to below the detection limit of clinical assays and reverse disease progression. Proposed eradication strategies involve reactivation of this latent reservoir. Multiple mechanisms are believed to be involved in maintaining HIV-1 latency, mostly through suppression of transcription. These include cytoplasmic sequestration of host transcription factors and epigenetic modifications such as histone deacetylation, histone methylation and DNA methylation. Therefore, strategies targeting these mechanisms have been explored for reactivation of the latent reservoir. In this review, we discuss current pharmacological approaches toward eradication, focusing on small molecule latency-reversing agents, their mechanisms, advantages and limitations. PMID:23270785

Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family.

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Cayrol, Corinne; Girard, Jean-Philippe

2018-01-01

Interleukin-33 (IL-33) is a tissue-derived nuclear cytokine from the IL-1 family abundantly expressed in endothelial cells, epithelial cells and fibroblast-like cells, both during homeostasis and inflammation. It functions as an alarm signal (alarmin) released upon cell injury or tissue damage to alert immune cells expressing the ST2 receptor (IL-1RL1). The major targets of IL-33 in vivo are tissue-resident immune cells such as mast cells, group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs). Other cellular targets include T helper 2 (Th2) cells, eosinophils, basophils, dendritic cells, Th1 cells, CD8 + T cells, NK cells, iNKT cells, B cells, neutrophils and macrophages. IL-33 is thus emerging as a crucial immune modulator with pleiotropic activities in type-2, type-1 and regulatory immune responses, and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases. The critical function of IL-33/ST2 signaling in allergic inflammation is illustrated by the fact that IL33 and IL1RL1 are among the most highly replicated susceptibility loci for asthma. In this review, we highlight 15 years of discoveries on IL-33 protein, including its molecular characteristics, nuclear localization, bioactive forms, cellular sources, mechanisms of release and regulation by proteases. Importantly, we emphasize data that have been validated using IL-33-deficient cells. © 2017 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd.

Study on the changes of serum IL-2, IL-6 and TNF-α levels in patients with chronic glomerulonephritis

International Nuclear Information System (INIS)

Xie Jianping; Feng Jiangchao; Zhang Guoyuan; Xiong Gang; Tu Lirong; Xia Chengyun

2003-01-01

Objective: To investigate the changes of serum IL-2, IL-6 and TNF-α levels in patients with chronic glomerulonephritis of various types and stages. Methods: Serum IL-2, IL-6 and TNF-α levels were measured with RIA in 71 patients with chronic glomerulonephritis and 36 controls. Results: 1) Serum levels of IL-6 and TNF-α were significantly higher in patients with chronic glomerulonephritis than those in controls (p<0.01) but serum IL-2 levels were significantly lower in the patients (p<0.01). 2)Serum IL-6 and TNF-α levels were positively correlated to BUN levels (p<0.01). 3)There were no significant differences of these cytokines levels among the different types of patients (i.e. general type n=18, nephrotic type n=33 and hypertensive type n=20). Conclusion: These cytokines participated in the pathogenesis of chronic glomerulonephritis. Monitoring the changes of their serum levels was helpful for the management of the disease

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

DEFF Research Database (Denmark)

Christensen, Ulla; Haagerup, Annette; Binderup, Helle

2006-01-01

) identified in a family based association study of two Danish samples comprising a total of 235 families with allergic diseases. None of the IL15 SNPs showed significant association and the haplotype analysis yielded inconsistent results in the two samples. In contrast, the two IL2 SNPs showed association...... 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...

Polio eradication in the African Region on course despite public health emergencies.

Science.gov (United States)

Okeibunor, Joseph C; Ota, Martin C; Akanmori, Bartholomew D; Gumede, Nicksy; Shaba, Keith; Kouadio, Koffi I; Poy, Alain; Mihigo, Richard; Salla, Mbaye; Moeti, Matshidiso R

2017-03-01

The World Health Organization, African Region is heading toward eradication of the three types of wild polio virus, from the Region. Cases of wild poliovirus (WPV) types 2 and 3 (WPV2 and WPV3) were last reported in 1998 and 2012, respectively, and WPV1 reported in Nigeria since July 2014 has been the last in the entire Region. This scenario in Nigeria, the only endemic country, marks a remarkable progress. This significant progress is as a result of commitment of key partners in providing the much needed resources, better implementation of strategies, accountability, and innovative approaches. This is taking place in the face of public emergencies and challenges, which overburden health systems of countries and threaten sustainability of health programmes. Outbreak of Ebola and other diseases, insecurity, civil strife and political instability led to displacement of populations and severely affected health service delivery. The goal of eradication is now within reach more than ever before and countries of the region should not relent in their efforts on polio eradication. WHO and partners will redouble their efforts and introduce better approaches to sustain the current momentum and to complete the job. The carefully planned withdrawal of oral polio vaccine type II (OPV2) with an earlier introduction of one dose of inactivated poliovirus vaccine (IPV), in routine immunization, will boost immunity of populations and stop cVDPVs. Environmental surveillance for polio viruses will supplement surveillance for AFP and improve sensitivity of detection of polio viruses. Copyright © 2016 World Health Organization. Published by Elsevier Ltd. Published by Elsevier Ltd.. All rights reserved.

Clinical significance of changes of serum IL-2, IL-6 and TNF-α levels after treatment in patients with periodontitis

International Nuclear Information System (INIS)

Wei Dong

2005-01-01

Objective: To investigate the changes of serum IL-2, IL-6 and TNF-α levels after one month of comprehensive treatment in patients with periodontitis. Methods: Serum IL-2, IL-6 and TNF-α levels were measured with RIA in 48 patients with periodontitis both before and after treatment as well as in 35 controls. Results: Before treatment, serum levels of IL-6, TNF- α in the patients were significantly higher and IL-2 levels were significantly lower than those in the controls (both P 0.05). However, the IL-2 levels were still significantly lower than those in controls (P<0.05). Conclusion: There was disturbance of immuno-modulation in patients with periodontitis as expressed by the changes of cytokines levels in the course of the disease. (authors)

Strategies to eradicate minimal residual disease in small cell lung cancer: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

Science.gov (United States)

Krug, L M; Grant, S C; Miller, V A; Ng, K K; Kris, M G

1999-10-01

In the last 25 years, treatment for small cell lung cancer (SCLC) has improved with advances in chemotherapy and radiotherapy. Standard chemotherapy regimens can yield 80% to 90% response rates and some cures when combined with thoracic irradiation in limited-stage patients. Nonetheless, small cell lung cancer has a high relapse rate due to drug resistance; this has resulted in poor survival for most patients. Attacking this problem requires a unique approach to eliminate resistant disease remaining after induction therapy. This review will focus on three potential strategies: high-dose chemotherapy with autologous bone marrow transplantation, matrix metalloproteinase inhibitors, and BEC2 plus BCG vaccination.

Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain.

Science.gov (United States)

Pichery, Mélanie; Mirey, Emilie; Mercier, Pascale; Lefrancais, Emma; Dujardin, Arnaud; Ortega, Nathalie; Girard, Jean-Philippe

2012-04-01

IL-33 (previously known as NF from high endothelial venules) is an IL-1 family cytokine that signals through the ST2 receptor and drives cytokine production in mast cells, basophils, eosinophils, invariant NKT and NK cells, Th2 lymphocytes, and type 2 innate immune cells (natural helper cells, nuocytes, and innate helper 2 cells). Little is known about endogenous IL-33; for instance, the cellular sources of IL-33 in mouse tissues have not yet been defined. In this study, we generated an Il-33-LacZ gene trap reporter strain (Il-33(Gt/Gt)) and used this novel tool to analyze expression of endogenous IL-33 in vivo. We found that the Il-33 promoter exhibits constitutive activity in mouse lymphoid organs, epithelial barrier tissues, brain, and embryos. Immunostaining with anti-IL-33 Abs, using Il-33(Gt/Gt) (Il-33-deficient) mice as control, revealed that endogenous IL-33 protein is highly expressed in mouse epithelial barrier tissues, including stratified squamous epithelia from vagina and skin, as well as cuboidal epithelium from lung, stomach, and salivary gland. Constitutive expression of IL-33 was not detected in blood vessels, revealing the existence of species-specific differences between humans and mice. Importantly, IL-33 protein was always localized in the nucleus of producing cells with no evidence for cytoplasmic localization. Finally, strong expression of the Il-33-LacZ reporter was also observed in inflamed tissues, in the liver during LPS-induced endotoxin shock, and in the lung alveoli during papain-induced allergic airway inflammation. Together, our findings support the possibility that IL-33 may function as a nuclear alarmin to alert the innate immune system after injury or infection in epithelial barrier tissues.

Polymorphisms of ST2-IL18R1-IL18RAP gene cluster: a new risk for autoimmune thyroid diseases.

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Wang, X; Zhu, Y F; Li, D M; Qin, Q; Wang, Q; Muhali, F S; Jiang, W J; Zhang, J A

2016-02-01

Interleukin 33 (IL33) / ST2 pathway and ST2-interlukin18 receptor1-interlukin18 receptor accessory protein (ST2-IL18R1-IL18RAP) gene cluster have been involved in many autoimmune diseases but few report in autoimmune thyroid diseases (AITD). In this study, we investigated whether polymorphisms of IL33, ST2, IL18R1, and IL18RAP are associated with Graves' disease (GD) and Hashimoto's thyroiditis (HT), two major forms of AITD, among a Chinese population. A total of 11 SNPs were explored in a case-control study including 417 patients with GD, 250 HT patients and 301 controls, including rs1929992, rs10975519, rs10208293, rs6543116, rs1041973, rs3732127, rs11465597, rs1035130, rs2293225, rs1035127, rs917997 of IL 33, ST2-IL18R1-IL18RAP gene cluster. Genotyping of these SNPs was performed using matrix-assisted laser desorption / ionization-time-of-flight mass spectrometer (MALDI-TOF-MS) platform from Sequenom. The frequencies of allele A and AA+AG genotype of rs6543116 (ST2) in HT patients were significantly increased compared with those of the controls (P = 0.029/0.021, OR = 1.31/1.62). And in another SNP rs917997, AA+AG genotype presented an increased frequency in HT subjects compared with controls (P = 0.046, OR = 1.53). Furthermore, the haplotype GAGCCCG from ST2-IL18R1-IL18RAP gene cluster (rs6543116, rs1041973, rs1035130, rs3732127, rs1035127, rs2293225, rs917997) was associated with increased susceptibility to GD with an OR of 2.03 (P = 0.022, 95% CI = 1.07-3.86). Some SNPs of ST2-IL18R1-IL18RAP gene cluster might increase the risk of susceptibility of HT and GD in Chinese Han population. © 2015 John Wiley & Sons Ltd.

Ontogeny and localization of the cells produce IL-2 in healthy animals.

Science.gov (United States)

Yamamoto, Mutsumi; Seki, Yoichi; Iwai, Kazuyuki; Ko, Iei; Martin, Alicia; Tsuji, Noriko; Miyagawa, Shuji; Love, Robert B; Iwashima, Makio

2013-03-01

IL-2 is a growth factor for activated T cells and is required for maintenance of naturally arising regulatory T cells (nTregs). Mice defective in IL-2/IL-2 receptor signaling pathways have impaired nTregs and suffer from lymphoproliferative disorders, suggesting that IL-2 is present and functional in healthy animals. However, the cellular source of IL-2 is currently unknown. To determine which cells produce IL-2 in healthy animals, we established mice carrying cre gene knock in at the il-2 locus (termed IL-2(cre)). When IL-2(cre) mice were crossed with EGFP reporter mice, EGFP was exclusively expressed by a fraction of CD4 T cells present in both lymphoid and non-lymphoid tissues. Live imaging of IL-2(cre) mice that carry the luciferase reporter showed concentrated localization of luciferase(+) cells in Peyer's patches. These cells were not observed in new born mice but appeared within 3days after birth. Reduction of antigen receptor repertoire by transgene expression reduced their number, indicating that recognition of environmental antigens is necessary for generation of these IL-2 producers in healthy animals. A substantial fraction of EGFP(+) cells also produce IL-10 and IFN-γ, a characteristic profile of type 1 regulatory T cells (Tr1). The data suggest that a group of Tr1 cells have addition roles in immune homeostasis by producing IL-2 along with other cytokines and help maintaining Tregs. Copyright © 2012 Elsevier Ltd. All rights reserved.

Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis

NARCIS (Netherlands)

Festen, E. A. M.; Goyette, P.; Scott, R.; Annese, V.; Zhernakova, A.; Lian, J.; Lefebvre, C.; Brant, S. R.; Cho, J. H.; Silverberg, M. S.; Taylor, K. D.; de Jong, D. J.; Stokkers, P. C.; Mcgovern, D.; Palmieri, O.; Achkar, J-P; Xavier, R. J.; Daly, M. J.; Duerr, R. H.; Wijmenga, C.; Weersma, R. K.; Rioux, J. D.

Objectives: Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBDs) known as Crohn's disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in coeliac

Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis

NARCIS (Netherlands)

Festen, E.A.M.; Goyette, P.; Scott, R.; Annese, V.; Zhernakova, A.; Lian, J.; Lefèbvre, C.; Brant, S.R.; Cho, J.H.; Silverberg, M.S.; Taylor, K.D.; de Jong, D.J.; Stokkers, P.C.; Mcgovern, D.; Palmieri, O.; Achkar, J.P.; Xavier, R.J.; Daly, M.J.; Duerr, R.H.; Wijmenga, C.; Weersma, R.K.; Rioux, J.D.

2009-01-01

Objectives: Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBDs) known as Crohn's disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in coeliac

Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis.

NARCIS (Netherlands)

Festen, E.A.; Goyette, P.; Scott, R.; Annese, V.; Zhernakova, A.; Lian, J.; Lefebvre, C.; Brant, S.R.; Cho, J.H.; Silverberg, M.S.; Taylor, K.D.; Jong, D.J. de; Stokkers, P.C.; Mcgovern, D.; Palmieri, O.; Achkar, J.P.; Xavier, R.J.; Daly, M.J.; Duerr, R.H.; Wijmenga, C.; Weersma, R.K.; Rioux, J.D.

2009-01-01

OBJECTIVES: Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBDs) known as Crohn's disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in coeliac

Establishment of IL-7 Expression Reporter Human Cell Lines, and Their Feasibility for High-Throughput Screening of IL-7-Upregulating Chemicals.

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Yeon Sook Cho

Full Text Available Interleukin-7 (IL-7 is a cytokine essential for T cell homeostasis, and is clinically important. However, the regulatory mechanism of IL-7 gene expression is not well known, and a systematic approach to screen chemicals that regulate IL-7 expression has not yet been developed. In this study, we attempted to develop human reporter cell lines using CRISPR/Cas9-mediated genome editing technology. For this purpose, we designed donor DNA that contains an enhanced green fluorescent protein (eGFP gene, drug selection cassette, and modified homologous arms which are considered to enhance the translation of the eGFP reporter transcript, and also a highly efficient single-guide RNA with a minimal off-target effect to target the IL-7 start codon region. By applying this system, we established IL-7 eGFP reporter cell lines that could report IL-7 gene transcription based on the eGFP protein signal. Furthermore, we utilized the cells to run a pilot screen campaign for IL-7-upregulating chemicals in a high-throughput format, and identified a chemical that can up-regulate IL-7 gene transcription. Collectively, these results suggest that our IL-7 reporter system can be utilized in large-scale chemical library screening to reveal novel IL-7 regulatory pathways and to identify potential drugs for development of new treatments in immunodeficiency disease.

Estimation by limiting dilution analysis of human IL 2-secreting T cells: detection of IL 2 produced by single lymphokine-secreting T cells

International Nuclear Information System (INIS)

Vie, H.; Miller, R.A.

1986-01-01

We present here a culture method for the estimation, in human blood, of the number of lymphocytes that can respond to mitogen by producing interleukin 2 (IL 2). T cells are cultured at limiting dilutions with PHA or Con A in the presence of Epstein Barr virus-transformed human lymphoblastoid cells (EB-LCL), and supernatants are tested 3 days later for IL 2 content by a cell proliferation assay. The distribution of negative wells follows the expected Poisson single-hit relationship, suggesting that the assay is sensitive to single cells of a single limiting cell type. On average, 16.3% of peripheral blood mononuclear cells can produce IL 2 in such clonal cultures (mean of 12 determinations; SD = 5.6%). Surprisingly, irradiation (up to 2000 rad) of the titrated responder cell population diminishes the estimated frequencies by less than 50%. The ability to detect IL 2 levels in cultures containing only a single, nonproliferating T lymphocyte allows us to estimate the amount of IL 2 generated by an individual effector cell during a 3-day culture interval after mitogen stimulation. The average responding, irradiated T cell generates 0.92 pg of IL 2 (median) within 3 days. The method presented provides a straightforward way to provide independent estimates of responding cell number and of lymphokine production per cell in a variety of clinical situations

Radioimmunotoxicological effect of enriched uranium on central and peripheral immune cells and the protective action of IL-1 and IL-2

International Nuclear Information System (INIS)

Zhu Shoupeng; Lai Guanhua; Wang Liuyi

1993-01-01

With accumulation of enriched uranium 235 U-UO 2 F 2 in organism, it was found that enriched uranium had injurious effect on the immune function of central and peripheral immune cells. After intravenous injection of enriched uranium the spontaneous 3 H-TdR incorporation in thymocytes and bone marrow cells decreased. Though the sensitivity of immune cells to 235 U-UO 2 F 2 was different, the thymocytes were destroyed more markedly. Also the proliferation ability of T and B lymphocytes were both inhibited by enriched uranium 235 U. As compared with them, spleen B lymphocytes were inhibited more markedly than T lymphocytes. At the same time spleen lymphocytes IL-1 production and IL 2 consumption were diminished. It should be noted that the inhibition of spleen B lymphocytes proliferation by enriched uranium 235 U-UO 2 F 2 was partially restored by exogenous IL-1 or IL-2. The recovery rate of protective action at the very most was 67.1 +- 11.2% with exogenous IL-1 and 50.2 +- 8.0% with IL-2. Moreover, both exogenous IL-1 and IL-2 had synergetic effect, and the recovery rate was elevated to 83.1 +-12.3%

Effects of flurbiprofen axetil on postoperative serum IL-2 and IL-6 levels in patients with colorectal cancer.

Science.gov (United States)

Jiang, W W; Wang, Q H; Peng, P; Liao, Y J; Duan, H X; Xu, M; Li, Y; Zhang, P B

2015-12-09

We explored the effects of flurbiprofen axetil on interleukin (IL)-2 and IL-6 levels in postoperative patients with colorectal cancer. A total of 120 patients (American Society of Anesthesiologists I and II) scheduled to undergo colorectal cancer surgery were randomly divided into 3 groups (N = 40 in each group): flurbiprofen axetil group (group F), morphine group (group M), and tramadol group (group T). Group M received 0.1 mg/kg morphine, group T received 1.5 mg/kg tramadol, and group F received 1.5 mg/kg flurbiprofen axetil. Patients in the 3 groups were administered treatments through intravenous injection 10 min before surgery. Serum IL-2 and IL-6 levels were detected. Postoperative adverse reactions were recorded, such as nausea, vomiting, and pruritus. The serum IL-6 level of the 3 groups increased 3 h after surgery. Compared with group M, IL-6 level was higher in group T and group F at 1 day after the surgery, and the differences between group M and the other groups were significant (P Flurbiprofen axetil promoted the secretion of IL-2 and inhibited IL-6; additionally, flurbiprofen axetil may have a lower incidence of adverse reactions compared to other treatments.

Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis

NARCIS (Netherlands)

Festen, E. A. M.; Goyette, P.; Scott, R.; Annese, V.; Zhernakova, A.; Lian, J.; Lefèbvre, C.; Brant, S. R.; Cho, J. H.; Silverberg, M. S.; Taylor, K. D.; de Jong, D. J.; Stokkers, P. C.; Mcgovern, D.; Palmieri, O.; Achkar, J.-P.; Xavier, R. J.; Daly, M. J.; Duerr, R. H.; Wijmenga, C.; Weersma, R. K.; Rioux, J. D.

2009-01-01

Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBDs) known as Crohn's disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in coeliac disease, type 1

Mutual enhancement of IL-2 and IL-7 on DNA vaccine immunogenicity mainly involves regulations on their receptor expression and receptor-expressing lymphocyte generation.

Science.gov (United States)

Zhang, Yonghong; Liang, Shuang; Li, Xiujin; Wang, Liyue; Zhang, Jianlou; Xu, Jian; Huo, Shanshan; Cao, Xuebin; Zhong, Zhenyu; Zhong, Fei

2015-07-09

Our previous study showed that IL-2 and IL-7 could mutually enhance the immunogenicity of canine parvovirus VP2 DNA vaccine, although the underlying mechanism remained unknown. Here, we used the OVA gene as a DNA vaccine in a mouse model to test their enhancement on DNA vaccine immunogenicity and to explore the molecular mechanism. Results showed that both IL-2 and IL-7 genes significantly increased the immunogenicity of OVA DNA vaccine in mice. Co-administration of IL-2 and IL-7 genes with OVA DNA significantly increased OVA-specific antibody titers, T cell proliferation and IFN-γ production compared with IL-2 or IL-7 alone, confirming that IL-2 and IL-7 mutually enhanced DNA vaccine immunogenicity. Mechanistically, we have shown that IL-2 significantly stimulated generation of IL-7 receptor-expressing lymphocytes, and that IL-7 significantly induced IL-2 receptor expression. These results contribute to an explanation of the mechanism of the mutual effects of IL-2 and IL-7 on enhancing DNA vaccine immunogenicity and provided a basis for further investigation on their mutual effects on adjuvant activity and immune regulation. Copyright © 2015 Elsevier Ltd. All rights reserved.

High IL-17E and Low IL-17C Dermal Expression Identifies a Fibrosis-Specific Motif Common to Morphea and Systemic Sclerosis

OpenAIRE

Lonati, Paola Adele; Brembilla, Nicolò Costantino; Montanari, Elisa; Fontao, Lionel; Gabrielli, Armando; Vettori, Serena; Valentini, Gabriele; Laffitte, Emmanuel; Kaya, Gurkan; Meroni, Pier-Luigi; Chizzolini, Carlo

2014-01-01

BACKGROUND: High interleukin (IL)-17A levels are characteristically found in the skin of systemic sclerosis (SSc) individuals. Our aim was to investigate whether the dermal expression of IL-17A and related IL-17 family members (i.e. IL-17C, IL-17E and IL-17F) could distinguish fibrotic from healthy skin and could show similarities in SSc and morphea, two disorders with presumed distinct pathogenesis, but characterized by skin fibrosis. METHODS: Biopsies were obtained from the involved skin of...

EFFECTS OF γс-CYTOKINES (IL-2, IL-7 AND IL-15 UPON IN VITRO MATURATION AND DIFFERENTIATION OF CD4+CD45RО+/CD8+CD45RО+ T CELLS

Directory of Open Access Journals (Sweden)

K. A. Yurova

2018-01-01

Full Text Available Effect of γс-cytokines (IL-2, IL-7 и IL-15 upon maturation and differentiation of cytotoxic and helper CD45RО+ Tcell population was studied in the homeostatic in vitro culture conditions. We have found that IL-2, IL-7 and IL-15 mediate maturation and differentiation of CD8 T cells central memory, replenishing the population of cells that exhibit effector functions. Action of IL-2 on CD4+ central memory T cells is accociated with generation of effector memory cells by reducing the number of immature effectors (CD62L–CD27+, whereas IL-7 promotes the formation of immature (CD62L–CD27+ effectors. IL-2, IL-7 and IL-15 initiate formation of terminally-differentiated cells in a subpopulation of CD8+CD45RO+ lymphocytes, providing a stable immunological memory to a pathogen reinfestation. 

EFFECTS OF γс-CYTOKINES (IL-2, IL-7 AND IL-15 UPON IN VITRO MATURATION AND DIFFERENTIATION OF CD4+CD45RО+/CD8+CD45RО+ T CELLS

Directory of Open Access Journals (Sweden)

K. A. Yurova

2018-01-01

Full Text Available Effect of γс-cytokines (IL-2, IL-7 и IL-15 upon maturation and differentiation of cytotoxic and helper CD45RО+ Tcell population was studied in the homeostatic in vitro culture conditions. We have found that IL-2, IL-7 and IL-15 mediate maturation and differentiation of CD8 T cells central memory, replenishing the population of cells that exhibit effector functions. Action of IL-2 on CD4+ central memory T cells is accociated with generation of effector memory cells by reducing the number of immature effectors (CD62L–CD27+, whereas IL-7 promotes the formation of immature (CD62L–CD27+ effectors. IL-2, IL-7 and IL-15 initiate formation of terminally-differentiated cells in a subpopulation of CD8+CD45RO+ lymphocytes, providing a stable immunological memory to a pathogen reinfestation.

Clinical significance of changes of serum IL-2, IL-6 and gastrin levels before and after treatment in patients with chronic eczema

International Nuclear Information System (INIS)

Mou Xudong; Ren Hong

2009-01-01

Objective: To explore the clinical significance of changes of serum IL-2, IL-6 and gastrin levels after treatment in patients with chronic eczema. Methods: Serum IL-2, IL-6 and gastin were detected with RIA both before and after treatment in 38 patients with chronic eczema and 35 controls. Results: Before treatment, serum IL-2 levels in the patients were significantly lower than those in the controls (P 0.05), however, the IL-2 levels were still significantly lower than those in controls (P>0.05). Conclusion: Serum IL-2, IL-6 and gastrin levels in the patients with chronic eczema were closely related to the severity of the diseases process and could be taken as indicator of treatment efficacy. (authors)

Reflux esophagitis triggered after Helicobacter pylori eradication: a noteworthy demerit of eradication therapy among the Japanese?

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Katsunori eIijima

2015-06-01

Full Text Available In the February 2013 Revision of Insured Medical Treatment, bacterial eradication for all Helicobacter pylori-positive individuals in Japan was covered under the insurance scheme. However, reflux esophagitis is believed to occur in approximately 10% of Japanese patients who undergo eradication therapy. Hence, the risk of reflux esophagitis among such cases should be carefully considered, particularly in the treatment for H. pylori-positive patients who are otherwise healthy. The eradication of Helicobacter pylori in cases of H. pylori-positive gastritis markedly suppresses gastric inflammation, and inhibits gastric mucosal atrophy and its progression to intestinal metaplasia. In a long-term follow-up study (10-20 years, eradication treatment was found to reduce the risk of subsequent gastric cancer. However, the fact that eradication-induced reflux esophagitis could increase the long-term risk of Barrett’s esophagus and esophageal adenocarcinoma should also be considered in the Japanese population. Appropriate treatment with proton pump inhibitors should be taken into consideration for patients undergoing eradication therapy in clinical practice.

Role of periostin, FENO, IL-13, lebrikzumab, other IL-13 antagonist and dual IL-4/IL-13 antagonist in asthma.

Science.gov (United States)

Agrawal, Swati; Townley, Robert G

2014-02-01

Asthma markedly diminishes quality of life due to limited activity, absences from work or school and hospitalizations. Patients with severe asthma which are not controlled despite taking effective therapy are most in need of new treatment approaches. IL-13 was demonstrated as 'central mediator of allergic asthma'. IL-13 has been implicated in the pathogenesis of asthma, idiopathic pulmonary fibrosis and COPD. IL-13 levels in the sputum and bronchial biopsy samples remain elevated in severe asthma despite the use of inhaled and systemic corticosteroids. Thus, IL-13 is a mediator involved in corticosteroid resistance. Periostin enhances profibrotic TGF-β signaling in subepithelial fibrosis associated with asthma. IL-13 induces bronchial epithelial cells to secrete periostin. Periostin may be a biomarker for Th2 induced airway inflammation. Lebrikizumab is a monoclonal antibody against IL-13. Lebrikizumab improved lung function in asthmatics who were symptomatic despite treatment with long acting beta agonist and inhaled corticosteroids and provided benefit in the treatment of severe uncontrolled asthma. Lebrikizumab block IL-13 signaling through the IL-13Rα1/IL-4Rα receptor. There was a larger reduction in FENO in the high periostin subgroup than in the low periostin subgroup (34.4 vs 4.3%). Serum CCL17, CCL13 and total IgE levels decreased in the lebrikizumab group.

Poliovirus Studies during the Endgame of the Polio Eradication Program.

Science.gov (United States)

Arita, Minetaro

2017-01-24

Since the beginning of Global Polio Eradication Initiative in 1988, poliomyelitis cases caused by wild poliovirus (PV) have been drastically reduced, with only 74 cases reported in 2 endemic countries in 2015. The current limited PV transmission suggests that we are in the endgame of the polio eradication program. However, specific challenges have emerged in the endgame, including tight budget, switching of the vaccines, and changes in biorisk management of PV. To overcome these challenges, several PV studies have been implemented in the eradication program. Some of the responses to the emerging challenges in the polio endgame might be valuable in other infectious diseases eradication programs. Here, I will review challenges that confront the polio eradication program and current research to address these challenges.

Tsetse eradication: Zanzibar

International Nuclear Information System (INIS)

2003-01-01

Tsetse flies (Glossina sp.) continue to make livestock production difficult or impossible throughout a very large part of Africa. One of the most promising techniques for eradicating tsetse from certain locations is the environmentally safe Sterile Insect Technique (SIT). In collaboration with the Tanzanian authorities, the Department of Technical Co-operation is sponsoring a programme, with technical support from the Joint FAO/IAEA Division, to eradicate tsetse from Zanzibar using the SIT. (IAEA)

The use of a sequential high dose recombinant interleukin 2 regimen after autologous bone marrow transplantation does not improve the disease free survival of patients with acute leukemia transplanted in first complete remission.

Science.gov (United States)

Blaise, D; Attal, M; Pico, J L; Reiffers, J; Stoppa, A M; Bellanger, C; Molina, L; Nedellec, G; Vernant, J P; Legros, M; Gabus, R; Huguet, F; Brandely, M; Hercend, T; Olive, D; Maraninchi, D

1997-05-01

We report the outcome of 50 consecutive patients with CR1 acute leukemia (AML = 22; ALL = 28) treated with autologous BMT, after cyclophosphamide and TBI, followed with a sequential high dose rIL2 regimen. rIL-2 (RU 49637 from Roussel-Uclaf, Romainville, France) was started after hematological reconstitution an average of 72 +/- 22 days post transplant. The schedule consisted of a continuous infusion over 5 cycles (Cycle 1: 5 days starting on day 1; cycle 2-5: 2 days starting on day 15, 29, 43 and 57). Patients were treated at 4 different dosages (12 (N = 40), 16 (N = 3), 20 (N = 2), 24 (N = 5) x 10(6) IU/m2/day). Toxicities were mainly related to capillary leak syndrome and thrombocytopenia. Patients received an average of 122 +/- 49 10(6) IU/m2. Two patients with AML died from toxicity. rIL-2 infusion was associated with very a high level of immune stimu-lation of both T-cells (P < 0.05) and natural killer (NK) cells (P < 0.05) and associated cytolytic functions (P < 0.05). With a minimal and median follow-up of 21 and 46 months, 3 year leukemia free survival is 41 +/- 6% overall, 39 +/- 10% and 43 +/- 8% for AML and ALL respectively. Relapse probabilities at 3 years are 59 +/- 11% for AML and 57 +/- 8% for ALL. We conclude that this short infusion of rIL-2 over 2 months, resulting in an increased immune stimulation, is not associated with a better leukemic control for patients with acute leukemia transplanted early after reaching first complete remission.

IL-6/IL-12 Cytokine Receptor Shuffling of Extra- and Intracellular Domains Reveals Canonical STAT Activation via Synthetic IL-35 and IL-39 Signaling.

Science.gov (United States)

Floss, D M; Schönberg, M; Franke, M; Horstmeier, F C; Engelowski, E; Schneider, A; Rosenfeldt, E M; Scheller, J

2017-11-09

IL-35 and IL-39 are recently discovered shared members of the IL-6- and IL-12-type cytokine family with immune-suppressive capacity. IL-35 has been reported to induce the formation of four different receptor complexes: gp130:IL-12β2, gp130:gp130, IL-12β2:IL-12β2, and IL-12β2:WSX-1. IL-39 was proposed to form a gp130:IL-23R receptor complex. IL-35, but not IL-39, has been reported to activate non-conventional STAT signaling, depending on the receptor complex and target cell. Analyses of IL-35 and IL-39 are, however, hampered by the lack of biologically active recombinant IL-35 and IL-39 proteins. Therefore, we engineered chimeric cytokine receptors to accomplish synthetic IL-35 and IL- 39 signaling by shuffling the extra- and intracellular domains of IL-6/IL-12-type cytokine receptors, resulting in biological activity for all previously described IL-35 receptor complexes. Moreover, we found that the proposed IL-39 receptor complex is biologically active and discovered two additional biologically active synthetic receptor combinations, gp130/IL-12Rβ1 and IL-23R/IL-12Rβ2. Surprisingly, synthetic IL-35 activation led to more canonical STAT signaling of all receptor complexes. In summary, our receptor shuffling approach highlights an interchangeable, modular domain structure among IL-6- and IL-12-type cytokine receptors and enabled synthetic IL-35 and IL-39 signaling.

Global eradication of measles: Are we poised?

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Raghavendra D Kulkarni

2017-01-01

Full Text Available Measles, a highly infectious viral disease is the next target for eradication following poliovirus. Decades of experience with highly effective vaccination has invigorated us to take on this virus. The task is not only Titanic but is laced with intricate issues. Recently, an outbreak of fever with rash occurred on a tertiary care teaching hospital campus and was confirmed serologically as measles outbreak by IgMELISA. Therefore, we searched the literature related to outbreaks, transmission of the measles virus, age groups involved, vaccination strategies, vaccination failure and epidemiological features of the disease and reviewed the possible reasons for such outbreaks and problems in the global eradication of the virus.

PTEN drives Th17 cell differentiation by preventing IL-2 production.

Science.gov (United States)

Kim, Hyeong Su; Jang, Sung Woong; Lee, Wonyong; Kim, Kiwan; Sohn, Hyogon; Hwang, Soo Seok; Lee, Gap Ryol

2017-11-06

T helper 17 (Th17) cells are a CD4 + T cell subset that produces IL-17A to mediate inflammation and autoimmunity. IL-2 inhibits Th17 cell differentiation. However, the mechanism by which IL-2 is suppressed during Th17 cell differentiation remains unclear. Here, we show that phosphatase and tensin homologue (PTEN) is a key factor that regulates Th17 cell differentiation by suppressing IL-2 production. Th17-specific Pten deletion ( Pten fl/fl Il17a cre ) impairs Th17 cell differentiation in vitro and ameliorated symptoms of experimental autoimmune encephalomyelitis (EAE), a model of Th17-mediated autoimmune disease. Mechanistically, Pten deficiency up-regulates IL-2 and phosphorylation of STAT5, but reduces STAT3 phosphorylation, thereby inhibiting Th17 cell differentiation. PTEN inhibitors block Th17 cell differentiation in vitro and in the EAE model. Thus, PTEN plays a key role in Th17 cell differentiation by blocking IL-2 expression. © 2017 Kim et al.

Resistance of polio to its eradication in Pakistan

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Sher Zunaira

2011-10-01

Full Text Available Abstract Background This study is based on EPI (Expanded Program on Immunization immunization surveys and surveillance of polio, its challenges in immunization and the way forward to overcome these challenges. Methods Several Government documents, survey reports and unpublished program documents were studied and online search was made to find information on EPI Pakistan. SPSS 16 and Microsoft Excel 2007 were used for the statistical analysis. Results Immunization against polio is higher in urban areas as compared to rural areas. Marked variation in vaccination has been observed in different provinces of Pakistan in the last decade. Secondly 10-20% of the children who have received their first dose of trivalent polio vaccine were deprived of their 2nd and 3rd dose because of poor performance of EPI and Lack of information about immunization. Conclusion In spite of numerous successes, such as the addition of new vaccines and raising immunization to over 100% in some areas, EPI is still struggling to reach its polio eradication goals. Inadequate service delivery, lack of information about immunization and limited number of vaccinators were found to be the key reason for poor performance of immunization and for large number of cases reported each year due to the deficiency of second and third booster dose.

Chemoresistance of human monocyte-derived dendritic cells is regulated by IL-17A.

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Selma Olsson Åkefeldt

Full Text Available Dendritic cells initiate adaptive immune responses, leading either to control cancer by effector T cells or to exacerbate cancer by regulatory T cells that inhibit IFN-γ-mediated Th1-type response. Dendritic cells can also induce Th17-type immunity, mediated by IL-17A. However, the controversial role of this cytokine in cancer requires further investigations. We generated dendritic cells from peripheral blood monocytes to investigate lifespan, phenotype and chemoresistance of dendritic cells, treated with IL-17A with or without IFN-γ. Studying the expression of Bcl-2 family members, we demonstrated that dendritic cells constitutively express one pro-survival Bcl-2 member: MCL1. Immature dendritic cells were CD40(lowHLADR(low CD1a(+ MCL1(+, did not express CD14, CD68 or BCL2A1, and displayed a short 2-day lifespan. IL-17A-treated DC exhibited a semi-mature (CD40(high HLADR(low pre-M2 (CCL22(+ CD206(+ CD163(+ IL1RN(+ IL-10(- CXCL10(- IL-12(- mixed (CD1a(+ CD14+ CD68(+ macrophage-dendritic cell phenotype. They efficiently exerted mannose receptor-mediated endocytosis and did not produce superoxide anions, in the absence of TLR engagement. Interestingly, IL-17A promoted a long-term survival of dendritic cells, beyond 12 days, that correlated to BCL2A1 induction, a pro-survival Bcl-2 family member. BCL2A1 transcription was activated by NF-κB, downstream of IL-17A transduction. Thus, immature dendritic cells only express MCL1, whereas IL-17A-treated dendritic cells concomitantly expressed two pro-survival Bcl-2 family members: MCL1 and BCL2A1. These latter developed chemoresistance to 11 of the 17 chemotherapy agents tested. However, high doses of either vinblastine or cytarabine decreased MCL1 expression and induced dendritic cell death. When IL-17A is produced in vivo, administration of anti-IL-17A biotherapy may impair dendritic cell survival by targeting BCL2A1 expression. Consequently, depending on the effector or regulatory role of dendritic

Eradication of poliomyelitis in South Africa

African Journals Online (AJOL)

An international campaign under the leadership of the. World Health Organisation is underway to eradicate polio from the world by the year 2000. South Africa may already be free of polio. However, to ensure eradication we need to move from a polio control programme to a polio eradication programme. This necessitates ...

Expression level and clinical significance of IL-2, IL-6 and TGF-β in elderly patients with goiter and hyperthyroidism.

Science.gov (United States)

Lv, L-F; Jia, H-Y; Zhang, H-F; Hu, Y-X

2017-10-01

To investigate the level of expression and the clinical significance of IL-2 (interleukin-2), IL-6 (interleukin-6) and TGF-β (transforming growth factor-β) in elderly patients with goiter and hyperthyroidism. Gender, age, course of disease, BMI (Body Mass Index), serum FT3 (Free triiodothyronine-3), FT4 (Free triiodothyronine-4), TT3 (Total triiodothyronine-3), TT4 (Total triiodothyronine-4), TSH (Thyroid Stimulating Hormone) and clinical manifestations on admission and other general clinical data and laboratory examination results were collected and statistically analyzed as case group in 128 elderly patients with goiter and hyperthyroidism. Additional 128 over 60-year-old patients with hyperthyroidism were selected as control group. The thyroid tissue of these patients and the control group were examined by fine needle aspiration biopsy. The expressions of IL-2, IL-6, TGF-β of the thyroid tissue in all patients were detected by immunohistochemistry, qRT-PCR (Real-time Quantitative Polymerase Chain Reaction) and Western blot method respectively, and the statistical analysis was carried out. p hyperthyroidism and thyroid enlargement (p hyperthyroidism, and symptoms of exophthalmos, the level of expression of IL-6 was significantly higher than that of patients without exophthalmos (p hyperthyroidism and symptoms of exophthalmos, and the patients with goiter, hyperthyroidism without symptoms of exophthalmos, IL-2 and TGF-β expression level were not different (p > 0.05). The expression levels of IL-2, IL-6, and TGF-β were significantly increased in the patients with senile goiter and hyperthyroidism, but in the senile patients with goiter, hyperthyroidism and exophthalmos symptoms, IL-6 levels were significantly higher than those without exophthalmos. The use of IL-2, IL-6, and TGF-β is of great significance in the diagnosis of goiter with hyperthyroidism, especially for elderly patients with atypical clinical symptoms of hyperthyroidism.

Structure and Mechanism of Receptoe Sharing by the IL-10R2 Common Chain

Energy Technology Data Exchange (ETDEWEB)

Yoon, Sung-il; Jones, Brandi C.; Logsdon, Naomi J.; Harris, Bethany D.; Deshpande, Ashlesha; Radaeva, Svetlana; Halloran, Brian A.; Gao, Bin; Walter, Mark R. (NIH); (UAB)

2010-06-14

IL-10R2 is a shared cell surface receptor required for the activation of five class 2 cytokines (IL-10, IL-22, IL-26, IL-28, and IL-29) that play critical roles in host defense. To define the molecular mechanisms that regulate its promiscuous binding, we have determined the crystal structure of the IL-10R2 ectodomain at 2.14 {angstrom} resolution. IL-10R2 residues required for binding were identified by alanine scanning and used to derive computational models of IL-10/IL-10R1/IL-10R2 and IL-22/IL-22R1/IL-10R2 ternary complexes. The models reveal a conserved binding epitope that is surrounded by two clefts that accommodate the structural and chemical diversity of the cytokines. These results provide a structural framework for interpreting IL-10R2 single nucleotide polymorphisms associated with human disease.

Structure and Mechanism of Receptor Sharing by the IL-10R2 Common Chain

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Yoon, Sung-il; Jones, Brandi C.; Logsdon, Naomi J.; Harris, Bethany D.; Deshpande, Ashlesha; Radaeva, Svetlana; Halloran, Brian A.; Gao, Bin; Walter, Mark R. (NIH); (UAB)

2010-07-19

IL-10R2 is a shared cell surface receptor required for the activation of five class 2 cytokines (IL-10, IL-22, IL-26, IL-28, and IL-29) that play critical roles in host defense. To define the molecular mechanisms that regulate its promiscuous binding, we have determined the crystal structure of the IL-10R2 ectodomain at 2.14 {angstrom} resolution. IL-10R2 residues required for binding were identified by alanine scanning and used to derive computational models of IL-10/IL-10R1/IL-10R2 and IL-22/IL-22R1/IL-10R2 ternary complexes. The models reveal a conserved binding epitope that is surrounded by two clefts that accommodate the structural and chemical diversity of the cytokines. These results provide a structural framework for interpreting IL-10R2 single nucleotide polymorphisms associated with human disease.

Ketamine, as adjuvant analgesics for patients with refractory cancer pain, does affect IL-2/IFN-γ expression of T cells in vitro?: A prospective, randomized, double-blind study.

Science.gov (United States)

Zhou, Naibao; Fu, Zhijian; Li, Hao; Wang, Kaiguo

2017-04-01

Ketamine has been used as an analgesic adjuvant with morphine in the treatment of refractory cancer pain recently. But both morphine and ketamine have been reported to produce a number of immunomodulatory effects. The current study was performed to assess whether the concentration of ketamine, as adjuvant analgesics for patient with refractory cancer pain, was related to its effect on T cells interleukin-2 (IL-2)/interferon-γ (IFN-γ) expression in vitro. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood of patients with refractory cancer pain over a Ficoll-Hypaque density gradient. T cells were isolated from by positive selection using anti-CD3 beads. T cells were then treated with vehicle (C group), morphine (200 ng/mL, M group), morphine (200 ng/mL), and different dose of ketamine (100, 200, 1000 ng/mL; MK1, MK5, MK10 group) for 24 hours before stimulation with anti-CD3 and anti-CD28. Then supernatant IL-2 and IFN-γ protein analysis, quantitative reverse transcription polymerase chain reaction (RT-PCR) for IL-2 and IFN-γ were done. There were no significant difference of supernatant IL-2 and IFN-γ among C group, M group, and MK1 group, but the mRNA of M group and MK1 group were decreased compared with C group (P ketamine dose-dependently suppressed IL-2 and IFN-γ of activated T lymphocyte of patients with refractory cancer pain in vitro, but the inhibitory action of low dose ketamine could be neglected.

Developing strategies for HIV-1 eradication

Science.gov (United States)

Durand, Christine M.; Blankson, Joel N.; Siliciano, Robert F.

2014-01-01

Highly active antiretroviral therapy (HAART) suppresses HIV-1 replication, transforming the outlook for infected patients. However, reservoirs of replication-competent forms of the virus persist during HAART, and when treatment is stopped, high rates of HIV-1 replication return. Recent insights into HIV-1 latency, as well as a report that HIV-1 infection was eradicated in one individual, have renewed interest in finding a cure for HIV-1 infection. Strategies for HIV-1 eradication include gene therapy and hematopoietic stem cell transplantation, stimulating host immunity to control HIV-1 replication, and targeting latent HIV-1 in resting memory CD4+ T cells. Future efforts should aim to provide better understanding of how to reconstitute the CD4+ T cell compartment with genetically engineered cells, exert immune control over HIV-1 replication, and identify and eliminate all viral reservoirs. PMID:22867874

Resveratrol prevents endothelial cells injury in high-dose interleukin-2 therapy against melanoma.

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Hongbing Guan

Full Text Available Immunotherapy with high-dose interleukin-2 (HDIL-2 is an effective treatment for patients with metastatic melanoma and renal cell carcinoma. However, it is accompanied by severe toxicity involving endothelial cell injury and induction of vascular leak syndrome (VLS. In this study, we found that resveratrol, a plant polyphenol with anti-inflammatory and anti-cancer properties, was able to prevent the endothelial cell injury and inhibit the development of VLS while improving the efficacy of HDIL-2 therapy in the killing of metastasized melanoma. Specifically, C57BL/6 mice were injected with B16F10 cells followed by resveratrol by gavage the next day and continued treatment with resveratrol once a day. On day 9, mice received HDIL-2. On day 12, mice were evaluated for VLS and tumor metastasis. We found that resveratrol significantly inhibited the development of VLS in lung and liver by protecting endothelial cell integrity and preventing endothelial cells from undergoing apoptosis. The metastasis and growth of the tumor in lung were significantly inhibited by HDIL-2 and HDIL-2 + resveratrol treatment. Notably, HDIL-2 + resveratrol co-treatment was more effective in inhibiting tumor metastasis and growth than HDIL-2 treatment alone. We also analyzed the immune status of Gr-1(+CD11b(+ myeloid-derived suppressor cells (MDSC and FoxP3(+CD4(+ regulatory T cells (Treg. We found that resveratrol induced expansion and suppressive function of MDSC which inhibited the development of VLS after adoptive transfer. However, resveratrol suppressed the HDIL-2-induced expansion of Treg cells. We also found that resveratrol enhanced the susceptibility of melanoma to the cytotoxicity of IL-2-activated killer cells, and induced the expression of the tumor suppressor gene FoxO1. Our results suggested the potential use of resveratrol in HDIL-2 treatment against melanoma. We also demonstrated, for the first time, that MDSC is the dominant suppressor cell than regulatory

IL-6-induced Bcl6 variant 2 supports IL-6-dependent myeloma cell proliferation and survival through STAT3

International Nuclear Information System (INIS)

Tsuyama, Naohiro; Danjoh, Inaho; Otsuyama, Ken-ichiro; Obata, Masanori; Tahara, Hidetoshi; Ohta, Tsutomu; Ishikawa, Hideaki

2005-01-01

IL-6 is a growth and survival factor for myeloma cells, although the mechanism by which it induces myeloma cell proliferation through gene expression is largely unknown. Microarray analysis showed that some B-cell lymphoma-associated oncogenes such as Bcl6, which is absent in normal plasma cells, were upregulated by IL-6 in IL-6-dependent myeloma cell lines. We found that Bcl6 variant 2 was upregulated by STAT3. ChIP assay and EMSA showed that STAT3 bound to the upstream region of variant 2 DNA. Expression of p53, a direct target gene of Bcl6, was downregulated in the IL-6-stimulated cells, and this process was impaired by an HDAC inhibitor. Bcl6 was knocked down by introducing small hairpin RNA, resulting in decreased proliferation and increased sensitivity to a DNA damaging agent. Thus, STAT3-inducible Bcl6 variant 2 appears to generate an important IL-6 signal that supports proliferation and survival of IL-6-dependent myeloma cells

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.

Neonatal plasma polarizes TLR4-mediated cytokine responses towards low IL-12p70 and high IL-10 production via distinct factors.

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Mirjam E Belderbos

Full Text Available Human neonates are highly susceptible to infection, which may be due in part to impaired innate immune function. Neonatal Toll-like receptor (TLR responses are biased against the generation of pro-inflammatory/Th1-polarizing cytokines, yet the underlying mechanisms are incompletely defined. Here, we demonstrate that neonatal plasma polarizes TLR4-mediated cytokine production. When exposed to cord blood plasma, mononuclear cells (MCs produced significantly lower TLR4-mediated IL-12p70 and higher IL-10 compared to MC exposed to adult plasma. Suppression by neonatal plasma of TLR4-mediated IL-12p70 production, but not induction of TLR4-mediated IL-10 production, was maintained up to the age of 1 month. Cord blood plasma conferred a similar pattern of MC cytokine responses to TLR3 and TLR8 agonists, demonstrating activity towards both MyD88-dependent and MyD88-independent agonists. The factor causing increased TLR4-mediated IL-10 production by cord blood plasma was heat-labile, lost after protein depletion and independent of lipoprotein binding protein (LBP or soluble CD14 (sCD14. The factor causing inhibition of TLR4-mediated IL-12p70 production by cord blood plasma was resistant to heat inactivation or protein depletion and was independent of IL-10, vitamin D and prostaglandin E2. In conclusion, human neonatal plasma contains at least two distinct factors that suppress TLR4-mediated IL-12p70 production or induce IL-10 or production. Further identification of these factors will provide insight into the ontogeny of innate immune development and might identify novel targets for the prevention and treatment of neonatal infection.

Neonatal Plasma Polarizes TLR4-Mediated Cytokine Responses towards Low IL-12p70 and High IL-10 Production via Distinct Factors

Science.gov (United States)

Belderbos, Mirjam E.; Levy, Ofer; Stalpers, Femke; Kimpen, Jan L.; Meyaard, Linde; Bont, Louis

2012-01-01

Human neonates are highly susceptible to infection, which may be due in part to impaired innate immune function. Neonatal Toll-like receptor (TLR) responses are biased against the generation of pro-inflammatory/Th1-polarizing cytokines, yet the underlying mechanisms are incompletely defined. Here, we demonstrate that neonatal plasma polarizes TLR4-mediated cytokine production. When exposed to cord blood plasma, mononuclear cells (MCs) produced significantly lower TLR4-mediated IL-12p70 and higher IL-10 compared to MC exposed to adult plasma. Suppression by neonatal plasma of TLR4-mediated IL-12p70 production, but not induction of TLR4-mediated IL-10 production, was maintained up to the age of 1 month. Cord blood plasma conferred a similar pattern of MC cytokine responses to TLR3 and TLR8 agonists, demonstrating activity towards both MyD88-dependent and MyD88-independent agonists. The factor causing increased TLR4-mediated IL-10 production by cord blood plasma was heat-labile, lost after protein depletion and independent of lipoprotein binding protein (LBP) or soluble CD14 (sCD14). The factor causing inhibition of TLR4-mediated IL-12p70 production by cord blood plasma was resistant to heat inactivation or protein depletion and was independent of IL-10, vitamin D and prostaglandin E2. In conclusion, human neonatal plasma contains at least two distinct factors that suppress TLR4-mediated IL-12p70 production or induce IL-10 or production. Further identification of these factors will provide insight into the ontogeny of innate immune development and might identify novel targets for the prevention and treatment of neonatal infection. PMID:22442690

Changes of serum levels of some relevant cytokine (IL-2, IL-6, TNF-α) after antithyroid treatment in patients with graves' disease

International Nuclear Information System (INIS)

Ren Xiaohua; Jiang Boyong

2010-01-01

Objective: To study the effect of antithyroid treatment on the changes of serum levels of IL-2, IL-6 and TNF-α in patients with Graves' disease. Methods: Serum levels of IL-2, IL-6 and TNF-α were measured with RIA in 30 patients with Graves' disease (both before and after treatment with antithyroid drug) and 30 controls. Results: Before treatment serum levels of IL-6 and TNF-α in the patients were significantly higher than those in controls (P 0.05). Conclusion: Changes of serum IL-2, IL-6 and TNF-α levels might be important in the pathogenesis of Graves' disease. (authors)

Leprosy: eradication or cure?

Science.gov (United States)

Kakar, S

1995-01-01

The National Leprosy Eradication Program (NLEP), launched in 1986, has brought medicine for leprosy to more people than ever before, covering 200 of India's 455 districts. Since 1988, the number of leprosy patients discharged as cured each year has been greater than the number of newly detected, thus moving the country closer to its goal of eradicating leprosy from India. A substantial number of the 3 million people with leprosy in India are likely to come under the coverage of the NLEP. The author, however, argues that the fight against leprosy and the NLEP should be considered in their historical context. Leprosy is therefore used to illustrate how the perhaps interchangeable terms eradication and cure are charged with history and custom. Historically, the focus on eradicating leprosy has had terrible consequences for the patient. In England, perceptions about leprosy are relevant to the situation India, for colonial policy on leprosy was largely derivative. In the 1880s, especially, leprosy excited the public imagination. Asylums adopted segregation and confinement during this period for people with leprosy and the colonial government in India supported that approach from 1882. The author concludes that while the NLEP is laudable, the program must not focus upon eradicating leprosy. It should instead focus upon the leprosy patient, who has for so long been denied and discriminated against. The individual must be placed at the center of any program. Some steps in this direction have been taken.

Thymosin alpha 1 (Ta-1) induction of spleen cell proliferation and production of interleukin 2 (IL2) after irradiation-induced depression of systematic cellular immunity (SCI)

International Nuclear Information System (INIS)

Gray, W.C.; Revie, D.R.; Oliver, J.H.; Hasslinger, B.J.; Suter, C.M.; Blanchard, C.L.; Goldstein, A.L.; Chretien, P.B.

1986-01-01

To assess the effects of Ta-1 on recovery from irradiation induced depression of SCI, C3H mice were given 400 rads (240kV) on each of 3 alternate days via head, chest and pelvic portals and assays performed 2 days after the last exposure. Compared with shams, total spleen cell counts and production of IL2, total peripheral blood lymphocyte and T-cell levels, and delayed type hypersensitivity to oxazolone (DTH-O) were all similarly depressed in the three portal groups (p < .0001). Following optimum doses of Ta-1, administered daily starting with the first day of irradiation, DTH-O in the head and chest groups was restored, but in the pelvic group was only partially corrected. Changes in total spleen cell counts and IL2 production paralleled and covaried with DTH-O (p < .0001). The results offer IL2 induced lymphocyte proliferation as a reparative mechanism after radiation-induced depression of SCI. The incomplete restoration of SCI in the pelvic group suggests that generation of IL2-producing spleen cells by Ta-1 requires pelvic and other bone marrow lymphocyte precursors

Influence of vitamin C and E supplementation on the eradication rates of triple and quadruple eradication regimens for Helicobacter pylori infection.

Science.gov (United States)

Demirci, Hakan; Uygun İlikhan, Sevil; Öztürk, Kadir; Üstündağ, Yücel; Kurt, Ömer; Bilici, Muammer; Köktürk, Furuzan; Uygun, Ahmet

2015-11-01

In our study, we aimed to assess the effect of vitamin E and C supplementation to triple and quadruple Helicobacter pylori eradication regimens. Four hundred patients with H. pylori infection were classified into four groups. Patients in group A (n=100) received amoxicillin, clarithromycin, and lansoprazole for 2 weeks. In group B, patients (n=100) received vitamins C and E for a month, in addition to amoxicillin, clarithromycin, and lansoprazole for 2 weeks. Patients in group C (n=100) received amoxicillin, clarithromycin, lansoprazole, and bismuth subcitrate for 2 weeks, whereas those in group D (n=100) received vitamins C and E for a month, in addition to amoxicillin, clarithromycin, lansoprazole, and bismuth subcitrate for 2 weeks. H. pylori eradication was assessed with the C14 urea breath test 2 months after the end of the therapy. The eradication rate was assessed using per-protocol (PP) and intention-to-treat (ITT) analyses. Three hundred forty-eight patients finished the study. The eradication of H. pylori was achieved in 63 of 84 patients (75%) by PP and 63 of 100 (63%) by ITT analysis in group A, 60 of 84 (71.4%) by PP and 60 of 100 (60%) by ITT analysis in group B, 72 of 89 (80.9 %) by PP and 72 of 100 (72%) by ITT analysis in group C, and 76 of 91 (83.5%) by PP and 76 of 100 (76%) by ITT analysis in group D. There was no remarkable change between groups A and B (p>0.05). Similar results were also found between groups D and C (p>0.05). This study revealed that supplementing vitamins C and E to either the triple or quadruple therapies did not provide an additional advantage for achieving significantly higher eradication rates for H. pylori.

Autocrine Regulation of UVA-Induced IL-6 Production via Release of ATP and Activation of P2Y Receptors

Science.gov (United States)

Kawano, Ayumi; Kadomatsu, Remi; Ono, Miyu; Kojima, Shuji; Tsukimoto, Mitsutoshi; Sakamoto, Hikaru

2015-01-01

Extracellular nucleotides, such as ATP, are released from cells in response to various stimuli and act as intercellular signaling molecules through activation of P2 receptors. Exposure to the ultraviolet radiation A (UVA) component of sunlight causes molecular and cellular damage, and in this study, we investigated the involvement of extracellular nucleotides and P2 receptors in the UVA-induced cellular response. Human keratinocyte-derived HaCaT cells were irradiated with a single dose of UVA (2.5 J/cm2), and ATP release and interleukin (IL)-6 production were measured. ATP was released from cells in response to UVA irradiation, and the release was blocked by pretreatment with inhibitors of gap junction hemichannels or P2X7 receptor antagonist. IL-6 production was increased after UVA irradiation, and this increase was inhibited by ecto-nucleotidase or by antagonists of P2Y11 or P2Y13 receptor. These results suggest that UVA-induced IL-6 production is mediated by release of ATP through hemichannels and P2X7 receptor, followed by activation of P2Y11 and P2Y13 receptors. Interestingly, P2Y11 and P2Y13 were associated with the same pattern of IL-6 production, though they trigger different intracellular signaling cascades: Ca2+-dependent and PI3K-dependent, respectively. Thus, IL-6 production in response to UVA-induced ATP release involves at least two distinct pathways, mediated by activation of P2Y11 and P2Y13 receptors. PMID:26030257

Grain dust induces IL-8 production from bronchial epithelial cells: the effect of dexamethasone on IL-8 production.

Science.gov (United States)

Park, H S; Suh, J H; Kim, H Y; Kwon, O J; Choi, D C

1999-04-01

Recent publications have suggested an active participation of neutrophils to induce bronchoconstriction after inhalation of grain dust (GD). To further understand the role of neutrophils in the pathogenesis of GD-induced asthma, this investigation was designed to determine whether human bronchial epithelial cells could produce IL-8 production and to observe the effect of dexamethasone on IL-8 production. We cultured Beas-2B, a bronchial epithelial cell line. To observe GD-induced responses, four concentrations (1 to 200 microg/mL) of GD were incubated for 24 hours and compared with those without incubation of GD. To evaluate the effect of pro-inflammatory cytokines on IL-8 production, epithelial cells were incubated with peripheral blood mononuclear cell (PBMC) culture supernatant, which was derived from the culture of PBMC from a GD-induced asthmatic subject under the exposure to 10 microg/mL of GD, and compared with those cultured without addition of PBMC supernatant. The level of released IL-8 in the supernatant was measured by enzyme-linked immunosorbent assay. To evaluate the effect of dexamethasone on IL-8 production, four concentrations (5 to 5000 ng/mL) of dexamethasone were pre-incubated for 24 hours and the same experiments were repeated. There was significant production of IL-8 from bronchial epithelial cells with additions of GD in a dose-dependent manner (P < .05), which was significantly augmented with additions of PBMC supernatant (P < .05) at each concentration. Compared with the untreated sample, pretreatment of dexamethasone could induced a remarkable inhibitions (15% to 55%) of IL-8 production from bronchial epithelial cells in a dose-dependent manner. These results suggest that IL-8 production from bronchial epithelial cells may contribute to neutrophil recruitment occurring in GD-induced airway inflammation. The downregulation of IL-8 production by dexamethasone from bronchial epithelial cells may contribute to the efficacy of this compound in

Membrane-bound IL-12 and IL-23 serve as potent mucosal adjuvants when co-presented on whole inactivated influenza vaccines.

Science.gov (United States)

Khan, Tila; Heffron, Connie L; High, Kevin P; Roberts, Paul C

2014-05-03

Potent and safe adjuvants are needed to improve the efficacy of parenteral and mucosal vaccines. Cytokines, chemokines and growth factors have all proven to be effective immunomodulatory adjuvants when administered with a variety of antigens. We have previously evaluated the efficacy of membrane-anchored interleukins (IL) such as IL-2 and IL-4 co-presented as Cytokine-bearing Influenza Vaccines (CYT-IVACs) using a mouse model of influenza challenge. Here, we describe studies evaluating the parenteral and mucosal adjuvanticity of membrane-bound IL-12 and IL-23 CYT-IVACs in young adult mice. Mucosal immunization using IL-12 and IL-23 bearing whole influenza virus vaccine (WIV) was more effective at eliciting virus-specific nasal IgA and reducing viral lung burden following challenge compared to control WIV vaccinated animals. Both IL-12 and IL-23 bearing WIV elicited the highest anti-viral IgA levels in serum and nasal washes. This study highlights for the first time the mucosal adjuvant potential of IL-12 and IL-23 CYT-IVAC formulations in eliciting mucosal immune responses and reducing viral lung burden. The co-presentation of immunomodulators in direct context with viral antigen in whole inactivated viral vaccines may provide a means to significantly lower the dose of vaccine required for protection.

Floating-bioadhesive gastroretentive Caesalpinia pulcherrima-based beads of amoxicillin trihydrate for Helicobacter pylori eradication.

Science.gov (United States)

Thombre, Nilima A; Gide, Paraag S

2016-01-01

An oral dosage form containing floating bioadhesive gastroretentive microspheres forms a stomach-specific drug delivery system for the treatment of Helicobacter pylori. To prepare and evaluate controlled release floating bioadhesive gastroretentive chitosan-coated amoxicillin trihydrate-loaded Caesalpinia pulcherrima galactomannan (CPG)-alginate beads (CCA-CPG-A), for H. pylori eradication. CCA-CPG-A beads were prepared by ionotropic gelation, using 2(3) factorial design with quantity of drug, combination of CPG with sodium alginate and concentration of calcium chloride as variables. Beads facilitated mucoadhesion to gastric mucosa with floating nature caused by chitosan coating for wide distribution throughout GIT. Developed beads were evaluated for characteristics like beads size-morphology, entrapment efficiency, DSC, XRD, FTIR, swelling ratio, in vitro mucoadhesion, in vitro drug release, in vitro floating and in vitro H. pylori growth inhibition studies. CCA-CPG-A beads were studied in Wistar rats for in vivo gastric mucoadhesion, in vivo H. pylori growth inhibition studies using PCR amplification of isolated DNA, rapid urease test. Developed beads possess drug release of 79-92%, entrapment efficiency of 65-89%, mucoadhesion of 61-89%. In vivo mucoadhesion study showed more than 85% mucoadhesion of beads even after 7th hour. In vitro-in vivo growth inhibition study showed complete eradication of H. pylori. CPG-alginate and chitosan in beads interacts with gastric mucosubstrate surface for prolonged gastric residence with floating bioadhesion mechanism for H. pylori eradication in rats. Floating bioadhesive CCA-CPG-A beads offer a promising drug delivery system for H. pylori eradication at lower dose, reduced adverse effect and enhance bioavailability.

Eradicative brachytherapy with hyaluronate gel injection into pararectal space in treatment of bulky vaginal stump recurrence of uterine cancer

International Nuclear Information System (INIS)

Kishi, Kazushi; Mabuchi, Yasushi; Sonomura, Tetsuo; Shirai, Shintaro; Noda, Yasutaka; Sato, Morio; Ino, Kazuhiko

2012-01-01

The purpose of this study is to develop a procedure for eradicative brachytherapy that can deliver a curative boost dose to bulky (>4 cm) vaginal stump recurrence of uterine cancer without risk of damaging surrounding organs. We separated risk organs (the rectum and sigmoid) from the target during brachytherapy, with a hyaluronate gel injection into the pararectal space via the percutaneous paraperineal approach under local anesthesia. The rectum anchored to the sacrum by native ligament was expected to shift posteriorly. We encountered a patient with bulky stump recurrence of uterine cancer, approximately 8 cm in maximum diameter. She was complaining of abdominal pain and constipation due to bowel encasement. Following 50 Gy of external beam radiotherapy, we applied a single fraction of brachytherapy under gel separation and delivered 14.5 Gy (50.8 GyE: equivalent dose in 2-Gy fraction calculated with linear quadratic model at α/β=3) to the target. The gel injection procedure was completed in 30 min without complications. A total irradiation dose of 100.8 GyE was delivered to the target and the cumulative minimum dose to the most irradiated rectosigmoidal volume of 2 cc (cumulative D 2cc ) was calculated as 58.5 GyE with gel injection, and was estimated to be 96 GyE without. Over three years, the local stump tumor has completely disappeared, with no complications. Brachytherapy with a pararectal gel injection can be a safe and effective eradicative option for bulky vaginal stump recurrence. (author)

LPS-induced release of IL-6 from glia modulates production of IL-1beta in a JAK2-dependent manner

LENUS (Irish Health Repository)

Minogue, Aedín M

2012-06-14

AbstractBackgroundCompelling evidence has implicated neuroinflammation in the pathogenesis of a number of neurodegenerative conditions. Chronic activation of both astrocytes and microglia leads to excessive secretion of proinflammatory molecules such as TNFα, IL-6 and IL-1β with potentially deleterious consequences for neuronal viability. Many signaling pathways involving the mitogen-activated protein kinases (MAPKs), nuclear factor κB (NFκB) complex and the Janus kinases (JAKs)\\/signal transducers and activators of transcription (STAT)-1 have been implicated in the secretion of proinflammatory cytokines from glia. We sought to identify signaling kinases responsible for cytokine production and to delineate the complex interactions which govern time-related responses to lipopolysaccharide (LPS).MethodsWe examined the time-related changes in certain signaling events and the release of proinflammatory cytokines from LPS-stimulated co-cultures of astrocytes and microglia isolated from neonatal rats.ResultsTNFα was detected in the supernatant approximately 1 to 2 hours after LPS treatment while IL-1β and IL-6 were detected after 2 to 3 and 4 to 6 hours, respectively. Interestingly, activation of NFκB signaling preceded release of all cytokines while phosphorylation of STAT1 was evident only after 2 hours, indicating that activation of JAK\\/STAT may be important in the up-regulation of IL-6 production. Additionally, incubation of glia with TNFα induced both phosphorylation of JAK2 and STAT1 and the interaction of JAK2 with the TNFα receptor (TNFR1). Co-treatment of glia with LPS and recombinant IL-6 protein attenuated the LPS-induced release of both TNFα and IL-1β while potentiating the effect of LPS on suppressor of cytokine signaling (SOCS)3 expression and IL-10 release.ConclusionsThese data indicate that TNFα may regulate IL-6 production through activation of JAK\\/STAT signaling and that the subsequent production of IL-6 may impact on the release of

Synergy between Common γ Chain Family Cytokines and IL-18 Potentiates Innate and Adaptive Pathways of NK Cell Activation.

Science.gov (United States)

Nielsen, Carolyn M; Wolf, Asia-Sophia; Goodier, Martin R; Riley, Eleanor M

2016-01-01

Studies to develop cell-based therapies for cancer and other diseases have consistently shown that purified human natural killer (NK) cells secrete cytokines and kill target cells after in vitro culture with high concentrations of cytokines. However, these assays poorly reflect the conditions that are likely to prevail in vivo in the early stages of an infection and have been carried out in a wide variety of experimental systems, which has led to contradictions within the literature. We have conducted a detailed kinetic and dose-response analysis of human NK cell responses to low concentrations of IL-12, IL-15, IL-18, IL-21, and IFN-α, alone and in combination, and their potential to synergize with IL-2. We find that very low concentrations of both innate and adaptive common γ chain cytokines synergize with equally low concentrations of IL-18 to drive rapid and potent NK cell CD25 and IFN-γ expression; IL-18 and IL-2 reciprocally sustain CD25 and IL-18Rα expression in a positive feedback loop; and IL-18 synergizes with FcγRIII (CD16) signaling to augment antibody-dependent cellular cytotoxicity. These data indicate that NK cells can be rapidly activated by very low doses of innate cytokines and that the common γ chain cytokines have overlapping but distinct functions in combination with IL-18. Importantly, synergy between multiple signaling pathways leading to rapid NK cell activation at very low cytokine concentrations has been overlooked in prior studies focusing on single cytokines or simple combinations. Moreover, although the precise common γ chain cytokines available during primary and secondary infections may differ, their synergy with both IL-18 and antigen-antibody immune complexes underscores their contribution to NK cell activation during innate and adaptive responses. IL-18 signaling potentiates NK cell effector function during innate and adaptive immune responses by synergy with IL-2, IL-15, and IL-21 and immune complexes.

Role of IL-1beta in type 2 diabetes

DEFF Research Database (Denmark)

Dinarello, Charles A; Donath, Marc Y; Mandrup-Poulsen, Thomas

2010-01-01

To understand the role of inflammation as the fundamental cause of type 2 diabetes and specifically to examine the contribution of IL-1beta.......To understand the role of inflammation as the fundamental cause of type 2 diabetes and specifically to examine the contribution of IL-1beta....

Helicobacter pylori eradication in complicated peptic ulcer: Beneficial in most?

Directory of Open Access Journals (Sweden)

Subair Mohsina

2016-01-01

Full Text Available Helicobacter pylori eradication therapy has a role in minimizing the complications of peptic ulcer disease, namely, bleeding, perforation, and obstruction. However, the precise role of H. pylori eradication therapy in the complicated ulcers remains inconclusive, especially in perforation and gastric outlet obstruction. The prevalence of H. pylori in peptic ulcer bleeding patients has been widely underestimated owing to the differences in diagnostic tests and patient characteristics, and hence, it is recommended that an initial negative test should be followed up by a delayed repeat testing to rule out false negativity. It is well established now that eradication of H. pylori in patients with bleeding ulcers reduces rebleeding and ulcer recurrence. Multiple studies have attributed high recurrence rates of duodenal ulcer following simple closure to a high prevalence of H. pylori infection. Eradication therapy decreases the recurrence rate of perforated ulcers, thus justifying the role of H. pylori eradication therapy following the primary surgical management of perforated ulcers. The role of H. pylori in duodenal ulcer with gastric outlet obstruction is yet to be evaluated clearly. There are some reports of resolution of gastric outlet obstruction following therapy for H. pylori, obviating the need for surgery. Clarithromycin-containing regimens are recommended as first-line in areas of low resistance, whereas bismuth-containing quadruple therapy is the first-line empirical treatment in areas of high clarithromycin resistance. Treatment of H. pylori is beneficial in most of the patients with complicated peptic ulcer disease, especially in reducing recurrence of ulcer with or without complications.

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

Directory of Open Access Journals (Sweden)

Aslam Ali Khan

2009-12-01

Full Text Available 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.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.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.

KYNA analogue SZR72 modifies CFA-induced dural inflammation- regarding expression of pERK1/2 and IL-1β in the rat trigeminal ganglion

DEFF Research Database (Denmark)

Lukács, M; Warfvinge, K; Kruse, L S

2016-01-01

modify the neurogenic inflammatory response in the trigeminal ganglion. METHODS: Inflammation in the trigeminal ganglion was induced by local dural application of Complete Freunds Adjuvant (CFA). Levels of phosphorylated MAP kinase pERK1/2 and IL-1β expression in V1 region of the trigeminal ganglion were...... investigated using immunohistochemistry and Western blot. FINDINGS: Pretreatment with one dose of SZR72 abolished the CFA-induced pERK1/2 and IL-1β activation in the trigeminal ganglion. No significant change was noted in case of repeated treatment with SZR72 as compared to a single dose. CONCLUSIONS......: This is the first study that demonstrates that one dose of KYNA analog before application of CFA can give anti-inflammatory response in a model of trigeminal activation, opening a new line for further investigations regarding possible effects of KYNA derivates....

Role of IL-1 beta and 5-HT2 receptors in midbrain periaqueductal gray (PAG) in potentiating defensive rage behavior in cat.

Science.gov (United States)

Bhatt, Suresh; Bhatt, Rekha; Zalcman, Steven S; Siegel, Allan

2008-02-01

Feline defensive rage, a form of aggressive behavior that occurs in response to a threat can be elicited by electrical stimulation of the medial hypothalamus or midbrain periaqueductal gray (PAG). Our laboratory has recently begun a systematic examination of the role of cytokines in the regulation of rage and aggressive behavior. It was shown that the cytokine, interleukin-2 (IL-2), differentially modulates defensive rage when microinjected into the medial hypothalamus and PAG by acting through separate neurotransmitter systems. The present study sought to determine whether a similar relationship exists with respect to interleukin 1-beta (IL-1 beta), whose receptor activation in the medial hypothalamus potentiates defensive rage. Thus, the present study identified the effects of administration of IL-1 beta into the PAG upon defensive rage elicited from the medial hypothalamus. Microinjections of IL-1 beta into the dorsal PAG significantly facilitated defensive rage behavior elicited from the medial hypothalamus in a dose and time dependent manner. In addition, the facilitative effects of IL-1 beta were blocked by pre-treatment with anti-IL-1 beta receptor antibody, while IL-1 beta administration into the PAG had no effect upon predatory attack elicited from the lateral hypothalamus. The findings further demonstrated that IL-1 beta's effects were mediated through 5-HT(2) receptors since pretreatment with a 5-HT(2C) receptors antagonist blocked the facilitating effects of IL-1 beta. An extensive pattern of labeling of IL-1 beta and 5-HT(2C) receptors in the dorsal PAG supported these findings. The present study demonstrates that IL-beta in the dorsal PAG, similar to the medial hypothalamus, potentiates defensive rage behavior and is mediated through a 5-HT(2C) receptor mechanism.

Loss of Dok-1 and Dok-2 in mice causes severe experimental colitis accompanied by reduced expression of IL-17A and IL-22

International Nuclear Information System (INIS)

Waseda, Masazumi; Arimura, Sumimasa; Shimura, Eri; Nakae, Susumu; Yamanashi, Yuji

2016-01-01

Appropriate immune responses and mucosal barrier functions are required for the maintenance of intestinal homeostasis. Defects in this defense system may lead to inflammatory disorders such as inflammatory bowel disease. Downstream of tyrosine kinases 1 (Dok-1) and its closest homolog, Dok-2, are preferentially expressed in immune cells, and play essential roles in the negative regulation of multiple signaling pathways in both innate and adaptive immunity. However, the function of these proteins in intestinal homeostasis remained unclear. Here we show that Dok-1/-2 double knockout (DKO) mice were highly susceptible to dextran sodium sulfate (DSS)-induced colitis compared with Dok-1 or Dok-2 single KO and wild type (WT) mice. Furthermore, DSS-treated Dok-1/-2 DKO mice exhibited increased colonic tissue damage accompanied by reduced proliferation of the epithelial cells relative to WT controls, suggesting that Dok-1/-2 DKO mice have defects in the repair of intestinal epithelial lesions. In addition, the levels of the Th17 cytokines IL-17A and IL-22, which have protective roles in DSS-induced colitis, were reduced in DSS-treated Dok-1/-2 DKO mice compared with WT mice. Taken together, our results demonstrate that Dok-1 and Dok-2 negatively regulate intestinal inflammation, apparently through the induction of IL-17A and IL-22 expression. - Highlights: • Dok-1 and Dok-2 play a cooperative role in protection against DSS-induced colitis. • Dok-1/-2 double KO (DKO) mice show extensive ulceration of the colon after DSS treatment. • Proliferation of colonic epithelium is inhibited in DSS-treated Dok-1/-2 DKO mice. • Expression of IL-17A and IL-22 is reduced in the colon of DSS-treated Dok-1/-2 DKO mice.

Loss of Dok-1 and Dok-2 in mice causes severe experimental colitis accompanied by reduced expression of IL-17A and IL-22

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Waseda, Masazumi; Arimura, Sumimasa [Division of Genetics, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, 108-8639 (Japan); Shimura, Eri [Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, 108-8639 (Japan); Nakae, Susumu [Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, 108-8639 (Japan); Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama, 332-0012 (Japan); Yamanashi, Yuji, E-mail: yyamanas@ims.u-tokyo.ac.jp [Division of Genetics, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, 108-8639 (Japan)

2016-09-09

Appropriate immune responses and mucosal barrier functions are required for the maintenance of intestinal homeostasis. Defects in this defense system may lead to inflammatory disorders such as inflammatory bowel disease. Downstream of tyrosine kinases 1 (Dok-1) and its closest homolog, Dok-2, are preferentially expressed in immune cells, and play essential roles in the negative regulation of multiple signaling pathways in both innate and adaptive immunity. However, the function of these proteins in intestinal homeostasis remained unclear. Here we show that Dok-1/-2 double knockout (DKO) mice were highly susceptible to dextran sodium sulfate (DSS)-induced colitis compared with Dok-1 or Dok-2 single KO and wild type (WT) mice. Furthermore, DSS-treated Dok-1/-2 DKO mice exhibited increased colonic tissue damage accompanied by reduced proliferation of the epithelial cells relative to WT controls, suggesting that Dok-1/-2 DKO mice have defects in the repair of intestinal epithelial lesions. In addition, the levels of the Th17 cytokines IL-17A and IL-22, which have protective roles in DSS-induced colitis, were reduced in DSS-treated Dok-1/-2 DKO mice compared with WT mice. Taken together, our results demonstrate that Dok-1 and Dok-2 negatively regulate intestinal inflammation, apparently through the induction of IL-17A and IL-22 expression. - Highlights: • Dok-1 and Dok-2 play a cooperative role in protection against DSS-induced colitis. • Dok-1/-2 double KO (DKO) mice show extensive ulceration of the colon after DSS treatment. • Proliferation of colonic epithelium is inhibited in DSS-treated Dok-1/-2 DKO mice. • Expression of IL-17A and IL-22 is reduced in the colon of DSS-treated Dok-1/-2 DKO mice.

The combination of IL-21 and IFN-alpha boosts STAT3 activation, cytotoxicity and experimental tumor therapy

DEFF Research Database (Denmark)

Eriksen, Karsten W; Søndergaard, Henrik; Woetmann, Anders

2008-01-01

such as IFN-alpha and IL-2 have multiple and severe side effects. Accordingly, they are generally used at sub-optimal doses, which limit their clinical efficacy. Here we hypothesized that a combination of IFN-alpha and IL-21, a novel cytokine of the IL-2 family with anti-cancer effects, will increase the anti......-cancer efficacy at sub-optimal cytokine doses. We show that the combined stimulation of target-cells with IFN-alpha and IL-21 triggers an increased STAT3 activation whereas the activation of other STATs including STAT1/2 is unaffected. In parallel, the combined stimulation with IFN-alpha and IL-21 triggers...... a selective increase in MHC class I expression and NK- and CD8(+) T-cell-mediated cytotoxicity. In an experimental in vivo model of renal carcinoma, the combined treatment of IFN-alpha and IL-21 also produces a significant anti-cancer effect as judged by an inhibition of tumor growth and an increased survival...

Clinical significance of determination of levels of several cytokines (IL-1β, IL-2, IL-10 and TNF) in expressed prostatic fluid (EPS) from patients with various types of chronic prostatitis

International Nuclear Information System (INIS)

Gao Juxing; Zhang Jiyun

2006-01-01

Objective: To investigate the levels of several cytokines in EPS from patients with different types of chronic prostatitis. Methods: The EPS levels of IL-1β, IL-2, IL-10 and TNF were determined with RIA in 86 patients with various types of chronic prostatitis as well as in 30 controls. Results: The EPS levels of IL-1β, IL-2 and TNF in all the 86 patients with various types of chronic prostatitis were significantly higher than those in the controls (P 10/HP, lecithin body < + +) (n=31) were significantly higher than those in patients with CPPS IIIB (WRC < 10/HP, lecithin body normal, n=29)(P<0.05 or P<0.01 ), while the IL-10 levels were significantly lower (P<0.01). Conclusion: EPS levels of the cytokines IL-β, IL-2, TNF and IL-10 might be of value for diagnosis and classification of chronic prostatitis. (authors)

Protein kinase CK2 modulates IL-6 expression in inflammatory breast cancer

Energy Technology Data Exchange (ETDEWEB)

Drygin, Denis, E-mail: ddrygin@cylenepharma.com; Ho, Caroline B.; Omori, Mayuko; Bliesath, Joshua; Proffitt, Chris; Rice, Rachel; Siddiqui-Jain, Adam; O' Brien, Sean; Padgett, Claire; Lim, John K.C.; Anderes, Kenna; Rice, William G.; Ryckman, David

2011-11-11

Highlights: Black-Right-Pointing-Pointer We examine the potential cross-talk between CK2 and IL-6. Black-Right-Pointing-Pointer Inhibition of CK2 by siRNA or CX-4945 inhibits expression of IL-6 in models of IBC. Black-Right-Pointing-Pointer Treatment of IBC patient in the clinic with CX-4945 reduces her IL-6 plasma levels. Black-Right-Pointing-Pointer We demonstrate that CK2 is a potential therapeutic target for IL-6 driven diseases. -- Abstract: Inflammatory breast cancer is driven by pro-angiogenic and pro-inflammatory cytokines. One of them Interleukin-6 (IL-6) is implicated in cancer cell proliferation and survival, and promotes angiogenesis, inflammation and metastasis. While IL-6 has been shown to be upregulated by several oncogenes, the mechanism behind this phenomenon is not well characterized. Here we demonstrate that the pleotropic Serine/Threonine kinase CK2 is implicated in the regulation of IL-6 expression in a model of inflammatory breast cancer. We used siRNAs targeted toward CK2 and a selective small molecule inhibitor of CK2, CX-4945, to inhibit the expression and thus suppress the secretion of IL-6 in in vitro as well as in vivo models. Moreover, we report that in a clinical trial, CX-4945 was able to dramatically reduce IL-6 levels in plasma of an inflammatory breast cancer patient. Our data shed a new light on the regulation of IL-6 expression and position CX-4945 and potentially other inhibitors of CK2, for the treatment of IL-6-driven cancers and possibly other diseases where IL-6 is instrumental, including rheumatoid arthritis.

Metabolic consequences of Helicobacter pylori infection and eradication

Science.gov (United States)

Buzás, György Miklós

2014-01-01

Helicobacter pylori (H. pylori) is still the most prevalent infection of the world. Colonization of the stomach by this agent will invariably induce chronic gastritis which is a low-grade inflammatory state leading to local complications (peptic ulcer, gastric cancer, lymphoma) and remote manifestations. While H. pylori does not enter circulation, these extragastric manifestations are probably mediated by the cytokines and acute phase proteins produced by the inflammed mucosa. The epidemiologic link between the H. pylori infection and metabolic changes is inconstant and controversial. Growth delay was described mainly in low-income regions with high prevalence of the infection, where probably other nutritional and social factors contribute to it. The timely eradication of the infection will lead to a more healthy development of the young population, along with preventing peptic ulcers and gastric cancer An increase of total, low density lipoprotein and high density liporotein cholesterol levels in some infected people creates an atherogenic lipid profile which could promote atherosclerosis with its complications, myocardial infarction, stroke and peripheral vascular disease. Well designed and adequately powered long-term studies are required to see whether eradication of the infection will prevent these conditions. In case of glucose metabolism, the most consistent association was found between H. pylori and insulin resistance: again, proof that eradication prevents this common metabolic disturbance is expected. The results of eradication with standard regimens in diabetics are significantly worse than in non-diabetic patients, thus, more active regimens must be found to obtain better results. Successful eradication itself led to an increase of body mass index and cholesterol levels in some populations, while in others no such changes were encountered. Uncertainities of the metabolic consequences of H. pylori infection must be clarified in the future. PMID:24833852

Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose (MTD) in Future Studies.

Science.gov (United States)

Paranjpe, Madhav G; Denton, Melissa D; Vidmar, Tom J; Elbekai, Reem H

2015-07-01

High doses in Tg.rasH2 carcinogenicity studies are usually set at the maximum tolerated dose (MTD), although this dose selection strategy has not been critically evaluated. We analyzed the body weight gains (BWGs), mortality, and tumor response in control and treated groups of 29 Tg.rasH2 studies conducted at BioReliance. Based on our analysis, it is evident that the MTD was exceeded at the high and/or mid-doses in several studies. The incidence of tumors in high doses was lower when compared to the low and mid-doses of both sexes. Thus, we recommend that the high dose in male mice should not exceed one-half of the estimated MTD (EMTD), as it is currently chosen, and the next dose should be one-fourth of the EMTD. Because females were less sensitive to decrements in BWG, the high dose in female mice should not exceed two-third of EMTD and the next dose group should be one-third of EMTD. If needed, a third dose group should be set at one-eighth EMTD in males and one-sixth EMTD in females. In addition, for compounds that do not show toxicity in the range finding studies, a limit dose should be applied for the 26-week carcinogenicity studies. © 2014 by The Author(s).

Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers

NARCIS (Netherlands)

Almeida, Afonso R. M.; Legrand, Nicolas; Papiernik, Martine; Freitas, António A.

2002-01-01

We show that the lymphoid hyperplasia observed in IL-2Ralpha- and IL-2-deficient mice is due to the lack of a population of regulatory cells essential for CD4 T cell homeostasis. In chimeras reconstituted with bone marrow cells from IL-2Ralpha-deficient donors, restitution of a population of

Clinical significance of determination of serum IL-2, IL-6 and GM-CSF levels after treatment in pediatric patients with bronchial asthma

International Nuclear Information System (INIS)

Wang Zhuo; Sun Jin; Yao Li

2009-01-01

Objective: To explore the clinical significance of changes of serum IL-2, IL-6 and GM-CSF levels after treatment in pediatric patients with bronchial asthma. Methods: Serum levels of IL-2, IL-6 and GM-CSF were measured with RIA in 36 pediatric patients with bronchiol asthma and 30 controls. Results: Before treatment, the serum levels of IL-6, GM-CSF were significantly higher in the patients than those in controls (P 0.05), Serum IL-2 levels were negatively correlated with the IL-6 and GM-CSF levels (r=-0.5846, -0.6018, P<0.01). Conclusion: These cytokines participated in the pathogenesis of bronchial asthma in pediatric patients. Mornitoring the changes of their serum levels was helpful for the management of the diseases. (authors)

Preferential binding to Elk-1 by SLE-associated IL10 risk allele upregulates IL10 expression.

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Daisuke Sakurai

Full Text Available Immunoregulatory cytokine interleukin-10 (IL-10 is elevated in sera from patients with systemic lupus erythematosus (SLE correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA (P = 2.7×10⁻⁸, OR = 1.30, but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively, and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1 detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele

Helicobacter pylori eradication: A randomised comparative trial of 7 ...

African Journals Online (AJOL)

Compliance and side-effects were assessed 2 weeks after the start of therapy and H. pylori eradication was assessed by stool antigen tests 4 weeks after treatment. Results. Both the intention-to-treat (ITT; N=120) and per protocol (PP; N=97) analyses showed no significant differences between the eradication rates of EAC 7 ...

Dose-dependent effects of Lactobacillus rhamnosus on serum interleukin-17 production and intestinal T-cell responses in pigs challenged with Escherichia coli.

Science.gov (United States)

Zhu, Yao-Hong; Li, Xiao-Qiong; Zhang, Wei; Zhou, Dong; Liu, Hao-Yu; Wang, Jiu-Feng

2014-03-01

The mechanism underlying the dose effect of probiotics on ameliorating diarrhea has not been fully elucidated. Here, low (1 × 10(9) CFU/ml) or high (1 × 10(11) CFU/ml) doses of Lactobacillus rhamnosus ATCC 7469 were administered orally to piglets for 1 week before F4 (K88)-positive enterotoxigenic Escherichia coli (F4(+) ETEC) challenge. Administration of a low, but not a high, dose of L. rhamnosus decreased the percentage of CD3(+) CD4(+) CD8(-) T cells in the peripheral blood. Notably, transiently increased serum concentrations of interleukin-17A (IL-17A) were observed after F4(+) ETEC challenge in pigs pretreated with a high dose of L. rhamnosus. Administration of L. rhamnosus increased the percentage of the small intestinal lamina propria CD3(+) CD4(+) CD8(-) cells and Peyer's patch CD3(+) CD4(-) CD8(-) and CD3(-) CD4(-) CD8(+) cells. The percentage of ileal intraepithelial CD3(+) CD4(-) CD8(+) cells increased only in the high-dose piglets. Administration of L. rhamnosus downregulated expression of ileal IL-17A after F4(+) ETEC challenge but had no effect on expression of gamma interferon (IFN-γ), IL-12, IL-4, and FOXP3 mRNA in the small intestine. Expression of jejunal IL-2, ileal transforming growth factor β1 (TGF-β1), and ileal IL-10 was upregulated in the low-dose piglets after F4(+) ETEC challenge. Our findings suggest that amelioration of infectious diarrhea in piglets by L. rhamnosus is associated with the generation of lamina propria CD3(+) CD4(+) CD8(-) T cells, the expansion of Peyer's patch CD3(+) CD4(-) CD8(-) and CD3(-) CD4(-) CD8(+) cells, and the attenuation of F4(+) ETEC-induced increase in CD3(+) CD4(+) CD8(+) T cells in the small intestine. However, consumption of high doses of L. rhamnosus may increase levels of serum IL-17A after F4(+) ETEC challenge, thus eliciting a strong proinflammatory response.

Trends in the eradication rates of Helicobacter pylori infection for eleven years

Science.gov (United States)

Yoon, Jai Hoon; Baik, Gwang Ho; Sohn, Kyoung Min; Kim, Dae Yong; Kim, Yeon Soo; Suk, Ki Tae; Kim, Jin Bong; Kim, Dong Joon; Kim, Jin Bae; Shin, Woon Geon; Kim, Hak Yang; Baik, Il Hyun; Jang, Hyun Joo

2012-01-01

AIM: To evaluate the trends in the eradication rate of Helicobacter pylori (H. pylori) over the past 11 years in a single center. METHODS: This retrospective study covered the period from January 2000 to December 2010. We evaluated 5746 patients diagnosed with gastric ulcers (GU), duodenal ulcers (DU), GU + DU, or nonpeptic ulcers associated with an H. pylori infection. We treated them annually with the 2 wk standard first-line triple regimen, proton pump inhibitor (PPI) + amoxicilin + clarithromycin (PAC; PPI, clarithromycin 500 mg, and amoxicillin 1 g, all twice a day). The follow-up test was performed at least 4 wk after the completion of the 2 wk standard H. pylori eradication using the PAC regimen. We also assessed the eradication rates of 1 wk second-line therapy with a quadruple standard regimen (PPI b.i.d., tripotassium dicitrate bismuthate 300 mg q.i.d., metronidazole 500 mg t.i.d., and tetracycline 500 mg q.i.d.) after the failure of the first-line therapy. Statistical analysis was performed with 95%CI for the differences in the annual eradication rates. RESULTS: A total of 5746 patients [2333 males (58.8%), 1636 females (41.2%); mean age of males vs females 51.31 ± 13.1 years vs 52.76 ± 13.6 years, P < 0.05, total mean age 51.9 ± 13.3 years (mean ± SD)] were investigated. Among these patients, 1674 patients were excluded: 35 patients refused treatment; 18 patients ceased H. pylori eradication due to side effects; 1211 patients had inappropriate indications for H. pylori eradication, having undergone stomach cancer operation or chemotherapy; and 410 patients did not undergo the follow-up. We also excluded 103 patients who wanted to stop eradication treatment after only 1 wk due to poor compliance or the side effects mentioned above. Finally, we evaluated the annual eradication success rates in a total of 3969 patients who received 2 wk first-line PAC therapy. The endoscopic and clinical findings in patients who received the 2 wk PAC were as follows

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.

Avaliação da expressão de interleucina 1 beta (IL-1β e antagonista do receptor de interleucina 1 (IL-1Ra em pacientes com hanseníase Evaluation of the expression of interleukin 1 beta(IL-1β and interleukin 1 receptor antagonist (IL-1Ra in leprosy patients

Directory of Open Access Journals (Sweden)

Rosane Dias Costa